Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-:1].[Si]([O:9][CH:10]([C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)[CH2:11][CH2:12][CH:13]1[C:16](=[O:17])[N:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:14]1[C:25]1[CH:38]=[CH:37][C:28]([O:29][CH2:30][CH2:31][CH2:32][N+:33]([CH3:36])([CH3:35])[CH3:34])=[CH:27][CH:26]=1)(C(C)(C)C)(C)C.Cl.C(=O)(O)[O-].[Na+]>CO>[Br-:1].[F:24][C:21]1[CH:20]=[CH:19][C:18]([N:15]2[C:16](=[O:17])[CH:13]([CH2:12][CH2:11][CH:10]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[OH:9])[CH:14]2[C:25]2[CH:26]=[CH:27][C:28]([O:29][CH2:30][CH2:31][CH2:32][N+:33]([CH3:34])([CH3:36])[CH3:35])=[CH:37][CH:38]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1C(=O)N(c2ccc(F)cc2)C1c1ccc(OCCC[N+](C)(C)C)cc1)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CO
Product: C[N+](C)(C)CCCOc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
180 mg of (3-{4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}propyl)trimethylammonium bromide are dissolved in 10 ml of methanol. 1 ml of a 0.1 M aqueous HCl solution is then added, and the reaction solution is stirred at room temperature overnight. The mixture is neutralized with dilute aqueous sodium bicarbonate solution and concentrated using a rotary evaporator. The residue is purified using a 10 g SiO2 cartridge (dichloromethane/methanol 5:1). The product is obtained as a hygroscopic solid. C30H35BrF2N2O3 (589) MS (ESI): M+-80
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]([C:21]2[C:26]([O:27][CH3:28])=[C:25]([CH3:29])[C:24]([CH3:30])=[C:23]([CH:31]=[O:32])[C:22]=2[CH3:33])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:6]=1.S([O-])(O)(=O)=O.[K+]>O1CCCC1>[F:4][C:5]1[CH:6]=[CH:7][C:8]([C@H:11]([C:21]2[C:26]([O:27][CH3:28])=[C:25]([CH3:29])[C:24]([CH3:30])=[C:23]([CH:31]([OH:32])[CH3:1])[C:22]=2[CH3:33])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:9][CH:10]=1
Reactant: COC(=O)CCCCC[C@H](c1ccc(F)cc1)c1c(C)c(C=O)c(C)c(C)c1OC
Reactant: C[Mg]Br
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CCCCC[C@H](c1ccc(F)cc1)c1c(C)c(C(C)O)c(C)c(C)c1OC
Reaction time: 0.5 h

Procedure:
To a solution of methylmagnesium bromide in tetrahydrofuran (1M, 54.3 ml) was added anhydrous tetrahydrofuran (90 ml). To the solution was added dropwise a solution of methyl (R)-7-(4-fluorophenyl)-7-(3-formyl-6-methoxy-2,4,5-trimethylphenyl)heptanoate (4.5 g, 10.9 mmol) in tetrahydrofuran (20 ml) at -78° C., followed by stirring for 30 minutes at the same temperature. To the reaction mixture, an aqueous solution of potassium hydrogensulfate, followed by subjected to extraction with ethyl acetate. The organic layer was washed with water, an aqueous solution of sodium hydrogencarbonate and water, in the order mentioned, and dried over magnesiumsulfate. The organic layer was distilled off under reduced pressure, and the residue was subjected to a silica gel column chromatography to give methyl (R)-7-(4-fluorophenyl)-7-[3-(1-hydroxyethyl)-6-methoxy-2,4,5-trimethylphenyl]heptanoate (4.4 g). Physico-chemical properties and spectral data of this compound are shown in [Table 5].
