Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:17]=[CH:18]\[C:19]([OH:21])=O)=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[H-].[Na+].[CH3:37][C:38]1([CH3:50])[C@@:42]23[C@H:48]([CH2:49][C@@H:39]1[CH2:40][CH2:41]2)[NH:47][S:44](=[O:46])(=[O:45])[CH2:43]3>C1COCC1.CCCCCC>[CH3:37][C:38]1([CH3:50])[C@@:42]23[C@H:48]([CH2:49][C@@H:39]1[CH2:40][CH2:41]2)[NH:47][S:44](=[O:45])(=[O:46])[CH2:43]3.[CH:1]([O:4][C:5](=[O:6])[C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:10]=[CH:9][C:8]=1[CH:17]=[CH:18][C:19]([N:47]1[C@H:48]2[CH2:49][C@@H:39]3[C:38]([CH3:50])([CH3:37])[C@@:42]2([CH2:41][CH2:40]3)[CH2:43][S:44]1(=[O:45])=[O:46])=[O:21])([CH3:2])[CH3:3]
Reactant: CC(C)OC(=O)c1c(/C=C\C(=O)O)cccc1C(F)(F)F
Agent: CC1(C)[C@H]2CC[C@@]13CS(=O)(=O)N[C@H]3C2
Agent: CCOC(=O)Cl
Agent: [H-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)c1c(C=CC(=O)N2[C@H]3C[C@H]4CC[C@@]3(CS2(=O)=O)C4(C)C)cccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 170.9 %

Procedure:
To a solution of (Z)-3-(2-(isopropoxycarbonyl)-3-(trifluoromethyl)phenyl)acrylic acid (0.90 g, 2.98 mmol) in 30 mL of THF at 0° C. was added triethylamine (0.46 mL, 3.28 mmol) followed by ethyl chloroformate (0.32 mL, 3.28 mmol). This mixture was stirred at 0° C. for 45 min. In a separate flask, to a suspension of hexane-washed sodium hydride (131 mg of 60% dispersion in mineral oil, 3.28 mmol) in 20 mL of THF was added (1R)-(+)-2,10-camphorsultam (706 mg, 3.28 mmol) as a solution in 5 mL of THF. The mixture was stirred at ambient temperature for 20 min, at which time gas evolution had ceased and a homogeneous solution was obtained. This solution was added to the mixed anhydride solution maintained at 0° C. and the resulting mixture was stirred at 0° C. for 5 min and then was allowed to warm to ambient temperature and was stirred for 1 h. TLC analysis showed the reaction was not complete. In a separate flask an additional portion of the anion of (1R)-(+)-2,10-camphorsultam was prepared as described above (from 130 mg, 0.6 mmol of (1R)-(+)-2,10-camphorsultam and 24 mg of 60% dispersion in mineral oil, 0.6 mmol of sodium hydride). This solution was added to the main reaction mixture and stirring was continued at ambient temperature for 30 min, at which time the reaction was complete. The reaction was quenched with water and diluted with ethyl acetate. The organics were washed with 1N HCl, sat'd aq NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, elution with 4:1 hexane/EtOAc) to afford 1.4 g (94%) of the title compound as a foam. LRMS (ESI): 500.2 (M+H)+.
Reaction SMILES: C(O[CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:26])[CH:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C@H:9]2[S:8][CH:7]=1)(=O)C.[BrH:27].C(Cl)Cl>>[Br:27][CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:26])[CH:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C@H:9]2[S:8][CH:7]=1
Reactant: Br
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)O
Solvent: ClCCl
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)C(CBr)=CS[C@H]12
Reaction time: 0.83 h

Procedure:
A cooled solution (in ice) of benzyl ester of 3-acetoxymethyl-7-(2-thienylacetamido)-2-cephem-4-carboxylic acid (77 mg., 0.15 mmole) is stirred while hydrogen bromide (0.5 ml.) in methylene chloride (0.32 mmole) is added dropwise. The reaction is stopped 50 minutes later by simply bubbling off the excess hydrogen bromide with nitrogen. Removal of the solvent affords the benzyl ester of 3-bromomethyl-7-(2-thienylacetamido)-2-cephem-4-carboxylic acid which is employed directly in Step C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:16]=[CH:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13].[CH:22](O)=O>>[C:12]([NH:11][CH2:10][CH2:9][N:8]1[C:7]2[CH:6]=[CH:5][C:4]([C:15]3[CH:16]=[CH:17][C:18](=[O:21])[NH:19][N:20]=3)=[CH:3][C:2]=2[N:1]=[CH:22]1)(=[O:14])[CH3:13]
Reactant: CC(=O)NCCNc1ccc(-c2ccc(=O)[nH]n2)cc1N
Reactant: O=CO
Product: CC(=O)NCCn1cnc2cc(-c3ccc(=O)[nH]n3)ccc21

