Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH:28]1(S(Cl)(=O)=O)C[CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([S:23]([CH:26]5[CH2:29][CH2:28]5)(=[O:24])=[O:25])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: O=S(=O)(Cl)C1CC1
Product: O=S(=O)(C1CC1)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 37 %

Procedure:
According to the procedure for compound 398 using cyclopropanesulfonyl chloride (81 mg, 0.57 mmol) afforded 17.1 mg (37% yield) of 401, as a solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1COCC1>[CH2:3]([O:10][CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: CCOC(=O)CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)COCc1ccccc1
Yield: 150933 %

Procedure:
To a stirred suspension of NaH (3 g, 0.1 mmol, 80% oil dispersion previously washed with hexanes), in THF (75 ml, distilled from Na) was added dropwise neat benzyl alcohol (10.3 g. 0.1 mmol) at rt. Stirring was continued until H2 evolution had ceased, then ethyl 4-chloroacetoacetate (8.23 g, 0.05 mmol) in THF (20 ml) was added dropwise to this solution in a cooling water bath. The reaction was stirred at rt overnight. The mixture was partitioned between ether and 1 N HCl, the layers separated, and the aqueous further extracted with ether (×2). The combined ether extracts were washed twice with water and then brine and dried (Na2SO4), filtered, and concentrated in vacuo to give 17.83 g crude product. Distillation (119-124° C., 0.2 mm Hg) afforded a yellow oil. (7.34 g, 62%)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C@H:15]([C:31]#[N:32])[CH:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[CH:5][CH:4]=1.[O:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][C@@H:41]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([S:57]([NH2:60])(=[O:59])=[O:58])=[CH:53][C:52]=2[S:61]([C:64]([F:67])([F:66])[F:65])(=[O:63])=[O:62])[CH2:42][S:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:35][CH2:34]1>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C@H:15]([C:31]#[N:32])[CH:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([NH:60][S:57]([C:54]4[CH:55]=[CH:56][C:51]([NH:50][C@H:41]([CH2:40][CH2:39][N:36]5[CH2:37][CH2:38][O:33][CH2:34][CH2:35]5)[CH2:42][S:43][C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)=[C:52]([S:61]([C:64]([F:67])([F:65])[F:66])(=[O:63])=[O:62])[CH:53]=4)(=[O:58])=[O:59])=[O:27])=[CH:29][CH:30]=3)[CH2:18][CH2:17]2)=[CH:7][CH:8]=1
Reactant: NS(=O)(=O)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Reactant: N#C[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Product: N#C[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(N[C@H](CCN4CCOCC4)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)cc2)CC1
Yield: 20.5 %

