Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2]OC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:34][C:35]1[C:40]([C:41]([C:43]2[CH:44]=[N:45][C:46]([NH2:49])=[CH:47][CH:48]=2)=O)=[CH:39][C:38]([C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[C:52]([O:58][CH3:59])[CH:51]=2)=[CH:37][N:36]=1>C1COCC1>[CH3:59][O:58][C:52]1[CH:51]=[C:50]([C:38]2[CH:39]=[C:40]3[C:41]([C:43]4[CH:48]=[CH:47][C:46]([NH2:49])=[N:45][CH:44]=4)=[CH:2][NH:34][C:35]3=[N:36][CH:37]=2)[CH:55]=[CH:54][C:53]=1[O:56][CH3:57]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(-c2cnc(N)c(C(=O)c3ccc(N)nc3)c2)cc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cnc3[nH]cc(-c4ccc(N)nc4)c3c2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.9 %

Procedure:
To a suspension of (methoxymethyl)triphenylphosphonium chloride (166 mg, 0.485 mmol) in THF (1 ml) at 0° C. under nitrogen was added potassium bis(trimethylsilyl)amide (97 mg, 0.485 mmol). The mixture was stirred at room temperature for 30 min, then it was added to [2-amino-5-(3,4-dimethoxy-phenyl)-pyridin-3-yl]-(6-amino-pyridin-3-yl)-methanone (34 mg, 0.097 mmol) in one portion. The reaction mixture was stirred for 2 hours, then quenched with wet methanol and concentrated in vacuo. The crude was diluted with 2 ml of 1,4-dioxane and treated with 0.1 ml of aqueous 70% perchloric acid. The mixture was stirred at 80° C. for 19 hours, diluted with THF/methanol (1:1), and treated with 2.0 g of PS-trisamine (Argonaut Technologies, 4 equivalents per equivalent of acid used) for 30 minutes. The resin was filtered off and washed with THF-MeOH (1:1). Purification was accomplished by flash chromatography on silica gel with a gradient, of methanol/dichloromethane afforded 5-[5-(3,4-dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-pyridin-2-ylamine as a yellow solid (9.7 mg, 29% yield). 1H NMR (DMSO-d6): δ 11.8 (s, 1H), 8.51 (d, J=2.0 Hz, 1H), 8.31 (d, J=2.0 Hz, 1H), 8.25 (d, J=2.0 Hz, 1H), 7.77 (dd, J=2.0, 10.0 Hz, 1H), 7.70 (d, J=2.5 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.24 (dd, J=2.0, 7.5 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H), 6.55 (d, J=8.5 Hz, 1H), 5.90 (broad s, 2H), 3.86 (s, 3H), 3.79 (s, 3H). HPLC/MS m/z 347.1 [MH]+.
Reaction SMILES: C1(COC(=O)[NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:15]2[C:18](=[O:19])[C:17](=[O:20])[C:16]=2OCC)C=CC=CC=1.C1CC=CCC=1>[Pd].C(O)C>[CH3:29][C:28]([O:27][C:25](=[O:26])[CH2:24][N:14]1[CH2:13][CH2:12][CH2:11][NH:10][C:16]2[C:17](=[O:20])[C:18](=[O:19])[C:15]1=2)([CH3:31])[CH3:30]
Reactant: CCOc1c(N(CCCNC(=O)OCc2ccccc2)CC(=O)OC(C)(C)C)c(=O)c1=O
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1CCCNc2c1c(=O)c2=O
Temperature: 20 °C
Reaction time: 5 h
Yield: 82.4 %

