Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH:14][CH3:15])=[CH:10][N:11]=[N:12][CH:13]=2)=[C:4]([O:16][CH3:17])[CH:3]=1.[CH3:18][S:19]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:25](Cl)=[O:26])(=[O:21])=[O:20].C(N(CC)C(C)C)(C)C.[Cl-].[NH4+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]([CH3:15])[C:25](=[O:26])[C:24]3[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=[C:22]([S:19]([CH3:18])(=[O:21])=[O:20])[CH:23]=3)=[CH:10][N:11]=[N:12][CH:13]=2)=[C:4]([O:16][CH3:17])[CH:3]=1
Reactant: CNc1cnncc1-c1ccc(F)cc1OC
Reactant: CS(=O)(=O)c1cc(C(=O)Cl)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(F)ccc1-c1cnncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 26.7 %

Procedure:
To a solution of 5-(4-fluoro-2-methoxyphenyl)-N-methylpyridazin-4-amine (27 mg, 116 μmol) in dichloromethane (1 mL) were added 3-(methylsulfonyl)-5-(trifluoromethyl)benzoyl chloride (66.4 mg, 232 mmol) and N,N-diisopropylethylamine (60 mg, 80.9 μL, 463 μmol). The clear, light brown solution was stirred at room temperature for 1.75 h and then poured on saturated aqueous ammonium chloride solution and dichloromethane and the layers were separated. The aqueous layer was extracted three times with dichloromethane. The organic layers were dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 0:100) to give the desired compound as a light brown solid (15 mg; 25%). MS (ESI+): m/z=483.09 ([M+H]+).
Reaction SMILES: C(N[C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:20][CH3:21])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][Cl:19])=[C:8]([NH2:22])[N:7]=1)CCC.FC(F)(F)C(O)=O.COC1N=C2C(N=1)=C(N)NC([O:42][C@@H:43]([CH3:46])[CH2:44][CH3:45])=N2.BrCCCCCl>C(OCC)(=O)C.C1CCCCC1>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]1[C:11]([O:20][CH3:21])=[N:10][C:9]2[C:13]1=[N:14][C:6]([O:42][C@@H:43]([CH3:46])[CH2:44][CH3:45])=[N:7][C:8]=2[NH2:22]
Reactant: CC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Agent: ClCCCCBr
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1

Procedure:
Prepared similarly to Intermediate 18 from 8-(methyloxy)-2-{[(1S)-1-methylpropyl]oxy}-1H-purin-6-amine trifluoroacetate and 1-bromo-4-chlorobutane with purification on an aminopropyl (NH2) cartridge using a 0-100% ethyl acetate-cyclohexane gradient.
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19][CH2:20][CH2:21][CH3:22])=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[CH2:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:25]#[CH:26].C(N(C(C)C)CC)(C)C>O1CCCC1.[Cu]I>[CH2:24]([C:25]1[N:3]=[N:2][N:1]([CH:4]2[CH2:23][N:8]3[C:9]4[C:14]([C:15]([CH2:16][C:17]([O:19][CH2:20][CH2:21][CH3:22])=[O:18])=[C:7]3[CH2:6][CH2:5]2)=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:26]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Reactant: C#CCc1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCOC(=O)Cc1c2n(c3ccccc13)CC(n1cc(Cc3ccccc3)nn1)CC2
Reaction time: 8 h