Procedure:
14.2 g (49.4 mmol) of 6-(3-amino-4-acetylaminoethylaminophenyl)-3(2H)-pyridazinone are refluxed for one hour in 60 ml of formic acid. Then the excess formic acid is distilled off in vacuo, the residue is mixed with 50 ml of ice water and then adjusted to pH 8-9 with concentrated ammonia solution. The product precipitated is suction filtered, washed with about 50 ml of cold water, then with 50 ml of ether and dried.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([P-:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[K+].F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1F>O1CCOCC1>[C:8]1([P:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[P:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Fc1ccccc1Nc1ccccc1F
Reactant: c1ccc([P-]c2ccccc2)cc1
Agent: [K+]
Solvent: C1COCCO1
Product: c1ccc(P(c2ccccc2)c2ccccc2Nc2ccccc2P(c2ccccc2)c2ccccc2)cc1

Procedure:
A 100-mL Schlenk flask equipped with a condenser was flashed with nitrogen thoroughly. To this flask was added KPPh2 (20 mL, 0.5 M in THF solution, Aldrich, 10 mmol). THF was removed in vacuo and a solution of di(2-fluorophenyl)amine (1.00 g, 4.88 mmol) in 1,4-dioxane (8 ml) was added with a syringe. The transparent, ruby reaction solution was heated to reflux with stirring. The reaction condition was monitored by 31P{1H} NMR spectroscopy, which revealed the completion of reaction in 2 d. The resulting yellow solution was evaporated to dryness in vacuo. The residue was treated with degassed deionized water (50 mL) and the product was extracted with deoxygenated dichloromethane (15 mL). The dichloromethane solution was separated from the aqueous layer, from which the product was further extracted with dichloromethane (15 mL×3). The combined organic solution was dried over MgSO4 and filtered. All volatiles were removed in vacuo to yield the product as a pale yellow crystalline solid; yield 2.1 g (80.15%). 1H NMR (CDCl3, 300 MHz) δ 7.10-7.23 (m, 24, Ar), 6.69-6.76 (m, 5, Ar and NH). 31P{1H} NMR (CDCl3, 121.5 MHz) δ−19.58. 31P{1H} NMR (Et2O, 121.5 MHz) δ−18.62. 13C NMR (CDCl3, 75 MHz) δ 146.51 (JCP=21.1), 135.78 (JCP=8.0), 134.14, 133.72 (JCP=21.1), 129.64, 128.53 (JCP=12.0), 128.46 (JCP=7.5), 126.34 (JCP=10.1), 121.51, 118.16. Anal. Calcd. for C36H29NP2: C, 80.43; H, 5.44; N, 2.61. Found: C, 80.04; H, 5.56; N, 2.69.
Reaction SMILES: [O-]CC.[Na+].[CH3:5][C:6]([C:9]([NH2:11])=[NH:10])([CH3:8])[CH3:7].Cl.[C:13]([OH:21])(=[O:20])/[C:14](=[C:16](\[CH:18]=O)/[Br:17])/Br>C(O)C.Cl>[Br:17][C:16]1[C:14]([C:13]([OH:21])=[O:20])=[N:10][C:9]([C:6]([CH3:8])([CH3:7])[CH3:5])=[N:11][CH:18]=1
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Reactant: CC(C)(C)C(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1ncc(Br)c(C(=O)O)n1
Temperature: 50 °C
Yield: 76.6 %

