Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].[CH2:21](O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl.O.CCCCCC.C(OCC)(=O)C>[CH2:21]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)Nc1cc([N+](=O)[O-])ccc1O
Reactant: OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc([N+](=O)[O-])ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
In a 50 mL 3-neck RBF equipped with N2-bubbler and thermo pocket, tert-butyl (2-hydroxy-5-nitrophenyl)carbamate (2.0 g), benzyl alcohol (1.02 g) and triphenyl phosphine (2.48 g) were taken in 10 mL DCM. The reaction mixture was cooled to 0° C. Diethyl azodicarboxylate (1.65 g) was dissolved in 10 mL DCM was added dropwise in the reaction. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was monitored on TLC using hexane:ethyl acetate (6:4) as mobile phase. After completion, the reaction was poured into water and extracted with DCM (3×50 mL). The DCM layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure at 40° C. Purification was carried out by column chromatography. Desired product eluted with 5% ethyl acetate in hexane to give, after concentration, 1.03 g of tert-butyl (2-(benzyloxy)-5-nitrophenyl)carbamate. 1H NMR: DMSO-d6 (400 MHz) 1.48 (s, 9H), 5.34 (s, 2H), 7.26 (d, 1H, J=9.2), 7.35 (m, 1H), 7.41 (m, 2H), 7.54 (d, 2H, J=6.8), 7.95 (dd, 1H, J=2.8, 9.2), 8.51 (s, 1H), 8.64 (d, 1H, J=2.8).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH:18]([CH3:20])[S:17](=[O:22])(=[O:21])[CH:16]([CH3:23])[CH2:15]1.[S:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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]>[CH3:20][CH:18]1[CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:26]4[CH:27]=[CH:28][S:24][CH:25]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH:16]([CH3:23])[S:17]1(=[O:22])=[O:21]
Reactant: OB(O)c1ccsc1
Reactant: CC1CC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC(C)S1(=O)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC1CC(c2c[nH]c3c(C(N)=O)cc(-c4ccsc4)cc23)CC(C)S1(=O)=O
Temperature: 100 °C
Yield: 101.4 %

Procedure:
5-bromo-3-(2,6-dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (0.050 g, 0.125 mmol) and 3-thienylboronic acid (0.016 g, 0.125 mmol) was dissolved in a 6:1 solution of 1,4 dioxane (3 mL)/water (0.5 mL) in a 20 mL microwave reaction vessel. Potassium carbonate (0.087 g, 0.626 mmol, 5 eq) was added and the solution was degassed with Nitrogen. PdCl2(dppf)2 (0.016 g, 0.021 mmol, 0.17 eq) was added and the reaction was heated in a microwave at 100° C. for 20 min. The solution was passed through a StratoSphere SPE PL-Thiol MP SPE column to remove palladium and purified on Gilson preparative HPLC using Acetonitrile/Water with 0.1% TFA. The desired fractions were concentrated, giving 0.051 g of a mixture of diasteriomers and their respective enantiomers.
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][C@@H:13]1[C@@H:17](/[CH:18]=[CH:19]/[C@@H:20]([O:26]C2CCCCO2)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:16]([O:33]C2CCCCO2)[CH2:15][C:14]1=[O:40])=[O:4]>C(O)(=O)C.O.O1CCCC1>[CH3:1][NH:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][C@@H:13]1[C@@H:17](/[CH:18]=[CH:19]/[C@@H:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:16]([OH:33])[CH2:15][C:14]1=[O:40])=[O:4]
Reactant: CCCCC[C@@H](/C=C/[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1C/C=C\CCCCOC(=O)NC)OC1CCCCO1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCCOC(=O)NC

