Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[N:8]2[CH:9]=[N:10][CH:11]=[C:7]2[CH:6]=[N:5][N:4]=1.[C:12]1([CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C(C)=CC=CC=1>[C:25]1([CH:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:19]2[CH2:20][CH2:21][N:22]([C:3]3[N:8]4[CH:9]=[N:10][CH:11]=[C:7]4[CH:6]=[N:5][N:4]=3)[CH2:23][CH2:24]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CSc1nncc2cncn12
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: Cc1ccccc1C
Product: c1ccc(C(c2ccccc2)N2CCN(c3nncc4cncn34)CC2)cc1

Procedure:
A solution of 6.68 gm of 4-(methylthio)-imidazo[1,5-d]-as-triazine, 15.1 gm of N-diphenylmethylpiperazine and 50 ml of xylene is refluxed for 19 hours. Upon evaporation to dryness, the residue is chromatographed on a silica gel dry column. The product is recrystallized from ethanol and has a melting point equal to 192°-193° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[C@H:12]([CH3:24])[CH2:11]2)=[O:9])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=1.[O:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:31]3[CH2:32][CH2:33][O:29][C:30]3=[O:34])=[CH:3][C:4]=2[S:25]([CH3:28])(=[O:27])=[O:26])=[O:9])[CH2:11][C@H:12]1[CH3:24]
Reactant: O=C1NCCO1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)C[C@H]2C)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3S(C)(=O)=O)C[C@H]2C)c(C)c1
Yield: 39.6 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[(R)-4-(2,4-dimethylphenyl)-3-methylpiperazin-1-yl]methanone (814 mg) and oxazolidin-2-one (168 mg), the title compound (327 mg) was obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]3[CH:15]=[CH:16][C:17]([O:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][C:13]=3[S:12][C:11]=2[CH:27]=1)[CH3:2].C1C[O:33]CC1>>[CH2:28]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]3[CH:15]=[CH:16][C:17]([O:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][C:13]=3[S:12](=[O:33])[C:11]=2[CH:27]=1)[CH3:29]
Reactant: CCN(CC)CCOc1ccc2c(c1)sc1cc(OCCN(CC)CC)ccc12
Reactant: C1CCOC1
Product: CCN(CC)CCOc1ccc2c(c1)S(=O)c1cc(OCCN(CC)CC)ccc1-2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a cooled solution (0° C.) of the product of Example 16A (347 mg, 0.83 mmol) in dry THF (2 mL), was added a solution of CF3CO3H in THF (4 M; 0.21 mL, 0.83 mmol). The reaction was stirred 30 minutes at 0° C., then for 30 minutes at room temperature, and concentrated under vacuum. The residue was purified by flash chromatography (35 g silica gel, 1:5:94 NH4OH-MeOH—CH2Cl2) to afford the title compound (360 mg, 100%).
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:16])[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][N:10]=2)=O)C.[C:17]1([NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23].C(=O)(O)[O-].[Na+]>>[NH:23]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:24]=[C:4]1[C:6]1[C:7](=[O:16])[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][N:10]=2
Reactant: CCOC(=O)c1cc2cccnc2[nH]c1=O
Reactant: Nc1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Product: O=c1[nH]c2ncccc2cc1-c1nc2ccccc2[nH]1
Temperature: 200 °C

