Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:19][CH2:18][C@@H:17]([O:20][Si](C(C)C)(C(C)C)C(C)C)[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]1=[O:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(OCC)(=O)C.CCCCCC>O1CCCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:19][CH2:18][C@@H:17]([OH:20])[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]1=[O:31]
Reactant: CC(C)[Si](O[C@@H]1CCC(c2cccc(F)c2F)C(=O)c2cccnc21)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1c2cccnc2[C@H](O)CC[C@H]1c1cccc(F)c1F
Temperature: -15 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
In a 250 mL round-bottom flask was dissolved (9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one (0.218 g, 0.49 mmol) in tetrahydrofuran (5 mL) to give a colorless solution. After cooling to −15° C. (ice-methanol bath) under nitrogen, TBAF (0.490 mL, 0.490 mmol) was added, and the resulting bright yellow solution was stirred at −15° C. for 1 h. It was quenched with sodium bicarbonate solution and diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers was washed with brine, dried and concentrated to give a tan oil. Flash column chromatography (25 g silica gel column) up to 100% ethyl acetate/hexane afforded the desired product (112 mg, 62%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.53 (dd, J=4.91, 1.64 Hz, 1H) 7.85 (dd, J=7.68, 1.64 Hz, 1H) 7.34 (dd, J=7.68, 4.91 Hz, 1H) 7.00-7.16 (m, 3H) 5.32 (s, 1H) 4.94-5.04 (m, 1H) 4.48 (dd, J=11.83, 3.02 Hz, 1H) 2.14-2.48 (m, 4H); 19F NMR (376 MHz, CHLOROFORM-d) δ ppm −138.24-−138.07 (m, 1F) −140.70-−140.50 (m, 1F).
Reaction SMILES: [C:1]([C:3]1[C:16]([NH:17][CH2:18][C:19]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[CH:22]=[CH:21][C:20]=2[F:32])=[C:15]([F:33])[CH:14]=[CH:13][C:4]=1[O:5][CH2:6][C:7]([O:9]C(C)C)=[O:8])#[N:2].[Li+].[OH-]>C1COCC1.O>[C:1]([C:3]1[C:16]([NH:17][CH2:18][C:19]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[CH:22]=[CH:21][C:20]=2[F:32])=[C:15]([F:33])[CH:14]=[CH:13][C:4]=1[O:5][CH2:6][C:7]([OH:9])=[O:8])#[N:2]
Reactant: CC(C)OC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1C#N
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(OCC(=O)O)ccc(F)c1NCc1cc(-c2cccc(F)c2)ccc1F
Reaction time: 3 h
Yield: 55.6 %

Procedure:
To a solution of isopropyl 2-[2-cyano-4-fluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetate (220 mg, 0.48 mmol, 1 eq) in a mixture of THF (10 mL) and water (10 mL) was added LiOH (20 mg, 0.96 mmol, 2 eq). The reaction was stirred for 3 h then the THF removed in vacuo. The aqueous solution that remained was acidified to pH 4 with 3M HCl and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was triturated with a mixture of 2-methoxy-2-methylpropane (5 mL) and petroleum ether (20 mL) to give the desired product as an off-white solid (110 mg, 56%).
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[CH2:26][CH2:27]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:27][CH2:26][C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([CH3:22])[CH:24]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(CCBr)c1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc(CCN(C)CCCC(C(N)=O)(c2ccccc2)c2ccccc2)c1

