Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH2:4][CH:5]2[CH:8]([CH:9]=1)[C:7]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])([CH2:10][N+:11]([O-])=O)[CH2:6]2)[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:11][CH2:10][C:7]1([CH2:14][C:15]([OH:17])=[O:16])[CH2:6][CH:5]2[CH:8]1[CH:9]=[C:3]([CH2:1][CH3:2])[CH2:4]2
Reactant: CCC1=CC2C(C1)CC2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCC1=CC2C(C1)CC2(CN)CC(=O)O
Reaction time: 2 h
Yield: 43.1 %

Procedure:
Tert-butyl [3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (1.09 g, 4.71 mmol) was dissolved in ethanol (10 mL) and water (5 mL). To the solution, iron powder (1.32 g, 23.5 mmol) and ammonium chloride (249.6 mg, 4.71 mmol) were added, and the mixture was stirred for 2 hours under heating to reflux. The mixture was allowed to cool, then diluted with saturated saline, a saturated aqueous solution of sodium bicarbonate, and ethyl acetate, and filtered through Celite to remove insoluble matter. The filtrate was separated into organic and aqueous layers. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. To the residue, a 4 N solution of hydrochloric acid in ethyl acetate (20 mL) was added, and the mixture was stirred at room temperature for 1 hour. Then, the solvent was distilled off under reduced pressure. The residue was suspended in dichloromethane. To the suspension, triethylamine was added dropwise, and the resulting powder was collected by filtration, then washed with dichloromethane, and then dried to obtain the compound of interest as a white powder (425.1 mg, 43%).
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[F:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([F:21])[CH:20]=1)[C:14](=[O:17])[CH2:15]Br.C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CN(C=O)C>[F:10][C:11]1[CH:12]=[C:13]([C:14](=[O:17])[CH2:15][NH:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5])[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: O=C(CBr)c1cc(F)cc(F)c1
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)NCC(=O)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of methyl α-aminoisobutyrate hydrochloride (10.3 g, 67.0 mmol), 3,5-difluorophenacyl bromide (15.0 g, 63.8 mmol), and K2CO3 (17.6 g, 128 mmol) in DMF (100 mL) was stirred at ambient temperature for 3 h. Saturated aqueous NaHCO3 (400 mL) was added and the mixture was extracted with EtOAc (1 L). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=272 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:3]([CH3:10])[C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.C(Cl)CCl.[CH:15]1[CH:16]=CC2N(O)N=[N:21][C:19]=2[CH:20]=1.N1CCCC1>O1CCCC1>[Br:1][C:2]1[N:3]([CH3:10])[C:4]([C:7]([N:21]2[CH2:16][CH2:15][CH2:20][CH2:19]2)=[O:9])=[CH:5][N:6]=1
Reactant: Cn1c(C(=O)O)cnc1Br
Reactant: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: Cn1c(C(=O)N2CCCC2)cnc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a suspension of methyl 2-bromo-1-methyl-1H-imidazole-5-carboxylate (2.18 g, 10 mmol) in tetrahydrofuran (60 mL) and water (6 mL) was added lithium hydroxide (0.72 mg, 30 mmol) and the reaction mixture was allowed to stir at room temperature for 2.5 h. The solvent was removed under reduced pressure and water was added followed by formic acid, the resulting precipitate was filtered, washed with water and dried under vacuum overnight to afford the 2-bromo-1-methyl-1H-imidazole-5-carboxylic acid (82%). 