Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH:10]([NH2:11])[CH2:9][CH:5]2[C:6]([CH3:8])([CH3:7])[CH:3]1[CH2:4]2.[CH2:12]1[CH2:18][S:15](=[O:17])(=[O:16])[O:14][CH2:13]1.O1CCC[CH2:20]1>O>[CH3:20][C@:3]12[CH2:4][C@H:5]([C:6]1([CH3:7])[CH3:8])[CH2:9][C@@H:10]([NH:11][CH2:13][CH2:12][CH2:18][S:15]([OH:14])(=[O:17])=[O:16])[C@@H:2]2[CH3:1]
Reactant: CC1C(N)CC2CC1C2(C)C
Reactant: C1CCOC1
Reactant: O=S1(=O)CCCO1
Solvent: O
Product: C[C@H]1[C@H](NCCCS(=O)(=O)O)C[C@@H]2C[C@@]1(C)C2(C)C
Temperature: 25 °C

Procedure:
To a solution of (1R,2R,3R,5S)-(−)-isopinocampheylamine (2.0 g, 13.0 mmol) in tetrahydrofuran (20 mL) was slowly added 1,3-propanesultone (1.56 g, 12.5 mmol). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid product was collected by filtration, washed with acetone (2×25 mL), and dried in a vacuum oven (50° C.), to afford compound EH (2.7 g, 80%). 1H NMR (DMSO, 500 MHz) δ ppm 3.32 (m, 2H), 3.09 (d, 2H), 2.67 (m, 2H), 2.30 (m, 2H), 1.96 (m, 4H), 1.75 (m, 2H), 1.18 (s, 3H), 1.11 (m, 4H), 0.90 (s, 3H). 13C NMR (DMSO, 125 MHz) δ ppm 55.97, 50.11, 47.55, 45.86, 41.15, 40.91, 38.94, 32.81, 31.61, 27.96, 23.85, 22.59, 21.21, [α]D=−17.2° (c=0.00083 in water), ES-MS 274 (M−1).
Reaction SMILES: CN(C=O)C.CO[C:8](=[O:43])[N:9]=[C:10](SC)[C:11]([C:28]1[CH:37]=[C:36]([O:38][CH3:39])[C:31]2[O:32][CH2:33][CH2:34][O:35][C:30]=2[C:29]=1[F:40])=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[O:21][N:20]=2)=[CH:15][CH:14]=1.[CH2:44]([O:46][C:47]([C:49]1[S:53][CH:52]=[N:51][C:50]=1[NH:54][NH2:55])=[O:48])[CH3:45]>C(N(CC)CC)C>[CH2:44]([O:46][C:47]([C:49]1[S:53][CH:52]=[N:51][C:50]=1[N:54]1[C:8](=[O:43])[NH:9][C:10]([CH:11]([C:28]2[CH:37]=[C:36]([O:38][CH3:39])[C:31]3[O:32][CH2:33][CH2:34][O:35][C:30]=3[C:29]=2[F:40])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[O:21][N:20]=3)=[CH:15][CH:14]=2)=[N:55]1)=[O:48])[CH3:45]
Reactant: CCOC(=O)c1scnc1NN
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C(F)(F)F)n2)cc1)c1cc(OC)c2c(c1F)OCCO2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1scnc1-n1nc(C(Nc2ccc(-c3noc(C(F)(F)F)n3)cc2)c2cc(OC)c3c(c2F)OCCO3)[nH]c1=O
Temperature: 85 °C
Reaction time: 16 h
Yield: 42.1 %