Procedure:
The title product (19.8 mg, yield: 20%) was prepared using a procedure similar to the one described for the synthesis of EXAMPLE 14. (R)-4-(4-((4′-Chlorobiphenyl-2-yl)(cyano)methyl)piperidin-1-yl)benzoic acid, hydrochloride salt (INTERMEDIATE 84, 44.9 mg, 0.1 mmol) and (R)-4-(4-morpholino-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 69, 54.4 mg, 0.1 mmol) were used as starting materials. The resulting product was purified by column chromatography (ISCO, 4 g silica gel column, eluting with 0→5% MeOH/DCM) followed by further purification by column chromatography (ISCO, 4 g silica gel column, eluting first with 0→100% EtOAc/hexanes and then with 0→5% MeOH/DCM), providing the title product.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:26]C)[N:6]2[CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([O-])=[O:22])=[CH:19][CH:18]=1.O1CCOCC1.C(Cl)CCl.[OH:38][N:39]1[C:43](=[O:44])[CH2:42][CH2:41][C:40]1=[O:45]>ClCCl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:26])[N:6]2[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:38][N:39]2[C:43](=[O:44])[CH2:42][CH2:41][C:40]2=[O:45])=[O:22])=[CH:24][CH:25]=1
Reactant: O=C1CCC(=O)N1O
Reactant: COCCOc1nc(N)c2nc(OC)n(Cc3ccc(C(=O)[O-])cc3)c2n1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COCCOc1nc(N)c2nc(O)n(Cc3ccc(C(=O)ON4C(=O)CCC4=O)cc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
4-[6-amino-8-methoxy-2-(2-methoxyethoxy)purin-9-ylmethyl]benzoate (2 mmol) is dissolved in dichloromethane or dioxane (10 mL) and EDC (2 mmol) is added. To this solution is added N-hydroxysuccinimide (2 mmol) and resulting mixture is stirred at room temperature for 1 hour. The mixture is taken to dryness in vacuo and the crude product is purified by silica gel chromatography to yield 2 mmol of product that is suitable for conjugation reactions involving primary amines.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][CH3:23])=[CH:4][C:5]([O:20][CH3:21])=[C:6]([CH:19]=1)[C:7]([NH:9][CH:10]1[CH2:14][N:13](CC)[N:12]([CH2:17][CH3:18])[CH2:11]1)=[O:8].Cl[O-].[Na+]>>[CH2:17]([N:12]1[CH2:11][CH:10]([NH:9][C:7](=[O:8])[C:6]2[CH:19]=[C:2]([Cl:1])[C:3]([NH:22][CH3:23])=[CH:4][C:5]=2[O:20][CH3:21])[CH:14]=[N:13]1)[CH3:18]
Reactant: CCN1CC(NC(=O)c2cc(Cl)c(NC)cc2OC)CN1CC
Agent: [Na+]
Agent: [O-]Cl
Product: CCN1CC(NC(=O)c2cc(Cl)c(NC)cc2OC)C=N1

Procedure:
In accordance with the procedure of Example 12, 5chloro-2-methoxy-4-(methylamino)-N-(1,2-diethyl-4-pyrazolidinyl)benzamide is reacted with sodium hypochlorite and the product is isolated.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]([C:10](O)=[O:11])=[CH:8][C:7]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:6]1.C(Cl)(=O)C(Cl)=O.C[N:30](C=O)C.N.O1CCOCC1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]([C:10]([NH2:30])=[O:11])=[CH:8][C:7]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:6]1
Reactant: O=C(O)c1cc(-c2ncccn2)nn1Cc1ccccc1F
Reactant: CN(C)C=O
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: NC(=O)c1cc(-c2ncccn2)nn1Cc1ccccc1F
Temperature: 25 °C
Yield: 91 %

Procedure:
To a mixture of 1-(2-fluorobenzyl)-3-(pyrimidin-2-yl)-1H-pyrazole-5-carboxylic acid, intermediate 9 (133 mg, 1 equiv) and oxalyl chloride (60 μL, 1.5 equiv) in chloroform (2.2 ml), was added DMF (3 μL, 0.1 equiv). The mixture was allowed to stir at room temperature and until the bubbling ceased. Then, to this mixture, was added a solution of 0.5 M ammonia in dioxane (2.7 ml, 3.0 equiv). The mixture was stirred at room temperature for 1 h. It was concentrated under vacuum. The resulting residue was suspended in ethyl acetate (200 ml) and washed with saturated solution of sodium bicarbonate (50 ml×2). The organic layer was washed with brine (10 ml), dried, filtered and evaporated to give 120 mg of 1-(2-fluorobenzyl)-3-(pyrimidin-2-yl)-1H-pyrazole-5-carboxamide (91%) as an orange solid.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:18])=[C:10](F)[C:11]=2[O:13][CH:14]([F:16])[F:15])[C:6](=[O:19])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1)[CH3:2].[CH3:23][CH:24]1[CH2:29][NH:28][CH2:27][CH2:26][NH:25]1>N1C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:18])=[C:10]([N:28]3[CH2:27][CH2:26][NH:25][CH:24]([CH3:23])[CH2:29]3)[C:11]=2[O:13][CH:14]([F:16])[F:15])[C:6](=[O:19])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1)[CH3:2]
Reactant: CC1CNCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(OC(F)F)c21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(C)C3)c(OC(F)F)c21
Reaction time: 2 h
Yield: 80.9 %

