Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:16]2[C@@H:15]3[CH2:17][C@@H:14]3[CH2:13][C:12]=2[C:11]([C:18]([OH:20])=O)=[N:10]1.[NH2:21][CH:22]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[CH2:23][OH:24]>>[OH:24][CH2:23][CH:22]([NH:21][C:18]([C:11]1[C:12]2[CH2:13][C@H:14]3[CH2:17][C@H:15]3[C:16]=2[N:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[N:10]=1)=[O:20])[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: NC(CO)c1cccnc1
Reactant: O=C(O)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Product: O=C(NC(CO)c1cccnc1)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method G using Intermediate 1 (see Example 1.1) and 2-amino-2-(pyridin-3-yl)ethanol. LCMS m/z=397.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.48 (td, J=4.7 and 3.5 Hz, 1H), 1.17 (td, J=7.9 and 4.7 Hz, 1H), 2.08-2.14 (m, 1H), 2.23-2.30 (m, 1H), 2.56 (bs, 1H), 2.93 (d, J=16.4 Hz, 1H), 3.03 (dd, J=16.4 and 6.2 Hz, 1H), 3.98-4.03 (m, 2H), 5.19-5.24 (m, 1H), 7.02 (t, J=8.0 Hz, 2H), 7.27 (dd, J=7.8 and 5.0 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.60-7.67 (m, 1H), 7.71 (d, J=8.0 Hz, 1H), 8.53 (bs, 1H), 8.66 (bs, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[S:5][CH:6]=1.[F:13][C:14]([F:30])([F:29])[C:15]1[O:19][N:18]=[C:17]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23](O)=[O:24])[N:16]=1>>[CH3:1][C:2]1[N:3]=[C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:23]([C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([C:17]4[N:16]=[C:15]([C:14]([F:29])([F:13])[F:30])[O:19][N:18]=4)[CH:21]=3)=[O:24])[CH2:9][CH2:8]2)[S:5][CH:6]=1
Reactant: Cc1csc(N2CCNCC2)n1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: Cc1csc(N2CCN(C(=O)c3cccc(-c4noc(C(F)(F)F)n4)c3)CC2)n1
Yield: 39 %

Procedure:
This compound was synthesized from 4-methyl-2-(piperazin-1-yl)thiazole and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (90 mg, yield 39%) as yellow viscous liquid. 1H NMR (400 MHz, CDCl3) δ 8.23-8.19 (m, 2H), 7.67-7.61 (m, 2H), 6.20 (m, 1H), 3.94 (m, 2H), 3.57 (m, 6H), 2.26 (m, 3H). MS (ESI) m/z: Calculated for C18H16F3N5O2S: 423.10. found: 424.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)[CH:3]=1.[C:32]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:35])[CH:33]=[CH2:34].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[C:37]([O:36][C:32](=[O:35])[CH:33]=[CH:34][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:23])([CH3:25])[CH3:24])[CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)[CH:3]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(Br)cc1C1=CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C=Cc1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Temperature: 135 °C
Yield: 34.2 %