Procedure:
To 5 ml of a DMF solution containing 113 mg of [2-(5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-[4-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester, 40 mg of 4-hydrazinothiazole-5-carboxylic acid ethyl ester (Example (185c)) and 0.030 ml of triethylamine were added. The resulting mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in 5 ml of methanol and 0.035 ml of acetic acid, and 103 mg of sodium cyanotrihydroborate was added thereto. The mixture was stirred at room temperature for 15 hours, and then 100 ml of ethyl acetate and 50 ml of water were added thereto. The organic layer was washed with 50 ml of water and then with 50 ml of saturated brine and was dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol-ethyl acetate) to give the title compound (57 mg).
Reaction SMILES: [CH2:1]([N:3]([CH3:17])[S:4]([C:7]1[CH:8]=[N:9][C:10]([Sn](C)(C)C)=[CH:11][CH:12]=1)(=[O:6])=[O:5])[CH3:2].[NH2:18][C:19]1[C:24]([C:25]2[S:34][C:28]3[C:29](=[O:33])[NH:30][CH2:31][CH2:32][C:27]=3[CH:26]=2)=[CH:23][C:22](Br)=[CH:21][N:20]=1>>[NH2:18][C:19]1[N:20]=[CH:21][C:22]([C:10]2[CH:11]=[CH:12][C:7]([S:4]([N:3]([CH2:1][CH3:2])[CH3:17])(=[O:6])=[O:5])=[CH:8][N:9]=2)=[CH:23][C:24]=1[C:25]1[S:34][C:28]2[C:29](=[O:33])[NH:30][CH2:31][CH2:32][C:27]=2[CH:26]=1
Reactant: Nc1ncc(Br)cc1-c1cc2c(s1)C(=O)NCC2
Reactant: CCN(C)S(=O)(=O)c1ccc([Sn](C)(C)C)nc1
Product: CCN(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3cc4c(s3)C(=O)NCC4)c2)nc1
Yield: 51.7 %

Procedure:
The final step of general method D was applied to N-ethyl-N-methyl-6-(trimethylstannyl)pyridine-3-sulfonamide (233 mg, 0.6 mmol) and 2-(2-amino-5-bromopyridin-3-yl)-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (194 mg, 0.6 mmol) to give 6′-amino-N-ethyl-N-methyl-5′-(7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-[2,3′-bipyridine]-5-sulfonamide as a yellow solid (140 mg, 0.31 mmol, 53% yield) after purification by reverse phase preparatory HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.91 (d, J=2.0 Hz, 1H), 8.85 (d, J=2.3 Hz, 1H), 8.26 (d, J=2.3 Hz, 1H), 8.10-8.19 (m, 2H), 7.73 (br. s, 1H), 7.33 (s, 1H), 6.62 (s, 2H), 3.44-3.50 (m, 2H), 3.09 (s, 2H), 2.86 (t, J=1.0 Hz, 1H), 2.72 (s, 3H), 1.01-1.09 (m, 3H); MS (EI) m/z=444.5 [M+1]+.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][CH:2]=1.C(O)(=[O:12])C>>[N+:1]1([O-:12])[C:9]2[CH:8]=[CH:7][CH:6]=[N:5][C:4]=2[NH:3][CH:2]=1
Reactant: CC(=O)O
Reactant: c1cnc2[nH]cnc2c1
Product: [O-][n+]1c[nH]c2ncccc21
Reaction time: 3 h