Procedure:
To a stirred solution of propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate (1 eq) (Synthesis described in WO07019675 A1) and prop-2-yn-1-ylbenzene (2 eq) in tetrahydrofuran (THF) (0.1M) at room temperature was added diisopropyl ethylamine (DIPEA) (5 eq) and CuI (5 eq). The reaction mixture was stirred overnight then quenched with NH4Cl sat and extracted with ethyl acetate (EA), washed with brine, dried over Na2SO4 and evaporated. Purification by combi-flash EA/Hex 0-100% afforded the desired compound which was used directly for next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[C:23]4[C:18](=[CH:19][C:20]([C:24](O)=[O:25])=[CH:21][CH:22]=4)[N:17](COCC[Si](C)(C)C)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:36])([CH3:35])[NH:3]1.S(Cl)(Cl)=O.[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C(=O)(O)[O-].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>ClC(Cl)C.CN(C1C=CN=CC=1)C.CCOC(C)=O.CN(C=O)C>[N:42]1([C:24]([C:20]2[CH:19]=[C:18]3[C:23]([C:15]([C:13]4[CH:12]=[CH:11][N:10]=[C:9]([NH:8][CH:6]5[CH2:5][C:4]([CH3:36])([CH3:35])[NH:3][C:2]([CH3:37])([CH3:1])[CH2:7]5)[N:14]=4)=[CH:16][NH:17]3)=[CH:22][CH:21]=2)=[O:25])[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1
Reactant: C1COCCN1
Reactant: CC1(C)CC(Nc2nccc(-c3cn(COCC[Si](C)(C)C)c4cc(C(=O)O)ccc34)n2)CC(C)(C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4cc(C(=O)N5CCOCC5)ccc34)n2)CC(C)(C)N1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A suspension of 3-[2-(2,2,6,6-Tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole-6-carboxylic acid (542 mg, 1.0 mmol) in dichloroethane was treated with 3 equivalents of thionyl chloride. A drop of DMF was added and the clear solution was stirred at room temperature for 10 min. This solution was added to a solution of morpholine (1.30 g, 14.9 mmol) in dichloroethane containing DMAP (5.00 mg). After 2 h the reaction mixture was given into a saturated bicarbonate solution, extracted with DCM and dried over sodium sulfate. After removal of the solvent the yellow residue was dissolved in THF and treated with 10 equivalents of TBAF under reflux for 8 h. The reaction mixture was given into EtOAc, washed with 2.5M NaOH, dried over sodium sulfate and concentrated. Purification via chromatography on silicagel (EtOAc/MeOH/ammonia:95/4/1 to 80/19/1) gave the title compound as a white solid. Yield: 250 mg (54%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([O:12][CH3:13])[C:4]=1[Cl:14].[CH2:15]([O:17][P:18]([O:22]CC)[O:19][CH2:20][CH3:21])[CH3:16]>C1(C)C=CC=CC=1>[Cl:14][C:4]1[C:5]([O:12][CH3:13])=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[CH2:2][P:18](=[O:22])([O:19][CH2:20][CH3:21])[O:17][CH2:15][CH3:16]
Reactant: COc1c([N+](=O)[O-])ccc(CBr)c1Cl
Reactant: CCOP(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(OC)c1Cl)OCC

Procedure:
To a solution of 1-(bromomethyl)-2-chloro-3-methoxy-4-nitrobenzene (Compound 54G, 900 mg, 3.21 mmol) in toluene (10 mL) was added triethylphosphite (586 mg, 3.53 mmol) and heated to reflux for 24 h. Toluene and triethylphosphite were distilled off under reduced pressure to provide the desired compound, 800 mg (79%). 1H NMR (300 MHz, CDCl3) δ 7.77 (d, 1H), 7.35 (d, 1H), 4.19-4.05 (m, 4H), 4.00 (s, 3H), 3.43 (d, 2H), 1.31 (t, 6H).
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])(=[O:3])[NH2:2].S(=O)(=O)(O)O.[CH3:19]O>>[S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O:10][CH3:19])=[O:9])(=[O:3])(=[O:4])[NH2:2]
Reactant: NS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(S(N)(=O)=O)c1
Yield: 70.2 %