Procedure:
Preparation C1, Step 1: A 22% solution of sodium ethoxide in ethanol (53 mL, 165 mmol) was added dropwise to a magnetically stirred suspension of tert-butylcarbamidine hydrochloride (20.0 g, 146 mmol) in ethanol (100 mL). When the addition was complete, the yellow suspension was warmed to 50° C., the heating mantle was removed, and a solution of mucobromic acid (15.7 g, 61 mmol) in ethanol (50 mL) was added dropwise at a rate which did not allow the temperature to exceed 55° C. When this addition was complete, a 22% solution of sodium ethoxide in ethanol (32 mL, 98 mmol) was added dropwise, then the mixture was allowed to cool to room temperature. The suspension was filtered, the solids were rinsed with ethanol (2×20 mL), and the combined filtrates were concentrated in-vacuo. The residue thus obtained was stirred in 2 N aqueous HCl (30 mL). The resulting solids were collected by filtration, rinsed with ice-cold water (2×20 mL), and air dried to yield 12.1 g of 5-Bromo-2-tert-butyl-pyrimidine-4-carboxylic acid as a beige powder. MS (ES+)=259, 261 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([OH:23])=O)[NH:6]2.[N:24]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>CN(C)C=O>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([NH2:24])=[O:23])[NH:6]2
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(N)=O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
A mixture of 4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (2.2 g), 1H-1,2,3-benzotriazol-1-ol (1.2 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.5 g) and N,N-dimethylformamide (30 ml) was stirred at room temperature for 1 hr, and then at 60° C. for 1 hr. 28% Aqueous ammonia (2.0 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hr. The reaction solution was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate. The mixture was washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil was crystallized from ethyl acetate-hexane to give the title compound (1.84 g, yield 84%) as colorless prism crystals.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([OH:15])[CH2:12][C@H:11]1[C:16]([OH:18])=[O:17])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:19](I)[CH3:20]>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([O:15][CH2:19][CH3:20])[CH2:12][C@H:11]1[C:16]([OH:18])=[O:17])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCO[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82.8 %

Procedure:
1.72 g of 60% sodium hydride in oil are added, under a nitrogen atmosphere, to a solution of 5 g of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid in 100 ml of THF, and the mixture is stirred for 45 minutes at RT. 3.27 g of ethyl iodide are then added, the mixture is refluxed for 3 hours and stirred for 18 hours while allowing the temperature to return to RT. The reaction mixture is concentrated under vacuum, the residue is taken up in 5% KHSO4 solution and extracted with EtOAc, the organic phase is dried over Na2SO4 and the solvent is evaporated off under vacuum. 4.5 g of the expected product are obtained in the form of an oil.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:29]=[CH:28][C:9]([C:10]([NH:12][C@H:13]2[C@@H:19]([OH:20])[CH2:18][CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:14]2)=[O:11])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[C:30]([O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=1)([CH3:33])([CH3:32])[CH3:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6]1[CH:29]=[CH:28][C:9]([C:10]([NH:12][C@H:13]2[C@H:19]([O:20][C:39](=[O:40])[C:38]3[CH:37]=[CH:36][C:35]([O:34][C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:43][CH:42]=3)[CH2:18][CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:14]2)=[O:11])=[CH:8][CH:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Oc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)[C@H](NC(=O)c2ccc(OC(C)(C)C)cc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](OC(=O)c2ccc(OC(C)(C)C)cc2)[C@H](NC(=O)c2ccc(OC(C)(C)C)cc2)C1
Temperature: 50 °C
Reaction time: 4 h
Yield: 41.3 %

Procedure:
262 mg of diethyl azadicarboxylate in 2 ml of tetrahydrofuran were added while stirring to 407 mg of the compound prepared in Example 16, 253 mg of 4-(tert-butoxy)-benzoic acid and 394 g of triphenylphosphine in 8 ml of tetrahydrofuran. After stirring at 50° C. for 4 hours, the solvent was removed under reduced pressure and the residue was taken up in 20 ml of cyclohexane and washed once with 20 ml of water and twice with 10 ml of 70% methanol/water each time. The aqueous-alcoholic phase was extracted twice with 10 ml of cyclohexane each time. The combined cyclohexane phases were dried over sodium sulphate and the solvent was removed under reduced pressure. The residual viscous oil was dissolved in 10 ml of hot heptane, seeded with pure end product and left to crystallize at room temperature for 18 hours and yielded 241 mg of tert-butyl (3R,4R)-3-(4-tert-butoxy-benzoylamino)-4-(4-tert-butoxy-benzoyloxy)-azepan-1-carboxylate of melting point 126-128° C. This compound can be reacted further as in Example 12b.
Reaction SMILES: [N+:1](/[C:4](=[CH:6]\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)/[CH3:5])([O-:3])=[O:2]>O>[N+:1]([CH:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:5])([O-:3])=[O:2]
Reactant: C/C(=C/c1ccccc1)[N+](=O)[O-]
Solvent: O
Product: CC(Cc1ccccc1)[N+](=O)[O-]
Yield: 41 %

