Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([OH:13])=O)[NH:10][C:5]2=[CH:4][CH:3]=1.[O:14]([CH2:21][CH2:22][NH2:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[O:14]([CH2:21][CH2:22][NH:23][C:11]([C:9]1[NH:10][C:5]2[C:6](=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:8]=1)=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCOc1ccccc1
Reactant: O=C(O)c1cc2nc(Cl)ccc2[nH]1
Product: O=C(NCCOc1ccccc1)c1cc2nc(Cl)ccc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (Preparation 6) and 2-phenoxyethylamine. On completion of the reaction, the mixture was partitioned between water and dichloromethane on a hydrophobic frit, washing with dichloromethane. The organic filtrate was concentrated in vacuo then triturated with dichloromethane/methanol/ethyl acetate to give the title compound as a white solid.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10](=[CH:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[C:9]1=[O:33])=O)(C)(C)C.[F:34][C:35]1[CH:36]=[CH:37][C:38]([CH3:50])=[C:39]([CH:41]=[N:42][C:43]([O:45][Si](C)(C)C)=[CH2:44])[CH:40]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:33])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][C:27]4[N:28]=[CH:29][CH:30]=[CH:31][N:32]=4)[CH2:44][C:43](=[O:45])[NH:42][CH:41]3[C:39]3[CH:40]=[C:35]([F:34])[CH:36]=[CH:37][C:38]=3[CH3:50])[C:11]2=[CH:12][CH:13]=1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)C(=Cc2cc(Cl)ccc2Oc2ncccn2)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2Oc2ncccn2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 3.5 %

Procedure:
In a manner similar to the method described in example 1e, 6-chloro-3-[5-chloro-2-(pyrimidin-2-yloxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1 g, 2 mmol) was reacted with 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (10 mL, 20 mmol) in toluene to give title compound as a white solid (Yield: 40 mg).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[C:15]([O-])(=[O:17])C.[NH4+].C(O)=O>O>[CH:15]([NH:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:17]
Reactant: CCOC(=O)c1c(N)sc2c1CCC2
Reactant: CC(=O)[O-]
Agent: [NH4+]
Solvent: O=CO
Solvent: O
Product: CCOC(=O)c1c(NC=O)sc2c1CCC2
Temperature: 25 °C
Yield: 97 %

Procedure:
A mixture of compound 2g [Compound of Formula 2 wherein R1=COOEt, R2, R3=(CH2)3] (10.0 g, 0.046 mol), ammonium acetate (3.64 g, 0.060 mol) and formic acid (35.74 mL, 0.946 mol) was stirred at 130-135° C. for 8 h. It was then cooled to room temperature and diluted with water (150 mL), extracted with ethyl acetate (3×100 mL), dried over Na2SO4, concentrated and purified by column chromatography to give pure compound of Formula (3g); 10.66 g; Yield: 97%; 1H NMR (200 MHz, CDCl3+DMSO-d6): δ 0.1.33 (t, J=8 Hz, 3H), 2.25-2.43 (m, 2H), 2.74-2.89 (m, 4H), 4.26 (q, J=8 Hz, 2H), 8.48 (s, 1H) 11.16 (bs, 1H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:2]1.[CH3:10][C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([NH:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]3[CH:27]=[C:28]([C:30](O)=[O:31])[S:29][C:22]=13)=[CH:15][CH:14]=2>>[CH3:10][C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([NH:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]3[CH:27]=[C:28]([C:30]([N:1]4[CH2:4][CH:3]([N:5]5[CH2:9][CH2:8][CH2:7][CH2:6]5)[CH2:2]4)=[O:31])[S:29][C:22]=13)=[CH:15][CH:14]=2
Reactant: C1CCN(C2CNC2)C1
Reactant: Cc1cc2cc(Nc3ccnc4cc(C(=O)O)sc34)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CC(N6CCCC6)C5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 1-azetidin-3-yl-pyrrolidine and 7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridine-2-carboxylic acid by a procedure analogous to Example 21B. MS: 312 (MH+); HPLC Rf: 3.211 min; HPLC purity: 96%.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([OH:29])[CH:23]=[CH:22]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:31][C:32]#[N:33].C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl>[CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([O:29][CH2:31][C:32]#[N:33])[CH:23]=[CH:22]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: Oc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccccc3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: N#CCOc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccccc3)ccc2c1
Reaction time: 1.17 h
Yield: 100.1 %