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[O:22])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6].[CH2:31]([NH2:35])[CH:32]([CH3:34])[CH3:33]>>[CH:25]1([CH2:24][NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:11]([CH3:14])=[CH:12][CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:28]=[CH:29][N:30]=[C:2]([NH:35][CH2:31][CH:32]([CH3:34])[CH3:33])[CH:3]=4)[CH:9]=3)=[CH:16][CH:17]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: CC(C)CN
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Product: Cc1ccc(NC(=O)c2ccnc(NCC(C)C)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-(isobutylamino)isonicotinamide was prepared from 2-chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide and isobutylamine using method C. NMR; δH [2H6]-DMSO 10.27,(1H, s), 8.62,(1H, t), 8.07,(1H, d), 7.93,(2H, d), 7.70-7.66,(2H, m), 7.43,(2H, d), 7.28,(1H, d), 6.88-6.84,(3H, m), 3.16,(2H, t), 3.09,(2H, t), 2.20,(3H, s), 1.83,(1H, m), 1.04,(1H, m), 0.90,(6H, d), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.02 min, MH+457.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1.BrCC1CCCCO1.[CH3:19][N:20]([CH3:48])[C:21]1[N:26]=[CH:25][C:24]([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[C:29]2([C:40]4=[CH:41][C:42]5[O:46][CH2:45][O:44][C:43]=5[CH:47]=[C:39]4[O:38][CH2:37]2)[C:30](=[O:36])[NH:31]3)=[CH:23][CH:22]=1.N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[CH3:19][N:20]([CH3:48])[C:21]1[N:26]=[CH:25][C:24]([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[C:29]2([C:40]4=[CH:41][C:42]5[O:46][CH2:45][O:44][C:43]=5[CH:47]=[C:39]4[O:38][CH2:37]2)[C:30](=[O:36])[N:31]3[CH2:2][C:3]2[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=2)=[CH:23][CH:22]=1
Reactant: CC(C)c1nc(CCl)cs1
Reactant: CN(C)c1ccc(-c2cccc3c2C2(COc4cc5c(cc42)OCO5)C(=O)N3)cn1
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: CC(C)c1nc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3c(-c4ccc(N(C)C)nc4)cccc32)cs1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 4-(chloromethyl)-2-isopropylthiazole to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 4′-[6-(dimethylamino)pyridin-3-yl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 4′-[6-(dimethylamino)pyridin-3-yl]-1′-{[2-(1-methylethyl)-1,3-thiazol-4-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (73%) as a colorless solid: mp 164-165° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ7.58 (d, J=2.3 Hz, 1H), 7.49 (s, 1H), 7.32 (dd, J=7.8, 7.8 Hz, 1H), 7.06 (d, J=7.9 Hz, 1H), 6.82-6.76 (m, 2H), 6.42-6.37 (m, 3H), 5.96 (d, J=19.0 Hz, 2H), 5.11 (d, J=16.0 Hz, 1H), 4.89 (d, J=16.0 Hz, 1H), 4.57 (d, J=9.4 Hz, 1H), 4.42 (d, J=9.4 Hz, 1H), 3.29-3.20 (m, 1H), 2.99 (s, 6H), 1.31 (d, J=6.9 Hz, 6H); 13C NMR (75 MHz, DMSO-d6) δ 177.5, 176.9, 157.9, 155.4, 149.9, 148.3, 146.6, 142.6, 141.5, 136.8 (2C), 129.2, 128.8, 125.2, 121.7, 121.1, 115.3, 108.6, 104.3, 102.6, 101.3, 93.2, 77.2, 57.8, 37.6, 32.4, 22.8, 22.7; MS (ES+) m/z 541.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=O)=[CH:5][CH:4]=1.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:27][C:28]1[CH:46]=[CH:45][CH:44]=[CH:43][C:29]=1[C:30]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]([CH2:41][CH3:42])[CH3:40])=[CH:35][CH:34]=1)=[O:31]>CC(N(C)C)=O>[CH:39]([C:36]1[CH:37]=[CH:38][C:33]([N:32]2[C:30](=[O:31])[C:29]3[C:28](=[CH:46][CH:45]=[CH:44][CH:43]=3)[N:27]=[C:9]2[C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:34][CH:35]=1)([CH2:41][CH3:42])[CH3:40]
Reactant: COc1ccc(C=O)cn1
Reactant: CCC(C)c1ccc(NC(=O)c2ccccc2N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCC(C)c1ccc(-n2c(-c3ccc(OC)nc3)nc3ccccc3c2=O)cc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
