Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[CH:3]=1.[N-:18]=[N+:19]=[N-:20].[Na+].O>CN(C=O)C>[N:18]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[CH:3]=1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: Clc1cc(Oc2ccc3[nH]ccc3c2)ncn1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1cc(Oc2ccc3[nH]ccc3c2)ncn1

Procedure:
490 mg (2.0 mMol) 5-(6-chloro-pyrimidin-4-yloxy)-indole (WO 03/099771; Stage 163.1) and 260 mg (4.0 mMol) NaN3 in 3 ml DMF are stirred for 3 h at 90° C. Then the reaction mixture is poured into water and extracted three times with EtOAc. The organic layers are washed twice with water and brine, dried (Na2SO4) and concentrated, yielding the title compound: MS: [M+1]+=253.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C@H:10]([CH3:13])[CH2:11]Cl)[CH:3]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:9][C@H:10]([CH3:13])[CH2:11][N:28]1[CH2:29][CH2:30][CH:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: C[C@H](CCl)COc1cccc(Cl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@@H](C)COc3cccc(Cl)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-chloro-3-{[(2S)-3-chloro-2-methylpropyl]oxy}benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 429.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:5]2[O:6][P:7](Cl)[O:8][C:9]3[C:15]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:14][C:13]([CH3:20])=[CH:12][C:10]=3[CH2:11][C:4]=2[CH:3]=1.C(N(CC)CC)C.[NH2:35][CH:36]1[CH2:41][C:40]([CH3:43])([CH3:42])[N:39]([CH3:44])[C:38]([CH3:46])([CH3:45])[CH2:37]1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:5]2[O:6][P:7]([NH:35][CH:36]3[CH2:37][C:38]([CH3:45])([CH3:46])[N:39]([CH3:44])[C:40]([CH3:43])([CH3:42])[CH2:41]3)[O:8][C:9]3[C:15]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:14][C:13]([CH3:20])=[CH:12][C:10]=3[CH2:11][C:4]=2[CH:3]=1
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Reactant: Cc1cc2c(c(C(C)(C)C)c1)OP(Cl)Oc1c(cc(C)cc1C(C)(C)C)C2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc2c(c(C(C)(C)C)c1)OP(NC1CC(C)(C)N(C)C(C)(C)C1)Oc1c(cc(C)cc1C(C)(C)C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.2 %