Procedure:
To a cooled (20° C.) flask containing 10% palladium on carbon (5.25 g) under nitrogen was added [3-[[(1,1-dimethylethyloxycarbonyl)methyl]-(2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)amino]propyl]carbamic acid phenylmethyl ester (5.25 g, 11.8 mmol) in ethanol (500 mL), followed by 1,4-cyclohexadiene (11 mL, 0.12 mol) over 5 min. After 5 hours, the suspension was filtered through Celite® with generous ethanol washing (1 L). The ethanol was evaporated and the residue was dissolved in dichloromethane and purified by flash chromatography (7.5 cm diameter, gradient elution with 2.5-3% methanol in dichloromethane) to yield (8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)acetic acid 1,1-dimethylethyl ester as a white solid (2.59 g, 82%, mp 167°-168° C.); IR (KBr, cm-1): 3200, 1800, 1720; MS (EI): 266 (M+, 42), 210 (33), 166 (37), 165 (100), 154 (58), 138 (37), 70 (58); 1H NMR (DMSO, 400 MHz): δ 8.62 (br s, NH), 4.38 (s, 2H), 3.36-3.27 (m, 4H), 1.91 (m, 2H), 1.40 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15]2[C:24]3[C:19](=[C:20]([F:26])[CH:21]=[CH:22][C:23]=3[F:25])[N:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:16]=2[CH3:33])[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C1(C)C=CC=CC=1>[N:8]1([C:5]2[C:4]([NH:14][C:15]3[C:24]4[C:19](=[C:20]([F:26])[CH:21]=[CH:22][C:23]=4[F:25])[N:18]=[C:17]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[C:16]=3[CH3:33])=[CH:3][C:2]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:7][N:6]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: C1COCCN1
Reactant: Cc1c(-c2ccccn2)nc2c(F)ccc(F)c2c1Nc1cc(Br)cnc1N1CCOCC1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2c(F)ccc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Prepared according to Procedure H using N-(5-bromo-2-morpholinopyridin-3-yl)-5,8-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (40.0 mg, 0.131 mmol) and morpholine in toluene to give N-(2,5-di-4-morpholinyl-3-pyridinyl)-5,8-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (CDCl3) δ ppm 8.68 (1H, d, J=3.9 Hz), 8.00 (1H, d, J=7.8 Hz), 7.78-7.96 (2H, m), 7.63 (1H, d, J=2.3 Hz), 7.34-7.44 (1H, m), 7.28-7.34 (1H, m), 7.11 (1H, ddd, J=12.8, 8.7, 3.9 Hz), 6.47 (1H, d, J=2.3 Hz), 3.87-4.01 (4H, m), 3.76-3.87 (4H, m), 3.15-3.49 (4H, m), 2.98-3.13 (4H, m), 2.26 (3H, s). Mass Spectrum (ESI) m/e=519.2 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)[N:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[NH:28][C:2]1[C:7]([Cl:8])=[C:6]([CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)[N:3]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cn2)nc(Cl)c1Cl
Reactant: COc1cccc(N)c1
Product: COc1cccc(Nc2nc(-c3ccc(C(F)(F)F)cn3)nc(C)c2Cl)c1