6-Methoxy-3-pyridinecarboxaldehyde (1.20 mmol), NaHSO3 (0.200 g, 1.90 mmol) and p-TsOH (0.024 g, 0.12 mmol) were added to a solution of 2-amino-N-(4-sec-butylphenyl)benzamide (0.340 g, 1.20 mmol) in DMA (10 mL). The mixture was heated and stirred at 150° C. overnight and concentrated in vacuo. The residue was dissolved in EtOAc, and washed with H2O, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 15% to 100% EtOAc in heptane, afforded the title compound as a white solid (26%). 1H-NMR (300 MHz, DMSO-d6): δ 8.11-8.27 (m, 2H), 7.89-7.91 (m, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.51-7.67 (m, 2H), 7.11-7.33 (m, 4H), 6.62 (d, J=8.0 Hz, 1H), 3.77 (s, 3H), 2.54-2.68 (m, 1H), 1.30-1.71 (m, 2H), 1.16 (d, J=7.0 Hz, 3H), 0.64 (t, J=7.4 Hz, 3H). MS (APCI) m/z: 386 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=2[F:30])=[N:10]1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH:32]1[C:37]([OH:39])=[O:38]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=2[F:30])[NH:12][C:13]([CH2:20][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH:32]2[C:37]([OH:39])=[O:38])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2c(F)cc(F)cc2F)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2c(F)cc(F)cc2F)=NC1c1ccc(F)cc1Br
Yield: 33.3 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(2,4,6-trifluorophenyl)-1,4-dihydropyrimidine-5-carboxylate (1.21 g, 2.2 mmol) was reacted with morpholine-3-carboxylic acid (0.29 g, 2.2 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.44 g, 33%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.Cl.[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][SH:18].[OH-].[K+].CS(C)=O>C(O)C>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([S:18][CH2:17][CH2:16][N:15]([CH3:19])[CH3:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN(C)CCS
Reactant: Nc1ccc2ccc(Cl)nc2n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: CN(C)CCSc1ccc2ccc(N)nc2n1
Temperature: 90 °C
Yield: 53.8 %

Procedure:
A mixture composed of 2-amino-7-chloro-1,8-naphthyridine (29.6 g), 2-dimethylaminoethanethiol hydrochloride (48 g), potassium hydroxide pellets (85% pure; 43.5 g) and dimethyl sulphoxide (300 cc) is heated for 2 hours at 90° C. The reaction mixture is then poured into distilled water (400 cc) and extracted with methylene chloride (6×250 cc). The extracts are washed with distilled water (300 cc), dried over magnesium sulphate and concentrated to dryness at 40° C. under reduced pressure. The residue obtained is taken up with ethanol (100 cc) and the insoluble product is separated by filtration, washed with ethanol (2×30 cc) and dried at 40° C. under reduced pressure (0.07 kPa). 2-Amino-7-(2-dimethylaminoethylthio)-1,8-naphthyridine (22 g), m.p. 174° C., is obtained.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([S:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]3)=[N:24]2)=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([S:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH:33]([NH:36][C:12]([C:9]4[CH:10]=[CH:11][C:5]5[O:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)=[O:14])[CH2:34][CH2:35]3)=[N:24]2)=[CH:19][CH:18]=1
Reactant: O=C1COc2ccc(C(=O)O)cc2N1
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Product: COc1ccc2ncc(SCCN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CO5)CC3)nc2c1

Procedure:
The title compound is prepared as an off-white solid (42 mg, 38% yield) following Scheme 3 and in analogy to Example 35 using 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid (42 mg, 0.22 mmol 1.0 eq) and 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (70 mg, 0.22 mmol, 1.0 eq) as starting materials.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]2[CH:6]=[C:7]([C:10]3[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=3)[CH2:8][O:9][C:4]=2[CH:3]=1.B(Cl)(Cl)Cl>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].C(Cl)Cl>[CH:11]1[C:10]([C@H:7]2[CH2:8][O:9][C:4]3[CH:3]=[C:2]([OH:1])[CH:19]=[CH:18][C:5]=3[CH2:6]2)=[CH:15][CH:14]=[C:13]([OH:16])[CH:12]=1