Procedure:
A mixture of 5-3 (300 mg, 1.37 mmol, 1 equiv) and 1,2-phenylenediamine (223 mg, 2.06 mmol, 1.5 equiv) in polyphosphoric acid (8 mL) was heated at 200° C. for 16 h. The hot rxn mixture was poured into ice water (50 mL), and the resulting mixture was allowed to stand until all polyphosphoric acid had dissolved. The acidic suspension was neutralized with saturated aqueous sodium bicarbonate solution, then extracted with ethyl acetate (5×100 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was suspended in ethyl acetate (50 mL) aided by sonication, and the solids were filtered to give 3-(1H-benzoimidazol-2-yl)-1H-[1,8]naphthyridin-2-one (5-4) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C:11](=[O:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C:11](=[O:12])[C@@:7]2([CH3:31])[CH2:6]1)/[C:17](=[CH:18]/[N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[O:3]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: C1CCNC1
Solvent: ClCCl
Product: COC[C@H]1OC(=O)/C(=C\N2CCCC2)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of wortmannin (30.0 mg, 70.0 μmol) in CH2Cl2 (200 μL) was added pyrrolidine (7.0 μL, 84 μmol) in CH2Cl2. The reaction mixture was stirred at room temperature for 1 h. The solvent and excess thiol were removed in vacuo and the product was purified by chromatography on SiO2 (hexanes/ethyl acetate 9:1, then 1:1) to give PX-867 (30.0 mg, 60.6 μmol, 86%) as an orange oil. The product was analyzed by several experimental methods and shown to be of the correct structure and of high purity as: [α]D−390 (c 0.0073, CH2Cl2, 23° C.); IR (KBr) 3337, 1740, 1684, 1617, 1570, 1261, 1221, 1099, 1018 cm−1; 1H NMR δ8.29 (s, 1H), 6.72 (s, 1H), 6.07 (dd, 1H, J=6.9, 4.8 Hz), 4.47 (dd, 1H, J=7.0, 1.9 Hz), 3.80-3.70 (m, 2H), 3.25 (s, 3H), 3.25-3.14 (m, 2H), 3.02-2.90 (m, 2H), 2.69 (br s, 1H), 2.58 (dd, 1H, J=19.1, 8.4 Hz), 2.39 (dd, 1H, J=14.6, 7.8 Hz), 2.32-2.08 (m, 2H), 2.06 (s, 3H), 1.99-1.95 (m, 5H), 1.84 (dd, 1H, J=14.5, 4.2 Hz), 1.56 (s, 3H), 0.86 (s, 3H); 13C NMR δ 217.5, 178.9, 169.9, 164.9, 153.9, 151.3, 137.6, 137.1, 129.2, 89.4, 82.1, 73.3, 67.7, 59.3, 55.2, 49.2 (2C), 42.6, 42.4, 37.8, 36.3, 25.6 (2C), 24.5, 22.4, 21.0, 16.3; MS (EI) m/z (rel. intensity) 499 (M+, 1), 439 (2), 365 (7), 167 (35), 149 (100); HRMS (EI) calculated for C27H33NO8 499.2206. found 499.2191
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[C:13]([OH:22])(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH2:16]>C1COCC1>[C:14]12[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH:16][C:2](=[O:4])[O:22][C:13]2=[O:21]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccccc1C(=O)O
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2c(=O)o1
Temperature: 0 °C
Yield: 70 %

Procedure:
An ice-cold solution of triphosgene (3.0 g, 10 mmol, 0.4 eq) in 10 mL of anhydrous THF was added to a mixture or solution of anthranilic acid (or 2-amino-benzoic acid) (25 mmol) in 15 mL of dry THF and cooled slowly. The mixture as then stirred or shaken for 24-48 h at room temperature nd cooled in a refrigerator (0° C. to −10° C.) for 12-24 h. The resulting solid was collected by filtration and washed with cold methyl t-butyl ether (MTBE) and dried to give the isatoic anhydride in 70-98% yield. About 30 isatoic anhydrides were prepared in this manner.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3B3OC(C)(C)C(C)(C)O3)[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C.[F:43][C:44]1[CH:49]=[C:48]([O:50][CH3:51])[C:47](I)=[CH:46][C:45]=1[C:53]1[CH:58]=[CH:57][C:56]([C:59]([O:61][CH3:62])=[O:60])=[CH:55][C:54]=1[CH3:63].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>O.CCO.C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=3[C:47]3[CH:46]=[C:45]([C:53]4[CH:58]=[CH:57][C:56]([C:59]([O:61][CH3:62])=[O:60])=[CH:55][C:54]=4[CH3:63])[C:44]([F:43])=[CH:49][C:48]=3[O:50][CH3:51])[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2cc(I)c(OC)cc2F)c(C)c1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(-c2cc(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c(OC)cc2F)c(C)c1