Procedure:
10.12 g (25.0 mmol) of 2,10-dimethyl-4,8-di-tert-butyl-6-chloro-12H-dibenzo[d,g][1,3,2]-dioxaphosphocine [GB-A-2 250 990, Example 1a, page 17], 10.5 ml (75.0 mmol) of triethylamine and 100 ml of toluene are charged at room temperature and under nitrogen to a 350 ml sulfonation flask. With stirring, a solution of 4.26 g (25.0 mmol) of 4-amino-1,2,2,6,6-pentamethylpiperidine [Beilstein EII, Vol. 22, page 321 (1953)] in 30 ml of toluene is added dropwise to this suspension. The reaction mixture is refiuxed for 2 hours, then cooled to room temperature and filtered. The filtrate is concentrated on a vacuum rotary evaporator. Crystallisation of the residue from hexane yields 7.7 g (57%) of 2,10-dimethyl-6-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)-4,8-di-tert-butyl-12H-dibenzo-[d,g][1,3,2]dioxaphosphocine (57%) (compound (101)) as a white powder, m.p. 207°-216° C. Analysis: calcd: C 73.57%; H 9.54%; N 5.19%; found: C 74.38%; H 10.03%; N 4.68%.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:7][C:8]([C@:10]1([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@@H:15](OS(C(F)(F)F)(=O)=O)[CH2:14][C@@H:13]2[C@H:11]1[C@@:12]2([F:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:9])[CH3:6]>CN(C)C=O.C(OCC)C>[CH2:5]([O:7][C:8]([C@:10]1([NH:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[C@H:15]([N:1]=[N+:2]=[N-:3])[CH2:14][C@@H:13]2[C@H:11]1[C@@:12]2([F:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:9])[CH3:6]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@H](OS(=O)(=O)C(F)(F)F)[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC)[C@@H]21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](N=[N+]=[N-])[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC)[C@@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
313 mg of sodium azide was added to 1.63 g of (1R,2R,3S,5R,6R)-2-t-butoxycarbonylamino-6-fluoro-3-trifluoromethanesulfonyloxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 16.3 mL of N,N-dimethylformamide, and the mixture was stirred for 1 hour at room temperature, and then for 20 hours at 35° C. 104 mg of sodium azide was further added thereto, and the mixture was stirred for 18 hours at 35° C. After being diluted with 50 mL of diethyl ether, the mixture was washed twice with water and then with a saturated aqueous solution of sodium chloride. The organic layers were dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane-ethyl acetate=5:1), thereby yielding 775 mg of (1R,2R,3R,5R,6R)-3-azido-2-t-butoxycarbonylamino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl[C:36]1[S:37][C:38]2[C:44]([F:45])=[CH:43][CH:42]=[C:41]([C:46]([F:49])([F:48])[F:47])[C:39]=2[N:40]=1.C(=O)([O-])[O-].[K+].[K+].N#N>O1CCOCC1.O>[F:45][C:44]1[C:38]2[S:37][C:36]([C:23]3[C:22]([NH2:34])=[N:21][CH:20]=[C:19]([C:17]4[CH:16]=[N:15][N:14]([CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)[CH:18]=4)[CH:24]=3)=[N:40][C:39]=2[C:41]([C:46]([F:49])([F:47])[F:48])=[CH:42][CH:43]=1
Reactant: Fc1ccc(C(F)(F)F)c2nc(Cl)sc12
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)ccc(F)c2s1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-{4-[6-amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB8) (60 mg, 0.127 mmol, 1 eq), 2-chloro-7-fluoro-4-trifluoromethyl-1,3-benzothiazole (42 mg, 0.153 mmol, 1.2 eq), and potassium carbonate (43 mg, 0.317 mmol, 2.5 eq) in 20% aq. dioxane (15 mL) was bubbledN2 gas for 15 min. Catalyst PdCl2dppf (5 mol %) was added to the stirred solution and N2 gas bubbling continued for another 10 min. The reaction mixture was then heated at 80° C. for 2 h. Cooling of the reaction mixture and evaporation of dioxane under reduced pressure yielded a brown residue. It was diluted with water (50 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield a yellowish-green solid. It was purified by column chromatography (50% ethyl acetate in hexane) to afford the BOC-protected title compound as yellowish-green solid; MS(ES+): m/z=563 [MH+]. To a solution of this Boc derivative (40 mg, 0.07 mmol) at 0-5° C. in dry DCM (10 ml) was added 4M HCl in dioxane (0.2 ml) dropwise and stirred the reaction mixture overnight at rt. Removed solvent under reduced pressure to afford the title compound as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=9.06-8.96 (brm, 1H), 8.85-8.73 (brm, 1H), 8.61 (d, J=2.0 Hz, 1H), 8.42 (s, 1H), 8.41 (d, J=2.0 Hz, 1H), 8.17 (very brs, 1H), 8.09 (s, 1H), 8.03 (dd, J=5.2, 8.4 Hz, 1H), 7.59 (t, J=8.4 Hz, 1H), 4.56-4.46 (mc, 1H), 3.41 (brd, J=12.4 Hz, 2H), 3.12 (brq, J=11.4 Hz, 2H), 2.31-2.11 (m, 4H). MS(ES+): m/z=463.05 (100) [MH+], 380.02 (80) [MH+-piperidine]. HPLC: tR=2.29 min (polar—5 min, ZQ2).
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([C:22]#[N:23])[CH:16]=[CH:15]2>C(O)C>[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([C:22]([NH:2][OH:3])=[NH:23])[CH:16]=[CH:15]2
Reactant: NO
Reactant: N#Cc1ccc2cc(Br)ccc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: N=C(NO)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C