Reactant: COc1ccc(C2=Cc3ccc(O)cc3OC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: Oc1ccc([C@H]2COc3cc(O)ccc3C2)cc1
Temperature: -78 °C
Yield: 95.3 %

Procedure:
A mixture of compound 3a (0.20 g, 0.78 mmol) as obtained in the above Example 3, n-Bu4NI (1.01 g, 2.73 mmol) and dry CH2Cl2 (5 mL) was stirred and cooled to −78° C. under nitrogen. Thereafter, a solution of BCl3 (1M, 2.73 mL, 2.73 mmol) in CH2Cl2 was added dropwise into the cold mixture. The resultant mixture was stirred and slowly warmed up to 0° C. over 2 hrs. After carefully quenching with ice water (10 mL), the mixture was stirred for a further 20 min, followed by neutralization with a saturated NaHCO3 solution (10 mL). After concentration in vacuo, the resultant residue was extracted with EtOAc (10 mL×5). The organic layers were combined and dried with anhydrous MgSO4. After filtration, the filtrate was concentrated in vacuo, followed by purification via silica gel column chromatography (ethyl acetate/n-hexane=1:3), thus giving the title compound 3b as a colorless crystal (0.18 g, 95% yield).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].N#N.C[O:10][C:11](=O)[C:12]1[CH:17]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:15]=[C:14]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:13]=1.O>CCOCC>[CH2:30]([O:29][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:15]=1)[CH2:11][OH:10])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(C(=O)OC)c1
Agent: N#N
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCCOc1cc(CO)cc(OCCCCCCCCCC)c1
Reaction time: 8 h
Yield: 99.2 %

Procedure:
To a 250 mL flame dried RBF, lithium aluminum hydride (LAH) (2.21 g, 58.2 mmol) and a magnetic stir bar were added. The flask was sealed with a rubber septum into which N2 inlet/outlet needles were added. Dry ether (10 mL) was added via a syringe to the RBF to wet the LAH. Some gas was evolved. Methyl-3,5-didecoxybenzoate (20.0 g, 44.6 mmol) was dissolved in dry ether (120 mL) and then cautiously added to the flask via a syringe over a period of 20 minutes. The dark grey solution was left to stir overnight. After approximately 18 hours, H2O (12 mL) was added very cautiously (drop wise) until the solution color changed from gray to bright white. The contents were then transferred to a 2 L separatory funnel. The reaction flask was alternately rinsed 3 times with distilled H2O (20 mL) and ether (20 mL). One final rinse was made with 1M HCl (20 mL). All rinses were emptied into a separatory funnel. Distilled H2O (200 mL) and ether (200 mL) were added to the separatory funnel. The contents of the separatory funnel were separated into an aqueous layer and an ether layer. The aqueous layer was washed 3 times with ether (200 mL). All ether fractions were combined and then washed 3 times with distilled H2O (200 mL). The ether layer was washed with saturated NaCl (125 mL) and then dried with MgSO4. MgSO4 was removed using gravity filtration. The ether layer was then concentrated using rotary evaporation. The result was a clear viscous liquid. The liquid solidified under a high vacuum after approximately 2 hours. This produced a 18.6 g yield or a 99.2% yield of the derivative. The NMR characterization data for this derivative is as follows. 1NMR (300 MHz, CDCl3): 0.90 (t, J=6.6, 6H, CH2CH3), 1.27-1.43 (m, 28H, CH2(CH2)7), 1.71-1.86 (m, 5H, OCH2CH2 & OH), 3.92 (t, J=6.6, 4H, OCH2), 4.60 (d, J=3.8, 2H, ArCH2OH), 6.37 (t, J=1.9, 1H, ArH), 6.48 (d, J=2.2, 2H, ArH). 13C NMR (75 MHZ, CDCl3): 14.23, 22.79, 26.14, 29.34, 29.44, 29.49, 29.70, 32.00, 65.51, 68.13, 100.56, 105.09, 143.28, 160.58.