Procedure:
Mcpba (8.7 g, 50 mmol) was added at room temperature to 3H-imidazo[4,5-b]pyridine (5.0 g, 42 mmol) in acetic acid (84 mL, 1469 mmol). The mixture was stirred for 3 hours. The resulting precipitate was filtered and rinsed with Et2O, it gave 4-azabenzimidazole-N-oxide. To 4-azabenzimidazole-N-oxide (2.00 g, 14.8 mmol) phosphorous oxychloride (25.00 mL, 266 mmol) was added at room temperature. The solution was heated to 90° C. for 18 h. The solution was cooled and the rest POCl3 was distilled off in vacuo. The residue was dissolved in CH3CN and quenched with slow addition of ice-water. The mixture was basified to PH 9 with 50% NaOH solution. At room temperature the resulting precipitates were filtered. The collected solid was dissolved in MeOH and insoluble residue was removed by filtration. The filtrates were concentrated and the residue was purified by flash chromatography over silica gel, using 3:7 EtOAc-hexane, gave 7-chloro-3H-imidazo[4,5-b]pyridine (1.20 g, 52.8%). To the mixture of di-tert-butylpyrocarbonate (1193 mg, 5465 μmol), 7-chloro-3H-imidazo[4,5-b]pyridine (0.763 g, 4968 μmol) in acetonitrile (15 mL), 4-(dimethylamino)pyridine (61 mg, 497 μmol) was added. The mixture was stirred at room temperature overnight. Evaporation of the solvent, flash chromatography of the residue over silica gel, using 0% to 25% EtOAc/hexane, gave tert-butyl 7-chloro-3H-imidazo[4,5-b]pyridine-3-carboxylate, Mass Spectrum (ESI) m/e=253.0 (M+1).
Reaction SMILES: O=P(Cl)(Cl)Cl.[NH2:6][C:7]1[N:8]=[CH:9][C:10]([C:26]2[CH:36]=[CH:35][C:29]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[CH:28][CH:27]=2)=[N:11][C:12]=1[C:13](=O)[NH:14][NH:15][C:16]([C:18]1[S:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24])=[O:17]>ClCCl>[NH2:6][C:7]1[N:8]=[CH:9][C:10]([C:26]2[CH:36]=[CH:35][C:29]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[CH:28][CH:27]=2)=[N:11][C:12]=1[C:13]1[O:17][C:16]([C:18]2[S:19][CH:20]=[CH:21][C:22]=2[O:23][CH3:24])=[N:15][N:14]=1
Reactant: COc1ccsc1C(=O)NNC(=O)c1nc(-c2ccc(C(=O)N(C)C)cc2)cnc1N
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccsc1-c1nnc(-c2nc(-c3ccc(C(=O)N(C)C)cc3)cnc2N)o1
Temperature: 100 °C
Yield: 23 %