Procedure:
In a similar manner as described in step 1 of Example 3, the title compound was prepared from 6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthol (0.250 g, 0.665 mmol), prepared in step 2 of Example 2, bromoacetonitrile (0.096 g, 0.80 mmol) and cesium carbonate (1.08 g, 3.33 mmol) with the exception that the reaction was complete after 70 minutes at ambient temperature. The crude material was dissolved in methylene chloride and filtered through silica gel (45 g, 200–300 mesh). The solvent was removed under reduced pressure to give {[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile as a beige solid (0.276 g, 100%), mp 156–157° C. Elemental Analysis for C29H22N2O Calc'd: C, 84.03; H, 5.35; N, 6.76. Found: C, 83.15; H, 5.46; N, 6.54.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[CH3:32][O-:33].[Na+]>CO>[CH3:32][O:33][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Yield: 44 %

Procedure:
The mixture of 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (46.0 mg, 0.1 mmol), 0.1 M NaOMe (4 ml) in methanol (2 mL) was refluxed overnight. The reaction mixture was concentrated and purified by reverse phase HPLC (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (20.0 mg, 44%).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.Br[CH:18]=[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)[CH3:20].N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu]I>[F:27][C:23]1[CH:22]=[C:21](/[C:19](/[CH3:20])=[CH:18]/[N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:16])=[CH:11][C:12]=3[C:13]3[CH2:14][CH2:15][N:2]([CH3:1])[CH2:3][CH2:4][C:5]2=3)[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: CC(=CBr)c1cccc(F)c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CCN(C)CC2)c1cccc(F)c1
Temperature: 25 °C

Procedure:
A mixture of 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234 mg, 1 mmol), 1-(1-bromoprop-1-en-2-yl)-3-fluorobenzene (258 mg, 1.2 mmol), L-proline (23 mg, 0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purged with nitrogen. The reaction mixture was heated at 85° C. overnight. An additional 1 eq. of reagents was added and the mixture heated for an additional 24 h. The DMF was evaporated and the residue was poured into water. The precipitate obtained was filtered and purified by silica gel chromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed by reverse phase HPLC to separate the isomers. 1HNMR (CD3OD, TFA salt) δ (ppm): 7.45 (m, 2H), 7.40 (d, 1H), 7.36 (s, 1H), 7.10 (m, 1H), 7.0 (m, 3H), 3.80 (m, 2H), 3.40 (m, 2H), 3.20 (m, 4H), 3.05 (s, 3H), 2.42 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: [C:1]([C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@H:12]3[CH2:24][C@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4])#[N:2].[N-:25]=[N+:26]=[N-:27].[Na+].Cl.C(N(CC)CC)C>CN(C=O)C>[CH3:4][C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@H:12]3[CH2:24][C@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][N:18]=2)[N:16]=1)=[O:8])([C:1]1[NH:27][N:26]=[N:25][N:2]=1)[CH3:5]
Reactant: CC(C)(C#N)NC(=O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@H]1C[C@@H]21
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@H]1C[C@@H]21)c1nnn[nH]1
Temperature: 110 °C
Yield: 29.3 %