Reaction SMILES: [NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[CH3:30][S:31]([O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)(=[O:33])=[O:32].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:30][S:31]([O:34][C:35]1[CH:36]=[CH:37][C:38]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C@H:3]([NH:12][C:13]([C:15]3([NH:21][C:22]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:28])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])[C:2]([NH2:1])=[O:29])=[CH:6][CH:7]=2)=[CH:39][CH:40]=1)(=[O:33])=[O:32]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Reactant: CS(=O)(=O)Oc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3ccc(OS(C)(=O)=O)cc3)cc2)C(N)=O)CCOCC1
Temperature: 85 °C
Reaction time: 25 h
Yield: 72 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 1, step (iii), 300 mg) in acetonitrile (7 mL) under nitrogen was treated with 4-(methylsulfonyloxy)phenylboronic acid (125 mg) followed by aqueous sodium carbonate (2M, 0.58 mL). Nitrogen was bubbled through the mixture and 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (5 mg) was added. The mixture was stirred at 85° C. for 25 h. The solvent was partially evaporated and then purified by chromatography on silica using ethyl acetate 50-100% isohexane as eluent to afford the sub-titled compound as a white solid (234 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@H:10]2[CH2:14][C@@H:13]([OH:15])[CH2:12][N:11]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2].ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O.CC1(C)N([O])C(C)(C)CCC1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C@H:10]2[CH2:14][C:13](=[O:15])[CH2:12][N:11]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1c1cc(F)cc(C#N)c1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@@H]1c1cc(F)cc(C#N)c1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of (2R,4R)-tert-butyl 2-(3-cyano-5-fluorophenyl)-4-hydroxypyrrolidine-1-carboxylate (I-13A) (0.52 g, 1.7 mmol) and trichloroisocyanuric acid (0.4 g, 1.7 mmol) in DCM (20 mL) at −10° C. was added 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) (27 mg, 0.17 mmol). The mixture was stirred at −10° C. for 15 minutes, then to room temperature over 1 hour and subsequently poured into cold aqueous NaHCO3 containing ice while stirring. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and reduced to dryness to yield (R)-tert-butyl 2-(3-cyano-5-fluorophenyl)-4-oxopyrrolidine-1-carboxylate (I-16). 1H NMR (400 MHz, CDCl3) δ 7.27-7.22 (m, 2 H), 7.12 (td, J=2.0, 8.8 Hz, 1 H), 5.33 (bs, 1 H), 4.06 (d, J=19.6 Hz, 1 H), 3.86 (d, J=19.6 Hz, 1 H), 3.15 (dd, J=10.0, 18.8 Hz, 1 H), 2.47 (dd, J=3.2, 18.8 Hz, 1 H), 1.35 (bs, 9 H). MS m/z 249.1 (M−56)+.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].[Cl:7][C:8]1[N:13]=[CH:12][C:11]([CH2:14][N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=[N:21][C:22](=[N:27][OH:28])[C:23]([F:26])([F:25])[F:24])=[CH:10][CH:9]=1.CC(C)([O-])C.[K+]>C(#N)C>[Cl:7][C:8]1[N:13]=[CH:12][C:11]([CH2:14][N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=[N:21][C:22](=[N:27][O:28][C:5](=[O:6])[NH:4][CH2:1][CH2:2][CH3:3])[C:23]([F:24])([F:25])[F:26])=[CH:10][CH:9]=1
Reactant: CCCN=C=O
Reactant: ON=C(N=c1ccccn1Cc1ccc(Cl)nc1)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCNC(=O)ON=C(N=c1ccccn1Cc1ccc(Cl)nc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