1H-NMR (300 MHz, CDCl3): 7.79 (s, 1H), 3.91 (s, 3H). LCMS (ESI+) 205.0 (MH+). To a solution of the carboxylic acid (1.68 g, 8.2 mmol) in anhydrous tetrahydrofuran (24 mL) was added EDC (1.53 g, 9.9 mmol) followed by HOBt (1.22 g, 9.1 mmol) and the reaction mixture was allowed to stir for 1 h at room temperature. A solution of pyrrolidine (1.03 ml, 12.4 mmol) in tetrahydrofuran (8 mL) was added and the reaction mixture was allowed to stir overnight at room temperature. The solvent was removed under reduced pressure and residue partitioned between ethyl acetate and 1 M aqueous potassium carbonate. The organic layer was dried (Na2SO4) and solvent evaporated under reduced pressure. Purification by flash column chromatography (silica, EtOAc/MeOH 9:1) afforded the title compound (95%). 1H NMR (300 MHz, CDCl3): 7.79 (s, 1H), 3.92 (s, 3H), δ 3.35 (bs, 4H), δ 1.97 (bs, 4H). LCMS (ESI+) 257.0 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:33][C:34]([C@@H:36]2[CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38][N:37]2C(OC(C)(C)C)=O)=[O:35])[C:10](=[O:32])[N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[NH:23][C:24]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[O:25])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.NC1C=CC=CC=1N1CCN(C(=O)[C@H](NC([C@@H]2CC3C(=CC=CC=3)CN2C(OC(C)(C)C)=O)=O)CC2C=CC(Cl)=CC=2)CC1.C(O)(=O)C1C=CC=NC=1.C1C=NC2N(O)N=NC=2C=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:33][C:34]([C@@H:36]2[CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38][NH:37]2)=[O:35])[C:10](=[O:32])[N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[NH:23][C:24]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[O:25])[CH2:15][CH2:16]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2NC(=O)c2cccnc2)CC1
Agent: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2N)CC1
Agent: O=C(O)c1cccnc1
Agent: On1nnc2cccnc21
Product: O=C(Nc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2)CC1)c1cccnc1

Procedure:
Following the procedure for the synthesis of Preparation XIX, tert-butyl 3-[N-((1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-{4-[2-(3-pyridylcarbonyl-amino)phenyl]piperazinyl}-ethyl)carbamoyl](3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate was prepared from tert-butyl 3-(N-{(1R)-2-[4-(2-aminophenyl)piperazinyl]-1-[(4-chlorophenyl)methyl]-2-oxoethyl}carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Preparation IX) (250 mg, 0.40 mmol), nicotinic acid (54 mg, 0.44 mmol) (Aldrich), 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide methiodide (227 mg; 0.76 mmol) and HOAT (62 mg; 0.46 mmol). The crude was concentrated in vacuo to afford of the desired compound (286 mg). MS (ESI, pos. ion) m/z: 723 (M+H), (ESI, neg. ion) m/z: 721 (M−H). Calc'd for C40H43ClN6O5: 723.26
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].I[CH:14]([CH3:16])[CH3:15]>CN(C=O)C>[CH:14]([S:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([CH3:16])[CH3:15]
Reactant: O=C(O)c1cccnc1S
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Sc1ncccc1C(=O)O
Reaction time: 0.5 h

Procedure:
2-Mercapto-nicotinic acid (5.0 g, 32.22 mmol) was dissolved in DMF (40 mL), and the solution was cooled to 0˜5° C. NaH (6.4 g, 161.1 mmol) was added thereto slowly, and the mixture was stirred at 0˜5° C. for 30 minutes. 2-Iodo-propane (9.65 mL, 96.66 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure and water was added to dilute the residue. 3N HCl was added to adjust the pH of the aqueous solution to 2˜3, and the mixture was extracted with EtOAc. The organic layer was dried with MgSO4 and concentrated under reduced pressure. The reaction product was used in the next step without a separate purification process.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[C:11]([C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=1)(=O)[CH3:12].CC([O-])(C)C.[K+]>C1COCC1>[Cl:10][C:6]1[CH:7]=[CH:8][N:9]=[C:2]2[C:3]=1[CH:4]=[CH:12][C:11]([C:14]1[C:19]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:17]=[CH:16][N:15]=1)=[N:1]2
Reactant: Nc1nccc(Cl)c1C=O