Procedure:
TBTU (160.4 mg, 0.4995 mmol) and Et3N (33.70 mg, 46.42 μL, 0.3330 mmol) were added to a solution of 4-(5-amino-6-(hydrazinecarbonyl)pyrazin-2-yl)-N,N-dimethylbenzamide (100 mg, 0.3330 mmol) and 3-methoxythiophene-2-carboxylic acid (52.67 mg, 0.3330 mmol) in CH2Cl2 (2.000 mL) and the resulting solution stirred at room temperature for 72 h. The reaction mixture was diluted with dichloromethane (5 mL) and water (5 mL) and the layers separated. The aqueous layer was extracted further with dichloromethane (3×5 mL), and the combined organic extracts dried over MgSO4, filtered and concentrated in vacuo to leave 4-[5-amino-6-[[(3-methoxythiophene-2-carbonyl)amino]carbamoyl]pyrazin-2-yl]-N,N-dimethyl-benzamide as a yellow oil. POCl3 (1.788 g, 1.087 mL, 11.66 mmol) was added to 4-[5-amino-6-[[(3-methoxythiophene-2-carbonyl)amino]carbamoyl]pyrazin-2-yl]-N,N-dimethyl-benzamide and the resulting mixture heated at 100° C. for 2 h. The reaction mixture was cooled to room temperature and ice/water added carefully with vigorous stirring between additions. The mixture was left to stir at room temperature for 20 min and then diluted with dichloromethane (10 mL) and the layers separated. The aqueous layer was extracted further with dichloromethane (2×5 mL) and combined organics dried over MgSO4 and concentrated in vacuo. Solid obtained is re-dissolved in CH2Cl2 and purified by column chromatography on the ISCO column companion system (12 g column, 0-5% MeOH/CH2Cl2). Product fractions were combined and concentrated in vacuo. This was purified further by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The product fractions were combined and freeze dried to give the product as a yellow solid (33.0 mg, 23% yield) 1H NMR (400 MHz, DMSO) d 2.98 (s, 3H), 3.01 (s, 3H), 4.07 (s, 3H), 7.30 (d, 1H), 7.56 (d, 2H), 7.70 (br s, 2H), 7.96 (d, 1H), 8.14 (d, 2H) and 8.97 (s, 1H) ppm; MS (ES+) 423.19
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].Cl[C:32]1[CH:33]=[CH:34][C:35]2[N:36]([N:38]=[C:39]([CH3:41])[N:40]=2)[N:37]=1>O1CCCC1>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([N:38]=[C:39]([CH3:41])[N:40]=4)[N:37]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: Cc1nc2ccc(Cl)nn2n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
4-(Diphenylmethoxy)-1-piperidinepropanol (743 mg) was dissolved in dried terahydrofuran (17 ml), followed by addition of sodium t-butoxide (241 mg). The mixture was heated to 60° C. and stirred for 30 minutes. After the mixture was cooled, 6-chloro-2-methyl[1,2,4]triazolo[1,5-b]pyridazine (384 mg) was added thereto, followed by reflux under heating for 21 hours. After the mixture was cooled, ice-water was added thereto, followed by extraction with ethyl acetate. The extract was washed with an aqueous sodium chloride saturated solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica-gel column chromatography and eluted with a mixture of ethyl acetate, methanol and triethylamine (50:5:1). Fractions containing the objective compound were collected. The resulting crystals were washed with ethylether and dried to yield the title compound (700 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:19])[NH:4][C:5](=[S:18])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:7]=1[NH2:8].[CH:20](O)=O>>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:6]2[C:7]3[N:8]=[CH:20][NH:1][C:2]=3[C:3](=[O:19])[NH:4][C:5]2=[S:18])=[CH:15][CH:14]=1
Reactant: O=CO
Reactant: COc1ccc(Cn2c(N)c(N)c(=O)[nH]c2=S)cc1
Product: COc1ccc(Cn2c(=S)[nH]c(=O)c3[nH]cnc32)cc1
Temperature: 100 °C
Yield: 16 %

Procedure:
5,6-Diamino-1-(4-methoxybenzyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.83 g, 3.0 mmol) was dissolved in formic acid (3.0 mL) and the resulting solution heated at 100° C. for 1 h. The excess formic acid was removed under reduced pressure and the residue dissolved in 10% potassium hydroxide solution (8 mL) and heated at 100° C. for 15 minutes. The reaction mixture was neutralized with 10% acetic acid and the resulting precipitate collected by filtration. The precipitate was recrystallised from ethanol: dimethylformamide and the isolated crystals dissolved in 1M potassium hydroxide solution, precipitated by neutralization with 10% acetic acid and collected by filtration. After drying, the title compound (0.14 g, 16%) was obtained.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[C:8]=1[F:16])(=O)=O.[C:19]([NH:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=1[F:36])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.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>[C:22]([O:21][C:19](=[O:20])[NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[C:8]=2[F:16])=[CH:29][C:28]=1[F:36])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1F
Reactant: N#Cc1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C#N)c(F)c2F)cc1F
Temperature: 90 °C
Yield: 92.9 %