Procedure:
In 60 ml of pyridine were dissolved 3.19 g (0.01 mole) of 1-ethyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 3.0 g (0.03 mole) of 2methylpiperazine, and the mixture was stirred at 105° to 110° C. for 2 hours. Then, the solvent was removed under reduced pressure. Water was added to the residue, and crystals precipitated were collected by filtration, washed with water and ethanol, and dried to obtain 3.23 g of 1-ethyl-6-fluoro-8-difluoromethoxy-7-(3-methylpiperazin-1-Yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid as pale yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1[CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22].[C:24]1([OH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[CH2:31](Cl)Cl>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1[CH:16]([C:27]1[CH:28]=[CH:29][C:24]([OH:30])=[CH:25][CH:26]=1)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:31])=[O:22]
Reactant: Oc1ccccc1
Reactant: ClCCl
Reactant: COc1c(C)c(C=CCCCC(=O)O)c(OC)c2ccccc12
Product: COC(=O)CCCCC(c1ccc(O)cc1)c1c(C)c(OC)c2ccccc2c1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 25.6 g of 6-(1,4-dimethoxy-3-methylnaphthalen-2-yl)-5-hexenoic acid and 23 g of phenol in 250 ml of methylene chloride was added 20.6 ml of boron trifluoride diethyl ether complex at 0° C. The solution was stirred at room temperature for 24 hours and poured into ice-water. The organic layer was separated, washed, dried, and evaporated. The residue was dissolved in 400 ml of methanol and 8 ml of c.HCl . The solution was heated at 60° C. for 1 hour, and the solvent was removed by evaporation. The residue was purified with column chromatography over silica gel using n-hexane/ethyl acetate (7/1-2/1) as an eluent to give 20.5 g of the titled compound as an oil.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:21]([OH:23])=[O:22])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=2)[NH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].IC.[CH3:26]COC(C)=O>CN(C=O)C>[CH3:26][O:22][C:21](=[O:23])[C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=2)[NH:13][CH:12]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccc(O)cc12)C(=O)O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]c2ccc(O)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
To a solution of BOC-5-hydroxy-tryptophan (5.9 g, 18.4 mmol) and iodomethane (3.43 mL) in DMF (80 mL) was added powered KHCO3 (3.68 g). The reaction mixture was stirred at rt for 4 hours. EtOAc (500 mL) was added and the mixture was washed with brine (500 mL) and water (500 mL). The organic phase was concentrated and the residual oil was triturated with CH2Cl2 (20 mL). The formed white solid was collected by filtration, washed with CH2Cl2 (20 mL) and dried to give the desired product (4.48 g, 73%). MS (DCI) m/z 335 (M+1)+.
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:15]=2)=[CH:11][C:10]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])C=C.C(O)(=O)C.C1([SiH3])C=CC=CC=1>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:31][C:25]1[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:24]=1[C:10]1[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:15]=2)[S:13][C:9]=1[C:5]1[NH:6][CH:7]=[CH:8][N:4]=1
Reactant: C=CCn1ccnc1-c1sc(-c2ccnc(NC(C)=O)c2)cc1-c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(-c2cc(-c3ccc(Cl)cc3Cl)c(-c3ncc[nH]3)s2)ccn1
Temperature: 40 °C
Reaction time: 24 h
Yield: 85.7 %