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (0.3 g-see Preparation 3), 3-methylphenethyl bromide (0.21 g), anhydrous potassium carbonate (0.5 g) and acetonitrile (20 ml) was heated under reflux for 8 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous sodium carbonate (30 ml), the layers separated and the aqueous layer extracted with dichloromethane (2×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (5%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as an oil, yield 0.23 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C@@H:13]([C:15](O)=[O:16])[C@H:12]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[N:27]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:15]([C@H:13]1[C@H:12]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[O:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:14]1)(=[O:16])[NH2:27]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](C(=O)O)C1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](C(N)=O)C1
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To a solution of (6R,7R)-4-(tert-butoxycarbonyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-6-carboxylic acid (450 mg) and 1H-benzotriazol-1-ol ammonium salt (211 mg) in DMF (5.8 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (265 mg), and the mixture was stirred overnight. To the reaction mixture was added distilled water, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (437 mg).
Reaction SMILES: C(N(CC)CC)C.[O:8]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].Cl>C(Cl)Cl>[S:16]([O-:18])(=[O:8])(=[O:17])[CH3:15].[O:8]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9]1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: OCC1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triethylamine (13.7 mL, 98 mmol) was added to a solution of tetrahydro-3-furanmethanol (10.0 g, 98 mmol) in methylene chloride (100 mL) at 0° C. followed by addition of methanesulfonyl chloride (12.3 g, 108 mmol) dropwise. The reaction mixture was stirred at 0° C. for 1 h and then allowed to warm to ambient temperature and stirred overnight. Aqueous hydrochloric acid (1N, 100 mL) was added and the two layers were separated. The organic layer was washed with 1N aqueous hydrochloric acid (100 mL×2), saturated aqueous sodium bicarbonate (100 mL×3), and brine (50 mL×1), respectively. The organic phase was dried over anhydrous sodium sulfate and concentrated to afford crude mesylate of tetrahydro-3-furanmethanol.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([NH:20][C:21]3[N:26]=[C:25]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:24]=[C:23]([NH:33][C:34]4[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=4)[N:22]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.[NH2:43][CH:44]1[CH2:48][CH2:47][CH2:46][CH:45]1[CH2:49][NH:50][C:51](=[O:57])[C:52]([O:54][CH2:55][CH3:56])=[O:53].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([NH:20][C:21]3[N:26]=[C:25]([O:27][CH2:28][C:29]([F:30])([F:32])[F:31])[N:24]=[C:23]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([C:38]([NH:43][CH:44]5[CH2:48][CH2:47][CH2:46][CH:45]5[CH2:49][NH:50][C:51](=[O:57])[C:52]([O:54][CH2:55][CH3:56])=[O:53])=[O:39])=[CH:41][CH:42]=4)[N:22]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(=O)NCC1CCCC1N
Reactant: O=C(O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)NCC1CCCC1NC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
iPr2NEt (0.5 mL) was added into a solution of 4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoic acid (300 mg), ethyl 2-(((2-aminocyclopentyl)methyl)amino)-2-oxoacetate (205 mg) and TBTU (201 mg) in THF (10 mL). The reaction was stirred at room temperature for 16 hours before being quenched by water. The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic phase was dried over MgSO4 and concentrated under vacuum to give the crude ethyl 2-(((2-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)cyclopentyl)methyl)amino)-2-oxoacetate which was used as was.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][OH:10].N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>O1CCCC1>[Si:20]([O:10][CH2:9][C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH2:1])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: Nc1ccc(Cl)cc1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cc(Cl)ccc1N
Reaction time: 24 h

Procedure:
To a stirred solution of 2-amino-5-chlorophenylmethanol (11.1 g, 70.4 mmol) in tetrahydrofuran (50 mL) was added imidazole (5.27 g, 77.5 mmol), followed by careful addition of tert-butyldimethylchlorosilane (10.62 g 70.4 mmol). The reaction mixture was stirred for 24 hours. Imidazole (528 mg, 7.75 mmol) and tert-butyldimethylchlorosilane (1.06 g, 7.03 mmol) were then added. After 1 hour the solid was filtered off and washed with diethyl ether (2×20 mL) and the filtrate was washed with water (10 mL), brine (10 mL), dried over magnesium sulfate and concentrated in vacuo to give the product as a brown oil, 18.83 g (98%).
Reaction SMILES: C[N:2]([C@@:10]1([CH3:15])[CH2:14][CH2:13][NH:12][CH2:11]1)[C:3](=O)OC(C)(C)C.C(N(CC)CC)C.[C:23]([C:25]1[C:30]2[N:31]=[C:32]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[O:33][C:29]=2[C:28](F)=[C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=2)[C:26]=1[CH3:47])#[N:24]>CS(C)=O>[C:23]([C:25]1[C:30]2[N:31]=[C:32]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[O:33][C:29]=2[C:28]([N:12]2[CH2:13][CH2:14][C@:10]([CH3:15])([NH:2][CH3:3])[CH2:11]2)=[C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=2)[C:26]=1[CH3:47])#[N:24]
Reactant: CN(C(=O)OC(C)(C)C)[C@@]1(C)CCNC1
Reactant: Cc1c(-c2cccc(F)c2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN[C@@]1(C)CCN(c2c(-c3cccc(F)c3)c(C)c(C#N)c3nc(C(=O)N(C)C)oc23)C1
Temperature: 150 °C
Yield: 21 %