Procedure:
3-sulfamoylbenzoic acid (150 mg, 0.746 mmol) was refluxed in the presence of concentrated Sulfuric acid (4.82 mg, 0.037 mmol) in methanol (5 mL) at 70° C. for overnight. Reaction was monitored by TLC. After completion of the reaction, Solvent was removed by vacuum and then compound was purified by flash chromatography afforded the methyl 3-sulfamoylbenzoate (115 mg, 0.524 mmol, 70.2% yield) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.53 (m, 1H), 8.18 (d, 1H, J=8.0 Hz), 8.08 (d, 1H, J=7.6 Hz), 7.57 (t, 1H, J=8.0 Hz), 3.92 (s, 3H). Mass [M+H]+:216.0
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Br[CH2:18][CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[N:25][CH:26]=1>>[Cl:27][C:24]1[N:25]=[CH:26][C:21]([O:20][CH2:19][CH2:18][N:3]2[C:4]3[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])=[CH:22][CH:23]=1
Reactant: Clc1ccc(OCCBr)cn1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CCOc1ccc(Cl)nc1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 5-[(2-bromoethyl)oxy]-2-chloropyridine: MS (ES) m/z 380 (M+1) and 382 (M+1, isotope).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:15]=[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:25])[N:17]1[CH2:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>ClCCl.CCCCCC>[O:25]=[C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16](=[O:15])[N:17]1[CH2:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 0 °C

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed aniline (5.73 g, 61.53 mmol, 1.10 equiv), dichloromethane (100 mL) and triethylamine (11.3 g, 111.67 mmol, 2.00 equiv). This was followed by the addition of 4-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]benzoyl chloride (16.7 g, 55.72 mmol, 1.00 equiv) in dichloromethane (100 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 3 h at 25° C. The resulting solution was diluted with 100 mL of hexane. The solids were collected by filtration. The filter cake was washed with 2×50 mL of HCl (1 M), 2×50 mL of saturated aqueous Na2CO3 and 2×100 mL of water. This resulted in 14 g (71%) of 4-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]-N-phenylbenzamide as a white solid. MS (ESI) m/z 357 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[CH:5][N:4]=1.CC(OC(C)=O)=O.C1C(=O)N([Br:25])C(=O)C1.O>CC(O)=O>[Br:25][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[N:6][C:7]=1[O:9][CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(OC)ncn1
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1ncnc(OC)c1Br
Temperature: 100 °C
Reaction time: 5 h
Yield: 95.9 %

Procedure:
To the solution of 4,6-dimethoxypyrimidine (5 g, 35.7 mmol) in HOAc (20 mL) at room temperature under argon was added Ac2O (4.6 g, 44.6 mmol). The resulting solution was heated at 100° C. for 10 min and then NBS (7.9 g, 44.6 mmol) was added. Heating was continued at 100° C. for 5 h. Analysis by HPLC/MS indicated that the reaction was complete. After the reaction mixture was cooled to room temperature, water (50 mL) was added. The resulting precipitate was collected by filtration and further washed with water (15 mL×3), then dried under vacuum. The title compound (7.5 g) was obtained as a white solid. 1H NMR (CDCl3): δ 4.05 (s, 6H), 8.32 (s, 1H). 13C NMR (CDCl3): δ 55.2, 89.0, 154.9, 166.8.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[ClH:17].[CH3:18][C:19]1[CH:20]=[C:21]([C:31]([F:34])([F:33])[F:32])[C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:23][CH:24]=1>>[ClH:17].[CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:9]=[CH:10][C:11]([C:12]([N:28]2[CH2:29][CH2:30][N:25]([C:22]3[C:21]([C:31]([F:34])([F:32])[F:33])=[CH:20][C:19]([CH3:18])=[CH:24][N:23]=3)[CH2:26][CH2:27]2)=[O:14])=[CH:15][CH:16]=1
Reactant: C[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Reactant: Cc1cnc(N2CCNCC2)c(C(F)(F)F)c1
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3)CC2)c(C(F)(F)F)c1
Yield: 10.5 %