Procedure:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one-methane (1.30 g, 2.18 mmol) (INTERMEDIATE 9), the title compound from Step B (1.30 g, 3.25 mmol), tetrakis(triphenylphosphine) palladium (250 mg, 10% mol) and sodium carbonate (507 mg, 4.79 mmol) in 50 ml of water/EtOH/toluene (1:2:4) was heated to reflux for 4 h. TLC (CH2Cl2:hexane/1:1) showed that the reaction was complete. The solvents were removed. Water (20 ml) was added. The organic was extracted with methylene chloride (3×30 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after flash column using CH2Cl2:hexane/8:2 as the elute. 1H NMR (CDCl3, 500 MHz): δ a mixture of 1:1 atopoisomers 7.98 (d, J=4.5 Hz, 1H), 7.89 (s, 2H), 7.68 (m, 4H), 7.42 (t, J=6.0 Hz, 1H), 7.30 (d, J=7.5 Hz, 0.5H), 7.26 (d, J=7.5 Hz, 0.5H), 7.07 (t, J=8.0 Hz, 1H), 6.87 (d, J=5.5 Hz, 0.5H), 6.85 (d, J=6.0 Hz, 0.5H), 5.63 (d, J=8.0 Hz, 0.5H), 5.41 (d, J=8.0 Hz, 0.5H), 5.00 (d, J=15.5 Hz, 0.5H), 4.92 (d, J=16.0 Hz, 0.5H), 4.17 (d, J=15.5 Hz, 0.5H), 3.95 (d, J=16.0 Hz, 0.5H), 3.95 (s, 3H), 3.88 (s, 3H), 3.84 (m, 1H), 2.32 (s, 1.5H), 2.28 (s, 1.5H), 0.64 (d, J=7.0 Hz, 1.5H), 0.62 (d, J=6.5 Hz, 1.5H). LC/MS M+744.2
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N)(=O)C1C=CC=CC=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:38]=[CH:37][CH:36]=[CH:35][C:22]=1[C:23]([NH:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[CH:29][NH:30]2)=[O:24]>CCOCC>[CH3:2][C:1]([NH:5][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:38]=[CH:37][CH:36]=[CH:35][C:22]=1[C:23]([NH:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[CH:29][NH:30]2)=[O:24])([CH3:4])[CH3:3]
Reactant: CC(C)(C)N
Reactant: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCCCCBr
Agent: NC(=O)c1ccccc1
Solvent: CCOCC
Product: CC(C)(C)NCCCCOc1ccccc1C(=O)Nc1cccc2[nH]ccc12