Procedure:
A solution of 7 g of 4-cyano-2,3-difluorophenyl trifluoromethanesulfonate in 400 mL of dioxane is admixed at ambient temperature with 8.67 g of N-Boc 4-amino-3-fluorophenylboronic acid, 7.235 g of sodium carbonate in solution in 100 mL of distilled water, and then 3.38 g of tetrakistriphenylphosphinepalladium. The reaction mixture is heated at 90° C. for 3 h and then concentrated to dryness under reduced pressure. The solid obtained is taken up in ethyl acetate; this organic phase is washed a number of times with distilled water and then with saturated sodium chloride solution, dried over magnesium sulfate and then concentrated to dryness under reduced pressure. The solid obtained is chromatographed on a silica column (eluent: cyclohexane/ethyl acetate, 90/10 by volume). Evaporation to dryness under reduced pressure of the fractions containing the expected product gives 7.89 g of tert-butyl(4′-cyano-3,2′,3′-trifluorobiphenyl-4-yl)carbamate in the form of a cream-white solid, whose characteristics are as follows:
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C@@H:7]2[CH2:12][CH2:11][CH2:10][N:8]2[CH3:9])[CH:4]=[CH:3][CH:2]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21]>CC(O)=O>[Br-:13].[CH3:9][N:8]1[CH2:10][CH2:11][CH2:12][C@H:7]1[C:5]1[CH:6]=[N+:1]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=[CH2:14])[CH:2]=[CH:3][CH:4]=1
Reactant: C=CCCCCCCBr
Reactant: CN1CCC[C@H]1c1cccnc1
Solvent: CC(=O)O
Product: C=CCCCCCC[n+]1cccc([C@@H]2CCCN2C)c1
Product: [Br-]
Yield: 75.7 %

Procedure:
To a stirred solution of (S)-nicotine (0.12 g, 0.71 mmol) in AcOH (2 ml) was added 8-bromo-oct-1-ene (0.34 g, 1.8 mmol). The mixture was heated at reflux for 3 days. AcOH was evaporated and the residue was dissolved in CHCl3. The mixture was washed with saturated aqueous NaHCO3, water and brine successively and dried. Evaporation of the solvent followed by titration with ether afforded 0.19 g (77%) of (S)-3-(1-methyl-pyrrolidin-2-yl)-1-oct-7-enyl-pyridinium bromide (NONB-7e) as a brown oil. 1H NMR (300 MHz, CDCl3) δ 9.70 (1H, d, J=6.0 Hz), 9.21 (1H, s), 8.41 (1H, d, J=8.1 Hz), 8.08 (1H, dd, J=8.1, 6.0 Hz), 5.72 (1H, m), 4.86–5.10 (4H, m), 3.50 (1H, t, J=8.4 Hz), 3.22 (1H, m), 2.41 (2H, m), 2.20 (3H, s), 1.80–2.10 (6H, m), 1.61 (1H, m), 1.20–1.44 (6H, m); 13C NMR (75 MHz, CDCl3) δ 146.12, 144.00, 143.28, 142.63, 138.22, 128.05, 114.20, 66.68, 61.67, 56.48, 40.29, 35.67, 33.30, 31.88, 28.33, 28.27, 25.76, 22.98; Anal. Calcd for C18H29BrN2.0.35HBr: C, 56.65; H, 7.75; N, 7.34. Found: C, 56.96; H, 7.98; N, 6.95.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][O:9]/[N:10]=[C:11](/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)\[C:12]#[N:13])[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C(=O)([O-])[O-].[K+].[K+]>CC(O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][N:10]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)/[C:12](=[N:21]/[OH:22])/[NH2:13])[CH:5]=[CH:4][CH:3]=1
Reactant: N#C/C(=N\OCc1cccc(N)n1)c1ccccc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: N/C(=N\O)C(=NOCc1cccc(N)n1)c1ccccc1
Temperature: 80 °C
Yield: 110.6 %

Procedure:
To a suspension of (2Z)-{[(6-aminopyridin-2-yl)methoxy]imino}(phenyl)acetonitrile (4 g, 15.85 mmol, 1 eq.) in iPrOH/H2O (10/1, 110 ml) were added hydroxylamine hydrochloride (3.30 g, 47.56 mmol, 3 eq.) and potassium carbonate (6.57 g, 47.56 mmol, 3 eq.). The reaction was heated to 80° C. for 6 h and the solvent was evaporated to ¾th. The residue was extracted with EtOAc (3×50 ml) and washed with aq. sat. NaCl. The organics were combined, dried over MgSO4 and concentrated to give (Z)-2-{[(6-aminopyridin-2-yl)methoxy]imino}-N′-hydroxy-2-phenylethanimidamide (5 g, 99% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:14]=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:16][NH:17][CH3:18]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:14][N:17]([CH3:18])[CH3:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNC
Reactant: O=CC1(c2cccc(F)c2)CCCCC1
Product: CN(C)CC1(c2cccc(F)c2)CCCCC1
Yield: 39.1 %