Procedure:
A flask was charged with 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (4-bromo-2-cyclohex-1-enyl-phenyl)-amide (79 mg, 0.16 mmol)(as prepared in Example 1, step (f)), t-butyl acrylate (41 mg, 0.32 mmol), cesium carbonate (57 mg, 0.18 mmol), (t-Bu3P)2Pd(0) (8.2 mg, 0.016 mmol), and 1 mL of dioxane and heated in a microwave reactor for 30 min at 135° C. The crude reaction mixture was loaded on a 10-g SPE column and the title compound was eluted with 10% EtOAc/hexanes to give 30 mg (34%) of a white solid. Mass spectrum (ESI, m/z): Calcd. for C30H40N4O4Si, 549.2 (M+H). found 548.9.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:48][C@@H:49]1[CH2:54][CH2:53][CH2:52][CH2:51][C@H:50]1[OH:55]>CN(C=O)C>[Br:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:48][C@@H:49]1[CH2:54][CH2:53][CH2:52][CH2:51][C@H:50]1[OH:55])=[O:9]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC(F)(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
5-Bromo-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (50.0 g, 0.166 mol) was dissolved in DMF (600 mL). To the solution was added TBTU (58.9 g, 0.183 mol), N,N-diisopropylethyl amine (142.6 mL, 0.83 mol) and (1R,2R)-2-amino-cyclohexanol (21.1 g, 0.183 mol). The reaction mixture was stirred for 3 h at room temperature. The solvent was evaporated in vacuo, the residue was dissolved in a mixture of ethyl acetate (1200 mL) and THF (300 mL). The solution was washed twice with water (700 mL) and the water phases were extracted with ethyl acetate (600 mL). Organic phases were pooled, dried with MgSO4 and concentrated to about 900 mL. The product precipitated upon stirring and cooling to 0° C. Filtration, washing with ethyl acetate/n-heptane (1:1) and drying in vacuo gave the title compound (53.1 g) as a white solid; MS (ISP) 397, 399 (M)+.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[N:9]=[C:10]([NH:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[S:11][CH:12]=1)[C:5](O)=[O:6].[NH2:33][CH:34]1[C:41](=[O:42])[N:40]2[CH:35]1[S:36](=[O:70])[CH2:37][C:38]([C:59]1[S:63][C:62]([C:64]3[CH:69]=[CH:68][N:67]=[CH:66][CH:65]=3)=[N:61][CH:60]=1)=[C:39]2[C:43]([O:45][CH:46]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH:46]([O:45][C:43]([C:39]1[N:40]2[CH:35]([S:36](=[O:70])[CH2:37][C:38]=1[C:59]1[S:63][C:62]([C:64]3[CH:65]=[CH:66][N:67]=[CH:68][CH:69]=3)=[N:61][CH:60]=1)[CH:34]([NH:33][C:5](=[O:6])[C:4](=[N:3][O:2][CH3:1])[C:8]1[N:9]=[C:10]([NH:13][C:14]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[S:11][CH:12]=1)[C:41]2=[O:42])=[O:44])([C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(-c4ccncc4)s3)CS(=O)C12
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(-c4ccncc4)s3)CS(=O)C12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 1 h
Yield: 7.5 %

Procedure:
The syn isomer of 2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetic acid (12.4 g) and 4-N,N-dimethylaminopyridine (0.05 g) are added to a solution of 7-amino-2-benzhydryloxycarbonyl-8-oxo-3-[2-(pyridin-4-yl)-thiazol-5-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene 5-oxide (15 g) in dry methylene chloride (100 cc), and a solution of N,N'-dicyclohexylcarbodiimide (6.93 g) in methylene chloride (120 cc) is then added (in the course of 30 minutes) after cooling to +5° C. The reaction mixture is then stirred for 1 hour at +5° C. and then for 4 hours at 25° C., after which it is partially concentrated, diluted again with ethyl acetate (500 cc) and filtered. The filtrate is poured into a mixture of distilled water (1 liter), ethyl acetate (1 liter) and acetic acid (10 cc). The organic phase is washed with a saturated solution of sodium bicarbonate (200 cc), distilled water (3×200 cc) and then a saturated solution of sodium chloride (200 cc), dried over sodium sulphate and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give the crude expected product (26.8 g) in the form of a hard brown foam, which can be purified in the following manner: the crude product (5 g) is redissolved in ethanol (120 cc) under reflux, decolorising charcoal (0.5 g) and silica (0.5 g) are added, the mixture is stirred and filtered and the filtrate is cooled in a bath of iced water. The precipitate is filtered off and washed with ethanol (2×10 cc) and then ether (2×20 cc) to give 2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-8-oxo-3-[2-(pyridin-4-yl)-thiazol-5-yl]-5-thia1-azabicyclo[4.2.0]oct-2-ene 5-oxide (2 g) in the form of an ochre powder.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH:12]([NH:14][CH2:15][CH2:16][S:17][C:18]1[N:19]=[CH:20][N:21]2[CH:25]=[CH:24][S:23][C:22]=12)=[O:13].[CH2:26]([Sn:30](Cl)([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH3:29].[Cl-].[NH4+]>C1COCC1>[CH:12]([NH:14][CH2:15][CH2:16][S:17][C:18]1[N:19]=[CH:20][N:21]2[CH:25]=[C:24]([Sn:30]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:26][CH2:27][CH2:28][CH3:29])[S:23][C:22]=12)=[O:13]
Reactant: O=CNCCSc1ncn2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SCCNC=O)c2s1
Reaction time: 0.17 h