Procedure:
By reaction and treatment in the same manner as in Example 87 and using (R)-4-(4-methyl-2-oxooxazolidin-3-yl)benzoic acid (422 mg) described in Preparation Example 37 and 1-(5-methyl-3-trifluoromethylpyridin-2-yl)piperazine hydrochloride (282 mg) described in Preparation Example 55, the title compound (51 mg) was obtained.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([C:10](O)=[O:11])=[CH:7][C:6]=1[CH2:13][O:14][CH2:15][O:16][CH3:17])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.[NH4+].[Cl-]>C1COCC1.[O-2].[O-2].[Mn+4]>[C:1]([C:5]1[O:9][C:8]([CH:10]=[O:11])=[CH:7][C:6]=1[CH2:13][O:14][CH2:15][O:16][CH3:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCOCc1cc(C(=O)O)oc1C(C)(C)C
Agent: [Mn+4]
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCOCc1cc(C=O)oc1C(C)(C)C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
Under cooling with ice, a solution of methyl ester of 5-tert-butyl-4-methoxymethoxymethylfuran-2-carboxylic acid (490 mg, 1.91 mmol) in THF (10 ml) was added to a suspension of lithium aluminum hydride (145 mg, 3.82 mmol) in THF (10 ml), followed by stirring for 1 hour. Under cooling with ice, the mixture was mixed with ethyl acetate and saturated aqueous NH4Cl, filtered and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and evaporated to remove the solvent. The thus obtained residue was dissolved in methylene chloride (20 ml) and mixed with manganese dioxide (2.49 g, 28.7 mmol), followed by stirring for 1 day. The reaction mixture was filtered and the filtrate was evaporated to remove the solvent; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:4) to give the titled compound (379 mg, 88%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CC(O)=O.[H][H]>CO>[NH2:11][C:9]1[C:8]([O:14][CH3:15])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[CH:10]=1
Reactant: [H][H]
Reactant: COc1cc(C(=O)O)c(F)cc1[N+](=O)[O-]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(C(=O)O)c(F)cc1N
Yield: 97.5 %

Procedure:
A solution of 2-fluoro-5-methoxy-4-nitrobenzoic acid (10 g, 46 mmol), HOAc (50 mL) and MeOH (50 mL) was hydrogenated using a hydrogen balloon overnight. The solution was then filtered through celite and concentrated to a residue, which was triturated with ether and ethyl acetate. The solid was filtered and dried to give the product as light yellow powder (8.3 g, 98%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.76 (s, 3 H) 5.88 (br s, 2 H) 6.36 (d, J=16 Hz, 1 H) 7.13 (d, J=8 Hz, 1 H) 12.32 (br s, 1 H). [M+H] calc'd for C8H8FNO3, 186; found 186.
Reaction SMILES: C([NH:11][CH2:12][CH2:13][CH2:14][C@H:15]([C:32]([NH:34][C:35]([CH3:43])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:36])=[O:33])[NH:16][C:17](=[O:31])[CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(OCC1C=CC=CC=1)=O.[ClH:44]>CO.[Pd]>[ClH:44].[C:25]1([CH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:17]([NH:16][C@@H:15]([C:32]([NH:34][C:35]([CH3:43])([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH3:36])=[O:33])[CH2:14][CH2:13][CH2:12][NH2:11])=[O:31])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(NC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)C(c1ccccc1)c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(NC(=O)[C@@H](CCCN)NC(=O)C(c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
Prepared according to the method described in Example 1(e) above from (R)-N5 -(Cbz)-N2 -(diphenylacetyl)-N-(1-methyl-1-phenylethyl)ornithine amide (4.21 g; from step (c) above) using 10% Pd/C (200 mg) in 150 mL of MeOH and 1 mL of concentrated HCl, yielding 3.88 g of sub-title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:27]([CH3:29])[CH3:28]>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH:27]([CH3:29])[CH3:28])[CH2:18]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1
Reactant: CC(C)I
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCCN(C(C)C)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[2-(3-piperidinyl)ethyl]-9H-purin-6-amine and 2-iodopropane.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15](Cl)=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH:29][C:15]([C:9]1[C:10]2[N:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[N:4][C:5]=2[CH:6]=[C:7]([N+:19]([O-:21])=[O:20])[C:8]=1[CH3:18])=[O:16])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC
Reactant: NCc1ccccc1
Product: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)NCc3ccccc3)c2nc1OC
Reaction time: 24 h