Procedure:
A mixture of (1aR,5aR)-2-(4-chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (cyano-dimethyl-methyl)-amide (100 mg, 0.293 mmol), sodium azide (28.5 mg, 0.439 mmol) and triethylamine hydrochloride (81 mg, 0.585 mmol) in DMF (2 mL) was heated in a heavy-walled sealed tube under microwave irradiation at 110° C. for 1 h. Another 50 mg sodium azide and 150 mg triethylamine hydrochloride were added, and the mixture was heated under microwave for another 5 h at 125° C. The mixture was purified by prep HPLC to give the title compound as a white solid (33 mg). LCMS m/z=385.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.35 (td, J=4.4, 3.4 Hz, 1H), 1.23 (td, J=7.8, 4.6 Hz, 1H), 1.757 (s, 3H), 1.764 (s, 3H), 2.21-2.28 (m, 1H), 2.66 (d, J=16.6 Hz, 1H), 2.71-2.75 (m, 1H), 2.79 (dd, J=16.6, 6.4 Hz, 1H), 7.54 (dd, J=5.4, 1.9 Hz, 1H), 8.26 (d, J=1.9 Hz, 1H), 8.42 (bs, 1H), 8.51 (d, J=5.4 Hz, 1H), 16.0 (bs, 1H).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3].Br[CH2:20][CH:21]1[CH2:23][CH2:22]1>>[CH:21]1([CH2:20][N:5]2[C:6]3[C:11](=[C:10]([C:13]([F:15])([F:16])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH:12]=[C:4]2[CH2:1][CH2:2][CH3:3])[CH2:23][CH2:22]1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: BrCC1CC1
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC1CC1

Procedure:
Synthesized as described in Example 4 using 2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and (bromomethyl)cyclopropane: 1H NMR (400 MHz, CDCl3) δ 7.49 (s, 2H), 6.57 (s, 1H), 4.05 (d, J=6.4 Hz, 2H), 2.76 (t, J=7.6 Hz, 2H), 1.83 (m, 2H), 1.16 (m, 1H), 1.08 (t, J=7.4 Hz, 3H), 0.60 (m, 2H), 0.35 (m, 2H); MS (ES) m/z 307 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[NH:9][CH:10]=1)=O.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[C:3]=1[CH2:4][C:6]1[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[NH:9][CH:10]=1
Reactant: COC(=O)c1cc(C(=O)c2c(F)cc(F)cc2F)c[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Cc2c(F)cc(F)cc2F)c[nH]1
Temperature: 70 °C

Procedure:
To a TFA 30 mL solution of methyl 4-(2,4,6-trifluorobenzoyl)-1H-pyrrole-2-carboxylate in a sealed tube was added triethylsilane (2.55 g, 22 mmol). The resulting reaction mixture was heated in an oil bath at 70° C. overnight. The reaction was concentrated and diluted with isopropylacetate and saturated sodium bicarbonate aqueous solution. The organic layer was separated. The aqueous layer was extracted with isopropylacetate twice. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and chromatographed on silica gel eluting with a gradient solvent mixture of AcOEt and hexanes to give the title compound (840 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][SH:18].C(=O)([O-])[O-].[Cs+].[Cs+].I[C@H:26]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27]1>CN(C)C=O>[C:34]([O:33][C:32]([NH:31][C@H:28]1[CH2:29][CH2:30][C@@H:26]([S:18][CH2:17][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=3)[O:6][C:2]=2[CH3:1])[CH2:27]1)=[O:38])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](I)C1
Reactant: COC(=O)c1ccc(-c2nc(CS)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(CS[C@@H]3CC[C@H](NC(=O)OC(C)(C)C)C3)c(C)o2)cc1
Temperature: 35 °C
Reaction time: 0.33 h
Yield: 91.6 %

