Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH:2][CH:3]([C:20]#[C:21][CH2:22][CH2:23][CH3:24])[CH2:4][S:5]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[CH:25](OC(=O)C)=[O:26]>C1COCC1>[OH:1][N:2]([CH:3]([CH2:4][S:5]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:6])=[O:7])[C:20]#[C:21][CH2:22][CH2:23][CH3:24])[CH:25]=[O:26]
Reactant: CC(=O)OC=O
Reactant: CCCC#CC(CS(=O)(=O)N1CCN(c2ccccn2)CC1)NO
Solvent: C1CCOC1
Product: CCCC#CC(CS(=O)(=O)N1CCN(c2ccccn2)CC1)N(O)C=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 52.6 %

Procedure:
To a solution of 1-{[2-(hydroxyamino)hept-3-yn-1-yl]sulfonyl}-4-pyridin-2-ylpiperazine (157 mg; 0.45 mmol) in THF (5 mL) was added a solution of acetyl formate (200 mg, prepared as described by Kolle et al., 1983, Helvetica Chimica Acta, 66(8), 2760-8) in THF (2 mL). The reaction mixture was stirred at rt for 5 h and concentrated under reduced pressure. Purification of the crude by flash chromatography on silica (EtOAc:c-Hex, gradient from 50:50 to 100:0) gave the title compound as a white foam (90 mg, 53% yield). HPLC, Rt: 3.04 min (purity: 97.9%). LC/MS, M+(ESI): 381.3, M−(ESI): 379.2. 1H NMR (DMSO-d6) δ: 8.39 (brs, 0.4H), 8.18 (m, 1H), 8.08 (brs, 0.6H), 7.48 (m, 1H), 6.66 (m, 2H), 5.53 (brs, 0.4H), 5.01 (brs, 0.6H), 3.63 (m, 5H), 3.36 (m, 6H), 2.14 (m, 2H), 1.49 (sx, J=7.2 Hz, 2H), 0.93 (t, J=7.3 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[Cl:16])=[O:6]
Reactant: Nc1cccc(F)c1C(=O)O
Reactant: Nc1ccccc1Cl
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: Nc1cccc(F)c1C(=O)Nc1ccccc1Cl
Yield: 60.3 %

Procedure:
Prepared according to Procedure A using 2-amino-6-fluorobenzoic acid (2.0 g, 12.9 mmol) and SOCl2 (2.3 mL, 32.2 mmol) in benzene (50 mL), followed by 2-chloroaniline (2.7 mL, 25.8 mmol) and CHCl3 (50 mL). The product was purified by chromatography in EtOAc/hexanes to provide 2.06 g of a pale orange solid (60%). 1H NMR (CDCl3) δ: 9.00 (d, J=17 Hz, 1H); 8.47 (d, J=8.3 Hz, 1H); 7.41 (d, J=8.0 Hz, 1H); 7.30 (t, J=7.9 Hz, 1H); 7.10-7.20 (m, 1H); 7.07 (t, J=7.7 Hz, 1H); 6.49 (d, J=8.3 Hz, 1H); 6.03 (br s, 2H). MS (ES): m/z 265.0 (M+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]C#N)=[CH:6][C:5]([CH2:11][C:12]2[S:13][C:14]3[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([F:23])[C:15]=3[N:16]=2)=[C:4]([CH3:24])[N:3]=1.O.[C:26]([O-:29])(O)=[O:27].[Na+]>Cl>[CH3:1][C:2]1[C:7]([CH2:8][C:26]([OH:29])=[O:27])=[CH:6][C:5]([CH2:11][C:12]2[S:13][C:14]3[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([F:23])[C:15]=3[N:16]=2)=[C:4]([CH3:24])[N:3]=1
Reactant: O=C([O-])O
Reactant: Cc1nc(C)c(Cc2nc3c(F)c(F)cc(F)c3s2)cc1CC#N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1nc(C)c(Cc2nc3c(F)c(F)cc(F)c3s2)cc1CC(=O)O
Reaction time: 8 h
Yield: 75 %

Procedure:
A solution of 2,6-dimethyl-5-(4,5,7-trifluorobenzothiazole-2-yl-methyl)-pyridin-3-yl-acetonitrile (0.50 g, 1.43 mmol) in 50% hydrochloric acid (HCl) (8 ml, 0.2 M) under nitrogen is warmed (90° C. bath) and stirred overnight. The reaction mixture is added to H2O (20 mL) and brought to pH 5 with NaHCO3. The solids are filtered and the aqueous extracted with ethyl acetate (5×30 mL). The solid and extracts are combined and purified by reverse-phase HPLC (acetonitrile/water, 0.05% HCl)to give 2,6-Dimethyl-5-(4,5,7-trifluoro-benzothiazole-2-ylmethyl)-pyridin-3-yl-acetic acid as a white solid (0.40 g, 75%): mp 211° C. dec 1H NMR (DMSO-d6, 300 MHz) δ 8.29 (s, 1 H), 7.85-7.74 (m, 1 H), 4.80 (s, 2 H), 3.86 (s, 2 H), 2.73 (s, 3 H), 2.67 (s, 3 H), ESI-LCMS m/z calcd for C17H13F3N2O2S: 366.1; found 367.0 (M+1)+. Anal. Calcd for C17H14ClF3N2O2S: C, 50.69; H, 3.50; N, 6.95; Cl, 8.80; S; 7.96. Found: C, 50.48; H, 3.63; N, 6.89; Cl, 8.97; S, 7.84.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:26])C=1>ClCCl.CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:10]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[O:26])=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)Nc1ncc(Sc2ccc(N)cc2)s1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)Nc1ncc(S(=O)c2ccc(N)cc2)s1
Yield: 71.4 %