Procedure:
To a solution of N-{4-[5-(1-allyl-1H-imidazol-2-yl)-4-(2,4-dichlorophenyl)-2-thienyl]pyridin-2-yl}acetamide (750 mg, 1.60 mmol) and tetrakis(triphenylphosphine)palladium (92.0 mg, 0.08 mmol) in DCM (12.0 mL) was added acetic acid (3.95 mL, 69.5 mmol) and phenylsilane (1.00 mL, 8.15 mmol) and the mixture was stirred for 24 hrs at 40° C. The reaction mixture was evaporated to remove volatiles and DCM added. To this solution was added saturated NaHCO3 and the resulting mixture was stirred for 30 min. The mixture was extracted with DCM (3×100 mL) and the combined DCM layers were washed with brine. The organics were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was partially purified by column chromatography (SiO2, elution with 3-6% MeOH in DCM) to give crude product which was further purified by column chromatography (SiO2, elution with 100% EtOAc) to provide 589 mg of the product (84%). LC/MS (FA) ES+ 431. 1H NMR (400 MHz, d6 DMSO) δ: 11.8-11.9 (br s, 1H), 10.6 (s, 1H), 8.39 (s, 1H), 8.32 (d, J=5.2 Hz, 1H), 7.71 (d, J=1.7 Hz, 1H), 7.69 (s, 1H), 7.45-7.49 (m, 2H), 7.42 (d, J=8.5 Hz, 1H), 6.90-7.15 (br s, 2H), 2.12 (s, 3H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH2:6]([C:9]1([NH:22][CH2:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[CH:26]=[CH:27][N:28]3[S:33]([C:36]2[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[CH:7]=[CH2:8].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:6]([C:9]1([N:22]([CH2:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[CH:26]=[CH:27][N:28]3[S:33]([C:36]2[CH:37]=[CH:38][C:39]([CH3:40])=[CH:41][CH:42]=2)(=[O:34])=[O:35])[C:1](=[O:4])[CH:2]=[CH2:3])[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1)[CH:7]=[CH2:8]
Reactant: C=CCC1(NCc2cccc3c2ccn3S(=O)(=O)c2ccc(C)cc2)CCN(C(=O)OC(C)(C)C)CC1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCC1(N(Cc2cccc3c2ccn3S(=O)(=O)c2ccc(C)cc2)C(=O)C=C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
Acryloyl chloride (0.360 g, 0.401 mmol) was added at 0° C. to a stirred solution of tert-butyl 4-allyl-4-((1-tosyl-1H-indol-4-yl)methylamino)piperidine-1-carboxylate (0.2 g, 0.382 mmol), diisopropylethylamine (0.32 mL, 1.91 mmol) in dichloromethane (5.0 mL). The reaction mixture was stirred at 0° C. for 30 min and was then allowed to warm to it and stirred for 4 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography (eluent: 5% ethyl acetate in hexane) to yield the title compound as a white solid (0.16 g, 72%). [LCMS RtE=0.774 min, [M+H-Boc]+=477.9]
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:32])[CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[CH:16][CH:15]=1)[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[NH2:37][C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[CH:44]=[N:43][CH:42]=[CH:41]2>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH:44]1[C:45]2[C:40](=[CH:39][C:38]([NH:37][C:11](=[O:13])[CH:10]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][O:21][Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:29]([CH3:30])[CH3:31])=[CH:18][CH:19]=3)[CH2:9][N:8]([CH3:32])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:47][CH:46]=2)[CH:41]=[CH:42][N:43]=1
Reactant: Nc1ccc2cnccc2c1
Reactant: CC(C)[Si](OCc1ccc(C(CN(C)C(=O)OC(C)(C)C)C(=O)O)cc1)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)[Si](OCc1ccc(C(CN(C)C(=O)OC(C)(C)C)C(=O)Nc2ccc3cnccc3c2)cc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(tert-butoxycarbonyl(methyl)amino)-2-(4-((triisopropylsilyloxy)methyl)phenyl)propanoic acid (E204) in pyridine was added was added EDC, DMAP, and 6-aminoisoquinoline, and the solution was stirred overnight at room temperature. The mixture was poured into NaHCO3(sat) and extracted with EtOAc. The organics were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-6% MeOH/CH2Cl2 gradient) gave pure tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-2-(4-((triisopropylsilyloxy)methyl)phenyl)propyl(methyl)carbamate (E205).
Reaction SMILES: C([O:8][P:9]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:28]2[C:29](=[O:47])[NH:30][C:31](=[O:46])[C:32]=2[C:33]2[C:41]3[C:36](=[CH:37][C:38]([N+:42]([O-:44])=[O:43])=[CH:39][CH:40]=3)[N:35]([CH3:45])[CH:34]=2)=[CH:20]1)(=[O:18])[O:10]CC1C=CC=CC=1)C1C=CC=CC=1.C1CC=CCC=1>C1COCC1.C(O)C.[Pd]>[CH3:45][N:35]1[C:36]2[C:41](=[CH:40][CH:39]=[C:38]([N+:42]([O-:44])=[O:43])[CH:37]=2)[C:33]([C:32]2[C:31](=[O:46])[NH:30][C:29](=[O:47])[C:28]=2[C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:19]([P:9](=[O:8])([OH:18])[OH:10])[CH:20]=2)=[CH:34]1
Reactant: Cn1cc(C2=C(c3cn(P(=O)(OCc4ccccc4)OCc4ccccc4)c4ccccc34)C(=O)NC2=O)c2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1cc(C2=C(c3cn(P(=O)(O)O)c4ccccc34)C(=O)NC2=O)c2ccc([N+](=O)[O-])cc21
Temperature: 37.5 °C
Yield: 53.6 %