Procedure:
Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13) 250 mg (0.80 mmol) and benzylamine 90 μL (0.84 mmol). Reaction was continued for 24 hours, and the crude product was eluted through a flash column (7:3 hexanes:ethyl acetate), 260 mg (84%), mp 171-173° C.; 1H NMR (CCl3): δ 8.32 (s, 1H), 7.32 (m, 5H), 6.12 (br s, 1H), 4.68 (d, 2H, J=5.6 Hz), 4.06 (s, 3H), 3.92 (s, 3H), 2.56 (s, 3H); MS (APCI): m/z 383 (M+1). Anal Calcd. for C19H18N4O5: C, 59.68; H, 4.74; N, 14.65. Found: C, 59.63; H, 4.94; N, 14.56.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][CH:14]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:11]([C:21](O)=[O:22])[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:38])[C:27]1[CH:36]=[C:35]([NH2:37])[CH:34]=[C:29]([C:30]([O:32][CH3:33])=[O:31])[CH:28]=1>>[CH3:33][O:32][C:30](=[O:31])[C:29]1[CH:34]=[C:35]([NH:37][C:21]([C:11]2[N:10]=[CH:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:12]=2[CH2:13][CH:14]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:22])[CH:36]=[C:27]([C:26]([O:25][CH3:24])=[O:38])[CH:28]=1
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: O=C(O)c1ncn(Cc2ccccc2)c1CC1CCCCCC1
Product: COC(=O)c1cc(NC(=O)c2ncn(Cc3ccccc3)c2CC2CCCCCC2)cc(C(=O)OC)c1
Yield: 20 %

Procedure:
The product of step b above (310 mg, 1.00 mmol) was reacted with 5-amino-isophthalic acid dimethyl ester (210 mg, 1.00 mmol) using essentially the same procedure as in Example 20, step d. The crude product was purified by flash column chromatography (silica, DCM/ethyl acetate 92:8) to afford colourless foam (110 mg, 20%). 1H NMR (300 MHz,CDCl3) 9.36 (1H, s), 8.53 (2H, s), 8.40 (1H, s), 7.35 (4H, m), 7.08 (2H, m), 5.12 (2H, s), 3.94 (6H, s), 1.90-1.22 (13H, m).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[CH:21]([CH2:22][CH2:23][C:24]=2Br)[CH:20]([NH:26][C:27](=[O:36])[CH2:28][O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:19]3=[O:37])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:38]([O:43]C)([O:41][CH3:42])[O:39][CH3:40]>>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[CH:21]([CH2:22][CH2:23][C:24]=2[P:38]([O:41][CH3:42])([O:39][CH3:40])=[O:43])[CH:20]([NH:26][C:27](=[O:36])[CH2:28][O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:19]3=[O:37])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Br)CCC12
Reactant: COP(OC)OC
Product: COP(=O)(OC)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)C2CC1
Yield: 25 %

Procedure:
A solution of 3-bromo-7-[(phenoxyacetyl)amino]-8-oxo-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (diphenylmethyl)ester (1.12 g, 2 mmol) in trimethyl phosphite (5 mL) was refluxed under nitrogen for two hours. After cooling, the reaction was poured into hexanes. The supernatant was removed and the residue purified by flash chromatography on silica gel (50% ethyl acetate/hexanes to 100% ethyl acetate) to provide 7-[(phenoxyacetyl)amino]-8-oxo-3-(dimethoxyphosphinyl)-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (diphenylmethyl)ester (300 mg; 25%):
Reaction SMILES: [CH3:1][CH2:2][N:3]([C:6]([NH:8][C@@H:9]1[CH2:24][N:23]([CH3:25])[C@H:22]2[C@@H:11]([C:12]3[C:17]4[C:18]([CH2:21]2)=[CH:19][NH:20][C:16]=4[CH:15]=[CH:14][CH:13]=3)[CH2:10]1)=[O:7])[CH2:4][CH3:5].[CH2:26]([N:28](CC)CC)C.ClS(N=C=O)(=O)=O>C(#N)C>[C:26]([C:19]1[NH:20][C:16]2[C:17]3[C:18]=1[CH2:21][C@@H:22]1[C@@H:11]([C:12]=3[CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]([NH:8][C:6](=[O:7])[N:3]([CH2:2][CH3:1])[CH2:4][CH3:5])[CH2:24][N:23]1[CH3:25])#[N:28]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Reactant: CCN(CC)CC
Agent: O=C=NS(=O)(=O)Cl
Solvent: CC#N
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C#N)c(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 31 %

