Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23].C(C1C=CC=CC=1C(Cl)=O)(=O)C1C=CC=CC=1>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:23]
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Reactant: COc1cccc(C(=O)Cl)c1
Agent: O=C(Cl)c1ccccc1C(=O)c1ccccc1
Product: COc1cccc(C(=O)Nc2ncn(Cc3ccccc3)c2C(N)=O)c1
Yield: 26 %

Procedure:
An amidation reaction and post-treatment were carried out according to the conditions of Example 1, using 2.2 g (10 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide prepared in Reference Example 2 and 3-methoxybenzoyl chloride separately prepared according to a conventional method, instead of benzoyl benzoyl chloride, to obtain a crude amide product. The crude amide product was purified by suspension in hot methanol to obtain 0.91 g of 4-(3-methoxybenzoylamino)-1-benzyl-5-imidazolecarboxamide (yield 26%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][C:35]1[C:36]([N:44]2[CH2:49][CH2:48][CH:47]([N:50]3[CH2:55][CH2:54][N:53]([S:56]([CH3:59])(=[O:58])=[O:57])[CH2:52][CH2:51]3)[CH2:46][CH2:45]2)=[CH:37][C:38]([O:42][CH3:43])=[C:39]([CH:41]=1)[NH2:40].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:39]3[CH:41]=[C:35]([CH3:34])[C:36]([N:44]4[CH2:49][CH2:48][CH:47]([N:50]5[CH2:51][CH2:52][N:53]([S:56]([CH3:59])(=[O:58])=[O:57])[CH2:54][CH2:55]5)[CH2:46][CH2:45]4)=[CH:37][C:38]=3[O:42][CH3:43])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)c(C)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)c(C)cc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 175 °C
Yield: 34.9 %

Procedure:
A mixture of 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide (Intermediate Example 1) (0.050 g, 0.11 mmol), 5-methyl-2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (Example 236, Step B) (0.041 g, 0.11 mmol) and para-toluenesulfonic acid (0.049 g, 0.26 mmol) in i-PrOH (5 mL) was heated in a microwave at 175° C. for 20 min. The reaction mixture was concentrated onto silica gel and purified by flash chromatography to afford the title compound (0.031 g, 35%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.24 (s, 1H), 9.42 (br. s., 1H), 8.48 (s, 1H), 8.34 (s, 1H), 8.25 (d, J=5.1 Hz, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.75 (d, J=8.9 Hz, 1H), 7.62 (t, J=7.7 Hz, 1H), 7.34-7.55 (m, 3H), 7.17-7.29 (m, 2H), 6.95-7.06 (m, 1H), 6.77 (s, 1H), 6.51 (d, J=5.2 Hz, 1H), 3.80 (s, 3H), 3.05-3.17 (m, 6H), 2.88 (s, 3H), 2.59-2.73 (m, 6H), 2.38-2.46 (m, 1H), 2.16 (s, 3H), 1.81-1.90 (m, 2H), 1.53-1.68 (m, 2H). MS (M−H, ES−) 806.
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(OC)C(CC)=CC=2)=[O:8])C=CC=CC=1.[C:25]([N:27]=[S:28]([CH2:35][C:36]1[C:41]([C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])=[C:40]([O:52][CH3:53])[C:39]([C:54]2[CH:58]=[CH:57][O:56][CH:55]=2)=[CH:38][CH:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)#[N:26]>>[C:25]([N:27]=[S:28]([CH2:35][C:36]1[C:41]([C:42]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[O:43])=[C:40]([O:52][CH3:53])[C:39]([C:54]2[CH:58]=[CH:57][O:56][CH:55]=2)=[CH:38][CH:37]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:8])#[N:26]
Reactant: COc1c(-c2ccoc2)ccc(CS(=NC#N)c2ccccc2)c1C(=O)OCc1ccccc1
Reactant: CCOC(=O)c1c(CS(=O)c2ccccc2)ccc(CC)c1OC
Product: COc1c(-c2ccoc2)ccc(CS(=O)(=NC#N)c2ccccc2)c1C(=O)OCc1ccccc1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 2, starting from benzyl 6-[(N-cyano-S-phenylsulphinimidoyl)methyl]-3-(furan-3-yl)-2-methoxybenzoate (Intermediate 225).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O:24][CH3:25])=[O:23].I[CH2:30][CH2:31][CH2:32][N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]([CH3:42])[C:34]1=[O:43].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O>[CH3:42][N:35]1[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[N:33]([CH2:32][CH2:31][CH2:30][N:9]2[CH2:10][CH2:11][C:6]3([N:5]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:4][N:3]([CH2:18][C:19]4[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=4)[C:22]([O:24][CH3:25])=[O:23])[C:2]3=[O:1])[CH2:7][CH2:8]2)[C:34]1=[O:43]
Reactant: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Reactant: Cn1c(=O)n(CCCI)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)n(C)c5ccccc54)CC3)C2=O)c1
Temperature: 65 °C
Yield: 78.2 %