Procedure:
A solution of {3-[4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-indol-1-yl}-phosphonic acid dibenzyl ester (50 mg, 0.08 mmol) (from step a) above) in a mixture of THF/ethanol (3 ml/6 ml) was treated with 10% Pd/C (75 mg) and 1,4-cyclohexadiene (0.5 ml) and warmed to 35-40° C. for 2 hr. The reaction was cooled, filtered through celite and evaporated to dryness. Crystals were obtained from THF/hexane to yielding 20 mg of {3-[4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-indol-1-yl}-phosphonic acid. (Yield 55 %)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)[CH:2]=1.Br.[OH:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[CH2:17][CH2:18][NH2:19]>ClCCl.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>[OH:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[CH2:17][CH2:18][NH:19][C:9](=[O:11])/[CH:8]=[CH:7]/[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)/C=C/c1cccnc1
Reactant: NCCc1cccc(O)c1
Agent: Br
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1cccnc1)NCCc1cccc(O)c1
Yield: 78.1 %

Procedure:
To a solution of trans-3-(3-pyridyl)acrylic acid (179 g) in dichloromethane (4.8 L), triethylamine (584 ml) and pivaloyl chloride (148 ml) were sequentially added under ice-cooling and stirring and stirred for 15 minutes. Subsequently, 3-hydroxyphenethylamine hydrobromide (263 g) was added at the same temperature and stirred for 2 hours. After the solvent was distilled out under reduced pressure, water was added to the residue and the precipitated crystal was filtered, washed with water and recrystallized in ethanol to yield the titled compound (251.4 g, 78%).
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[C:3]([C:10]([OH:12])=O)[CH:2]=1.[NH2:13][C:14]1[CH:15]=[N:16][N:17](COCC[Si](C)(C)C)[C:18]=1[C:19]1[C:20]([O:27][CH3:28])=[N:21][CH:22]=[C:23]([CH:26]=1)[C:24]#[N:25].ClC1(OC)N=C(OC)N=CN1.CN1CCOCC1>C(#N)C>[C:24]([C:23]1[CH:26]=[C:19]([C:18]2[C:14]([NH:13][C:10]([C:3]3[CH:2]=[N:1][N:5]4[CH:6]=[CH:7][CH:8]=[N:9][C:4]=34)=[O:12])=[CH:15][NH:16][N:17]=2)[C:20]([O:27][CH3:28])=[N:21][CH:22]=1)#[N:25]
Reactant: O=C(O)c1cnn2cccnc12
Reactant: COc1ncc(C#N)cc1-c1c(N)cnn1COCC[Si](C)(C)C
Agent: COC1=NC(Cl)(OC)NC=N1
Solvent: CN1CCOCC1
Solvent: CC#N
Product: COc1ncc(C#N)cc1-c1n[nH]cc1NC(=O)c1cnn2cccnc12
Temperature: 50 °C
Reaction time: 48 h
Yield: 15.3 %