Procedure:
At 40°, 300 mg. of (5Z,13E)-(8R,11R,12R,15S)-1-(N-methylcarbamoyloxy)-11,15-bis(tetrahydropyran-2-yloxy)-5,13-prostadien-9-one was agitated with 9 ml. of a mixture of glacial acetic acid/water/tetrahydrofuran (65/35/10) for 6 hours. The mixture was then evaporated to dryness under vacuum. After purifying the residue by chromatography on silica gel (ether/ethyl acetate 7+3), 145 mg. of the title compound was obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[NH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[CH:7]=1
Reactant: Nc1cccc2ccccc12
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2cccc3ccccc23)c1
Yield: 51.6 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3) (0.4 g, 1.53 mmol) in dioxane (5 ml) was added to a mixture of 1-aminonaphthalene (0.22 g, 1.53 mmol) in dioxane (1 ml) and NaHCO3 (0.26 g, 3.09 mmol) in water (3 ml), and the resultant solution was stirred at room temperature until the completion of the reaction (control by TLC). The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with petroleum ether-ethyl acetate (gradient from 2:1 to 1:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.29 g, 51%) as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 3.69 (3H, s); 6.56 (1H, d, J=16.0 Hz); 7.16 (1H, dd, J=7.0 and 1.4 Hz); 7.27-8.14 (11H, m); 10.25 (1H, s).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[NH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][C:11]([O:15][CH3:16])=[CH:10][CH:9]=3)=[CH:2]1.[H-].[Na+].Br[CH2:20][C:21]1[C:22]([F:31])=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25].[Cl-].[NH4+]>CN(C)C=O.ClCCl.CCCCCC>[F:31][C:22]1[C:21]([CH2:20][N:7]2[C:8]3[C:13](=[CH:12][C:11]([O:15][CH3:16])=[CH:10][CH:9]=3)[CH:14]=[C:6]2[C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[CH:30][CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1cccc(CBr)c1F
Reactant: COc1ccc2[nH]c(-c3ccoc3)cc2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: ClCCl
Product: COC(=O)c1cccc(Cn2c(-c3ccoc3)cc3cc(OC)ccc32)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.2 %

Procedure:
To a solution of 2-furan-3-yl-5-methoxyindole (200 mg) in N,N-dimethylformamide (4.7 mL) was added sodium hydride (dispersed in liquid paraffin, minimum 55%, 62 mg) under cooling with ice, and the mixture was stirred at room temperature for one hour. Then a solution of methyl 3-bromomethyl-2-fluorobenzoate (278 mg) in N,N-dimethylformamide (0.2 mL) was added, and the mixture was stirred at 80° C. for 15 hours. The reaction mixture was allowed to cool to ambient temperature. A saturated aqueous ammonium chloride solution-water (2/1) were added to the reaction mixture and this resulting mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (72 mg).
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:25]([CH2:27][NH2:28])[OH:26]>>[OH:26][CH2:25][CH2:27][NH:28]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1
Reactant: NCCO
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=C1/C(=C(\NCCO)c2ccccc2)Sc2ccccc21
Yield: 13 %

Procedure:
Prepared as in Example 1 from 2-benzoyl-benzo[b]thiophen-3-ol, phosphorus(V) chloride and an aqueous 40% ethanolamine solution with a yield of 13% of theory. M.p. 122°-123° C. (ethyl acetate/petroleum ether 1:1)
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:18][O:19][C:20](=[O:46])[C@H:21]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=1)[NH:22][C:23]([C:25]1([CH2:30][CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH2:29][CH2:28][CH2:27][CH2:26]1)=[S:24].C(N(C(C)C)CC)(C)C>ClCCl.CN(C=O)C.O>[CH3:18][O:19][C:20](=[O:46])[C@H:21]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([NH:45][C:8]([C:7]2[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][C:6]=2[CH3:11])=[O:10])=[CH:41][CH:40]=1)[NH:22][C:23]([C:25]1([CH2:30][CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH2:29][CH2:28][CH2:27][CH2:26]1)=[S:24]
Reactant: Cc1ccnc(C)c1C(=O)O
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=S)C1(CCCCS(C)(=O)=O)CCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(C)ccnc2C)cc1)NC(=S)C1(CCCCS(C)(=O)=O)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
To an ice cold solution of 2,4-dimethyl-3-pyridinecarboxylic acid (0.3 mmol, 45 mg) in dichloromethane (2 mL) containing one drop of DMF, was added oxalyl chloride (0.39 mmol, 49.5 mg) at 0° C. The reaction mixture was stirred for 30 min at this temperature, was allowed to warm to room temperature and was stirred for an additional 2 h. The solution was concentrated and the residue was dried under high vacuum. To a mixture of above acid chloride and 4-amino-N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]thioxomethyl]-L-phenylalanine methyl ester (0.2 mmol, 88 mg) in dichloromethane (3 mL) was added diisopropylethylamine (1 mmol, 0.175 mL) at room temperature. After the solution had stirred for 15 h, TLC analysis of the mixture did not detect any starting material remaining. The solution was diluted with water (20 mL) and dichloromethane (20 mL) and the layers were separated. The aqueous phase was extracted with dichloromethane (10 mL) and the combined organic extracts were washed with brine (300 mL). The dried (MgSO4) solution was filtered and evaporated to dryness and the residual material was purified by RP-HPLC to obtain 74 mg (65%) of 4-[[(2,4-dimethylpyridin-3-yl)carbonyl]amino]-N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]thioxomethyl]-L-phenylalanine methyl ester as an amorphous colorless solid. HRMS: Obs. mass, 574.2389. Calcd. mass, 574.2409 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[O:10][C:3]=12.[CH3:18][C:19]1[C:27]([NH2:28])=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][NH:23]2>>[CH3:18][C:19]1[C:27]([NH:28][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=4)[O:10][C:3]=23)=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][NH:23]2
Reactant: Cc1c(N)ccc2[nH]ccc12
Reactant: Cc1ccc(-c2cc3nccc(Cl)c3o2)cc1
Product: Cc1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4C)c3o2)cc1