Procedure:
To a solution of 2-acetylamino-5-(4-aminophenylthio)thiazole (6.6 g) in a mixture of dichloromethane (300 ml) and N,N-dimethylformamide (50 ml) was dropwise added the solution of 3-chloroperbenzoic acid (5.9 g) in dichloromethane (100 ml) at 5° C. with stirring. The mixture was stirred at 5° C. for 2 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was poured into 10% aqueous sodium bicarbonate. The solution was extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1), washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give 2-acetylamino-5-(4-aminophenylsulfinyl)thiazole (5.0 g, yield: 71.1%). mp: 194°-196° C. (dec.)
Reaction SMILES: O=[C:2]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[C:15]([O:17]C)=O.[N+]([O-])(O)=O.[NH2:23][C:24]([NH2:26])=[NH:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(O)(=O)C>[NH2:26][C:24]1[N:23]=[C:15]([OH:17])[C:3]2[CH2:4][CH2:5][CH2:6][CH:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:8][C:2]=2[N:25]=1
Reactant: COC(=O)C1CCCC(c2ccccc2)CC1=O
Reactant: N=C(N)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Solvent: O
Product: Nc1nc(O)c2c(n1)CC(c1ccccc1)CCC2
Temperature: 25 °C

Procedure:
A mixture of Example 11A (1.86 g, 7.55 mmol), guanidine nitrate (1.84 g, 15.1 mmol), and potassium carbonate (2.09 g, 15.1 mmol) was heated in N,N-dimethylformamide (7.5 mL) at 120° C. overnight. After this time, the mixture was cooled to room temperature and poured into water. The liquid was adjusted to pH 5 with acetic acid, then the precipitate was collected by filtration, washed with water, and air-dried. It was further dried by azeotroping with toluene to yield the title compound. 1H NMR (300 MHz, DMSO-d6) δ 10.73 (m, 1H), 7.26 (m, 5H), 6.26 (s, 2H), 3.10 (s, 1H), 3.00 (dd, J=14.67, 6.35 Hz, 1H), 2.60 (t, J=13.68 Hz, 1H), 2.39 (d, J=13.48 Hz, 1H), 2.10 (m, 1H), 1.88 (m, 3H), 1.22 (m, 1H); MS (DCI+) m/z 256 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([N:40]1[CH2:39][CH2:38][N:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH3:29])[CH:32]=2)[CH2:42][CH2:41]1)=[O:16]
Reactant: Nc1onc(-c2ccccc2Cl)c1C(=O)O
Reactant: COc1cccc(N2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1cccc(N2CCN(C(=O)c3c(-c4ccccc4Cl)noc3N)CC2)c1
Yield: 67.9 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(2-chlorophenyl)isoxazol-4-carboxylic acid (440 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (516 mg, 1.25 mmol, 68%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:10][CH2:11][C:12]([O:14]CC)=[O:13])=[N:4][CH:5]=[N:6][C:7]=1[CH2:8][CH3:9].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O>[Cl:1][C:2]1[C:3]([O:10][CH2:11][C:12]([OH:14])=[O:13])=[N:4][CH:5]=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCOC(=O)COc1ncnc(CC)c1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1ncnc(OCC(=O)O)c1Cl
Temperature: 25 °C
Yield: 60.8 %

Procedure:
Ethyl 2-(5-chloro-6-ethylpyrimidin-4-yloxy)acetate (2.6 g) was dissolved in ethanol (50 ml). A solution containing sodium hydroxide (0.7 g) dissolved in water (10 ml) was added thereto in a dropwise manner, and subsequently the mixture was stirred for an hour at room temperature. After completion of the reaction, water was added to the reaction liquid. Subsequently, the reaction liquid was acidified using citric acid. The organic layer was extracted with ethyl acetate and then was dried over anhydrous magnesium sulfate. The ethyl acetate was removed under reduced pressure. The obtained crystals were washed with hexane to give 1.4 g of the desired product having a melting point of 158° C. to 159° C.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]([C:19]([O:21][CH3:22])=[O:20])=[C:11]([CH2:23][CH2:24][CH3:25])[N:10]=1)C1C=CC=CC=1.C1COCC1.[H][H]>[C].[Pd].C(O)C>[OH:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]([C:19]([O:21][CH3:22])=[O:20])=[C:11]([CH2:23][CH2:24][CH3:25])[N:10]=1
Reactant: CCCc1nc(OCc2ccccc2)c(C(=O)OC)cc1C(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCc1nc(O)c(C(=O)OC)cc1C(=O)OC
Yield: 89.2 %

