Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[CH:15]=[C:16]([CH2:18][OH:19])[N:17]=[C:13]2[N:12]=[C:11]([CH3:20])[C:10]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[CH:15]=[C:16]([CH:18]=[O:19])[N:17]=[C:13]2[N:12]=[C:11]([CH3:20])[C:10]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: Cc1nc2nc(CO)cn2c(-c2ccc(Cl)cc2Cl)c1C(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1nc2nc(C=O)cn2c(-c2ccc(Cl)cc2Cl)c1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a stirred solution of crude tert-butyl 5-(2,4-dichlorophenyl)-2-(hydroxymethyl)-7-methylimidazo[1,2-a]pyrimidine-6-carboxylate (400 mg) in CH2Cl2 (6 mL) was added Dess-Martin periodinane (605 mg, 1.43 mmol). After 2 h, the reaction was concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with satd aq NaHCO3 and brine prior to drying over MgSO4. Filtration, concentration under reduced pressure and purification by silica gel chromatography afforded tert-butyl 5-(2,4-dichlorophenyl)-2-formyl-7-methylimidazo[1,2-a]pyrimidine-6-carboxylate (90 mg, 41% for the two steps) as a light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[S:32][C:13]3=[N:14][C:15]([N:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[CH:16][C:17](=[O:18])[N:12]3[N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.NN>CCO.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[S:32][C:13]3=[N:14][C:15]([N:19]4[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:23][CH2:24]4)=[CH:16][C:17](=[O:18])[N:12]3[N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)n3nc(-c4cccc([N+](=O)[O-])c4)sc3n2)CC1
Agent: [Ni]
Agent: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2cc(=O)n3nc(-c4cccc(N)c4)sc3n2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.7 %

Procedure:
To a solution of tert-butyl 4-(2-(3-nitrophenyl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate (769 mg, 1.677 mmol) in EtOH (12 ml) at room temperature is added Raney® 2400 nickel (98 mg, 1.677 mmol) followed by hydrazine (0.526 ml, 16.77 mmol) dropwise and the mixture is stirred at room temperature for 4 hours. The reaction is monitored by TLC and LMCMS and additional nickel and hydrazine is added until completion. The mixture is filtered over celite and concentrated in vacuo to give crude tert-butyl 4-(2-(3-aminophenyl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate (443 mg, 1.034 mmol, 61.6% yield) as a tan solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][C:13](O)=O)=[CH:3]1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.[CH3:36][S:37]([NH:40][C:41]1[CH:42]=[CH:43][C:44]2[O:49][CH2:48][CH:47]([CH2:50][NH2:51])[O:46][C:45]=2[CH:52]=1)(=[O:39])=[O:38]>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][CH2:13][NH:51][CH2:50][CH:47]2[CH2:48][O:49][C:44]3[CH:43]=[CH:42][C:41]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:52][C:45]=3[O:46]2)=[CH:3]1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)OC(CN)CO2
Reactant: Cn1cc(CCC(=O)O)c2ccccc21
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(CCCNCC2COc3ccc(NS(C)(=O)=O)cc3O2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
1-Methylindole-3-propionic acid (1.2 g, 6.0 mmole), 1-hydroxybenzotriazole hydrate (0.97 g, 7.2 mmole) and 1,3-diisopropylcarbodiimide (1.1 ml, 7.2 mmole) were combined in 100 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 7-methylsulfonylamino-2,3-dihydro-1,4-benzodioxin-2-methanamine (1.9 g, 7.2 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Fractions containing product were concentrated and washed with a minimum amount of THF to remove a by-product and to give 2.1 g (79%) of the desired product, (7-methylsulfonyl-2,3-dihydro-benzo[1,4]dioxin-2ylmethyl)-4-(1-methyl-1H-indol-3-yl)-propanamide, as a fluffy white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:49])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[C:25]([CH3:48])=[N:26][N:27](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:28]=4)[CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7].Cl>>[CH3:1][N:2]([CH3:49])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[C:25]([CH3:48])=[N:26][NH:27][CH:28]=4)[CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7]
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCN(C(=O)NCCN(C)C)CC3)c2c1
Agent: Cl
Product: Cc1n[nH]cc1-c1ccc2nccc(N3CCN(C(=O)NCCN(C)C)CC3)c2c1
Yield: 9.4 %