Procedure:
The title compound was prepared by procedure E using 7-chloro-2-(4-methylphenyl)furo[3,2-b]pyridine (27.00 mg; 0.11 mmol; 1.00 eq.) instead of 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine, and 4-methyl-1H-indol-5-ylamine (17.01 mg; 0.12 mmol; 1.05 eq.) instead of 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one, and was obtained as a beige solid (19 mg, 48%). (HPLC (method F): 95%, RT: 4.21 min); 1H NMR (500 MHz, DMSO-d6) δ [ppm] 11.14 (s, 1H), 8.53 (s, 1H), 7.94 (d, J=5.5, 1H), 7.85 (d, J=8.1, 2H), 7.38 (t, J=2.7, 1H), 7.35 (s, 1H), 7.33-7.27 (m, 3H), 7.00 (d, J=8.4, 1H), 6.52 (s, 1H), 6.09 (d, J=5.5, 1H), 2.37 (s, 3H), 2.36 (s, 3H); MS (m/z) 354 [M+H]+, RT: 4.1 min.
Reaction SMILES: I[C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:7][N:6]1[CH3:26].[C:27]([O:30][CH2:31][CH3:32])(=[O:29])C>C(O)C1C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:31]([O:30][C:27]([C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH:18][C:19]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:25])[CH2:7][N:6]1[CH3:26])=[O:29])[C:32]1[CH:11]=[CH:17][CH:3]=[CH:4][CH:5]=1
Reactant: CCOC(C)=O
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(I)c(c34)C[C@H]2N(C)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: OCc1ccccc1
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C(=O)OCc5ccccc5)c(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
300 mg (0.644 mmol) of 3-(2-iodo-6-methyl-8α-ergolinyl)-1,1-diethylurea is heated, after adding 0.169 ml (0.709 mmol) of tri-m-butylamine, in 4 ml of benzyl alcohol, combined under a carbon monoxide atmosphere with 7 mg (0.031 mmol) of palladium(II) acetate, and kept at 100°-110° C. for 2.5 hours under vigorous agitation. After cooling to room temperature, the reaction solution is diluted with ethyl acetate and extracted with saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over magnesium sulfate, the ethyl acetate is removed by distillation under reduced pressure and then the benzyl alcohol is distilled off under a high vacuum. By column chromatography on 150 g of silica gel in a system of dichloromethane/ethanol=10:1 and recrystallization from ethanol/hexane, 166 mg of 8α-(3,3-diethylureido)-6-methylergoline-2-carboxylic acid benzyl ester is produced from the crude product (54.5%), mp 226°-229° C.
Reaction SMILES: [CH3:1][C:2](=[CH2:30])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][C:11]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)=[CH:12][CH:13]=3)[C@@:8]3([CH2:28][O:27][C:26]([NH2:29])=[N:25]3)[C:7]=2[CH:6]=1.O.S(=O)(=O)(O)[OH:33].C(=O)([O-])[O-].[K+].[K+]>CO>[NH2:29][C:26]1[O:27][CH2:28][C@:8]2([N:25]=1)[C:9]1[CH:10]=[C:11]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:12]=[CH:13][C:14]=1[O:15][C:16]1[C:7]2=[CH:6][C:5]([O:4][CH2:3][C:2]([CH3:1])([OH:33])[CH3:30])=[CH:18][CH:17]=1
Reactant: C=C(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2
Reactant: O=S(=O)(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(O)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2
Temperature: 25 °C