Procedure:
A dimethyl sulfoxide (0.5 ml) solution of the above-mentioned tert-butyl methyl[(3S)-3-methylpyrrolidin-3-yl]carbamate (I-348) and triethylamine (172 μl, 1.23 mmol) was added to a dimethyl sulfoxide (4.5 ml) solution of 4-cyano-7-fluoro-6-(3-fluorophenyl)-N,N,5-trimethyl-1,3-benzoxazole-2-carboxamide (I-184) (300 mg, 0.878 mmol) stirred in an oil bath at 150° C., followed by stirring in an oil bath at 150° C. for 30 minutes. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=1:1→1:2, v/v). The obtained yellow foamy substance was dissolved in dichloromethane (3 ml), and with cooling with ice, trifluoroacetic acid (6 ml) was added, followed by stirring at room temperature for 8 hours. The reaction liquid was concentrated under reduced pressure, then an aqueous saturated sodium hydrogencarbonate solution was added, followed by extraction with chloroform. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, the residue obtained by concentration was purified by preparative TLC (eluent, chloroform:methanol=10:1, v/v), and the obtained eluate was purified in slurry with a mixed solvent of isopropyl ether and hexane to obtain the entitled compound (80.0 mg, 21%) as a pale yellow solid.
Reaction SMILES: [NH2-].[Na+].[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[CH2:6][C:5]1=[O:16].[CH3:17]OS([O-])(=O)=O>C1(C)C(C)=CC=CC=1>[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH3:17])[C:7](=[O:15])[CH2:6][C:5]1=[O:16]
Reactant: CN1C(=O)CC(=O)Nc2ccccc21
Reactant: COS(=O)(=O)[O-]
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CN1C(=O)CC(=O)N(C)c2ccccc21
Reaction time: 3 h

Procedure:
2 g of sodium amide are added to a suspension of 9.5 g of 1-methyl 1,2,4,5-tetrahydro 2,4-diketo 3H-1,5-benzodiazepine, obtained in the example XIV, in 30 c.c. of xylene, and the whole is heated for about thirty minutes, while agitating, treated with 20 c.c. of methyl-sulfate and as soon as the exothermic reaction has ceased, this is heated and boiled for three hours. The solvent is evaporated under reduced presure, the residue is taken up in 200 c.c. of a 10% solution of caustic soda, and after agitation, suction filtered, and purified upon crystallisation in 90% ethanol. Yield 4.5 g; melting point: 240°-242° C.
Reaction SMILES: Cl[C:2]1[CH:26]=[CH:25][C:5]2[C:6](=[O:24])[C:7]3[CH:14]=[C:13]([O:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.[C:27]1([NH2:34])[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH2:33].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC([O-])(C)C.[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].CC(O)(C)C.C1(C)C=CC=CC=1>[NH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[NH:34][C:2]1[CH:26]=[CH:25][C:5]2[C:6](=[O:24])[C:7]3[CH:14]=[C:13]([O:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: Nc1ccccc1N
Reactant: O=C1c2ccc(Cl)cc2CCc2ccc(OCCN3CCOCC3)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: Nc1ccccc1Nc1ccc2c(c1)CCc1ccc(OCCN3CCOCC3)cc1C2=O
Yield: 74 %

Procedure:
For the preparation of the compound by method C, 0.67 g (1.8 mmol) of 2-chloro-7-(2-morpholin-4-yl-ethoxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one, 1.0 (9.2 mmol) g of 1,2-phenylenediamine, 0.05 g (0.22 mmol) of Pd(OAc)2, 0.10 g (0.21 mmol) of 2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.70 g (6.2 mmol) of KOt-Bu, 5 ml of toluene and 1 ml of t-BuOH are used. Yield: 74%; C27H29N3O3 (Mr=443.55))
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH:14]=O.[BH3-]C#N.[Na+]>CO>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][NH:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CCN
Reactant: O=Cc1cccs1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCNCc1cccs1
Reaction time: 1 h
Yield: 30.1 %