Procedure:
A 1.6 N n-butyllithium/n-hexane solution (11.7 ml) was added to a solution of 1.19 g of 7-(2-formylaminoethyl)thioimidazo[5,1-b]thiazole in 50 ml of THF at −55° C. under an argon atmosphere. The mixture was stirred at that temperature for 10 min. Tri-n-butylstannyl chloride (2.24 ml) was added thereto, and the mixture was stirred for 20 min. The temperature of the reaction solution was raised to −30° C. over a period of one hr, during which time 3.34 ml of a 1.6 N n-butyllithium/n-hexane solution and 2.4 ml of tri-n-butylstannyl chloride were added. An aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate, followed by washing with brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation, and the residue was purified by column chromatography on silica gel (ethyl acetate only to dichloromethane:methanol=20:1) to prepare 1.615 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:28][CH2:29][C:30]#[C:31][CH2:32][OH:33].C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([NH:28][CH2:29][C:30]#[C:31][CH2:32][OH:33])=[O:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: NCC#CCO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCC(=O)NCC#CCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
4-[(tert.-butoxycarbonyl)amino]butanoic acid (5.20 g, 25.6 mmol, prepared in analogy to Houssin et al., (1988) Synthesis 3, 259-261) was dissolved in anhydrous tetrahydrofuran (20 mL), carbonyldimidazole (CDI) (4.56 g, 28.1 mmol) was added and the resulting clear solution was stirred at room temperature for 2 h. Then, the primary amine 11 (3.11 g 25.6 mmol) and trietylamine (7.10 mL, 50.9 mmol) were added and stirring was continued at room temperature for 2 h. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel, 40 g, chloroform/ethylacetate 1:1) to give compound 12 (3.59 g, 52%) as a light yellow oil (Rf 0.3, chloroform/ethyl acetate 1:1).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([C:15]2[CH2:19][C@:18]([C:24]3[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=3)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:14]=[C:13]([C:15]2[CH2:19][C@:18]([C:24]3[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=3)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=2)[CH:12]=[CH:11][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cc(C2=NO[C@@](c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C2=NO[C@@](c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O

Procedure:
To a solution of tert-butyl 2-methyl-4-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzoate (64.87 mmol, 33 g) in dichloromethane (300 mL) was added trifluoroacetic acid (389.2 mmol, 44.6 g) at 0° C. After addition the reaction was brought to room temperature and the mixture stirred over night after which time LC-MS analysis showed a complete conversion. The crude mixture was concentrated and the residue dissolved in 300 mL of ethylacetate, washed with brine, dried over MgSO4 and evaporated to yield crude title product which was purified over a silica gel column (eluent: CH2Cl2/EtOAc) to obtain the desired product as pale yellow foam. LCMS (Method GR) RT 1.23 min, [M+H]+ 450/452; 1H-NMR (CDCl3, 400 MHz): 2.7 (s, 3H), 3.70 (d, 2H), 4.10 (d, 2H), 7.60 (s, 3H), 7.01 (d, 1H), 8.15 (d, 2H), 7.01 (d, 1H), 8.15 (d, 2H), 11.40 (s, 1H); 19F-NMR (CDCl3, 376 MHz): −79.38.
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:22][C:16]=3[S:15](=[O:32])(=[O:31])[N:14]=2)[C:3]1=[O:33].[CH:34](=O)[CH2:35][CH:36]([CH3:38])[CH3:37]>CN(C)C(=O)C>[CH2:24]([O:23][C:21]1[CH:20]=[CH:19][C:17]2[NH:18][C:13]([C:4]3[C:3](=[O:33])[N:2](/[N:1]=[CH:34]/[CH2:35][CH:36]([CH3:38])[CH3:37])[C:11]4[C:6]([C:5]=3[OH:12])=[CH:7][CH:8]=[CH:9][CH:10]=4)=[N:14][S:15](=[O:32])(=[O:31])[C:16]=2[CH:22]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)CC=O
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc21
Solvent: CC(=O)N(C)C
Product: CC(C)C/C=N/n1c(=O)c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc21
Temperature: 165 °C
Yield: 71.1 %