Procedure:
Z-2-nitro-3-phenyl-2-propene (151 mg 1 mmol) was reacted with yeast (5 g) and water (5 ml) according to Method I. The product was isolated as a racemic mixture of products in 41% yield. Reaction according to method II also resulted in a racemic mixture of products in 38% yield.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH2:32]([NH:39][CH2:40][CH2:41][C:42]#[N:43])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[CH2:32]([N:39]([CH:18]=[C:17]1[C:16]2[C:15]([CH3:30])([C:14]3[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]4([CH3:31])[CH:8]([C:13]=3[C:21](=[O:22])[C:20]=2[OH:19])[CH2:9][CH2:10][CH:11]4[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]1=[O:24])[CH2:40][CH2:41][C:42]#[N:43])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: N#CCCNCc1ccccc1
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN(CCC#N)Cc2ccccc2)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added 3-benzylamino-propionitrile (73 μL, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 592 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([OH:10])[CH2:7][NH:6]1)=[O:4].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18]Cl)=[CH:14][C:13]=1[Cl:20]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[C:13]([Cl:20])[CH:14]=1)=[O:4]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)C1CC(O)CN1
Product: COC(=O)[C@@H]1C[C@@H](O)CN1Cc1ccc(Cl)c(Cl)c1
Yield: 70 %

Procedure:
As described for Example 64a, 4-hydroxy-pyrrolidine-2-carboxylic acid methyl ester (10 mmol) was converted, using 1,2-dichloro-4-chloromethyl-benzene instead of 1-chloro-3-chloromethyl-benzene, to the title compound (2.14 g) in 70% yield as yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH:5]([CH2:20][S:21]C(=O)C)[CH2:6][C:7]1[S:11][C:10]([NH:12]C(OC(C)(C)C)=O)=[N:9][CH:8]=1)C>Cl>[NH2:12][C:10]1[S:11][C:7]([CH2:6][CH:5]([CH2:20][SH:21])[C:4]([OH:25])=[O:3])=[CH:8][N:9]=1
Reactant: CCOC(=O)C(CSC(C)=O)Cc1cnc(NC(=O)OC(C)(C)C)s1
Agent: Cl
Product: Nc1ncc(CC(CS)C(=O)O)s1
Temperature: 25 °C
Yield: 33.3 %

Procedure:
A solution of 2-acetylsulfanylmethyl-3-(2-tert-butoxycarbonylamino-thiazol-5-yl)-propionic acid ethyl ester (43 mg; 0.11 mmol) in concentrated HCl (1.5 mL) was refluxed under argon for 1.5 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to yield 30 mg of the crude product. The crude product was purified by preparative HPLC to afford the title compound (8 mg; 21%) as the hydrochloride salt.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][O:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26].C(NC(C)C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I.O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][O:13][C:9]2=[C:10]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2onc(-c3ccc(Cl)cc3)c2c1O
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1nc(C#C[Si](C)(C)C)c2onc(-c3ccc(Cl)cc3)c2c1O
Temperature: 25 °C
Yield: 34.9 %

Procedure:
A mixture of 7-bromo-3-(4-chloro-phenyl)-4-hydroxy-isoxazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (150 mg, 0.38 mmol), tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.04 mmol), copper (I) iodide (14 mg, 0.08 mmol), trimethylsilylacetylene (107 μl, 0.76 mmol), diisopropylamine (321 μl, 2.27 mmol), and tetrahydrofuran (3.8 ml) was refluxed for eighteen hours before it was cooled to room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of hexanes and dichloromethane to give the title compound as a yellow solid (55 mg); MS (m/z): 415.34 (M+H+); 413.37 (M−H+).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:18]=[N:19][C:20]([C:23](O)=[O:24])=[N:21][CH:22]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>CN(C)C=O>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:18]=[N:19][C:20]([C:23]([N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)=[O:24])=[N:21][CH:22]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ncc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(c1ncc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1)N1CCOCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrimidinecarboxylic acid (E177b) (130 mg, 0.37 mmol) was dissolved in dimethylformamide (4 ml), treated with 1,1′-carbonyldiimidazole (180 mg, 1.11 mmol) and left to stir under argon at room temperature for 5 hours. The mixture was treated with morpholine (0.19 ml, 2.22 mmol) and allowed to stir at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the resulting residue purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.5:1.5:95) to afford the title compound (E177). MS (ES+) m/e 409 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14]([N:16]([CH2:20][CH3:21])[CH2:17][CH2:18][NH2:19])[CH3:15].[OH-].[NH4+]>CCO>[N+:11]([C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:19][CH2:18][CH2:17][N:16]([CH2:20][CH3:21])[CH2:14][CH3:15])([O-:13])=[O:12]
Reactant: CCN(CC)CCN
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCN(CC)CCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 40 °C