Procedure:
A mixture of methyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (400 mg, 0.962 mmol, 1 equiv), 1-(3-iodopropyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (304.8 mg, 0.962 mmol, 1 equiv), and potassium carbonate (399 mg, 2.88 mmol, 3 equiv) was heated at 65° C. for 16 h. The reaction was cooled to ambient temperature and worked up using ethyl acetate and water. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified using preparatory thin layer chromatography in 5% methanol in dichloromethane to afford the title compound as an oil (427 mg, 78%); 1H NMR (400 MHz, DMSO-d6): δ 1.61 (d, 2H, J=13.2 Hz), 1.85 (t, 2H, J=7.2 and 6.8 Hz); 2.34 (d, 2H, J=6.4 Hz); 2.64-2.66 (m, 2H); 2.89 (s, 3H); 3.843 (s, 3H); 3.91 (t, 2H, J=6.4 and 6.8 Hz); 4.58 (s, 2H); 4.62 (s, 2H); 6.78 (t, 1H, J=7.2 Hz); 6.86 (d, 2H, J=8.8 Hz); 7.01-7.07 (m, 2H); 7.13-7.14 (m, 1H); 7.21-7.26 (m, 3H); 7.52-7.58 (m, 2H); 7.88 (s, 1H); 7.90 (s, 1H); MS for C33H37N5O4 m/z 568.13 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].[CH:10](=O)[C:11]1[CH:21]=[C:18]([O:19][CH3:20])[C:16]([OH:17])=[C:13]([O:14][CH3:15])[CH:12]=1>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[S:9][C:10]([C:11]3[CH:21]=[C:18]([O:19][CH3:20])[C:16]([OH:17])=[C:13]([O:14][CH3:15])[CH:12]=3)=[N:1][C:2]=2[CH:7]=1
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: Nc1cc(Cl)ccc1S
Solvent: CN(C)C=O
Product: COc1cc(-c2nc3cc(Cl)ccc3s2)cc(OC)c1O
Temperature: 80 °C
Yield: 47.2 %

Procedure:
In a DMF (3 mL) solvent in the presence of Na2S2O5 (120.3 mg, 0.63 mmol), a solution including 2-amino-4-chlorobenzenethiol (100 mg, 0.63 mmol) and syringaldehyde (115.3 mg, 0.63 mmol) was heated at a temperature of 80° C. for 22 hours. After DMF was evaporated, water was added thereto. The produced precipitate was filtered, and washed with water to obtain Compound 126.
Reaction SMILES: CCC.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([NH2:15])[CH2:13][CH3:14])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37])(OCC)=O>O.C(#N)C>[C:28]1(=[O:37])[N:15]([CH:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH3:4])=[CH:7][CH:8]=2)[CH2:13][CH3:14])[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: CCC(N)c1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCC
Solvent: O
Product: CCC(c1ccc(OC)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 38.1 %