Procedure:
The title compound was prepared from 4,5-dichloro-6-methyl-2-[5-(trifluoromethyl)-2-pyridinyl]pyrimidine (100 mg, 0.325 mmol) and m-anisidine (37 μl, 0.325 mmol) similar to Example 11 as a pale white solid (26 mg, 20%). 1H NMR (CDCl3): 9.05 (dd, J=0.8, 1.4 Hz, 1H), 8.53 (d, J=8.4 Hz, 1H), 8.06 (dd, J=2.3, 8.3 Hz, 1H), 7.57 (t, J=2.3 Hz, 1H), 7.36 (s, 1H), 7.31 (t, J=8.1 Hz, 1H), 7.18–7.14 (m, 1H), 6.75–6.72 (m, 1H), 3.88 (s, 3H), 2.71 (s, 3H).
Reaction SMILES: OS(O)(=O)=O.C[C:7]1[C:12](C)=[CH:11][CH:10]=[CH:9][N+:8]=1[O-:14].C([O-])([O-])=O.[Na+].[Na+].[N+:21]([O-])([OH:23])=[O:22]>>[N+:21]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N+:8]=1[O-:14])([O-:23])=[O:22]
Reactant: Cc1ccc[n+]([O-])c1C
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])c1cccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 400 mL of concentrated H2SO4 was added slowly 130 g of impure 2,3-dimethylpyridine N-oxide. Fuming HNO3 (330 mL) was slowly added at a rate to keep the temperature between 120° C. and 170° C. After addition was complete, the temperature was held at 103° C. for 3 hours and then the reaction was cooled. The crude reaction was added to 1 kg ice in a large pan, then, with stirring, 1.1 kg Na2CO3 was added. After cooling to room temperature, the solids were removed by suction filtration from the solution. The filtrate was extracted with chloroform. The solids were washed with hot chloroform (3 times). The combined reduced organic extracts yielded 110 g of the crude desired nitropyridine N-oxide as an orange solid. ##STR8##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[CH2:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22]C(C)(C)C)=O)[CH2:16]1.Cl.[C:36](Cl)(=O)[CH:37](C)[CH3:38]>O1CCOCC1.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[C:9]([CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH:37]([CH3:38])[CH3:36])[CH2:16]2)=[N:10][NH:11][C:12]1=[O:13]
Reactant: CC(C)C(=O)Cl
Reactant: COc1ccc(-c2ccc(-n3c(C[C@@H]4CCN(C(=O)OC(C)(C)C)C4)n[nH]c3=O)c(F)c2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(-n3c(C[C@@H]4CCN(C(=O)C(C)C)C4)n[nH]c3=O)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 50 mL round bottom flask was placed 1,1-dimethylethyl (3S)-3-({4-[3-fluoro-4′-(methyloxy)-4-biphenylyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl}methyl)-1-pyrrolidinecarboxylate (0.342 mmol). Added to the flask was 4N HCl in dioxane (2 mL). The flask was capped and the contents were stirred at room temperature for 1 h. The solution was concentrated in vacuo. Added to the flask in succession were dichloromethane (3 mL) and N,N-diisopropylethylamine (0.200 mL). The flask was cooled to 0° C. in an ice bath. In a separate vial, isobutryl chloride (0.348 mmol) was taken up with dichloromethane (2 mL) and was added to the cold solution dropwise via pipette. The reaction was stirred for 2 h while the ice bath was allowed to warm to room temperature. The reaction was then diluted with dichloromethane (20 mL) and washed with saturated aq NH4Cl. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. Reverse phase HPLC (10-70% acetonitrile/water+0.1% NH4OH) was utilized in purifying the title compound (65 mg, 43%). MS(ES)+ m/e 439.1 [M+H]+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7]([CH2:10][CH2:11][OH:12])[C:5]=2[CH:6]=1.[C:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=O)[CH2:14][CH3:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][C:13]1([CH2:14][CH3:15])[C:8]2[NH:9][C:4]3[C:5]([C:7]=2[CH2:10][CH2:11][O:12]1)=[CH:6][CH:1]=[CH:2][CH:3]=3)[CH3:22]
Reactant: CCOC(=O)CC(=O)CC
Reactant: OCCc1c[nH]c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)CC1(CC)OCCc2c1[nH]c1ccccc21
Yield: 67.6 %

Procedure:
A mixture of tryptophol (1.612 g, 10 mmol), ethyl propionylacetate (1.730 g, 12 mmol), and p-toluenesulfonic acid monohydrate (0.20 g) in benzene (70 mL) was heated to reflux for 5 hours. It was quenched with ethyl acetate and washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, evaporated to dryness. Flash chromatography on silica gel provided 1.943 g (68%) of the title compound as a solid. mp<80° C. 1H NMR (300 MHz, CDCl3) δ 9.06 (br, 1H), 7.50 (d, 1H), 7.36 (d, 1H), 7.14 (t, 1H), 7.12 (t, 1H), 4.18 (q, 2H), 4.03 (m, 1H), 3.94 (m, 1H), 2.99 (d, 1H), 2.88 (d, 1H), 2.78 (m, 2H), 2.14 (m, 1H), 2.01 (m, 1H), 1.25 (t, 3H), 0.82 (t, 3H); ESI (+) MS m/e=288 (MH+), ESI (−) MS m/e=286 (MH−).
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:28])[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[CH:13]=1)[CH3:4].[CH2:29]([O:31][C:32]1[CH:37]=[C:36]([O:38][CH2:39][CH3:40])[N:35]=[C:34]([CH2:41][C:42](O)=[O:43])[N:33]=1)[CH3:30]>>[CH2:3]([O:5][C:6](=[O:28])[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([C:42](=[O:43])[CH2:41][C:34]2[N:35]=[C:36]([O:38][CH2:39][CH3:40])[CH:37]=[C:32]([O:31][CH2:29][CH3:30])[N:33]=2)[CH2:26][CH3:27])[CH:13]=1)[CH3:4]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OCC)c1
Reactant: CCOc1cc(OCC)nc(CC(=O)O)n1
Agent: Cl
Product: CCOC(=O)Cc1cncc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)Cc2nc(OCC)cc(OCC)n2)c1