Procedure:
27 mg N-[2-(dimethylamino)ethyl]-4-[6-(3-methyl-1-trityl-1H-4-pyrazolyl)-4-quinolyl]-1-piperazine carboxamide obtained in Example 197 and 0.32 mL of 5 N hydrochloric acid were reacted in the same manner as in Example 162, to give 1.6 mg of the title compound as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(=O)(O)[O-].[Na+].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>Cl>[CH2:20]([O:19][C:17]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])=[O:18])[CH3:21]
Reactant: CCOC(=O)Cl
Reactant: Nc1cccc(C(=O)O)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)Nc1cccc(C(=O)O)c1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A mixture composed of 3-aminobenzoic acid (20 g), 1 M aqueous sodium bicarbonate solution (730 cc) and ethyl chloroformate (14 cc) is left with stirring for 30 minutes at 5° C. 2.5 N hydrochloric acid (300 cc) is then added to the reaction mixture. The precipitate formed is separated by filtration, washed with water (3×200 cc) and dried at 40° C. under reduced pressure (0.07 kPa). 3-Ethoxycarbonylaminobenzoic acid (25 g), m.p. 198° C., is thereby obtained.
Reaction SMILES: [CH:1]1([C@H:7]([NH:20][S@](C(C)(C)C)=O)[C:8]2[CH:13]=[CH:12][C:11]([P:14]([CH3:19])(=[O:18])[O:15][CH2:16][CH3:17])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:27].O1CCOCC1>>[ClH:27].[NH2:20][C@@H:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:8]1[CH:9]=[CH:10][C:11]([P:14]([CH3:19])(=[O:18])[O:15][CH2:16][CH3:17])=[CH:12][CH:13]=1
Reactant: CCOP(C)(=O)c1ccc([C@@H](N[S@@](=O)C(C)(C)C)C2CCCCC2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCOP(C)(=O)c1ccc([C@@H](N)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 4-((S)-cyclohexyl((S)-1,1-dimethylethylsulfinamido)methyl)phenyl(methyl)phosphinate, 27-c, (5.0 g, 12.5 mmol) was dissolved in HCl/dioxane (100 mL) and the mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated under vacuum and the residue was washed with ethyl acetate to provide the product, 27-d, (4.2 g, 90%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]3[N:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]5[NH:23][C:24]([NH:32][C:19]=5[CH:18]=4)=[C:25]4[CH:31]=[CH:30][C:28](=[O:29])[CH:27]=[CH:26]4)[NH:16][C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.I[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44](=[O:51])[C:43](=[O:52])[CH:42]=1>CO.CN(C=O)C.O>[O:51]=[C:44]1[C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:41]([O:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:29][C:28]2[CH:30]=[CH:31][C:25]([C:24]3[NH:23][C:20]4[CH:21]=[CH:22][C:17]([C:15]5[NH:14][C:11]6[CH:12]=[CH:13][C:8]([N:5]7[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]7)=[CH:9][C:10]=6[N:16]=5)=[CH:18][C:19]=4[N:32]=3)=[CH:26][CH:27]=2)=[CH:42][C:43]1=[O:52]
Reactant: O=C1C=C(OCCCCCCI)c2ccccc2C1=O
Reactant: CN1CCN(c2ccc3nc(-c4ccc5c(c4)NC(=C4C=CC(=O)C=C4)N5)[nH]c3c2)CC1
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2ccc3[nH]c(-c4ccc5[nH]c(-c6ccc(OCCCCCCOC7=CC(=O)C(=O)c8ccccc87)cc6)nc5c4)nc3c2)CC1
Reaction time: 0.25 h
Yield: 30.1 %