Procedure:
A vial was charged with (S)-2′-(2-methylallyloxy)-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (41.17 mg, 0.103 mmol) and water (0.5 mL) giving a suspension. Sulfuric acid (110 μL, 2.061 mmol) was added, and the mixture became a cloudy solution. The vial was sealed and placed in a 70° C. oil bath for 8 h. The mixture was cooled to RT, and potassium carbonate was added until bubbling ceased. The resulting suspension was extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on a 12-g Redi-Sep column eluting with 0-10% MeOH/DCM to give a white solid. The solid was dissolved in methanol and purified further by reverse-phase HPLC (10-90% CH3CN/H2O with 0.1% TFA). The fractions containing product were combined in saturated aq. sodium bicarbonate solution and extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give (S)-1-(2-amino-2′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yloxy)-2-methylpropan-2-ol as a white solid. MS m/z=418.2 [M+H]+. Calculated Mass for C24H24N3O4: 418.2.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([C@@H:27]5[CH2:31][CH2:30][CH2:29][C@H:28]5[C:32]([O:34]C)=[O:33])=[O:26])=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)=[N:9][C:8]=2[CH:36]=1.CO>C1COCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([C@@H:27]5[CH2:31][CH2:30][CH2:29][C@H:28]5[C:32]([OH:34])=[O:33])=[O:26])=[CH:21][CH:20]=4)=[CH:17][CH:18]=3)=[N:9][C:8]=2[CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4cc(F)ccc4s3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4cc(F)ccc4s3)cc2)cc1
Temperature: 60 °C
Yield: 81.4 %

Procedure:
A solution of 1 N aqueous sodium hydroxide solution (1 mL) was added to trans-methyl 2-({4′-[(5-fluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylate (55 mg, 0.12 mmol) in THF (2 mL). Methanol was added until the mixture became homogeneous, and the resulting solution was heated at 60° C. for 1 h. The reaction was concentrated under reduced pressure to remove excess solvents, and the residue was partitioned between water and chloroform/isopropanol (4:1). The aqueous layer was adjusted to pH 2 by addition of aqueous phosphoric acid solution, with stirring. The organic layer was then separated, dried (Na2SO4), and concentrated under reduced pressure. The residue was suspended in acetone, and the resulting solid was collected by filtration and dried in vacuo to provide the title compound (45 mg, 84%). 1H NMR (300 MHz, acetone-d6) δ 10.40-10.10 (br s, 1H), 8.15 (d, 2H), 8.01 (d, 2H), 7.87-7.82 (m, 5H), 7.41 (dd, 1H), 7.05-6.95 (m, 1H), 4.26-4.17 (m, 1H), 3.43-3.34 (m, 1H), 2.31-2.23 (m, 1H), 1.98-1.70 (m, 5H); LC-MS m/z 461.3 (MH+), retention time 3.56 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:4]=1[CH:5]=O.[CH2:15]([O:22][NH2:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([BH3-])#N.[Na+].Cl.[OH-].[Na+]>ClCCl>[CH2:15]([O:22][NH:23][CH2:5][C:4]1[C:3]([O:2][CH3:1])=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=1[O:13][CH3:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Reactant: NOCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(OC)c(CNOCc2ccccc2)c(OC)c1
Reaction time: 0.12 h
Yield: 82.8 %

Procedure:
2,4,6-Trimethoxybenzaldehyde (12.42 g, 63.3 mmol) and O-benzylhydroxylamine (7.80 g, 63.3 mmol) were stirred in dichloromethane (65 mL) at rt overnight. The solvent was removed under reduced pressure. The crude residue was dissolved in ethanol (550 mL) and sodium cyanoborohydride (12.0 g, 189.9 mmol) was added dropwise. The mixture was stirred for 5-10 min, then 12 N HCl was added dropwise until pH became below 3. The reaction mixture was stirred for additional 3 h and 1 N NaOH was added until pH>8. The product was extracted with dichloromethane. The organic phase was dried over Na2SO4 and concentrated under vacuo. The residue was purified by flash chromatography (5% ether in dichloromethane) to give 15.9 g of O-benzyl-N-(2,4,6-trimethoxy-benzyl)hydroxylamine as an oil (83% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[C:14]3[C:20]4([N:23]([CH3:31])[C:24](=[O:30])[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH2:21][CH2:22][C:17]([CH2:32]OS(C5C=CC(C)=CC=5)(=O)=O)([CH2:18][CH2:19]4)[CH2:16][N:15]3[C:44](=[O:47])[C:45]=2[OH:46])=[O:11])=[CH:4][C:3]=1[CH3:48].[C-:49]#[N:50].[K+]>CC(N(C)C)=O>[C:49]([CH2:32][C:17]12[CH2:22][CH2:21][C:20]([N:23]([CH3:31])[C:24](=[O:30])[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])([C:14]3[N:15]([C:44](=[O:47])[C:45]([OH:46])=[C:12]([C:10]([NH:9][CH2:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:48])[CH:4]=4)=[O:11])[N:13]=3)[CH2:16]1)[CH2:19][CH2:18]2)#[N:50]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC23CCC(N(C)C(=O)C(=O)N(C)C)(CC2)c2nc(C(=O)NCc4ccc(F)c(C)c4)c(O)c(=O)n2C3)cc1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(CNC(=O)c2nc3n(c(=O)c2O)CC2(CC#N)CCC3(N(C)C(=O)C(=O)N(C)C)CC2)ccc1F
Temperature: 160 °C
Yield: 19.3 %