Procedure:
[5-(2-Ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester, dihydrochloride and (4,6-diethoxy-pyrimidin-2-yl)-acetic acid were reacted as described in Example 8, Step 6 to provide {5-[2-({N-[2-(4,6-diethoxy-pyrimidin-2-yl)-acetyl]-N-ethyl-amino}-methyl)-4-trifluoromethyl-phenyl]-pyridin-3-yl}-acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:29])[C:7]([CH2:18][NH:19][C:20]([NH:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>>[CH2:34]([O:33][C:31]([N:26]1[CH2:27][CH2:28][CH:23]([NH:22][C:20]([NH:19][CH2:18][C:7]2[C:6](=[O:29])[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:8]=2)=[O:21])[CH2:24][CH2:25]1)=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)NC1CCNCC1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)NC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
4-[3-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-ureido]-piperidine-1-carboxylic acid benzyl ester was prepared starting from intermediate N and benzyl chloroformate MS calcd. for C30H30ClN4O4 [(M+H)+] 545.2, obsd. 545.0.
Reaction SMILES: [Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][C:5]2[O:6][C@@H:7]([CH2:10][OH:11])[CH2:8][O:9][C:4]=2[CH:3]=1.[H-].[Na+].[S:17](Cl)(=[O:20])(=[O:19])[NH2:18]>CN(C=O)C.O>[S:17](=[O:20])(=[O:19])([O:11][CH2:10][CH:7]1[O:6][C:5]2[CH:12]=[C:13]([Cl:14])[C:2]([Cl:1])=[CH:3][C:4]=2[O:9][CH2:8]1)[NH2:18]
Reactant: NS(=O)(=O)Cl
Reactant: OC[C@H]1COc2cc(Cl)c(Cl)cc2O1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NS(=O)(=O)OCC1COc2cc(Cl)c(Cl)cc2O1
Reaction time: 0.5 h

Procedure:
(2S)-6,7 dichloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethanol (2.0 g, 8.5 mmol), prepared according to the procedure described in Example 11 above, in DMF (20 mL) was cooled in an ice bath. Then, 95% sodium hydride (0.28 g, 11 mmol) was added under argon and the reaction mixture was stirred 30 min. Sulfamoyl chloride (1.97 g, 17 mmol) was added and the reaction mixture was stirred with ice bath cooling. After 1 h, the reaction mixture was diluted with water (50 mL) and extracted three times with ethyl acetate. The combined ethyl acetate was washed with brine, dried (Na2SO4) and evaporated in vacuo to an oil, which was purified by flash column chromatography (ethyl acetate/heptane 1:1) to yield a white solid. The white solid was recrystallized from benzene to yield the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[O:17])[CH:11]=1.C(N(CC)CC)C>[Br-].C([N+]1C(C)=C(CCO)SC=1)C.C(O)C>[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[O:17])[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])[OH:5])[CH:11]=1
Reactant: O=Cc1cccnc1
Reactant: O=Cc1ccccc1Cl
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(c1cccnc1)C(O)c1ccccc1Cl

Procedure:
160 g (1.14 mol) of 2-chlorobenzaldehyde, 122 g (1.14 mol) of 3-pyridinealdehyde, 50 g (0.2 mol) of 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazoliumbromide and 60.6 g (0.6 mol) of triethylamine in one liter of ethanol were heated at 75° C. for 13 hours. Thereafter, the ethanol was distilled off and the residue was dissolved in methylene chloride. The solution was washed twice with water and then extracted twice with 300 ml of 4N hydrochloric acid. The acidic aqueous phase was then rendered slightly alkaline with 4N sodium hydroxide solution and extracted three times with fresh methylene chloride. After the solvent had been distilled off, the crude product was stirred with isopropanol, filtered off under suction and dried to give a product of melting point 92° C.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1.O1CCCC1>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:1][C:2]2[C:15]3[NH:14][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[S:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cccc2c1Nc1ccccc1S2
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2cccc3c2Nc2ccccc2S3)cc1
Temperature: 25 °C
Yield: 59.8 %