Procedure:
To a stirring 25 mL MeOH solution of 1.40 g (10 mmol) of methyl β-alaninate hydrochloride and 1.34 g (12 mmol) of thiophene carboxaldehyde was added 1.26 g (20 mmol) of NaCNBH3. After 1 hour, 25 mL of saturated KHCO3 was added to the reaction. The reaction mixture was then filtered, and the resulting filtrate was extracted with 50 mL of DCM. The organic layer was treated as described above in Example 7, and the residue was chromatographed to yield 0.60 g (30%) of product. Analysis calculated for C9H13NO2S (M.W. 199.27): C, 54.25; H, 6.58; N, 7.03. Found: C, 54.02; H, 6.63; N, 6.77.
Reaction SMILES: [NH2:1][OH:2].[C:3]([O:12][CH2:13][CH3:14])(=[O:11])/[CH:4]=[CH:5]\[C:6]([O:8][CH2:9][CH3:10])=[O:7]>ClCCl>[OH:2][NH:1][C@H:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][C:3]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: NO
Solvent: ClCCl
Product: CCOC(=O)C[C@H](NO)C(=O)OCC
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
Hydroxylamine free base (50% aqueous solution, 45.0 g, 0.68 mol) was added dropwise to diethyl maleate (100.0 g, 0.56 mol) under nitrogen. The reaction temperature was maintained below 55° C. with an ice bath. The mixture was stirred for 30 minutes. Dichloromethane (100 ml) was added to the reaction mixture and the organic layer was collected and dried using anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to give crude diethyl N-hydroxyaspartate (103 g, 89% yield). The product was analyzed by NMR spectroscopy and found to be greater than 95% pure.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]34[CH2:22][CH2:21][C:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])([CH2:19][CH2:20]3)[O:17][CH2:16]4)=[CH:11][CH:10]=2)O1.I[C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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].ClCCl.C(COC)OC>[N+:36]([C:33]1[CH:34]=[CH:35][C:30]([C:9]2[CH:10]=[CH:11][C:12]([C:15]34[CH2:20][CH2:19][C:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])([CH2:21][CH2:22]3)[O:17][CH2:16]4)=[CH:13][CH:14]=2)=[CH:31][CH:32]=1)([O-:38])=[O:37]
Reactant: COC(=O)CC12CCC(c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)(CC1)CO2
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: COC(=O)CC12CCC(c3ccc(-c4ccc([N+](=O)[O-])cc4)cc3)(CC1)CO2
Temperature: 25 °C
Yield: 79 %

Procedure:
To a round bottom flask containing methyl 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (800 m g, 2.07 mmol), 1-iodo-4-nitrobenzene (619 mg, 2.49 mmol) and K3PO4 (528 mg, 2.49 mmol) was added dimethoxyethane (24 ml) at room temperature. The mixture was stirred at room temperature and degassed after the addition of EtOH (8 ml) and water (3.2 ml). PdCl2(dppf) dichloromethane adduct (85 mg, 0.10 mmol) was added and the mixture was heated to 8° C. in an oil bath for overnight. The reaction mixture was then concentrated to dryness and taken up in DCM. The slurry was dried over sodium sulfate and filtered through a pad of celite. The filtrate was concentrated and purified by column chromatography affording the title compound as off-white solid (624 mg, 79% yield). LC/MS, ESI-MS(+): 382.4, RT: 1.49 (Condition E).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:34])[CH2:7][CH:8]([N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([CH2:22][C:23]2[C:24]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:25]=3[S:26][CH:27]=2)[C:14]1=[O:33])[CH2:9][C:10]([OH:12])=[O:11].Cl>O.CO>[CH3:32][C:31]1[C:24]2[C:23]([CH2:22][N:15]3[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[N:13]([CH:8]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][C:6]([OH:34])=[O:5])[C:14]3=[O:33])=[CH:27][S:26][C:25]=2[CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)CC(CC(=O)O)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cccc2scc(Cn3c(=O)n(C(CC(=O)O)CC(=O)O)c4ccccc43)c12
Reaction time: 2 h
Yield: 86.8 %