Procedure:
Using the procedure of Example 30 but at 50° C. and replacing tert-pentylamine by tert-butylamine and 2-(3-chloropropoxy)-N-1H-indol-4-yl)benzamide by 2-(4-bromobutoxy)-N-(1H-indol4-yl)benzamide, and with chromatography on silica (eluant: CHCl3 /acetone/TEA of 6:3:1), the residue was taken up in ether to obtain 2-[4-[1,1-dimethylethylamino]butoxy]-N-(1H-indol-4-yl)benzamide melting at 147° C. The acid fumarate, which melted at 224°-225° C. with sublimation after crystallization from ethanol, was prepared.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@:10]1([CH:50]1[CH2:52][O:51]1)[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:54]>CO.O1CCCC1>[NH2:54][CH2:52][CH:50]([C@:10]12[O:32][C@:13]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)([O:12][CH2:11]1)[C@H:14]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C@@H:15]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:51]
Reactant: [NH4+]
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@@](C5CO5)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(O)CN)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 55 °C
Reaction time: 16 h
Yield: 50.9 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-(oxiran-2-yl)-6,8-dioxabicyclo[3.2.1]octane 10a (0.4 g, 0.56 mmol) in a methanol/tetrahydrofuran mixture (v/v=1/2, 9 mL) was added ammonium hydroxide (2 mL, 10 mmol). The mixture was heated to 55° C. and stirred for 16 hours. The resulting mixture was extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with water (30 mL×2) and saturated brine (30 mL×2) in turn, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=6/1 to give the title compound 10b as colourless oil (0.21 g, 51.2%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.48 (m, 2H), 7.40 (m, 1H), 7.33 (m, 4H), 7.26 (m, 6H), 7.18 (m, 3H), 7.05 (m, 2H), 7.04 (m, 2H), 6.85 (m, 2H), 4.90 (m, 1H), 4.77 (m, 3H), 4.26 (d, 1H), 4.11 (d, 2H), 4.00 (m, 2H), 3.91 (m, 3H), 3.85 (t, 1H), 3.71 (m, 4H), 2.71 (m, 1H), 2.56 (m, 1H), 1.26 (t, 3H).
Reaction SMILES: [N+:1]([N:4]=[N:5][CH2:6][NH:7][CH2:8][CH2:9][CH2:10][C@H:11]([NH:20][C:21](=[O:44])[C@H:22]([CH2:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[C@@H:23]([N:27]([CH:35]=[O:36])[O:28]C1CCCCO1)[CH2:24][CH2:25][CH3:26])[C:12](=[O:19])[NH:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1)([O-:3])=[O:2]>C(O)(=O)C>[N+:1]([N:4]=[N:5][CH2:6][NH:7][CH2:8][CH2:9][CH2:10][C@H:11]([NH:20][C:21](=[O:44])[C@H:22]([CH2:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[C@@H:23]([N:27]([CH:35]=[O:36])[OH:28])[CH2:24][CH2:25][CH3:26])[C:12](=[O:19])[NH:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1)([O-:3])=[O:2]
Reactant: CCC[C@@H]([C@@H](CC1CCCCC1)C(=O)N[C@@H](CCCNCN=N[N+](=O)[O-])C(=O)Nc1nccs1)N(C=O)OC1CCCCO1
Solvent: CC(=O)O
Product: CCC[C@@H]([C@@H](CC1CCCCC1)C(=O)N[C@@H](CCCNCN=N[N+](=O)[O-])C(=O)Nc1nccs1)N(O)C=O
Temperature: 40 °C
Yield: 81.1 %

Procedure:
(2R,3S)-3-(Formyl-2-tetrahydropyranyloxyamino)-2-(cyclohexylmethyl)hexanoic acid [(1S)-4-(nitroimino-amino)methylamino-1-(1,3-thiazol-2-ylcarbamoyl)-1-butyl]amide (115 mg, 0.180 mmol) is dissolved in 2 mL of 80% acetic acid and heated at 40° C. for 20 h. Concentration in vacuo and trituration with dichloromethane—ether provided 81 mg of (2R,3S)-3-(formyl-hydroxyamino)-2-(cyclohexylmethyl)hexanoic acid [(1S)-4-(nitroimino-amino)methylamino-1-(1,3-thiazol-2-ylcarbamoyl)-1-butyl]amide as a solid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:40]3[N:44]([CH3:45])[C:43]4[CH:46]=[CH:47][CH:48]=[CH:49][C:42]=4[N:41]=3)=[CH:35][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:45][N:44]1[C:43]2[CH:46]=[CH:47][CH:48]=[CH:49][C:42]=2[N:41]=[C:40]1[NH:39][C:36]1[CH:37]=[CH:38][C:33]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=2)=[CH:34][CH:35]=1
Reactant: Cn1c(Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc2ccccc21
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccccc6n5C)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 83 °C
Reaction time: 15 h
Yield: 50.1 %