Procedure:
Hoechst 33258 (3.0 g, 5 mmol) was dissolved in a hot mixture of isopropanol-water (24 mL/12 mL) and neutralized with ammonium hydroxide (3 mL). The precipitate was filtered, triturated with Et2O and dried in vacuo to obtain the free base of bisbenzimidazole. A 1.0 M solution of Bu4NOH in MeOH (0.6 mL, 0.6 mmol) was added to the solution of bisbenzimidazole (1.635 g, 3.85 mmol) in MeOH (30 mL), stirred for 15 min and concentrated to dryness in vacuo. Iodonaphthoquinone 505 (1.485 g, 3.87 mmol) in DMF (30 mL) was added to the tetrabutyl ammonium salt and the mixture was stirred for 48 h. The reaction mixture was suspended in H2O, the crude product was filtered, washed with H2O, dried and purified by flash chromatography (MeOH/CHCl3 1:9, 1:5) to afford 514 as a yellow solid (790 mg, 30%). 1H NMR (CDCl3/MeOH-d4) 8.21 (s, 1H), 8.09 (d, J=7.6 Hz, 1H), 8.05 (d, J=8.7 Hz, 2H), 7.85-7.95 (m, 2H), 7.48-7.75 (m, 4H), 7.14 (bs, 1H), 7.10-6.98 (m 3H), 4.21 (t, J=6.3 Hz, 2H), 4.08 (t, J=6.2 Hz, 2H), 2.65-2.75 (m, 4H), 2.40 (s, 3H), 1.80-2.15 (m, 4H), 1.60-1.75 (m, 4H). MS (LSIMS, 3-NBA) 725.2 (M++1).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[CH2:21]([NH:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)c1ccc(-c2ccc(CCN)cc2)cc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(CCNCc3ccccc3)cc2)cc1
Reaction time: 1 h
Yield: 92.5 %

Procedure:
To a solution of methyl 4′-(2-aminoethyl)-1,1′-biphenyl-4-carboxylate hydrochloride (420 mg) and benzaldehyde (153 mg) in dichloromethane (5 ml) was stirred for 3 hours, and the mixture was evaporated in vacuo. To the residue in methanol (10 ml) was added sodium borohydride (65 mg) on ice cooling, and stirred at the same temperature for 1 hour. The resulting mixture was poured into saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed (hexane—ethyl acetate) over silica gel to afford methyl 4′-[2-(benzylamino)ethyl]-1,1′-biphenyl-4-carboxylate (460 mg) as a colorless powder.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13](=[O:24])[CH2:14][C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=1[F:23])=[O:5])C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CO>[F:21][C:20]1[CH:19]=[C:18]([F:22])[CH:17]=[C:16]([F:23])[C:15]=1[CH:14]1[C:13](=[O:24])[NH:12][C:11]2[CH:10]=[CH:9][N:8]=[N:7][C:6]=2[C:4]1=[O:5]
Reactant: CCOC(=O)c1nnccc1NC(=O)Cc1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1Nc2ccnnc2C(=O)C1c1c(F)cc(F)cc1F
Reaction time: 18 h
Yield: 97.2 %

Procedure:
The product from Step 2 (0.307 g) and potassium carbonate (0.25 g) were stirred in dry DMF (10 ml) at 110° C. for 2 hours and then cooled and stood for 18 hours. The DMF was evaporated and the resulting brown solid was triturated with diethyl ether and the organic phase decanted. The solid was dissolved in water then acidified with dilute hydrochloric acid to neutrality. Most of the aqueous phase was then evaporated, leading to precipitation of a black solid that was filtered, and the yellow/brown aqueous phase was evaporated to dryness, affording a residue that was dissolved in methanol, the insoluble inorganic salts were filtered and the organic phase was evaporated to dryness to give 7-(2,4,6-trifluorophenyl)-5H-pyrido[3,2-c]pyridazine-6,8-dione as a light brown/beige solid (0.258 g).
Reaction SMILES: [CH3:1][O:2][C:3]12[CH2:11][CH:7]3[CH2:8][CH:9]([CH2:10]1)[C:5]([NH2:12])([CH2:6]3)[CH2:4]2.Cl[CH2:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]#[N:23])=[O:16].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O>[CH3:1][O:2][C:3]12[CH2:11][CH:7]3[CH2:8][CH:9]([CH2:10]1)[C:5]([NH:12][CH2:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]#[N:23])=[O:16])([CH2:6]3)[CH2:4]2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Reactant: COC12CC3CC(C1)C(N)(C3)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC12CC3CC(C1)C(NCC(=O)N1CCC[C@H]1C#N)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.6 %