Procedure:
Lithium hydroxide monohydrate (7.2 mg, 0.17 mmol) is dissolved in water (1.0 mL) and it is added into the solution of 3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-pentanedioic acid monomethyl ester (25 mg, 0.057 mmol) in methanol (1.0 mL) at room temperature. The mixture is stirred for 2 hr and then 1.0 M HCl solution (0.5 mL) is added along with water (10 mL). The mixture is extracted with EtOAc (3×10 mL) and the organic layers are combined, dried over MgSO4 and concentrated to give crude product. Purification by preparative TLC using 5% MeOH in CH2Cl2 with 1% acetic acid afforded 21 mg (87%) of 3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-pentanedioic acid. LCMS (ESMS): m/z 425.22 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1.[CH3:16][C:17]1[C:18]([CH2:23][NH2:24])=[N:19][CH:20]=[CH:21][CH:22]=1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:24][CH2:23][C:18]2[C:17]([CH3:16])=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:10])[CH:5]=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: Cc1cccnc1CN
Reactant: Nc1nc(C(=O)O)cc(-c2ccco2)n1
Solvent: CN(C)C=O
Product: Cc1cccnc1CNC(=O)c1cc(-c2ccco2)nc(N)n1
Reaction time: 2 h
Yield: 35.2 %

Procedure:
A suspension of 2-amino-6-(2-furyl)pyrimidine-4-carboxylic acid (206 mg, 1.0 mmol) in DMF (5 mL) was treated with N,N′-carbonyldiimidazole (162 mg, 1.0 mmol), stirred for 2 h, treated with 3-methylpyridine-2-methanamine (244 mg, 2.0 mmol), stirred for 2 h, poured onto water (50 mL) and extracted with EtOAc (2×25 mL). The extracts were washed with water, concentrated in vacuo, and the crude product was triturated with ether to give the title compound (109 mg, 35%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:22]#[N:23])[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:22]1[NH:28][N:27]=[N:26][N:23]=1)[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CC[C@H](C#N)NC(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC[C@@H](NC(=O)OCc1ccccc1)c1nnn[nH]1
Yield: 84.3 %

Procedure:
A mixture of tert-butyl (4R)-4-(benzyloxycarbonylamino)-4-cyanobutyrate (1.53 g, 4.8 mmol), ammonium chloride (0.28 g, 5.2 mmol), sodium azide (0.345 g, 5.3 mmol) and dry DMF (6 ml) was stirred and heated at 90°-95° C. under argon for 20 hours. The mixture was cooled and concentrated and the residue partitioned between ice-cooled water (40 ml) and ethyl acetate (30 ml) with the pH of the aqueous phase being adjusted to 3 by the addition of 10% aqueous citric acid solution (ca. 10 ml). The aqueous layer was extracted with further ethyl acetate (3×30 ml) and the combined organic solution washed with water (4×25 ml), dried (MgSO4) and evaporated. A solution of the residue in dichloromethane (3 ml) was added dropwise to stirred hexane (20 ml) and the precipitate was collected, washed with hexane and dried to give tert-butyl (4R)-4-(benzyloxycarbonylamino)-4-(tetrazol-5-yl)butyrate (1.462 g, 84%), m.p. 99°-101° C.
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:18][C:19]1([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:21][O:20]1>CN(C=O)C>[F:1][C:2]1[C:10]2[N:9]([CH2:18][C:19]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)([OH:20])[CH3:21])[C:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC1(c2ccncc2)CO1
Reactant: CN1CCc2[nH]c3c(F)cccc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cccc(F)c3n2CC(C)(O)c2ccncc2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A flask was charged with 6-fluoro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.2 g, 5.8 mmol) in DMF (10 mL) and stirred for 5 min. NaH (60% in hexane) (705 mg, 17.6 mmol) was added and the mixture stirred at RT for 10 min. Then 4-(2-methyloxiran-2-yl)pyridine (1.56 g, 11.6 mmol) was added and the mixture stirred at RT for 16 h. The progress of reaction was monitored by TLC. The reaction mixture was poured into ice water and filtered. The filtrate was washed with water and concentrated. The residue was recrystallized from ether to get pure product. 1H NMR (DMSO-d6, HCl salt) δ (ppm): 8.70 (d, 2H), 8.0 (d, 2H), 7.40 (m, 1H), 7.20 (d, 1H), 6.85 (m, 1H), 6.10 (m, 1H), 4.58 (d, 1H), 4.38 (m, 2H), 4.22 (m, 1H), 3.20 (m, 3H), 2.90 (s, 3H), 1.60 (d, 3H).