Procedure:
A mixture of N-[2-[[[(4-fluoro-3-methylphenyl)methyl]amino]carbonyl]-6,7,8,9-tetrahydro-3-hydroxy-7-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-4-oxo-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl]-N,N′,N′-trimethyl-ethanediamide, Intermediate 28, (50 mg, 0.073 mmol) and KCN (47.6 mg, 0.731 mmol) in DMA (1.5 mL) was heated at 160° C. in a sealed tube for 3 h. The mixture was then cooled and the product purified by preparative HPLC to afford the title compound (8 mg, 0.014 mmol, 19.30% yield) as off-white solid. 1HNMR (500 MHz, CDCl3) δ: 11.97 (1H, br. s.), 9.61 (1H, br. s.), 7.18-7.26 (2H, m), 6.94 (1H, t, J=9.00 Hz), 4.56-4.68 (2H, m), 4.41-4.50 (1H, m), 3.61 (1H, d, J=15.87 Hz), 3.41-3.52 (1H, m), 3.05 (3H, s), 3.03 (3H, s), 3.01 (3H, s), 2.50 (2H, d, J=2.75 Hz), 2.27 (3H, d, J=1.83 Hz), 2.15-2.21 (3H, m), 1.96-2.05 (2H, m), 1.72-1.81 (1H, m), 1.57-1.69 (1H, m). LCMS (M+H)=539.4.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[C:23]2=[O:38])[O:11][CH:10]1[C@H:39]([OH:72])[C@@H:40]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[NH:41][CH2:42][CH2:43][CH2:44][NH:45][C:46](=[O:64])[C@H:47]([C@@H:59]([OH:63])[CH:60]([CH3:62])[CH3:61])[NH:48]C(=O)OCC1C=CC=CC=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:48][C@@H:47]([C@@H:59]([OH:63])[CH:60]([CH3:61])[CH3:62])[C:46]([NH:45][CH2:44][CH2:43][CH2:42][NH:41][C@@H:40]([C@H:39]([CH:10]1[C@@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[C@@H:13]([O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:16])[CH3:17])[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[C:23]2=[O:38])[O:11]1)[OH:72])[C:65]([O:67][C:68]([CH3:70])([CH3:71])[CH3:69])=[O:66])=[O:64]
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@@H](NC(=O)OCc4ccccc4)[C@@H](O)C(C)C)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@@H](N)[C@@H](O)C(C)C)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Yield: 91.9 %

Procedure:
tert-Butyl (5S,12S)-12-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-[(1S)-1-hydroxy-2-methylpropyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (208 mg, 0.2 mmol, obtained from Example 1) was hydrogenated in methanol (2 ml) using 10% palladium on carbon (42 mg) under atmospheric pressure to provide tert-butyl (2S,3R)-2-[(3-{[(2S,3S)-2-amino-3-hydroxy-4-methylpentanoyl]amino}propyl)amino]-3-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]-3-hydroxypropanoate (167 mg, 92%) as a white amorphous solid.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=O)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:21]>>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][N:32]3[CH2:33][CH2:34][CH:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[NH:22][C:20](=[O:21])[CH:19]([CH3:35])[CH3:18])[CH2:30][CH2:31]3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Reactant: CC(C)C(=O)Nc1ccccc1C1CCNCC1
Product: CCn1c2ccccc2c2cc(CN3CCC(c4ccccc4NC(=O)C(C)C)CC3)ccc21

Procedure:
Prepared by Procedure AA and Scheme AJ using 9-ethyl-9H-carbazole-3-carbaldehyde and 2-methyl-N-[2-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 454.1 (M+H)+.