5 ml of anhydrous acetonitrile was added to 11 mg (0.13 mmol) of normal propyl isocyanate, 40 mg (0.12 mmol) of the N-[1-((6-chloropyridin-3-yl)methyl)pyridin-2(1H)-ylidene]-2,2,2-trifluoro-N′-hydroxyacetimidamide (1-499) synthesized by the method in Synthetic Example 7 and 4 mg (0.04 mmol) of potassium-t-butoxide were added thereto, and the resulting mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and ethyl acetate and a saturated saline solution were added thereto to perform liquid separation. The ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and purified by a TLC plate (one sheet of 0.5 mm plate, evolved with hexane:ethyl acetate=1:3) to obtain the subject material. Amount obtained 16 mg (yield 32%).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[NH:8][C:7]([C:9](OCC)=[O:10])=[C:6]([NH:14][C:15](=[NH:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:5]=1.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[CH2:16]([C:15]1[NH:20][C:9](=[O:10])[C:7]2[NH:8][C:4]([CH3:3])=[CH:5][C:6]=2[N:14]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCC(=N)Nc1cc(C)[nH]c1C(=O)OCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCc1nc2cc(C)[nH]c2c(=O)[nH]1
Temperature: 25 °C

Procedure:
Aqueous sodium hydroxide solution (6M, 138 mL) was added dropwise to a solution of ethyl 5-methyl-3-pentanimidamido-1H-pyrrole-2-carboxylate (58.9 g, 0.2 mol) in ethanol (550 mL) cooled in an ice-bath. The reaction mixture was heated at reflux for 2.5 hours then cooled to room temperature. Water (700 mL) was added and the pH adjusted to pH 6.5 using aqueous citric acid (2M). The resultant mixture was stirred for 45 minutes then filtered and the solid material washed with water. The material was dried in a vacuum oven at 50° C. to give the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:29])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][CH2:18][CH2:19]N2CCSCC2)=[C:12]([N+:26]([O-:28])=[O:27])[CH:11]=1)=[O:5]>C(Cl)Cl.CO>[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:29])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][CH2:18][CH2:19][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:12]([N+:26]([O-:28])=[O:27])[CH:11]=1)=[O:5]
Reactant: COC(=O)CCNC(=O)c1ccc(NCCCN2CCSCC2)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCNC(=O)c1ccc(NCCCCc2ccccc2)c([N+](=O)[O-])c1

Procedure:
The same procedure is used as in (1). Rf value: 0.51 (silica gel; methylene chloride/methanol=19:1)
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][N:11]([Si](C(C)C)(C(C)C)C(C)C)[C:6]2=[CH:5][C:4]=1[B:22]([OH:25])[O:23]C.Cl>C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][NH:11][C:6]2=[CH:5][C:4]=1[B:22]([OH:25])[OH:23]
Reactant: COB(O)c1cc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)nc1OC
Agent: Cl
Solvent: C1CCOC1
Product: COc1nc2cc[nH]c2cc1B(O)O
Temperature: 25 °C
Yield: 98.1 %

Procedure:
To a solution of methyl hydrogen 5-methoxy-1-(triisopropylsilyl)-1H-pyrrolo [3,2-b]pyridin-6-ylboronate (1.5 g, 4.14 mmol) (from 65236-015) in THF (10 mL) was treated with HCl (4M in 1,4-dioxane) for 1 hr at 0° C., checked with LC/MS: ˜50% conversion, thus additional 1.3 ml HCl (4M in 1,4-dioxane) was added, stirred at rt over night. Most of the solvent was removed on rotary vacuo, and the residue as a white solid was triturated with Et2O (3 ml), filtration and washing with Et2O (2×3 mL) to afford the expected product, 5-methoxy-1H-pyrrolo[3,2-b]pyridin-6-ylboronic acid (0.78 g, 98%) as a white solid. 1H-NMR (500 MHz, MeOD) δ ppm 1.04-1.12 (m, 1 H) 1.18 (d, J=7.32 Hz, 1 H) 4.28-4.33 (m, 4 H) 6.74 (d, J=2.44 Hz, 1 H) 7.89 (d, J=3.05 Hz, 1 H) 8.42 (s, 1 H); Mass spec 193.20 Calc for C8H9BN2O3 192.07.