Procedure:
The title compound was prepared from 1-(3-fluorophenyl)cyclohexane-carbaldehyde (103 mg, 0.50 mmol) and dimethylamine (2.0 M in THF, 2.5 ml, 5.0 mmol) according to General Procedure H2.The crude product was purified by column chromatography (SiO2, MeOH/CH2Cl2, MeOH from 0% to 15%) to give 1-(1-(3-fluorophenyl)cyclohexyl)-N,N-dimethylmethanamine (46 mg, 39%) as a clear oil. 1H NMR (CDCl3): δ 1.32-1.38 (m 3H), 1.49-1.56 (m, 3H), 1.59-1.66 (m, 2H), 1.99 (s, 6H), 2.05-2.09 (m, 2H), 2.33 (s, 2H), 6.83-6.88 (m, 1H), 7.08 (d, J=8.0 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 7.23-7.29 (m, 1H). 13C NMR (CDCl3) δ 22.4, 26.8, 34.4, 43.6, 48.6, 72.9, 112.2, 112.4, 114.6, 114.8, 123.2, 129.4, 129.5, 162.0, 164.5.ESI MS m/z 236.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C1(O)C=CC=CC=1.Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>>[CH3:27][O:26][C:24](=[O:25])[CH2:23][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: COC(=O)CBr
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Solvent: Oc1ccccc1
Product: COC(=O)COc1ccc(C(=O)OC)cc1[N+](=O)[O-]

Procedure:
Using methyl 4-hydroxy-3-nitrobenzoate as the phenol and methyl 2-bromoacetate as the alkylating agent in the general procedure for alkylation of substituted-2-nitrophenols gives a light yellow solid: 1H NMR (DMSO-d6, 400 MHz): δ ppm 8.39 (d, J=2.0 Hz, 1H), 8.15 (dd, J=8.8, 2.3 Hz, 1H), 7.44 (d, J=8.8 Hz, 1H), 5.16 (s, 2H), 3.87 (s, 3H), 3.71 (s, 3H). ESI-MS: m/z 270.1 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:17])[C@@H:4]([C@H:13]([CH3:16])[O:14][CH3:15])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[Li+].[OH-]>O1CCOCC1.O>[C:6]([NH:5][C@@H:4]([C:3]([OH:17])=[O:2])[C@H:13]([CH3:16])[O:14][CH3:15])([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](NC(=O)OC(C)(C)C)[C@H](C)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CO[C@@H](C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Yield: 90.1 %