Reactant: CC(=O)c1ncccc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: FC(F)(F)c1cccnc1-c1ccc2c(Cl)ccnc2n1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
Dissolve 2-amino-4-chloronicotinaldehyde (78 mg, 0.5 mmol) and 2-acetyl-3-trifluoromethylpyridine (95 mg, 0.5 mmol) in anhydrous THF (2.0 mL) and cool it to −20° C. under N2 atmosphere. Add in portion t-BuOK (112 mg, 1.0 mmol) to the reaction mixture and stir the mixture at 10° C. for 2 hours. Concentrate the reaction mixture under vacuum, dilute the residue with saturated aq. ammonium chloride (10 mL), filter the solid, wash the solid with water and dry under high vacuum to afford desired product as a cream colored solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:6](O)=[O:7].[CH3:15][NH:16][CH3:17]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:6]([N:16]([CH3:17])[CH3:15])=[O:7]
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: CNC
Solvent: ClCCl
Product: COc1cc(C(=O)N(C)C)cc([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
3-Methoxy-5-nitrobenzoic acid (1 g; 5.1 mmol; 1 eq) is preactivated with n-(3-dimethyl aminopropyl)-n′-ethylcarbodiimide hydrochloride (1.2 g; 6.1 mmol; 1.2 eq) in DCM (30 mL) for 10 mM. Dimethylamine (343 mg; 7.6 mmol; 1.5 eq) is then added and the reaction mixture stirred overnight. After quenching the reaction mixture with water, the organic phase is washed with water and citric acid (5%) and dried over MgSO4. The solvent is evaporated to dryness according 1.1 g (97%) of the title compound as a red oil. 1H NMR (DMSO-d5) δ 7.83-7.77 (m, 1H), 7.74-7.68 (m, 1H), 7.27-7.21 (m, 1H), 3.87 (s, 3H), 3.08 (s, 3H), 2.96 (s, 3H). HPLC (max plot) 91.9%; Rt 2.52 min.
Reaction SMILES: Cl[C:2]1[C:3]2[S:22][CH2:21][CH2:20][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11](C3C=CC=CC=3)[CH2:10][CH2:9]2)[N:7]=1.[CH:23]1([NH:29]C2C3SCCC=3N=C(N3CCN(C4C=CC(C(OCC)=O)=CC=4)CC3)N=2)CCC[CH2:25][CH2:24]1>O1CCOCC1>[N:8]1([C:6]2[N:7]=[C:2]([CH2:25][CH2:24][CH2:23][NH2:29])[C:3]3[S:22][CH2:21][CH2:20][C:4]=3[N:5]=2)[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: Clc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2
Reactant: CCOC(=O)c1ccc(N2CCN(c3nc4c(c(NC5CCCCC5)n3)SCC4)CC2)cc1
Solvent: C1COCCO1
Product: NCCCc1nc(N2CCNCC2)nc2c1SCC2
Yield: 78.9 %

Procedure:
1.0 g (4.4 mmol) of (2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)propylamine (V) and 1.9 g (21.8 mmol) of piperazine (VI) are placed in 10 mL of dioxane, then reacted for 0.7 hours at 150° C. in the microwave. Then the reaction mixture is extracted with water and ethyl acetate, and the organic phase is dried and evaporated to dryness. The residue is triturated with petroleum ether and suction filtered. 0.97 g of product VII (80%) is obtained as a powder.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][O:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[C:6]=2[CH:17]=1.[CH3:18][N:19](C)C=O.C(Cl)(Cl)Cl.[C-]#N.[Na+]>O>[O:16]=[C:7]1[C:6]2[CH:17]=[C:2]([C:18]#[N:19])[CH:3]=[CH:4][C:5]=2[CH2:11][O:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]1=2
Reactant: O=C1c2cc(Br)ccc2COc2ccccc21
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc2c(c1)C(=O)c1ccccc1OC2

Procedure:
Reflux a mixture of 9.13 gm. (0.0316 mole) of 9-bromo-6,11-dihydro-11-oxodibenz[b,e]oxepin, 6.03 gm. (0.0673 mole) of cuprous cyanide and 32 ml. of dimethylformamide for 4 hours with vigorous stirring. Cool the reaction mixture and shake with a mixture of 45 ml. of chloroform, 32 ml. of saturated sodium cyanide solution and 32 ml. of water until all solids have dissolved. Separate the organic layer and wash with aqueous sodium cyanide solution and water. Dry over anhydrous magnesium dulfate. Remove the solvent to obtain the title product (yield 7.43 gm., m.p. 116°-127° C.).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[Si:18]([O:25][CH:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>O1CCCC1>[Si:18]([O:25][CH:26]1[CH2:31][CH2:30][C:29](=[CH:9][C:7]#[N:8])[CH2:28][CH2:27]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CCC(=CC#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