Procedure:
Chloro-2,4-dinitrobenzene 1 (1.00 g, 4.937 mmol) was dissolved in anhydrous EtOH (20 mL) in a small argon purged flask and warmed in an oil bath to 40° C. Addition of N,N-diethylethylenediamine 2a (0.63 g, 5.430 mmol) occurred dropwise. The reaction was stirred at reflux for 24 hours then cooled to room temperature. The mixture was basified by the addition of aqueous 1M ammonium hydroxide solution to adjust pH to 10-11. The solid that precipitated was collected on a sintered glass funnel and briefly dried. Recrystallization of the crude solid from EtOH yielded a yellow powder 3a N′-(2,4-Dinitro-phenyl)-N,N-diethyl-ethane-1,2-diamine. Yield: 0.94 grams (67.4%). 1H NMR (DMSO) δ: 0.99 (t, 6H, J=7.1), 2.56 (m, 4H), 2.70 (t, 2H, J=6.1), 3.49 (q, 2H, J=5.5), 7.19 (d, 1H, J=9.7), 8.28 (dd, 1H, J=9.5, 2.6), 8.67 (d, 1H), 9.05 (br s, 1H); MS (APCI): 283 (MH+, 100%)
Reaction SMILES: C([O:5][C:6](=[O:48])[CH2:7][CH:8]([NH:20][C:21](=[O:47])[C@H:22]([CH3:46])[NH:23][C:24](=[O:45])[C@H:25]([CH:42]([CH3:44])[CH3:43])[NH:26][C:27](=[O:41])[C@H:28]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)[NH:29][C:30](=[O:32])[CH3:31])[CH:9]([OH:19])[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(C)(C)C>C(Cl)Cl.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>[C:30]([NH:29][C@H:28]([C:27]([NH:26][C@H:25]([C:24]([NH:23][C@H:22]([C:21]([NH:20][CH:8]([C:9](=[O:19])[CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:7][C:6]([OH:48])=[O:5])=[O:47])[CH3:46])=[O:45])[CH:42]([CH3:44])[CH3:43])=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CCCc1ccccc1)C(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)NC(CC(=O)O)C(=O)CCCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.3 %

Procedure:
N-(N-Acetyl-Tyrosinyl-Valinyl-Alaninyl)-3-amino-4-hydroxy-7-phenyl heptanoic acid t-butyl ester (166 mg, 0.0991 mmol), was dissolved in CH2Cl2 (5 mL) and PDC (56 mg, 0.149 mmoL), was added. The resulting mixture was stirred at rt for 6h. The mixture was filtered through Celite and the solvent was concentrated in vacuo. The residue was chromatographed over silica (95:5, CH2Cl2 :MeOH) to provide the ketone (28 mg) and S.M (33 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]1[C:14]([CH3:16])([CH3:15])[CH:13]=[CH:12][CH2:11][N:10]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:9]1=[O:28])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]1[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][N:10]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:9]1=[O:28])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(CN2CC=CC(C)(C)C(NC(=O)OC(C)(C)C)C2=O)c(OC)c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(CN2CCCC(C)(C)C(NC(=O)OC(C)(C)C)C2=O)c(OC)c1
Reaction time: 1.5 h
Yield: 84.6 %

Procedure:
[1-(2,4-Dimethoxy-benzyl)-4,4-dimethyl-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl]-carbamic acid tert-butyl ester (260 mg, 0.64 mmol) was dissolved in methanol (10 ml). Palladium on charcoal (30 mg, 10%) was added and the mixture was hydrogenated at room temperature for 90 minutes. The catalyst was filtered off and the filtrate was evaporated. The residue was purified by flash chromatography (heptane/ethyl acetate=1:1) to yield 220 mg (84%) of [1-(2,4-dimethoxy-benzyl)-4,4-dimethyl-2-oxo-azepan-3-yl]-carbamic acid tert-butyl ester as a colourless oil; MS: m/e=407.4 (MH+).