Procedure:
To a solution of N-Boc-O-methyl-D-threonine methyl ester (8.09 mmol) in 1,4-dioxane (10 mL) is added a solution of LiOH (24.3 mmol) in water (20 mL). After stirring for 2–3 h, the solvents are removed in vacuo and the residue partitioned between water and ether. The aqueous layer is acidified with solid citric acid to approximately pH 3, then extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried with MgSO4, filtered and concentrated in vacuo to yield 1.70 g (90%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[CH3:12][N:13](C=O)C>O.[C-]#N.[C-]#N.[Zn+2].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>[CH:8]1[C:9]2[C:4](=[CH:3][C:2]([C:12]#[N:13])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc2cnccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1ccc2cnccc2c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Under N2, a mixture of 6-bromoisoquinoline (400 mg, 1.9 mmol), Zn(CN)2 (446 mg, 3.8 mmol) and Pd(PPh3)4 (40 mg) in DMF (20 mL) was stirred at 100° C. for 1 hour. Cooled the mixture to room temperature and dissolved in water. Followed standard aqueous/EtOAc workup and purified by column chromatography (PE:EtOAc=10:1).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:56]([CH3:58])[CH3:57])[C:7]([N:9]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][C@H:10]1[C:15]1[NH:19][C:18]2[C:20]3[C:25]([CH:26]=[CH:27][C:17]=2[N:16]=1)=[CH:24][C:23]([C:28]1[CH:29]=[C:30]2[C:53](=[CH:54][CH:55]=1)[C:34]1[NH:35][C:36]([C@@H:38]4[CH2:42][C@H:41]([CH2:43][O:44][CH3:45])[CH2:40][N:39]4C(OC(C)(C)C)=O)=[N:37][C:33]=1[CH:32]=[CH:31]2)=[CH:22][CH:21]=3)=[O:8])=[O:4].Cl.[CH3:60][O:61][C@H:62]([CH3:72])[C@H:63]([NH:67][C:68]([O:70][CH3:71])=[O:69])[C:64]([OH:66])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:71][O:70][C:68]([NH:67][C@@H:63]([C@H:62]([O:61][CH3:60])[CH3:72])[C:64]([N:39]1[CH2:40][C@@H:41]([CH2:43][O:44][CH3:45])[CH2:42][C@H:38]1[C:36]1[NH:35][C:34]2[C:53]3[C:30]([CH:31]=[CH:32][C:33]=2[N:37]=1)=[CH:29][C:28]([C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[C:18]1[NH:19][C:15]([C@@H:10]4[CH2:11][C@H:12]([CH3:14])[CH2:13][N:9]4[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:56]([CH3:58])[CH3:57])=[N:16][C:17]=1[CH:27]=[CH:26]2)=[CH:55][CH:54]=3)=[O:66])=[O:69]
Reactant: COC[C@H]1C[C@@H](c2nc3ccc4cc(-c5ccc6c(ccc7nc([C@@H]8C[C@H](C)CN8C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c76)c5)ccc4c3[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC[C@H]1C[C@@H](c2nc3ccc4cc(-c5ccc6c(ccc7nc([C@@H]8C[C@H](C)CN8C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c76)c5)ccc4c3[nH]2)N(C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)C1
Reaction time: 1 h
Yield: 91.7 %

Procedure:
(2S,4S)-tert-Butyl 2-(2′-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-methylpyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (120 mg, 0.152 mmol) was dissolved in DCM (5 mL) and treated with HCl (4.0 mL in dioxane, 1 mL). After stirring for 1 h, the reaction mixture was concentrated under reduced pressure. The crude residue was treated with (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (35 mg, 0.18 mmol), HATU (69 mg, 0.18 mmol), DMF (1 mL) and DIPEA (0.26 mL, 1.5 mmol). After 20 min, the reaction was quenched with water. The product was purified by reverse-phase HPLC to afford methyl (S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (120 mg). MS (ESI) m/z 862 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[CH2:10][CH2:11][O:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:13][O:12][CH2:11][CH2:10][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCn1cc([N+](=O)[O-])cn1
Temperature: 60 °C
Yield: 76 %

Procedure:
A mixture of 4-nitro-1H-pyrazole (1 equiv), 1-bromo-2-methoxyethane (1.05 equiv), potassium carbonate (1.5 equiv) and acetonitrile (0.44 M) was stirred and heated to 60° C. for 6 h. The resultant mixture was evaporated and the residue was purified by flash chromatography (2.5% MeOH in DCM) to afford the desired product as a yellow solid (76% yield). 1H NMR (400 MHz, CHLOROFORM-d1) δ ppm 8.25 (s, 1H), 8.08 (s, 1H), 4.34-4.31 (t, J=4.8 Hz, 2H), 3.77-3.74 (t, J=4.8 Hz, 2H), 3.37 (s, 3H).