Procedure:
1-Phthalimido-1-4′-methoxyphenyl)propane. To a stirred solution of 1-(4′-methoxyphenyl)propylamine (2.5 grams, 15.2 mmol) and sodium carbonate (1.74 grams, 16.4 mmol) in a mixture of water (50 milliliters) and acetonitrile (50 milliliters) was added N-carbethoxyphthalimide (3.34 grams, 15.2 mmol). The resulting suspension was stirred for 4.5 hours at room temperature, the acetonitrile was removed in vacuo and a solid formed. The slurry was filtered and the solid was washed with water and air dried to afford 1.73 grams (39%) of crude product as a white powder. The crude product was recrystallized from hexane/ethyl acetate and dried in vacuo (60° C., <1 mm) to afford 1.71 grams (38%) of the product as white crystals: mp 85-86° C.; 1H NMR (DMSO-d6) δ 7.92-7.79 (m, 4H), 7.46-7.28 (m, 2H), 6.97-6.83 (m, 2H), 5.19-5.06 (m, 1H), 3.72 (s, 3H), 2.56-2.13 (m, 2H), 0.87 (t, J=7.3 Hz, 3H); 13C NMR (DMSO-d6) δ 167.8, 1.5, 134.6, 131.7, 131.0, 128.6, 123.1, 113.7, 55.2, 54.9, 23.8, 11.3. Anal. Calculated for C18H17NO3. Theoretical: C, 73.20; H, 5.80; N, 4.74. Found: C, 73.24; H, 5.74, N, 4.86. HPLC 100%.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:19][CH2:18][C@@H:16]([OH:17])[C@@H:14]([OH:15])[C@:12]2([F:20])[OH:13])=[C:4](N)[N:3]=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:24]>C(O)C(N)(CO)CO.Cl>[F:20][C@:12]1([OH:13])[C@H:14]([OH:15])[C@H:16]([OH:17])[CH2:18][O:19][C@H:11]1[N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:24])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: Nc1nc(N)c2ncn([C@@H]3OC[C@@H](O)[C@@H](O)[C@@]3(O)F)c2n1
Agent: Cl
Agent: NC(CO)(CO)CO
Product: Nc1nc2c(ncn2[C@@H]2OC[C@@H](O)[C@@H](O)[C@@]2(O)F)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
2,6-Diamino-9-(2-fluoro-β-D-arabinosyl)purine (61.2 mg, 0.21 mmol) was dissolved in 50 mM Tris-HCl buffer solution (20 mL, pH 7.0), and adenosine deaminase (71 units) was added to the resultant solution, followed by stirring at room temperature for 1.5 hours. The resultant reaction mixture was subjected to filtration by use of a membrane filter (PTFE, 0.5 μm), and the filtrate was prepared into 60 mL of an aqueous solution. The aqueous solution was purified by means of reverse-phase ODS column chromatography (80 mL, 0 to 2% aqueous acetonitrile), to thereby yield 60.4 mg of the title compound as colorless crystals (yield: 100%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:29][CH3:30])[C:19]=3[O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:14]2=[O:31])=[CH:7][CH:6]=1)(=O)C.N>CO>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:29][CH3:30])[C:19]=3[O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:14]2=[O:31])=[CH:7][CH:6]=1
Reactant: CCCCCOc1c(OC)ccc2c1CCN(CCc1ccc(OC(C)=O)cc1)C2=O
Agent: N
Solvent: CO
Product: CCCCCOc1c(OC)ccc2c1CCN(CCc1ccc(O)cc1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
4-[2-(6-Methoxy-1-oxo-5-pentyloxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl acetate (720 mg, 1.69 mmol, 1 eq) was dissolved in methanol (10 ml), and aqueous ammonia (10 ml) was added. The mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and water (20 ml) was added to the residue. The mixture was extracted twice with ethyl acetate (30 ml). The organic layers were combined, washed with a 1N aqueous hydrochloric acid solution (10 ml) and saturated brine (50 ml), and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1/1) to give 2-[2-(4-hydroxyphenyl)ethyl]-6-methoxy-5-pentyloxy-3,4dihydro-2H-isoquinolin-1-one (396 mg, 61.0%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([Cl:28])[CH:26]=3)[NH:21][CH:20]=2)O)=[C:11]([F:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(OC)=CC(C(OC)C2C3C(=NC=C(Cl)C=3)NC=2)=C(F)C=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH2:17][C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([Cl:28])[CH:26]=3)[NH:21][CH:20]=2)=[C:11]([F:29])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(O)c2c[nH]c3ncc(Cl)cc23)c(F)cc1OCc1ccccc1
Agent: CC[SiH](CC)CC
Agent: COc1cc(C(OC)c2c[nH]c3ncc(Cl)cc23)c(F)cc1OCc1ccccc1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Cc2c[nH]c3ncc(Cl)cc23)c(F)cc1OCc1ccccc1
Reaction time: 2 h