Procedure:
To a solution of cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.227 mmol) in ethylene glycol dimethyl ether (3 mL) and water (1.5 mL) under nitrogen was added N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-benzo[d]imidazol-2-amine (0.099 g, 0.28 mmol), tetrakis(triphenylphosphine) palladium (0) (0.013 mg, 0.011 mmol), and sodium carbonate (0.060 mg, 0.568 mmol). The solution was stirred at 83° C. for 15 h. The resulting yellow mixture was concentrated in vacuo to give a yellow oil. Purification by preparative HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 20 min at 21 mL/min using a 8μ Hypersil HS C18, 250×21 mm column, tr=7.3-11.2 min.) afforded cis-3-{4-[(1-methyl-1H-benzo[d]imidazol-2-yl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as an off-white solid (0.061 g, 50%): 1H NMR (DMSO-d6, 400 MHz) δ 9.17 (s, 1H), 8.23 (s, 1H), 8.08 (d, 2H), 7.62 (d, 2H), 7.42 (m, 1H), 7.33 (m, 1H), 7.08 (m, 1H), 4.80 (m, 1H), 3.76 (s, 3H), 2.50-2.07 (m, 12H), 1.80-1.60 (m, 8H); RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=5.92 min., 99%; m/z 537 (MH+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH2:17][C:16](=[O:18])[NH:15][C:14]3[CH:19]=[C:20]([Cl:26])[C:21]([N:23]([CH3:25])[CH3:24])=[CH:22][C:13]=3[N:12]=2)[CH:8]=[CH:9][CH:10]=1)=O.[C:27]([NH:30][C:31]([NH2:33])=[S:32])(=[NH:29])[NH2:28]>C1COCC1.CCOC(C)=O>[Cl:26][C:20]1[C:21]([N:23]([CH3:25])[CH3:24])=[CH:22][C:13]2[N:12]=[C:11]([C:7]3[CH:6]=[C:5]([C:3]4[N:33]=[C:31]([NH:30][C:27]([NH2:29])=[NH:28])[S:32][CH:2]=4)[CH:10]=[CH:9][CH:8]=3)[CH2:17][C:16](=[O:18])[NH:15][C:14]=2[CH:19]=1
Reactant: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(C(=O)CBr)c1)=N2
Reactant: N=C(N)NC(N)=S
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3csc(NC(=N)N)n3)c1)=N2
Temperature: 60 °C
Yield: 16.4 %

Procedure:
A mixture of 4-(3-bromoacetyl-phenyl)-8-chloro-7-dimethylamino-1,3-dihydro-benzo[b][1,4]diazepin-2-one (130 mg) (Example 193a) and N-amidino-thiourea (35 mg) in THF (3 mL) was heated at 60° C. for 1 h. The mixture was diluted with AcOEt and washed with sat. NaHCO3 solution and with brine. The organic layer was dried and evaporated and the residue was purified by chromatography on silica gel using AcOEt/MeOH (20:1) as eluent. The purified product was crystallyzed from acetone to give the title compound (22 mg) as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:28][S:29]([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)(=[O:31])=[O:30]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[O:9])=[CH:6][N:5]=[C:4]([NH:38][CH:35]2[CH2:36][CH2:37][N:32]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:33][CH2:34]2)[N:3]=1
Reactant: CCS(=O)c1ncc(C(=O)c2ccc(Cl)cc2)c(N)n1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3ccc(Cl)cc3)c(N)n2)CC1