Procedure:
The product of Example 304F (0.220 g, 0.48 mmol) and isovaleraldehyde (0.77 mL, 7.18 mmol) in N,N-dimethylacetamide (1.5 mL) were reacted at 130° C. for 35 minutes in a microwave reactor in a sealed tube. The reaction was concentrated under a stream of nitrogen warmed through a manifold heated to 165° C. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.181 g, 72%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:22]=[C:23]([O:25][CH:26]([CH3:28])[CH3:27])[CH:24]=1)[C:9]([NH:11][C:12]1[N:17]=[CH:16][C:15]([C:18]([O:20]C)=[O:19])=[CH:14][CH:13]=1)=[O:10])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].O.Cl>C1COCC1>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:22]=[C:23]([O:25][CH:26]([CH3:28])[CH3:27])[CH:24]=1)[C:9]([NH:11][C:12]1[N:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1)=[O:10])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(OCC(C)C)cc(OC(C)C)c2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)COc1cc(OC(C)C)cc(C(=O)Nc2ccc(C(=O)O)cn2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
Methyl 6-[(3-isobutoxy-5-isopropoxybenzoyl)amino]-3-pyridinecarboxylate (230 mg, 0.62 mM) was dissolved in THF (8 ml) and a 2M NaOH solution (1.2 ml, 2.40 mM) was added. Water (7 ml) was added to the reaction mixture until it became monophasic. The reaction was stirred for 6 hours at ambient temperature and was then acidified to pH=1 with 1N aqueous HCl. The white solid which precipitated from the mixture was isolated by filtration and dried to give the title compound as a colourless solid (195 mg); H1 NMR δ (d6-DMSO) 0.99 (6H d) 1.12 (6H d) 2.00 (1H sept) 3.80 (2H d) 4.65 (1H sept) 6.62 (1H s) 7.19 (2H s) 8.30 (2H s) 8.86 (1H s) 11.09 (1H s br); [M+H]373; [M−H] 371.
Reaction SMILES: [C:1]1([C:6]2[O:7][C:8]3[CH:18]=[C:17]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[C:16](B4OC(C)(C)C(C)(C)O4)=[CH:15][C:9]=3[C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[CH2:5][CH2:4][CH2:3][CH:2]=1.Cl[C:35]1[CH:36]=[CH:37][C:38]2[O:50][CH2:49][N:41]3[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:47]=4[CH:48]=[C:40]3[C:39]=2[N:51]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O>[C:1]1([C:6]2[O:7][C:8]3[CH:18]=[C:17]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[C:16]([C:35]4[CH:36]=[CH:37][C:38]5[O:50][CH2:49][N:41]6[C:42]7[CH:43]=[CH:44][CH:45]=[CH:46][C:47]=7[CH:48]=[C:40]6[C:39]=5[N:51]=4)=[CH:15][C:9]=3[C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Clc1ccc2c(n1)-c1cc3ccccc3n1CO2
Reactant: CNC(=O)c1c(C2=CCCC2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(C2=CCCC2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5ccccc5n3CO4)cc12
Temperature: 110 °C
Reaction time: 2 h
Yield: 22.9 %

Procedure:
To a degassed solution of 2-(cyclopent-1-en-1-yl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (110 mg, 0.23 mmol), 2-chloro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (70 mg, 0.27 mmol), K3PO4(123 mg, 0.46 mmol) in 1,4-Dioxane (5 mL) and H2O (0.5 ml) was added Pd(dba)3 (5 mg) and X-Phos (5 mg) under N2, then the mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled to RT and filtered. The filtrate was washed with H2O, brine, extract with DCM, and dried over Na2SO4. After concentration, the residue was purified by prep-HPLC to give the product of 2-(cyclopent-1-en-1-yl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)benzofuran-3-carboxamide (30 mg, yield: 23%). 1H-NMR (CDCl3, 400 MHz) δ 7.88 (s, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.56 (s, 1H), 7.47 (s, 2H), 7.27˜7.33 (m, 2H), 7.14˜7.20 (m, 2H), 6.74 (s, 1H), 6.10 (s, 1H), 5.99 (s, 2H), 3.32 (s, 3H), 3.01 (d, J=4.8 Hz, 3H), 2.83 (d, J=6.8 Hz, 2H), 2.73 (s, 3H), 2.62 (t, J=6.8 Hz, 2H), 2.00˜2.08 (m, 2H). MS (M+H)+: 569.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:38]=[CH:37][C:17]([CH2:18][N:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:20]2)=[CH:16][CH:15]=1.[CH2:39](O)[C:40]1[O:44][CH:43]=[CH:42][CH:41]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C1(C)C=CC=CC=1>[O:44]1[CH:43]=[CH:42][CH:41]=[C:40]1[CH2:39][O:13][C:14]1[CH:38]=[CH:37][C:17]([CH2:18][N:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:20]2)=[CH:16][CH:15]=1
Reactant: OCc1ccco1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccco3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A toluene solution (1.74 g) of 40% diethyl azodicarboxylate was added dropwise slowly to a mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (873 mg), furfuryl alcohol (0.216 ml), triphenyl phosphine (984 mg), and tetrahydrofuran (20 ml) at room temperature. After the solution was stirred overnight at room temperature, the reaction solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[4-(2-furylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (624 mg, yield: 58%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:14]([OH:16])=O)=[C:8]([CH3:13])[N:9]2[CH3:12])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[CH2:23]([NH2:27])[CH2:24][CH2:25][CH3:26]>>[CH2:23]([NH:27][C:14]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:9]([CH3:12])[C:8]=1[CH3:13])=[O:16])[CH2:24][CH2:25][CH3:26]
Reactant: COc1ccc2c(C(=O)O)c(C)n(C)c2c1
Reactant: CCCCN
Agent: O=C(Cl)C(=O)Cl
Product: CCCCNC(=O)c1c(C)n(C)c2cc(OC)ccc12
Yield: 70.6 %