Procedure:
To a suspension of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (22.0 mg, 0.135 mmol, 6.56 equiv), 5-(4-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-6-methoxynicotinonitrile (7.1 mg, 0.020 mmol, 1 equiv), and 2-chloro-2,4-dimethoxy-1,3,5-triazine (23.7 mg, 0.135 equiv, 6.56 equiv) in acetonitrile (2 mL) was added 4-methylmorpholine (23 uL, 0.21 mmol, 10 equiv) at 24° C. After 2 days, the reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution (2 mL), saturated aqueous sodium chloride solution (2 mL), and ethyl acetate (5 mL). The organic was separated, and the aqueous was extracted with ethyl acetate (2×5 mL). The combined organic was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was dissolved in ethanol (3 mL) and 6 N aqueous hydrochloric acid (1 mL) and heated to 50° C. After 5 h, the reaction mixture was concentrated in vacuo and purified by preparative HPLC to afford a white solid (1.1 mg, 15% yield). 1H NMR (400 MHz, CDCl3), δ: 9.72 (s, 1H), 8.80 (dd, J=7.0, 1.6 Hz, 1H), 8.74 (s, 1H), 8.66 (m, 1H), 8.54 (d, J=2.2 Hz, 1H), 8.47 (s, 1H), 8.22 (d, J=1.9 Hz, 1H), 7.04 (dd, J=7.0, 4.2 Hz, 1H), 4.11 (s, 3H). LCMS (ESI): M+H=361.1
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Cl:13]N1C(=O)CCC1=O>>[NH2:1][C:2]1[C:3]([Cl:13])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(Cl)c(N)c1
Product: COC(=O)c1ccc(Cl)c(N)c1Cl

Procedure:
This material was prepared by chlorination of methyl 3-amino-4-chlorobenzoate with N-chlorosuccinimide. The product was isolated as a solid, m.p. 50°-52° C. The product was characterized by IR and 1H NMR spectroscopy and combustion analysis.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:10]([C:18]([OH:20])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:21][C:22]1[N:27]=[CH:26][C:25]([C@H:28]([NH2:30])[CH3:29])=[CH:24][N:23]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.CCOC(C)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:15])=[O:16])[CH:11]=[C:10]([C:18]([NH:30][C@@H:28]([C:25]3[CH:24]=[N:23][C:22]([CH3:21])=[N:27][CH:26]=3)[CH3:29])=[O:20])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ncc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(S(C)(=O)=O)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3cnc(C)nc3)cc(S(C)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(methylsulfonyl)biphenyl-3-carboxylic acid (1.0 g, 3.44 mmol) in N,N-dimethylformamide (10 mL) were added (R)-1-(2-methylpyrimidin-5-yl)ethanamine (900 mg, 5.58 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (3.0 g, 7.89 mmol) and N,N-diisopropylethylamine (3.0 mL, 17.22 mmol). The reaction mixture was stirred for 16 hours at 25° C. LC-MS indicated the reaction was complete. The reaction solution was diluted with EtOAc and washed with water, sat. aq. NaHCO3, brine and dried over anhydrous MgSO4. The residue was purified by silica gel column and preparative HPLC to afford the final product as a light color solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:8]3[CH:17]=[C:16]4[O:18][CH2:19][O:20][C:15]4=[CH:14][C:9]=3[S:10][C:11]=2[CH:12]=O)=[CH:4][CH:3]=1.[N:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][CH:24]=1.C(OC(=O)C)(=O)C.C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:8]3[CH:17]=[C:16]4[O:18][CH2:19][O:20][C:15]4=[CH:14][C:9]=3[S:10][C:11]=2/[CH:12]=[C:29](\[C:26]2[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=2)/[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccncc1
Reactant: O=Cc1sc2cc3c(cc2c1Oc1ccc(Cl)cc1)OCO3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)/C(=C/c1sc2cc3c(cc2c1Oc1ccc(Cl)cc1)OCO3)c1ccncc1
Temperature: 100 °C

Procedure:
A solution containing 85 mmol of the product obtained in Step E, 127 mmol of ethyl 4-pyridylacetate and 75 ml of acetic anhydride is heated at 100° C. for 18 hours. After returning to ambient temperature, the reaction mixture is hydrolysed by saturated NaHCO3 solution and extracted with ethyl acetate. The organic phases are then washed with water and then with NaCl solution, dried over calcium sulphate, filtered and concentrated under reduced pressure. Chromatography over silica gel (dichloromethane/ethanol : 98/2) allows the expected product to be isolated.