Procedure:
To a solution of methyl 4-[5-methyl-4-(sulfanylmethyl)-1,3-oxazol-2-yl]benzoate (870 mg, 3.30 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL) maintained under an atmosphere of nitrogen at 35° C. was added cesium carbonate (2.5 g, 7.65 mmol, 2.32 equiv). After stirring at 35° C. for 20 min, tert-butyl N-[(1S,3S)-3-iodocyclopentyl]carbamate (1.25 g, 4.02 mmol, 1.22 equiv) was then added. The resulting solution was allowed to stir for 50 min at 35° C. under nitrogen after which the product was precipitated by the addition of 50 mL water. The solid was collected by filtration, washed with water then dried in a vacuum oven to give 1.35 g (91%) of methyl 4-[4-([[(1R,3S)-3-[[(tert-butoxy)carbonyl]amino]cyclopentyl]sulfanyl]methyl)-5-methyl-1,3-oxazol-2-yl]benzoate as a white solid.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:16])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>C(#N)C>[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:16])=[CH:11][CH:12]=3)[CH2:6][CH2:5]2)=[CH:31][CH:30]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCCCOC(=O)CCc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCOC(=O)CCc1ccc(N2CCN(Cc3ccc(Cl)cc3)CC2)cc1

Procedure:
A mixture of 20.0 g. (68.8 mmole) n-butyl 3-[4-(piperazin-1-yl)-phenyl]-propionate, 200 ml. acetonitrile, 10.4 g. (75.6 mmole) pulverised potassium carbonate and 12.2 g. (75.6 mmole) 4-chlorobenzyl chloride is heated for 36 hours at reflux temperature, filtered with suction and the filtrate evaporated. The residue is taken up in diethyl ether and the hydrochloride precipitated out by adding hydrogen chloride-containing diethyl ether. It is filtered off with suction, recrystallised from isopropanol and dried. Yield 29.0 g. (87% of theory) of hydrochloride; m.p. 222°-225° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:15][CH:14]=1.[C:27](Cl)(=[O:31])[C:28](Cl)=[O:29]>>[C:23]([O:22][C:20]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([N:12]2[C:3]3[CH:4]=[CH:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:1][C:28](=[O:29])[C:27]2=[O:31])=[CH:14][CH:15]=1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(Nc2ccc3ccccc3c2N)cc1
Product: CC(C)(C)OC(=O)Nc1ccc(-n2c(=O)c(=O)[nH]c3c4ccccc4ccc32)cc1
Yield: 37.7 %

Procedure:
1-Amino-2-(4-tertbutoxycarbonylaminophenyl)aminonaphthalene (700 mg, 2.0 mmol) and oxalyl chloride (330 mg, 2.6 mmol) were used in a process similar to Example 1(3) to give the titled compound (304 mg, yield 38%).
Reaction SMILES: [OH:1][C:2]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.[O:19]([CH2:26][C:27](O)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:18][S:15]([C:12]1[CH:13]=[CH:14][C:9]([C:7]2[C:2]3([CH2:6][CH2:5][CH2:4][CH2:3]3)[O:1][C:27](=[O:28])[C:26]=2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: O=C(O)COc1ccccc1
Reactant: CS(=O)(=O)c1ccc(C(=O)C2(O)CCCC2)cc1
Product: CS(=O)(=O)c1ccc(C2=C(Oc3ccccc3)C(=O)OC23CCCC3)cc1