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(4-chloro-phenyl)-methanone (Example 362) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(4-chloro-phenyl)-methanone. MS (M+H)+, 410
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([C:10]2[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:12]=[CH:13][CH:14]=2)[S:8][CH:9]=1)[CH2:3][OH:4].[Br:22]N1C(=O)CCC1=O.O>O1CCCC1>[Br:22][C:12]1[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]([C:7]2[S:8][CH:9]=[C:5]([CH:2]([OH:1])[CH2:3][OH:4])[N:6]=2)=[CH:14][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)n1cccc1-c1nc(C(O)CO)cs1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(Br)ccc1-c1nc(C(O)CO)cs1
Temperature: 0 °C
Reaction time: 14 h
Yield: 48.4 %

Procedure:
t-Butyl 2-[4-(1,2-dihydroxyethyl)-1,3-thiazol-2-yl]-1H-pyrrole-1-carboxylate (868 mg, 2.80 mmol) synthesized in Example (9c) was dissolved in tetrahydrofuran (30 mL), and cooled to 0° C. N-Bromosuccinimide (498 mg, 2.80 mmol) was added, and stirring was carried out at room temperature for 14 hours under nitrogen atmosphere. Water (20 mL) was added, and extraction was carried out with diethyl ether (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-30%) to afford the desired compound (527 mg, yield 48%) as a pale yellow oil.
Reaction SMILES: CN1C=C(CN(C)C(C2N(C3C=CC(F)=CC=3)C(S)=NC=2)=[O:10])C(C)=N1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:37]([C:38](N(OC)C)=[O:39])=[CH:36][N:35]=[C:34]2[S:44]([CH2:47][C:48]2[C:53]([F:54])=[CH:52][CH:51]=[C:50]([F:55])[C:49]=2[F:56])(=[O:46])=[O:45])=[CH:29][CH:28]=1.[OH-].[Li+].C1COCC1>O.CO>[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:37]([C:38]([OH:10])=[O:39])=[CH:36][N:35]=[C:34]2[S:44]([CH2:47][C:48]2[C:53]([F:54])=[CH:52][CH:51]=[C:50]([F:55])[C:49]=2[F:56])(=[O:45])=[O:46])=[CH:29][CH:28]=1
Reactant: Cc1nn(C)cc1CN(C)C(=O)c1cnc(S)n1-c1ccc(F)cc1
Reactant: CON(C)C(=O)c1cnc(S(=O)(=O)Cc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnc(S(=O)(=O)Cc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1

Procedure:
1-(4-Fluorophenyl)-2-((2,3,6-trifluorobenzyl)sulfonyl)-1H-imidazole-5-carboxylic acid (22) was prepared in a similar manner as that described for the synthesis of compound 7 using 1-(4-fluorophenyl)-N-methoxy-N-methyl-2-((2,3,6-trifluorobenzyl)sulfonyl)-1H-imidazole-5-carboxamide (21) (50 mg, 0.11 mmol), lithium hydroxide (10 mg, 0.44 mmol), THF (0.1 mL), methanol (0.2 mL), and water (0.4 mL).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[S:19][C:20]([CH2:28][CH2:29][CH2:30]Cl)=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:22]=3)[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na+].[I-:33]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[S:19][C:20]([CH2:28][CH2:29][CH2:30][I:33])=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:22]=3)[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(=O)OC(C)(C)C)CCC3)sc1CCCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(=O)OC(C)(C)C)CCC3)sc1CCCI
Temperature: 80 °C
Reaction time: 48 h
Yield: 32.9 %

Procedure:
Ethyl 2-(1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-5-(3-chloropropyl)thiazole-4-carboxylate (23F) (0.943 g, 2.02 mmol) was dissolved in Acetonitrile (10 mL). To this reaction mixture was added NaI (0.309 g, 2.06 mmol) and heated to 80° C. The reaction was stirred for 48 hours. The reaction was filtered and concentrated under reduced pressure. The crude material was dissolved in EtOAc, washed with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure to provide 0.370 g (97%) of the desired product ethyl 2-(1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-5-(3-iodopropyl)thiazole-4-carboxylate (23G): LC/MS (APCI): m/z 557.2 (M+H).