Procedure:
To a stirred solution of the amino compound obtained by step V (0.16 g, 0.95 mmol) in DMSO (4.0 mL) was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.17 g, 0.96 mmol) and K2CO3 (0.4 g, 2.9 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. The reaction mixture was diluted with EtOAc and washed with water ad brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{[(1-methoxytricyclo[3.3.1.03,7]non-3-yl)amino]acetyl}pyrrolidine-2-carbonitrile (0.12 g) in 41% yield. m/z (M+1) 304; 1H NMR (CDCl3) 300 MHz δ 4.82-4.75 (m, 1H), 3.75-3.40-m, 4H), 3.27 (s, 3-H), 2.47-2.40 (m, 1H), 2.35-1.68 (13H), 1.57-1.41 (m, 2H).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:22][C:21](/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]4)=[C:27]([O:37][CH3:38])[CH:26]=3)=[N:20][C:19]=2[C:39]([OH:41])=O)=[CH:14][CH:13]=1.Cl.[Cl:43][CH2:44][CH2:45][NH2:46].C(N(C(C)C)CC)(C)C.O.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C.C(Cl)CCl>[Cl:43][CH2:44][CH2:45][NH:46][C:39]([C:19]1[N:20]=[C:21](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]3)=[C:27]([O:37][CH3:38])[CH:26]=2)[NH:22][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=1)=[O:41]
Reactant: COc1cc(/C=C/c2nc(C(=O)O)c(-c3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Reactant: NCCCl
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cc(/C=C/c2nc(C(=O)NCCCl)c(-c3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.6 %

Procedure:
HOBT (65 mg) and EDC (92 mg) were sequentially added to a solution of 5-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-1H-imidazole-4-carboxylic acid (100 mg), 2-chloroethylamine hydrochloride (56 mg) and IPEA (0.25 mL) in DMF (3 mL). The reaction solution was stirred at room temperature for two hours. Then, ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: ethyl acetate->ethyl acetate:methanol=5:1) to obtain 19 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[C:6]([NH2:16])[C:5]=1[NH2:17].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].O.[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O>CCO>[CH3:1][O:2][C:3]([C:4]1[C:5]2[N:17]=[C:33]([C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=3[C:30]([F:29])([F:39])[F:40])[NH:16][C:6]=2[CH:7]=[C:8]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[CH:9]=1)=[O:18]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: COC(=O)c1cc(N2CCOCC2)cc(N)c1N
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(N2CCOCC2)cc2[nH]c(-c3ccccc3C(F)(F)F)nc12
Temperature: 25 °C
Yield: 69.2 %

Procedure:
To a mixture of 2,3-diamino-5-morpholin-4-yl-benzoic acid methyl ester (73; 600 mg, 2.39 mmol) in EtOH (60 ml) was added sodium metabisulfite (373 mg, 1.96 mmol), H2O (2 ml) and 2-trifluoromethylbenzaldehyde (74; 990 mg, 5.69 mmol). The resulting reaction mixture was stirred under reflux for 3 h. It was then cooled to room temperature and concentrated under reduced pressure. Purification by chromatography afforded 6-morpholin-4-yl-2-(2-trifluoromethyl-phenyl)-1H-benzoimidazole-4-carboxylic acid methyl ester 75 (670 mg, 69.2%) as a yellow solid.
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[C:6]1[NH:16][C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]3[CH2:20][CH2:19][C:18]4([C:29](=[O:30])[C:28]5[C:23](=[C:24]([OH:40])[C:25]6[C:36](=[O:37])[CH:35]=[C:34](OC)[C:32](=[O:33])[C:26]=6[C:27]=5[OH:31])[C:21]4=[O:22])[C:11]=3[C:12]=2[OH:17])[CH:7]=1.[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(#N)C.O>CN(C=O)C>[OH:31][C:27]1[C:26]2[C:32](=[O:33])[C:34]([NH:48][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:35][C:36](=[O:37])[C:25]=2[C:24]([OH:40])=[C:23]2[C:21](=[O:22])[C@:18]3([C:11]4[C:12]([OH:17])=[C:13]5[C:8]([CH:7]=[C:6](/[CH:5]=[CH:4]/[CH:3]=[CH:2]/[CH3:1])[NH:16][C:14]5=[O:15])=[CH:9][C:10]=4[CH2:20][CH2:19]3)[C:29](=[O:30])[C:28]=12
Reactant: C/C=C/C=C/c1cc2cc3c(c(O)c2c(=O)[nH]1)C1(CC3)C(=O)c2c(O)c3c(c(O)c2C1=O)C(=O)C(OC)=CC3=O
Reactant: NCc1ccccc1
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: C/C=C/C=C/c1cc2cc3c(c(O)c2c(=O)[nH]1)[C@@]1(CC3)C(=O)c2c(O)c3c(c(O)c2C1=O)C(=O)C(NCc1ccccc1)=CC3=O