Procedure:
Using a procedure similar to the one used in example 1 but using (1-hydroxycyclopentyl)-(4-(methylsulfonyl)phenyl)methanone from example 21, Step 3 and phenoxyacetic acid the title compound was obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[C:13]2[CH:14]=[C:15]([O:20][CH2:21][CH2:22][CH2:23][C:24]([NH:26][C:27]3[CH:28]=[C:29]([C:33]([OH:35])=O)[N:30]([CH3:32])[CH:31]=3)=[O:25])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[C:11](=[O:36])[N:10]2[CH2:37][CH2:38][CH2:39][C@H:9]2[C@@H:8]1[O:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][O:42]1)=[O:6])[CH:2]=[CH2:3].CCN=C=NCCCN(C)C.Cl.C(OC(N1C2C=C(OCCCC(O)=O)C(OC)=CC=2C(=O)N2CCCC2C1OC1CCCCO1)=O)C=C.[NH2:96][C:97]1[CH:102]=[CH:101][C:100]([C:103]2[CH:104]=[C:105]([C:109]([O:111][CH3:112])=[O:110])[N:106]([CH3:108])[CH:107]=2)=[CH:99][CH:98]=1>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:19][O:18][C:16]1[C:15]([O:20][CH2:21][CH2:22][CH2:23][C:24]([NH:26][C:27]2[CH:28]=[C:29]([C:33](=[O:35])[NH:96][C:97]3[CH:102]=[CH:101][C:100]([C:103]4[CH:104]=[C:105]([C:109]([O:111][CH3:112])=[O:110])[N:106]([CH3:108])[CH:107]=4)=[CH:99][CH:98]=3)[N:30]([CH3:32])[CH:31]=2)=[O:25])=[CH:14][C:13]2[N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C@@H:8]([O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[C@@H:9]3[CH2:39][CH2:38][CH2:37][N:10]3[C:11](=[O:36])[C:12]=2[CH:17]=1
Reactant: C=CCOC(=O)N1c2cc(OCCCC(=O)Nc3cc(C(=O)O)n(C)c3)c(OC)cc2C(=O)N2CCC[C@H]2[C@@H]1OC1CCCCO1
Reactant: COC(=O)c1cc(-c2ccc(N)cc2)cn1C
Agent: C=CCOC(=O)N1c2cc(OCCCC(=O)O)c(OC)cc2C(=O)N2CCCC2C1OC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1c2cc(OCCCC(=O)Nc3cc(C(=O)Nc4ccc(-c5cc(C(=O)OC)n(C)c5)cc4)n(C)c3)c(OC)cc2C(=O)N2CCC[C@H]2[C@@H]1OC1CCCCO1
Reaction time: 3 h

Procedure:
A solution of Alloc-THP protected PBD-Py acid 14a (150 mg, 0.23 mmol, 1.0 equivalent) was dissolved in DMF. EDCl (2.49 g, 13.02 mmol, 2.0 eq) and DMAP (1.989 g, 16.28 mmol, 2.5 eq) were added to the stirred solution of 13 at room temperature and the mixture was allowed to stir for 30 minutes after which the MPB-ester 7 (67.83 mg, 0.29 mmol, 1.25 eq) was added. The reaction mixture was allowed to stir for a further 3 hour at which point TLC showed completion of reaction. The reaction was quenched by pouring it onto a mixture of ice/water mixture and the resulting mixture was extracted with ethyl acetate (3×150 mL). The combined extracts were sequentially washed with citric acid (50 mL), saturated aqueous NaHCO3 (50 mL), water (50 mL), brine (50 mL) and finally dried over MgSO4. Excess ethyl acetate was evaporated by rotary evaporator under reduced pressure and the crude product was directly used in the next step without further purification. m/z (+EI) calc. for C45H52N6O11 (M)+ 852.93. found 854.87 ([M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5](Br)=[CH:4][CH:3]=1.[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12].O1CCOCC1.O>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(OCC)(=O)C>[CH3:8][C:6]1[N:7]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=1[C:15]#[C:14][Si:11]([CH3:13])([CH3:12])[CH3:10]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1nc(N)ccc1Br
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(N)ccc1C#C[Si](C)(C)C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
To a mixture of 6-amino-3-bromo-2-methylpyridine (200 mg, 1.0 mmol), trimethylsilylacetylene (0.22 mL, 1.6 mmol), copper (I) iodide (9.9 mg, 0.052 mmol), and 1,4-dioxane (1.5 mL) was added bis(triphenylphosphine)palladium (II) chloride (73 mg, 0.10 mmol), which was stirred under nitrogen atmosphere for 3 hours and 30 minutes at 100° C. The reaction mixture was allowed to room temperature, water was added to the reaction mixture at the same temperature, ethyl acetate was added, and the mixture was filtered through a Celite pad. The organic layer of the filtrate was separated and washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure, and the residue thus obtained was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (140 mg, 57%, purity: 86%).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[S:5](Cl)([C:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:13]([N:14]([CH3:16])[CH3:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6].[OH-].[Na+]>C(Cl)(Cl)Cl>[S:5]([NH:3][CH2:2][CH2:1][NH2:4])([C:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:13]([N:14]([CH3:16])[CH3:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: NCCN
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CN(C)c1cccc2c(S(=O)(=O)NCCN)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.9 %