To a solution of 1.0 M of potassium tert-butoxide in tetrahydrofuran (46.0 mL) at 0° C. was added drop wise a solution of diethyl cyanomethylphosphonate (7.80 mL, 0.0482 mol) in tetrahydrofuran (80 mL). The reaction was warmed to room temperature and then cooled at 0° C. again. To the reaction mixture was a solution of 4-(tert-butyl(dimethyl)silyl)oxycyclohexanone (10.0 g, 0.04378 mol) in tetrahydrofuran (40 mL). The reaction was allowed to warm up to room temperature and stirred overnight. After being quenched with water, the mixture was extracted with ether. The combined organic layers were washed with water, brine, dried over MgSO4 and evaporated to dryness. The crude mixture was purified on silica gel, eluting with 0 to 20% EtOAc in hexanes, to give the desired product (8.54 g, 77.58%). LCMS (M+H) 252.4.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:18][C:19]1([CH:34]=O)[CH2:23][CH:22]2[CH:24]([CH3:33])[C:25]([N+:30]([O-:32])=[O:31])=[C:26]([CH3:29])[C:27]([CH3:28])=[C:21]2[O:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(=O)C.O>[N+:30]([C:25]1[CH:24]([CH3:33])[CH:22]2[CH2:23][C:19]([CH2:18][N:15]3[CH2:16][CH2:17][N:12]([C:9]4[CH:8]=[CH:7][C:6]([N:1]5[CH:5]=[CH:4][N:3]=[CH:2]5)=[CH:11][CH:10]=4)[CH2:13][CH2:14]3)([CH3:34])[O:20][C:21]2=[C:27]([CH3:28])[C:26]=1[CH3:29])([O-:32])=[O:31]
Reactant: c1cn(-c2ccc(N3CCNCC3)cc2)cn1
Reactant: CC1=C2OC(C)(C=O)CC2C(C)C([N+](=O)[O-])=C1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CC1=C2OC(C)(CN3CCN(c4ccc(-n5ccnc5)cc4)CC3)CC2C(C)C([N+](=O)[O-])=C1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
0.7 g of 1-(4-imidazol-1-ylphenyl)-piperazine and 0.7 g of 2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran-2-aldehyde were dissolved in 20 ml of methylene chloride and 1 ml of acetic acid as a catalyst was added, followed by stirring at room temperature for 30 minutes. To the resulting reaction solution, 1.2 g of sodium triacetoxyborohydride was added, followed by stirring at room temperature for 30 minutes. After the completion of the reaction, the reaction solution was poured into water, neutralized with an aqueous saturated sodium hydrogen carbonate solution and then extracted with chloroform. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration and concentrating under reduced pressure, 1.3 g of the objective product was obtained.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](F)[N:20]=1.S([O-])([O-])(=O)=O.[Mg+2]>CN(C=O)C.CCCCCC.O>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=2)[N:20]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: Fc1cccc(F)n1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cccc(Oc2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
A reaction flask was loaded with 4-trifluoromethylphenol (8.4 g), anhydrous potassium carbonate (8.6 g), and DMF (15 ml), followed by stirring at room temperature for 15 minutes. To this mixture, 2,6-difluoropyridine (6.0 g) dissolved in DMF (15 ml) was dropwise added in one hour. Thereafter, the temperature was raised up to 60° C., and the mixture was stirred for six hours. Water was added to the reaction mixture, and extraction was carried out with hexane, followed by addition of magnesium sulfate to the extracted liquid for drying. After filtration to remove magnesium sulfate, hexane was removed by an evaporator to give 2-fluoro-6-(4-trifluoromethylphenoxy)-pyridine (8.0 g).