Procedure:
2.48 g hydroxylamine-hydrochloride and 5.68 ml triethylamine are added to 4.10 g of 6-bromo-2-cyano-naphthalene in 100 ml of ethanol and the reaction mixture is refluxed for four hours. After cooling to ambient temperature the solvent is distilled off in vacuo using the rotary evaporator and the flask residue is divided between water and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried on magnesium sulphate and evaporated down.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[C:24]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:25]C([O-])=O.O>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH2:25][C:24]([O:30][CH2:31][CH3:32])=[O:29])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)c1cccc(Cl)n1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(=O)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
To a solution of 6-chloro-2-pyridinecarboxylic acid (10 g, 63.5 mmol) in tetrahydrofuran (150 ml) was added 1,1′-carbonylbis-1H-imidazole (11.3 g, 69.8 mmol), and the mixture was heated under reflux for 30 min. The reaction solution was cooled, and monoethyl malonate magnesium salt (10 g, 34.9 mmol) was added. The mixture was stirred at room temperature for 30 min. To the reaction solution was added water (200 ml) and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl-acetate=4:1) to give ethyl 3-(6-chloro-2-pyridyl)-3-oxopropionate (7.96 g, 55%) as a brown oil. IR ν maxKBrcm−1: 1738, 1713, 1651, 1645. Anal. Calcd for C10H10NO3Cl: C, 52.76; H, 4.43; N, 6.15. Found: C, 52.63; H, 4.55; N, 6.02. 1H-NMR (CDCl3)δ: 1.20-1.40 (3H, m), 4.15 (2H×2/3, s), 4.14-4.32 (2H, m), 6.35 (1H×1/3, s), 7.37 (1H×1/3, d, J=6.6 Hz), 7.53 (1H×2/3, d, J=7.0 Hz), 7.70-8.02 (2H, m), 12.31 (1H×1/3, s).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:13].[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH:36]=O)=[N:28]1>CO.N1CCCCC1>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](/[CH:36]=[C:7]2\[O:8][C:4]3[C:3]([C:12]([N:14]4[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]4)=[O:13])=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[N:28]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(O)ccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 84.7 %

Procedure:
A solution of tert-butyl 4-(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-carbonyl)piperazine-1-carboxylate (0.048 g, 0.13 mmol) in methanol (2.0 mL) was added with 1H-indazole-3-carboxaldehyde (0.025 g, 0.17 mmol). Then, the mixture was added with 7 drops of piperidine, and the mixture was stirred at 50° C. for 4 hours. The solid formed was removed by filtration, the filtrate was concentrated, and then the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (97:3→90:10)) to obtain tert-butyl (Z)-4-{2-[(1H-indazol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-carbonyl}piperazine-1-carboxylate (0.054 g, 85%).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:19])[CH:17]=[CH2:18]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:8][C:16](=[O:19])[CH:17]=[CH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)Cl
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 69.6 %

Procedure:
To a solution of benzyl alcohol (4.76 mL, 0.046 mol), 4-dimethylamino-pyridine (“DMAP,” 0.790 g, 0.0065 mol) and triethylamine (12.85 mL, 0.09297 mol) in dichloromethane (92 mL) was added a solution of acryloyl chloride (7.54 mL, 0.09297 mol) slowly at 0° C., and the mixture was stirred at 0° C. for 2.5 hours. The mixture was quenched with aqueous sodium bicarbonate, and the quenched mixture was extracted with dichloromethane (2×100 mL). The extracts were combined, dried (MgSO4), and rotary evaporated to give a yellow oil. The oil was purified by column chromatography, eluting with hexanes/ethyl acetate (95:5) to give 5.19 g (64%) of acrylic acid benzyl ester as a clear oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].ClCCl>N1C=CC=CC=1>[C:13]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ccc(OCCO)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCCOc1ccc(C=O)cc1
Temperature: 0 °C

Procedure:
A mixture of the crude 4-(2-hydroxyethoxy)benzaldehyde (30 g, 0.18 mol) and acetic anhydride (40 g, 0.40 mol) was dissolved in 125 mL of dry pyridine and heated at reflux for 3 hr, after which time the reaction mixture was poured onto ca. 200 g of crushed ice. The crude oil was taken up into 150 mL of dichloromethane and washed twice with 5% HCl (2×75 mL) and once with brine (1×75 mL). The organic layer was then dried with sodium sulfate and the solvent was removed under reduced pressure. The crude residue was distilled at 148° C. (1×10-3 mm) to give 12.9 g (25% overall yield) of a slightly cloudy liquid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[CH3:33][C:34](C1C=CC(C(F)(F)F)=CC=1)=O.C(O[BH3-])(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:33][CH3:34])[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(CC)C2)c1
Temperature: 25 °C