Procedure:
Twenty (20) mg (37.1 μmol) fredericamycin are dissolved in 1 ml DMF under argon, then 4.76 mg (44.50 μmol) benzylamine are added at room temperature. According to HPLC (RP18, acetonitrile/water), a homogenous new product has formed after 3 h. The reaction mixture is concentrated at high vacuum until dry.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=3[CH3:39])[CH2:28][CH2:27]2)=[O:25])=[C:20]([S:40]([CH3:43])(=[O:42])=[O:41])[CH:19]=1>>[CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[N:11]1[C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:27][CH2:28][N:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=3[CH3:39])[CH2:30][CH2:31]2)=[O:25])=[C:20]([S:40]([CH3:43])(=[O:41])=[O:42])[CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@H](COCc5ccccc5)CCS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 70.1 %

Procedure:
Using (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (536 mg) described in Preparation Example 1 and (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (1.0 g) described in Preparation Example 110 and by the reaction and treatment in the same manner as in Example 4, the title compound (950 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]2)=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[N:13][C:12]([C:15]#[N:16])=[CH:11][N:10]=2)=[N:6][CH:7]=1.[O-]CC.[Na+].Br[CH2:37][CH2:38][CH2:39][CH2:40]Br>C(O)C>[NH:21]1[CH2:22][CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:3]2[C:2]([N:1]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:7][N:6]=[C:5]([NH:8][C:9]3[N:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=3)[CH:4]=2)[CH2:20]1
Reactant: BrCCCCBr
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2N)C1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cnc(Nc2cc(NCC3CCCNC3)c(N3CCCC3)cn2)cn1
Yield: 29 %

Procedure:
tert-Butyl 3-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (40 mg, 0.094 mmol) (Synthesis 101-C) was dissolved in ethanol (2 mL) and treated with sodium ethoxide (34 mg, 0.509 mmol) and 1,4-dibromobutane (44 mg, 0.208 mmol) at between 70 and 80° C. for 96 h. The reaction was quenched with water and the aqueous phase extracted with dichloromethane. The combined organic phases were evaporated and the residue was treated with a 20% solution of TFA in dichloromethane for 20 min. The solution was evaporated and the residue was purified by HPLC to give 5-(4-(piperidin-3-ylmethylamino)-5-(pyrrolidin-1-yl)pyridin-2-ylamino)pyrazine-2-carbonitrile (10.3 mg, 29%).
Reaction SMILES: [CH:1]1([N:6]2[C:11]([CH3:12])=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([F:21])[F:20])[CH:14]=3)[C:9](=[O:22])[C:8]([C:23](O)=[O:24])=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:59][C:60]1[O:64][C:63]([CH2:65][NH2:66])=[N:62][N:61]=1>CN(C=O)C>[CH3:59][C:60]1[O:64][C:63]([CH2:65][NH:66][C:23]([C:8]2[C:9](=[O:22])[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([F:20])[F:21])[CH:14]=3)=[C:11]([CH3:12])[N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]=2)=[O:24])=[N:62][N:61]=1
Reactant: Cc1nnc(CN)o1
Reactant: Cc1c(-c2cccc(C(F)F)c2)c(=O)c(C(=O)O)cn1C1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nnc(CNC(=O)c2cn(C3CCCC3)c(C)c(-c3cccc(C(F)F)c3)c2=O)o1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 1-cyclopentyl-5-(3-difluoromethyl-phenyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 9, 116 mg, 0.334 mmol), HBTU (140 mg, 0.369 mmol), DIPEA (116 μL, 0.668 mmol) in DMF (1 mL) is stirred for 15 min at room temperature. C-(5-methyl-1,3,4-oxadiazol-2-yl)-methylamine (46 mg, 0.407 mmol) is added and the reaction mixture is stirred for 72 h at room temperature. The reaction mixture is purified by preparative reversed-phase HPLC (XBridge, gradient of methanol in water, 0.3% NH4OH, 60° C.). Yield: 67 mg (45% of theory); ESI mass spectrum: [M+H]+=443; Retention time HPLC: 0.98 min (Z003_001).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20]([C:22]1([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[CH2:24][CH2:23]1)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1([C:25]2[CH:30]=[CH:29][C:28]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=3)=[CH:27][CH:26]=2)[CH2:23][CH2:24]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(=O)O)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6 using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.