Reaction SMILES: Cl.CN.CN.[BH3-][C:7]#[N:8].[Na+].[C:10]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([N:21]2[C:30]3[C:25](=[CH:26][C:27]([CH:36]=O)=[C:28]([CH:31]([O:34][CH3:35])[O:32][CH3:33])[N:29]=3)[CH2:24][CH2:23][CH2:22]2)=[O:20])=[N:16][CH:17]=1)#[N:11]>CO>[C:10]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([N:21]2[C:30]3[C:25](=[CH:26][C:27]([CH2:36][NH:8][CH3:7])=[C:28]([CH:31]([O:34][CH3:35])[O:32][CH3:33])[N:29]=3)[CH2:24][CH2:23][CH2:22]2)=[O:20])=[N:16][CH:17]=1)#[N:11]
Reactant: [BH3-]C#N
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2C(=O)Nc1ccc(C#N)cn1
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNCc1cc2c(nc1C(OC)OC)N(C(=O)Nc1ccc(C#N)cn1)CCC2
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A tube was charged with methylamine hydrochloride (7.79 mg, 0.115 mmol) followed by methylamine (2 M in MeOH, 0.058 ml, 0.115 mmol) and NaCNBH3 (14.5 mg, 0.231 mmol). Then, a suspension of N-(5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-6-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 36, 22 mg, 0.058 mmol) in MeOH (1 ml) was added, the tube was sealed and the reaction mixture was stirred at 70° C. for 1 h. The reaction mixture was quenched with water and concentrated until the organic solvents had mostly been removed. Water was added and the mixture was extracted with DCM (3×). The organic phase was then dried over Na2SO4, filtered and evaporated. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, DCM/(DCM/(7 M NH3 in MeOH) 9/1) 100:0 to 50:50) to give the title compound as a yellow resin. (UPLC-MS 3) tR 0.72 min; ESI-MS 397.3 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:22])[C@H:10]2[NH:14][C:15]([N:17]=[CH:18]N(C)C)=[S:16])[C:7]=1[C:23]([O:25][CH:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])(=[O:3])[CH3:2].Br[CH2:40][C:41]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:42].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:22])[C@H:10]2[NH:14][C:15]2[S:16][C:40]([C:41](=[O:42])[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:18][N:17]=2)[C:7]=1[C:23]([O:25][CH:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:24])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=S)N=CN(C)C)[C@H]2SC1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](Nc3ncc(C(=O)c4ccccc4)s3)[C@H]2SC1
Reaction time: 1 h
Yield: 64.5 %

Procedure:
A mixture of 720 mg of (6R-trans)-3-[(acetyloxy)methyl]-7-[[[[(dimethylamino)methylene]amino]thioxomethyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, 260 mg of 2-bromo-1-phenylethanone and 90 mg of potassium carbonate in 15 ml of dry acetonitrile was stirred for about 1 hour, then filtered and the filtrate evaporated, giving 526 mg of the desired product.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:21][C:22]([C:24]2[C:33]([NH:34]C(=O)OCC3C=CC=CC=3)=[CH:32][C:31]3[C:26](=[CH:27][C:28]([CH:45](O)[CH3:46])=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:10]1)=O)(C)(C)C.C(N(S(F)(F)[F:54])CC)C.C([O-])(O)=O.[Na+].Br.CC(O)=O>C(Cl)Cl>[NH2:34][C:33]1[C:24]([C:22]([NH:21][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[N:11]2[CH2:12][CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10]2)=[O:23])=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[C:28]([CH:45]([F:54])[CH3:46])[CH:27]=2
Reactant: CC(O)c1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)Nc3cnccc3N3CCC[C@H](NC(=O)OC(C)(C)C)C3)nc2c1
Reactant: CCN(CC)S(F)(F)F