Procedure:
(4-Benzyloxy-2-fluoro-5-methoxy-phenyl)-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol 223a and 3-[(4-benzyloxy-2-fluoro-5-methoxy-phenyl)-methoxy-methyl]-5-chloro-1H-pyrrolo[2,3-b]pyridine 223b (48 mmol) were combined with acetonitrile (1.4 L), trifluoroacetic acid (21 mL, 288 mmol) and triethylsilane (31 mL, 192 mmol). The resulting mixture was stirred for two hours at reflux. The solvent was removed under reduced pressure. Ethyl acetate (6 L) was added and the organic layer was washed with aqueous potassium carbonate saturated solution. The layers were separated and the aqueous layer was back-extracted with ethyl acetate (2 L). The combined organic portions were dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the desired compound 224 which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][C:14]=2[F:21])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6]>C(O)C.[Pd]>[CH2:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:3]2[C:2]([F:1])=[C:10]([F:11])[CH:9]=[CH:8][C:4]=2[C:5]([OH:7])=[O:6])=[C:14]([F:21])[CH:15]=1)[CH3:20]
Reactant: C#Cc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
The product of Step C, 3,4-difluoro-2-[(4-ethynyl-2-fluorophenyl)amino]benzoic acid (300 mg, 1.03 mmol), was dissolved in absolute ethanol (30 mL) and 5% Pd/C (30 mg) added. This mixture was stirred under an atmosphere of hydrogen (60 psi) for 2 hours at room temperature. The Pd/C was removed over Celite®, which was washed well with additional ethanol, then the solvent removed from the resultant filtrate under reduced pressure to afford 2-[(4-ethyl-2-fluorophenyl)amino]-3,4-difluorobenzoic acid as an off-white solid (280 mg, 92%); m.p. (EtOAc/hexanes) 199-201° C. 1H NMR [400 MHz, (CD3)2SO] δ 14.10 (br s, 1 H), 9.31 (br s, 1 H), 7.80 (ddd, J=8.5, 6.1, 1.9 Hz, 1 H), 7.09 (dd, J=12.4, 1.5 Hz, 1 H), 7.04-6.92 (m, 3 H), 2.52 (q, J=7.6 Hz, 2 H), 1.17 (t, J=7.5 Hz, 3 H).
Reaction SMILES: Cl.[C:2]([NH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([S:20]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[C:28]([Cl:33])[CH:29]=4)[CH:24]=3)(=[O:22])=[O:21])[CH2:16][CH2:15]2)=[O:13])[CH2:8][CH2:7]1)(=[NH:4])[CH3:3].[C:34]([O:37][CH:38]([O:40][C:41](C1C=C([N+]([O-])=O)C=CC=1O)=[O:42])[CH3:39])(=[O:36])[CH3:35].C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:34]([O:37][CH:38]([O:40][C:41]([CH2:3][C:2]([NH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([S:20]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[C:28]([Cl:33])[CH:29]=4)[CH:24]=3)(=[O:22])=[O:21])[CH2:16][CH2:15]2)=[O:13])[CH2:8][CH2:7]1)=[NH:4])=[O:42])[CH3:39])(=[O:36])[CH3:35]
Reactant: CC(=N)N[C@H]1CC[C@H](C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Reactant: CC(=O)OC(C)OC(=O)c1cc([N+](=O)[O-])ccc1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC(C)OC(=O)CC(=N)N[C@H]1CC[C@H](C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1

Procedure:
A solution of 1-(trans-4-acetimidoylaminocyclohexane-1-ylcarbonyl)-4-(6-chloronaphthalene-2-sulfonyl)piperazine hydrochloride (100 mg), 0-(1-acetoxyethoxycarbonyl)-4-nitrophenol (63 mg) and diisopropylethylamine (72 mg) in DMF (4 ml) was stirred at 50t for 15 hours. The reaction solution was concentrated, and the residue was dissolved in ethyl acetate, washed with water, sodium hydrogen carbonate aqueous solution and brine, dried and concentrated. The residue was purified with silica gel column chromatography (ethyl acetate) to give a colorless solid of the title compound (89 mg).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26]>>[F:20][C:21]([F:30])([F:31])[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH:26][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: NCc1cccc(C(F)(F)F)c1
Product: FC(F)(F)c1cccc(CNc2nccc(-n3cnc4ccccc43)n2)c1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 3-trifluoromethylbenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 370.2 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.58 (br s, 1H); 8.39 (br s, 1H); 7.85 (d, J=8.2 Hz, 1H); 7.69 (s, 1H); 7.61 (d, J=7.6 Hz, 1H); 7.57 (d, J=7.6 Hz, 1H); 7.49 (m, 1H); 6.85 (d, J=5.3 Hz, 1H); 6.38 (br s, 1H); 4.81 (d, J=6.2 Hz, 2H).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[N+](C1C=CC([O:18][C:19](=O)[C@H:20]([CH:32]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:33]([OH:35])=[O:34])[NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=CC=1)([O-])=O>CN(C)C=O>[C:22]([NH:21][C@H:20]([C:19]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:18])[CH:32]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:33](=[O:34])[OH:35])([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23]
Reactant: O=C(N[C@H](C(=O)Oc1ccc([N+](=O)[O-])cc1)C(Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Product: O=C(N[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(Cc1ccccc1)C(=O)O)OCc1ccccc1