Procedure:
107 mg (0.5 mmol) of 1-amino-10H-phenothiazine was dissolved in 4 ml of pyridine. Then 2 ml of a solution of 115 mg (0.55 mmol) of 4-methoxybenzenesulfonyl chloride in tetrahydrofuran was added thereto under stirring at room temperature. After stirring at room temperature overnight, the reaction mixture was concentrated. Then ethyl acetate and water were added to the residue and the organic layer was separated, washed with water and dried over magnesium sulfate. After concentrating, the residue was purified by silica gel column chromatography and recrystallized from ethanol. Thus 115 mg of the title compound was obtained.
Reaction SMILES: CO.C1C[O:6][CH2:5]C1.[H-].[Na+].Cl[C:11]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:14]=[C:13]([NH:23][S:24](=[O:36])(=[O:35])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[C:12]=1[O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[O:44][CH3:45]>CN(C=O)C>[CH3:5][O:6][C:11]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:14]=[C:13]([NH:23][S:24](=[O:36])(=[O:35])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[C:12]=1[O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[O:44][CH3:45]
Reactant: C1CCOC1
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)Nc1ccc(C(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)Nc2ccc(C(C)C)cc2)nc(-c2ccncc2)nc1OC
Temperature: 80 °C

Procedure:
To a mixture of methanol (1 ml) and THF (2 ml) was added sodium hydride (100 mg, 60% dispersion in mineral oil) followed by the addition of 4-i-propyl-phenyl sulfamic acid-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (100 mg, Referential Example 1e)). DMF (0.5 ml) was added and the reaction mixture was heated to 80° C. for 20 h. The solvents were evaporated, water (14 ml) and a 10% solution of citric acid was added until the pH was 3. The precipitate was filtered off and washed with water to give 4-i-propyl-phenyl sulfamic acid-[6-methoxy-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (100 mg). tR=5.08 min, (LC); [M+H]+=522.45 (ES+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1([C:29](Cl)=[O:30])[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:29]([C:16]2([CH2:15][CH2:14][CH2:13][CH2:12][Br:11])[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:22]3[C:17]2=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:30])=[CH:5][CH:4]=1
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNC(=O)C2(CCCCBr)c3ccccc3-c3ccccc32)cc1

Procedure:
Prepared analogously to Example 1 from 4-methoxybenzylamine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][CH:10]([C:13]3[S:14][C:15]([C:18]([O-:20])=O)=[CH:16][N:17]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[N:22]1[CH:23]=[CH:24][N:25]2[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[CH:27][C:26]=12.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[N:22]1[CH:23]=[CH:24][N:25]2[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:18]([C:15]3[S:14][C:13]([CH:10]4[CH2:9][CH2:8][N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH2:12][CH2:11]4)=[N:17][CH:16]=3)=[O:20])=[CH:27][C:26]=12
Reactant: NCc1ccn2ccnc2c1
Reactant: O=C([O-])c1cnc(C2CCN(c3ccccc3)CC2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(NCc1ccn2ccnc2c1)c1cnc(C2CCN(c3ccccc3)CC2)s1
Reaction time: 8 h

Procedure:
Lithium 2-(1-phenylpiperidin-4-yl)thiazole-5-carboxylate (28.8 mg, 0.098 mmol), imidazo[1,2-a]pyridin-7-ylmethanamine (17.31 mg, 0.118 mmol), 4-methylmorpholine (49.6 mg, 0.490 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (55.9 mg, 0.147 mmol) were combined in a vial with dichloromethane (2.5 ml) and the reaction was stirred overnight. The mixture was partitioned between dichloromethane and saturated sodium bicarbonate. The organic layers were dried with sodium sulfate, filtered, and concentrated. Trituration of the crude material with dichloromethane provided the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.21 (t, J=5.9 Hz, 1H), 8.49 (dd, J=7.0, 0.9 Hz, 1H), 8.34 (s, 1H), 7.91-7.88 (m, 1H), 7.52 (d, J=1.2 Hz, 1H), 7.43-7.38 (m, 1H), 7.26-7.16 (m, 2H), 7.01-6.93 (m, 2H), 6.84 (dd, J=7.0, 1.7 Hz, 1H), 6.81-6.72 (m, 1H), 4.48 (d, J=5.9 Hz, 2H), 3.81-3.73 (m, 2H), 3.24-3.01 (m, 1H), 2.90-2.78 (m, 2H), 2.19-2.09 (m, 2H), 1.90-1.73 (m, 2H); MS (ESI(+)) m/e 418 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH3:11])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>CN(C)C=O.[Cl-].[Li+]>[NH2:1][C:2]1[C:10]2[O:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH3:11])[CH2:7][C:6]=2[C:5]([Br:17])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1(C)Cc2cccc(N)c2O1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C)Cc2c(Br)ccc(N)c2O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 106.6 %