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (47 mg, 0.11 mmol), and 4-Trifluoromethylacetophenone (20 mg, 0.11 mmol), in 1,2 dichloroethane (0.7 ml) was added sodium acetoxyborohydride (29 mg, 0.14 mmol) and acetic acid (6.6 μl, 0.12 mmol). The reaction stirred at room temperature with little product. The reaction was heated at 50° C., then reflux over 48 hours. The solution was concentrated in vacuo, and purified by silica gel chromatography to give the above pictured by product. Calcd for C28H36F3NO2 (M+H) 475.59, Found 476.4.
Reaction SMILES: CN(C)C=O.Cl.[NH:7]([CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([OH:20])[CH2:16][C:17]([NH2:19])=[O:18])[C:8]([NH2:10])=[NH:9].[C:21]([Cl:29])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1>[ClH:29].[NH:7]([CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([O:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][C:17]([NH2:19])=[O:18])[C:8]([NH2:10])=[NH:9]
Reactant: N=C(N)NCCCC[C@H](O)CC(N)=O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N=C(N)NCCCC[C@@H](CC(N)=O)OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into 2.5 ml of dimethylformamide, was dissolved 2.09 of (S)-7-guanidino-3-hydroxyheptanamide hydrochloride followed by 1.7 ml of pyridine. To the solution, while being cooled in ice, was added slowly and dropwise 2.6 ml of benzoyl chloride. The mixture was stirred for 30 minutes while cooling in ice and for further two hours at room temperature. The reaction mixture was diluted with 20 ml of ice water, the separated oily layer was separated, and the aqueous layer was admixed with 600 mg of sodium chloride. The aqueous layer was passed through a column of Diaion® HP-20 which had been equilibrated with 0.5 M aqueous sodium chloride solution, and the column was washed successively with 0.5 M, 0.2 M and 0.1 M aqueous sodium chloride solutions, and with water. The fractions eluted with 20 to 40% (v/v) aqueous methanol were collected and concentrated under reduced pressure to yield 820 mg of (S)-7-guanidino-3-benzoyloxyheptanamide hydrochloride in oily form. NMR: 1.4-2.0 (CH2 x3), 2.65 (CH2), 3.17 (CH2), 5.50 (CH), 7.2-8.1 (COC6H5).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH2:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[C:23]([F:24])=[C:22]([F:25])[CH:21]=[CH:20][C:12]=1[C:13]([NH:15][O:16][CH2:17][CH2:18][OH:19])=[O:14]>O1CCCC1.[Pd].CO>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[C:23]([F:24])=[C:22]([F:25])[CH:21]=[CH:20][C:12]=1[C:13]([NH:15][O:16][CH2:17][CH2:18][OH:19])=[O:14]
Reactant: C=Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(Cl)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(Cl)c1
Reaction time: 6 h

Procedure:
A solution of the product of Example 2, Step D, 2-(2-chloro-4-vinyl-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide (0.291 g, 0.789 mmol) in tetrahydrofuran (16 mL) was hydrogenated over 10% palladium on carbon (0.08 g) at 6900 psig at room temperature for 17 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to afford a crystalline solid. The solid was dissolved in methanol and concentrated to near dryness. Ether (10 mL) was added and the mixture was allowed to stand at ambient temperature for 6 hours. during which crystallization ensued. The white crystals were filtered, washed with a small volume of ether, and dried in vacuo at 60° C. overnight yielding 2-(2-chloro-4-ethyl-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide (222 mg): m.p. 142.5–145° C.; 1H NMR (400 MHz, DMSO-d6) δ 11.94 (br s, 1 H), 8.85 (br s, 1 H), 7.44 (br t, J=6.4 Hz, 1 H), 7.30 (d, J=2.0 Hz, 1 H), 7.22–7.15 (m, 1 H), 7.05 (dd, J=8.3, 2.0 Hz, 1 H), 6.75 (dd, J=8.3, 6.3 Hz, 1 H), 4.71 (br s, 1 H), 3.89 (br s, 2 H), 3.59 (br s, 2 H), 2.54 (q, J=7.6 Hz, 2 H), 1.15 (t, J=7.6 Hz, 3 H); 19F NMR (376 MHz, DMSO-d6) δ −132.7, −142.0; MS (APCI+)=371.0. Anal. Calcd/found for C17H17ClF2N2O3: C, 55.07/55.14; H, 4.62/4.51; N, 7.56/7.38; F, 10.25/9.98.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@:10]2([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:11](=[O:12])[C@@H:6]([C@:7]([CH3:28])([CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C@@H:8]([O:18][CH2:19][O:20][CH3:21])[CH2:9]2)[C:5](=[O:29])[C:4]=1[Si](C)(C)C.[Li]N1C(C)(C)CCCC1(C)C.[C:45](Cl)(=[O:49])[CH:46]([CH3:48])[CH3:47].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:45]([C@:6]12[C:11](=[O:12])[C@:10]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])([CH2:9][C@H:8]([O:18][CH2:19][O:20][CH3:21])[C@@:7]1([CH3:28])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:3]([O:2][CH3:1])=[CH:4][C:5]2=[O:29])(=[O:49])[CH:46]([CH3:48])[CH3:47]
Reactant: COCO[C@H]1C[C@@]2(CC=C(C)C)C(=O)[C@H](C(=O)C([Si](C)(C)C)=C2OC)[C@]1(C)CCC=C(C)C
Reactant: CC(C)C(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li]N1C(C)(C)CCCC1(C)C
Solvent: C1CCOC1
Product: COCO[C@H]1C[C@@]2(CC=C(C)C)C(=O)[C@](C(=O)C(C)C)(C(=O)C=C2OC)[C@]1(C)CCC=C(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 28.8 %