Procedure:
L-Proline (2.8 Kg) and N-carbobenzoxy-β-benzyl-L-aspartic acid p-nitrophenyl ester (10.5 Kg) are dissolved in a mixture of dimethylformamide (25-30 L) and distilled water (9-13 L). The pH of the solution is adjusted to 7.5-8.0 and maintained in this range by addition of diisopropylethylamine. The mixture is stirred at 20°-30° C. until the reaction is complete. The solution is diluted with ethyl acetate (45-55 L) and extracted with dilute hydrochloric acid (15-20 L). The aqueous layer is back extracted with ethyl acetate (8-12 L). The combined organic layers are washed three times with dilute hydrochloric acid (10-15 L). The organic layer is extracted with dilute sodium bicarbonate. Ethyl acetate (40-60 L) is added to the aqueous layer and the pH is adjusted to about 3.0 by addition of dilute hydrochloric acid. The organic layer is washed two times with dilute hydrochloric acid (10-30 L) and concentrated in vacuo below 55° C. to 20-30 L.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[CH:44][C:45]([C:48]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[O:49])=[N:46][CH:47]=1.COC(=O)C1C=CC(Br)=CC=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:43]=[CH:44][C:45]([C:48]([N:50]6[CH2:55][CH2:54][O:53][CH2:52][CH2:51]6)=[O:49])=[N:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: O=C(c1ccc(Br)cn1)N1CCOCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Agent: COC(=O)c1ccc(Br)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCOCC4)nc3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (81 mg) and (5-bromo-pyridin-2-yl)-morpholin-4-yl-methanone (45 mg) obtained in the same manner as Step A in Example 1-D-79 instead of 4-bromobenzoic acid methyl ester in Example 1-D-08, in the same manner as Example 1-D-08, a crude product of [5-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-2-yl]-morpholin-4-yl-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 1, to obtain the desired compound (D-85) as a colorless powder (37 mg, 50%).
Reaction SMILES: [C:1]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([O:17][CH3:18])[N:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>ClCCl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[O:16][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:13][CH:12]=[N:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCCC(=O)c1c[nH]c2c(OC)nccc2c1=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(OC)nccc2c1OS(C)(=O)=O
Reaction time: 1 h
Yield: 71 %

Procedure:
4.93 g of 3-butyryl 8-methoxy-1,7-naphthyridin-4(1H)-one and 4.2 ml of triethylamine were dissolved into 70 ml of dichloromethane, and a solution of methanesulfonyl chloride (1.85 ml) in dichloromethane (10 ml) was added dropwise at a temperature of 0° C. to 5° C. The resulting mixture was stirred for 1 hour at the same temperature. Water was added, and the resulting mixture was extracted with dichloromethan three times, and the organic phase was washed with water and then brine, dried over magnesium sulfate and distilled under reduced pressure. Ether was added to the residue to give 4.61 g (71%) of the titled compound as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([NH2:19])=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C)C=O>[CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[NH:19][S:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:37])=[O:36])[N:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CNc2ccc3c(N)cccc3n2)o1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(CNc2ccc3c(NS(=O)(=O)c4ccccc4)cccc3n2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N2-(5-Methyl-furan-2-ylmethyl)-quinoline-2,5-diamine (example 26, step A+B, 200 mg, 0.791 mmol) was dissolved in 2 mL N,N-dimethylformamide. N,N-Diisopropyl ethyl amine (104 mg; 0.806 mmol) and benzenesulfonyl chloride (155 mg, 0.876 mmol) were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 50 mL water and extracted three times with ethyl acetate (50 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The residue purified by flash chromatography on silica gel (cyclohexane/ethyl acetate/methanol 100:0:0->0:90:10 gradient). The title compound was obtained as a yellow solid (130 mg, 42%), MS: m/e=394.1 (M+H+).