Procedure:
A stirred solution of 1.2 grams (0.005 mole) of 7-amino-2-ethoxycarbonyl-2,3-dihydro-2-methylbenzofuran in 50 mL of N,N-dimethylformamide was cooled in an ice-water bath, and 1.0 gram (0.005 mole) of N-bromosuccinimide was added. Upon completion of the addition, the reaction mixture was stirred at the ice-water bath temperature for about one hour and then allowed to warm to ambient temperature, where it stirred for about 18 hours. The reaction mixture was diluted with an aqueous 10% lithium chloride solution, and extracted with two portions of ethyl acetate. The combined extracts were washed with 50 mL of an aqueous 10% lithium chloride solution and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residual oil, which was subjected to column chromatography on silica gel, with 1:4 ethyl acetate:heptane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 1.6 grams of 7-amino-4-bromo-2-ethoxycarbonyl-2,3-dihydro-2-methylbenzofuran. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(N1C2C=C(C=NC)C=CC=2N=C1N)C(C)C.C1(C)C=CC([S:24]([CH:27]([N+]#[C-])C2C=CC(F)=CC=2)(=[O:26])=[O:25])=CC=1.CN.[CH2:40]([N:44]1[C:48]2[CH:49]=[C:50]([C:53]3[N:57]([CH3:58])[CH:56]=[N:55][C:54]=3[C:59]3[CH:64]=[CH:63][C:62]([F:65])=[CH:61][CH:60]=3)[CH:51]=[CH:52][C:47]=2[N:46]=[C:45]1[NH2:66])[CH:41]([CH3:43])[CH3:42].C[OH:68]>>[CH3:27][S:24]([OH:25])(=[O:26])=[O:68].[CH3:27][S:24]([OH:25])(=[O:26])=[O:68].[CH2:40]([N:44]1[C:48]2[CH:49]=[C:50]([C:53]3[N:57]([CH3:58])[CH:56]=[N:55][C:54]=3[C:59]3[CH:60]=[CH:61][C:62]([F:65])=[CH:63][CH:64]=3)[CH:51]=[CH:52][C:47]=2[N:46]=[C:45]1[NH2:66])[CH:41]([CH3:43])[CH3:42]
Reactant: [C-]#[N+]C(c1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1
Reactant: CO
Agent: CC(C)Cn1c(N)nc2ccc(-c3c(-c4ccc(F)cc4)ncn3C)cc21
Agent: CN
Agent: CN=Cc1ccc2nc(N)n(CC(C)C)c2c1
Product: CS(=O)(=O)O

Procedure:
Beginning with 1-isobutyl-2-amino-6-(methyliminomethyl)-1H-benzimidazole (142 mg, 0.52 mmol), α-(p-toluenesulfonyl)-4-fluorobenzylisocyanide (302 mg, 1.05 mmol), methanol (2.5 ml), and methylamine (1.3 ml, 2M in tetrahydrofuran), 1-(isobutyl)-2-amino-6-(1-methyl-4 (4-fluorophenyl)-1H-imidazol-5-yl)-1H-benzimidazole may be prepared essentially as described in EXAMPLE 72. Treatment with 1 equivalent of methanesulfonic acid provides the title compound (114 mg).
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[C:20](Cl)([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:21]>O1CCCC1>[C:20]([NH:10][C:9]1[CH:11]=[CH:12][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:7][CH:8]=1)([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:21]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Nc1ccc(-n2ccnc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1ccc(-n2ccnc2)cc1
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of 4-(1H-imidazol-1-yl)-aniline (14 g; ~88.2 mmol) in 400 ml dry tetrahydrofuran was added dry triethylamine (14.0 ml; ~102 mmol). Ethoxalyl chloride (11.2 ml; 100 mmol) was added dropwise and the reaction mixture was stirred for 2 h. The solvent was removed under reduced pressure, and the residue was stirred with water to give the title compound (19.2 g; 85%). M.p. 177°-180° C.