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(F)c1ccc2cc(N)c(C(=O)Nc3cnccc3N3CCC[C@H](N)C3)nc2c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Benzyl [2-{[(4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}pyridin-3-yl)amino]carbonyl}-7-(1-hydroxyethyl)quinolin-3-yl]carbamate (8.0 mg, 0.012 mmol) (from Example 15, step 6) was dissolved in DCM (0.3 mL), cooled to −78° C., and then treated with diethylaminosulfur trifluoride (50 mg, 0.3 mmol). The resulting reaction mixture allowed to warm to room temperature and stirred at room temperature for 2 h. The reaction mixture was poured into ice-water containing NaHCO3, extracted three times with DCM, dried over Na2SO4, filtered and concentrated under reduced pressure. HBr in AcOH (8.0 M; 0.20 mL, 1.6 mmol) was added to the residue. The reaction mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The residue was diluted with MeOH and neutralized with small amounts of NH4OH. The mixture was filtered and purified by preparative LC-MS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with NH4OH) to give the title compound. LCMS calc. for C22H26FN6O (M+H)+: m/z=409.1. Found: 409.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]([S:18]([NH:21][C:22]2[O:26][N:25]=[C:24]([CH3:27])[C:23]=2[CH3:28])(=[O:20])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1.[CH2:29]1OC(O)C[O:31][CH:30]1O>C(Cl)Cl.C(OCC)(=O)C>[CH3:27][C:24]1[C:23]([CH3:28])=[C:22]([NH:21][S:18]([C:13]2[C:12]([C:3]3[CH:4]=[CH:5][C:6]([CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:7][C:2]=3[NH:1][CH2:29][CH2:30][OH:31])=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:20])=[O:19])[O:26][N:25]=1
Reactant: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(CC(C)C)cc2N)c1C
Reactant: OC1COC(O)CO1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(CC(C)C)cc2NCCO)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared from the compound of Example 32 and glycolaldehyde dimer as described for Example 58, with stirring at room temperature for 2 hours. Following workup, chromatography on silica gel with 4:1 methylene chloride/ethyl acetate afforded the title compound as a white solid, mp 45-53° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[N:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][C:20]=2[CH3:28])[C:9]([C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)[CH3:2].[NH:30]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[N:31]1.C([O-])(=O)C.[K+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:30]1[CH:34]=[C:33]([C:15]2[CH:16]=[CH:17][C:12]([C:9]3[N:8]([C:19]4[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][C:20]=4[CH3:28])[C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:29])=[CH:11][CH:10]=3)=[CH:13][CH:14]=2)[CH:32]=[N:31]1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(I)cc2)n1-c1ccc(C(N)=O)cc1C
Reactant: CC1(C)OB(c2cc[nH]n2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(-c2ccc(-c3cn[nH]c3)cc2)n1-c1ccc(C(N)=O)cc1C
Temperature: 100 °C

Procedure:
A mixture of 3-[1-(4-Carbamoyl-2-methyl-phenyl)-5-(4-iodo-phenyl)-1H-pyrrol-2-yl]-propanoic acid ethyl ester (127 mg, 0.252 mmol), 1H-pyrazole boronic acid pinacol ester (147 mg, 0.75 mmol), potassium acetate (222 mg, 2.3 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (60.0 mg, 0.074 mmol) in anhydrous DMF (4 mL) was degassed with nitrogen and then heated at 100° C. for 16 h. The mixture was then diluted with ethyl acetate (50 mL) and washed with water (30 mL). After drying the organic layer over anhydrous Na2SO4, the solvent was removed to obtain a crude product which is purified by silica gel flash chromatography (33 mg, 28%).