Procedure:
To a solution of ethylenediamine (635 mg, 10.6 mmol) in chloroform (10 ml), a solution of dansyl chloride (285 mg, 1.06 mmol) in chloroform (12 ml) was dropwise added, and the reaction mixture was stirred at room temperature overnight, followed by addition of a bit of 1 N sodium hydroxide thereto for hydrolysis of unreacted dansyl chloride. The reaction mixture was concentrated, and the residue was combined with acetone. Insoluble materials were removed by filtration, and the filtrate was concentrated. Water (50 ml) was added to the residue, and extracted with ethyl acetate three times. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in a small amount of ethyl acetate, a bit of n-hexane was added thereto, and the resultant mixture was allowed to stand at room temperature overnight. The precipitate was collected and recrystallized from ethyl acetate to give Compound (1) (124 mg). Yield, 63 %.
Reaction SMILES: [N:1]([CH2:4][C:5]1[O:9][N:8]=[C:7]([CH3:10])[CH:6]=1)=[C:2]=[O:3].[N+:11](=[C:13]1[N:17]=[CH:16][N:15]=[C:14]1[C:18]([NH2:20])=[O:19])=[N-:12]>CS(C)=O>[CH3:10][C:7]1[CH:6]=[C:5]([CH2:4][N:1]2[C:2](=[O:3])[N:17]3[CH:16]=[N:15][C:14]([C:18]([NH2:20])=[O:19])=[C:13]3[N:11]=[N:12]2)[O:9][N:8]=1
Reactant: Cc1cc(CN=C=O)on1
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Solvent: CS(C)=O
Product: Cc1cc(Cn2nnc3c(C(N)=O)ncn3c2=O)on1
Temperature: 0 °C
Yield: 99.9 %

Procedure:
5-Isocyanatomethyl-3-methyl-isoxazole (735 mg, 5.32 mmol) was diluted in DMSO (1.5 mL) and added to a solution of 5-diazoimidazole-4-carboxamide (250 mg, 1.83 mmol) in 2 mL DMSO. The reaction mixture was stirred at room temperature for 16 hours before the addition of sufficient ice water to cause precipitation of the crude product which was collected by vacuum filtration and washed with Et2O (1 reaction volume title compound as a yellow solid (503 mg, 98% yield). 1H NMR (400 MHz, d6-DMSO) δ ppm: 8.86 (1H, s), 7.84 (1H, s), 7.71 (1H, s), 6.51 (1H, s), 5.64 (2H, s), 2.21 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=[O:7].[CH2:14]=O.Cl>>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:5]2[C:4]=1[CH2:14][O:7][C:6]2=[O:8]
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: C=O
Agent: Cl
Product: COc1ccc2c(c1OC)COC2=O

Procedure:
3,4-dimethoxybenzoic-acid (5.0 g, 27 mmol) was added to Formalin (36 ml) saturated with hydrogen chloride gas, and stirred with bubbling hydrogen chloride gas at 65° C. for 2 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (16 ml), followed by neutralizing with dilute aqueous ammonia (concentrated aqueous ammonia:water=2:3). The precipitated crystals were collected by filtration, washed with water, followed by drying to give 4.0 g of 4,5-dimethoxyphthalide.