Procedure:
This material was prepared from the reaction of 6-methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid (1.12 g, 5.11 mmole) 16c with oxalyl chloride (0.682 ml, 13.6 mmole) and butan-1-amine (1.51 ml, 15.33 mmole) in a manner as previously described for example 16d to give a yellow solid (0.990 g, 71%). 1H NMR (300 MHz, CDCl3) δ 8.01 (1H, d, J=8.6 Hz), 7.31 (1H, dd, J=2.3, 8.6 Hz), 7.25 (1H, d, J=2.3 Hz), 6.32 (1H, s), 4.34 (3H, s), 4.09 (3H, s), 3.95 (2H, m), 3.16 (3H, s), 2.10 (2H, m), 1.92 (2H, m), 1.44 (3H, t, J=7.4 Hz); ESIMS (MH+): 275.15.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:4]=[N:3]1.[C:25](Cl)(=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([CH2:23][NH:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:5][N:4]=[N:3]1
Reactant: CCCCCC(=O)Cl
Reactant: Cn1nnnc1C(=NOCc1cccc(CN)n1)c1ccccc1
Solvent: ClCCl
Product: CCCCCC(=O)NCc1cccc(CON=C(c2ccccc2)c2nnnn2C)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.5 %

Procedure:
To a solution of 1-{6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}methanamine (0.21 g, 0.649 mmol, 1 eq.) in 2 ml of DCM was added TEA (0.197 g, 1.94 mmol, 3 eq.) followed by hexanoyl chloride (0.131 g, 0.974 mmol, 1.5 eq.). The reaction was stirred 4 h at room temperature and the solvent was evaporated. The crude was purified by chromatography on silica gel to give N-({6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}methyl)hexanamide (0.182 g, 62% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:20][CH2:21][O:22][CH3:23])[S:6]([C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]([N+:16]([O-:18])=[O:17])[C:10]=1Cl)(=[O:8])=[O:7].[H-].[Na+].[OH2:26]>>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:20][CH2:21][O:22][CH3:23])[S:6]([C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]([N+:16]([O-:18])=[O:17])[C:10]=1[OH:26])(=[O:8])=[O:7]
Reactant: O
Reactant: COCCN(CCOC)S(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: [H-]
Agent: [Na+]
Product: COCCN(CCOC)S(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Yield: 55 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, N,N-di-(2-methoxyethyl)-2,6-dichloro-3-nitrobenzenesulfonamide (800 mg, 2.07 mmol), 60% NaH (248 mg, 6.21 mmol) and water (45 μL, 2.48 mmol) were reacted to form the desired product (420 mg, 55%). EI-MS (m/z) 366.89, 368.81 (M−).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:24]2[C:25]3=[C:26]4[C:21](=[CH:22][CH:23]=2)[CH:20]=[CH:19][C:18]([C:27]2[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH:28]=2)=[C:17]4[CH:16]=[CH:15][C:14]3=[C:13]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:12]=1.C1C(=O)N([Br:50])C(=O)C1.O>CN(C=O)C>[Br:50][C:20]1[C:21]2[C:26]3=[C:25]4[C:24](=[CH:23][CH:22]=2)[C:11]([C:2]2[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=2)=[CH:12][C:13]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[C:14]4[CH:15]=[CH:16][C:17]3=[C:18]([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)[CH:19]=1
Reactant: c1ccc(-c2cc(-c3ccc4ccccc4c3)c3ccc4ccc(-c5ccc6ccccc6c5)c5ccc2c3c45)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cc(-c2ccc3ccccc3c2)c2ccc3c(-c4ccccc4)cc(-c4ccc5ccccc5c4)c4ccc1c2c34

Procedure:
5.4 g of 1,6-dinaphthalene-2-yl-3-phenylpyrene was dispersed into 60 ml of DMF, and 1.9 g NBS in DMF solution was dropped therein at room temperature. After 3 days reaction, 150 ml of water was added to it and the deposited crystal was filtrated, followed by water and ethanol washing of the crystal.