Procedure:
680 mg of terguride (2 mmol) is dissolved in 120 ml of acetonitrile and 5.5 ml of triethylamine and, under ice cooling, a solution of 3.5 ml of chlorosulfonyl isocyanate in 40 ml of acetonitrile is added dropwise thereto under an argon atmosphere. The ice bath is removed and the mixture allowed to stand for two days at room temperature. To facilitate isolation of the polar by-products, the mixture is combined with 20 ml of diethylamine and stirred for three hours at room temperature. Then the mixture is diluted with methylene chloride, extracted with 1N sodium hydroxide solution, and the water phase is once more extracted. The combined organic phases are dried with sodium sulfate and evaporated. The residue is chromatographed on silica gel with a mixture of methylene chloride and methanol, thus isolating 229 mg (31% of theory) of crude 3-(2-cyano-6-methyl-8α-ergolinyl)-1,1-diethylurea. Ater crystallizing from ethyl acetate, 92 mg is obtained as the pure compound.
Reaction SMILES: [C:1]([N:3]=[C:4]([S:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)SCC1C=CC=CC=1)#[N:2].[CH2:21]([NH2:24])[C:22]#[CH:23]>>[C:1]([NH:3][C:4](=[N:24][CH2:21][C:22]#[CH:23])[S:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)#[N:2]
Reactant: N#CN=C(SCc1ccccc1)SCc1ccccc1
Reactant: C#CCN
Product: C#CCN=C(NC#N)SCc1ccccc1

Procedure:
Dibenzyl cyanodithioimidocarbonate [prepared by the procedure described in Ann., 355, 196 (1907)] is reacted with about an equimolar amount of propargylamine according to the general procedure of Example 14, and the title product is thereby produced.
Reaction SMILES: N#N.[CH3:3][C:4]1[O:5][C:6]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[C:7]([C:9]([OH:11])=O)[N:8]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:42][O:43][CH2:44][C:45]1[S:49][C:48]([CH2:50][N:51]2[N:55]=[C:54]([NH2:56])[CH:53]=[N:52]2)=[N:47][CH:46]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:42][O:43][CH2:44][C:45]1[S:49][C:48]([CH2:50][N:51]2[N:55]=[C:54]([NH:56][C:9]([C:7]3[N:8]=[C:4]([CH3:3])[O:5][C:6]=3[C:12]3[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=3)=[O:11])[CH:53]=[N:52]2)=[N:47][CH:46]=1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Reactant: COCc1cnc(Cn2ncc(N)n2)s1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCc1cnc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(C)c3)n2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-methyl-5-(m-tolyl)oxazole-4-carboxylic acid (WO 2009/077990, p. 112) (61.0 mg, 0.28 mmol) in CH2Cl2 (1.5 mL) was treated at rt with DMAP (8.5 mg, 0.07 mmol), HOBt (45.6 mg, 0.34 mmol), EDC (135 mg, 0.70 mmol) and DIPEA (0.19 mL, 1.12 mmol) and the resulting mixture was stirred for 30 min at rt. A solution of 2-((5-(methoxymethyl)thiazol-2-yl)methyl)-2H-1,2,3-triazol-4-amine (63 mg, 0.28 mmol) in CH2Cl2 (1.5 mL) was then added and the reaction mixture was stirred overnight at rt. The mixture was diluted with CH2Cl2 (5.0 mL), the layers were separated and the org. phase was washed with water (5.0 mL) dried over Na2SO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (4:6 hept-EA) gave the title compound as a colorless oil: TLC: rf (4:6 hept-EA)=0.29. LC-MS-conditions 07: tR=0.92 min, [M+H]+=425.09.