Procedure:
A 1 dram vial equipped with a stir bar is charged with 14.3 mg (0.030 mmol, 1 equiv.) of 51 and 150 μL of THF. The solution was cooled to −78° C. in a dry ice/acetone bath, and 300 μL of a solution of LiTMP (0.5M in THF, 0.150 mmol, 5 equiv.) was added dropwise. The yellow solution was stirred at −78° C. for 10 minutes followed by warming to 0° C. in a water/ice bath for 10 minutes and then recooling to −78° C. prior to addition of 15.7 μL (0.15 mmol, 5 equiv.) of isobutyryl chloride. The reaction was stirred 30 minutes prior to quenching by the addition of 500 μL of saturated aqueous ammonium chloride. The solution was transferred to a separatory funnel with 15 mL of hexane, and the organic layer was washed sequentially saturated aqueous 10% aqueous hydrochloric acid, water, and brine; dried with MgSO4; and concentrated in vacuo. The crude product was found to contain an inseparable mixture of product and 51. The mixture was purified by silica gel chromatography (Rf=0.25 in 9:1 hexane:ethyl acetate) and carried forward as a mixture. A 1 dram vial equipped with a stir bar is charged with 9.0 mg (0.016 mmol, 1 equiv.) of the mixture followed by 100 μL of THF. The vial was cooled in a water/ice bath and 18 μL of TBAF (1.0 M in THF, 0.018, 1.1 equiv.) is added. The mixture is stirred for 15 min at which time it is transferred to a separatory funnel, and the organic layer is washed sequentially saturated aqueous sodium bicarbonate, water, and brine. The organic layer is then dried with MgSO4 and concentrated in vacuo to give a yellow oil. The crude product is purified by preparative TLC (Rf=0.25 in 3:1 hexane:ethyl acetate) to give 4.1 mg (53% yield) of 56 as a clear oil. 1H NMR (500 MHz, CDCl3) δ 5.85 (s, 1H), 5.07-4.96 (m, 2H), 4.61 (dd, J=6.8, 15.5 Hz, 2H), 3.82 (s, 3H), 3.58 (dd, J=5.2, 11.3 Hz, 1H), 3.32 (s, 3H), 2.48 (ddd, J=7.5, 14.5, 34.2 Hz, 2H), 2.18-2.04 (m, J=5.9, 13.2, 17.3 Hz, 4H), 1.96 (s, 1H), 1.77 (dd, J=11.4, 13.4 Hz, 1H), 1.67 (d, J=3.0 Hz, 6H), 1.64 (s, 3H), 1.59 (s, 3H), 1.55 (s, 3H), 1.30-1.21 (m, J=2.6, 2.6 Hz, 1H), 1.14 (s, 3H), 1.12 (d, J=6.5 Hz, 3H), 1.05 (d, J=6.5 Hz, 3H). HRMS-ESI (m/z): [M+H]+ calculated for C28H42O6, 475.3054. found, 475.3045.
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].[NH2:19][C@@H:20]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)[C:21]([O:23][CH3:24])=[O:22].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH:16]1[C:17]2[CH:5]([CH2:4][O:3][C:1]([NH:19][C@@H:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)[C:21]([O:23][CH3:24])=[O:22])=[O:2])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
Fmoc-Cl (27.6 g, 107.2 mmol) in 1,4-dioxane (950 mL) was added dropwise to a solution of (S)-methyl 2-amino-3-(4-nitrophenyl)propanoate (3A; 20 g, 89.3 mmol) and K2CO3 (14.8 g , 107.2 mmol) in water (80 mL) and 1,4-dioxane (150 mL) on an ice bath. After being stirred for 2 hours at room temperature, the mixture was poured into 1.2 L of water to precipitate a white solid, which was filtered and washed with cold water. The solid was dried under vacuum for 3 hours to give 40 g of (S)-methyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-nitrophenyl)propanoate 3B, which was directly used in step 2.