Procedure:
A mixture of dimethyl 2-(benzyloxy)-6-propylpyridine-3,5-dicarboxylate (53.8 g), 10% palladium carbon (containing 55% water, 20 g), THF (50 mL), and ethanol (50 mL) was stirred at room temperature for 1 hour in a hydrogen atmosphere. The catalyst was filtered off, and then, the obtained filtrate was concentrated under reduced pressure. The obtained solid was washed with diethyl ether to obtain the title compound (35.4 g).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[CH2:22][CH:21]([CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:26][CH2:25]3)[C:19](=[O:20])[C:14]2=[CH:15][C:16]=1[O:17][CH3:18]>C(OCC)(=O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[CH2:22][CH:21]([CH2:23][CH:24]3[CH2:25][CH2:26][N:27]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:28][CH2:29]3)[C:19](=[O:20])[C:14]2=[CH:15][C:16]=1[O:17][CH3:18].[C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5]
Reactant: O=C(O)/C=C\C(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCOC(C)=O
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 25 °C

Procedure:
Maleic acid (1.161 g, dissolved in 35 ml of acetone) is slowly added to a solution of Donepezil (3.79 g) in ethyl acetate (70 ml) with stirring at room temperature. The mixture is stirred for 3 hours at room temperature and concentrated at vacuum to give the title compound.
Reaction SMILES: C1(C#C)C=CC=CC=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11].[Si]([O:22][CH2:23][CH2:24][O:25][CH2:26][N:27]1[C:35](I)=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]1=[O:29])(C(C)(C)C)(C)C>>[OH:22][CH2:23][CH2:24][O:25][CH2:26][N:27]1[C:35]([C:14]#[C:13][Si:10]([CH3:12])([CH3:11])[CH3:9])=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]1=[O:29]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1c(I)n(COCCO[Si](C)(C)C(C)(C)C)c(=O)[nH]c1=O
Solvent: C#Cc1ccccc1
Product: Cc1c(C#C[Si](C)(C)C)n(COCCO)c(=O)[nH]c1=O

Procedure:
In place of phenylacetylene in Example 38 (2), 0.82 ml (6 mmol) of trimethylsilylacetylene was used to react with 880 mg (2 mmol) of 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-6-iodothymine for producing 1-[(2-hydroxyethoxy)methyl]-6-(2-trimethylsilylethynyl)thymine in the same manner as Example 38 (2). The obtained compound was dissolved in 100ml of methanol, was added to 1 ml of 1N sodium hydroxide aqueous solution and allowed to react for two minutes at room temperature. Then the reaction solution was neutralized with hydrochloric acid and concentrated. The resultant was distributed between ethyl acetate and aqueous layers, and the ethyl acetate layer then concentrated to dryness. The residue was crystallized from toluene/ethanol to obtain 170 mg of the target compound (Yield: 38%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[S:22][CH:23]=2)[N:3]=1.C1CCN2C(=NCCC2)CC1.I[CH2:43][CH2:44][CH2:45][OH:46].O>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:14]=[CH:13][N:12]([CH2:43][CH2:44][CH2:45][OH:46])[N:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[S:22][CH:23]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cc[nH]n1
Reactant: OCCCI
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccn(CCCO)n1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
50 mg (0.092 mmol) of the compound from Example 5 were dissolved in 0.8 ml of DMF, 15 mg (0.101 mmol) of DBU and 21 mg (0.111 mmol) of 3-iodopropanol were added and the mixture was stirred at 120° C. overnight. A little water and ethyl acetate were added to the mixture, and the two phases formed were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were concentrated on a rotary evaporator and the residue was purified by thick-layer chromatography (toluene:acetonitrile=3:1).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.Br[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18]>C(O)C>[CH2:15]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1)[CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CCBr
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CCOc1ccc(CC(=O)O)cc1
Temperature: 25 °C

Procedure:
Aqueous sodium hydroxide solution (2.0 M; 32.9 mL, 65.8 mmol) was added in one portion to a stirred solution of p-hydroxyphenylacetic acid (5.00 g, 32.9 mmol) in ethanol (200 mL) at room temperature. After stirring for 15 min 1-bromo-3-methylbutane (4.97 g, 3.94 mL, 32.9 mmol) was added in one portion and the resulting solution heated at reflux for 12 h. The reaction was cooled to room temperature then evaporated to dryness. The residue was partitioned between dichloromethane (150 mL) and aqueous hydrochloric acid solution (1.0 M; 150 mL). The layers were separated and the aqueous phase was washed with dichloromethane (2×100 mL). The organic extracts were combined, dried (magnesium sulfate) and evaporated to dryness. The resulting white solid residue was used without purification in the preparation of R8782/83/1. LC/MS: 3.30 min; z/e 221, calcd (M−1) 221. 1H NMR (400 MHz: CDCl3): 7.25 (2H), 6.95 (2H), 4.05 (2H), 3.65 (2H), 1.95 (1H), 1.75 (2H), 1.05 (6H). The absolute regiochemistry of the product was unambiguously assigned using an HMBC correlation experiment.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21]([OH:23])=O)[NH:3]1.[CH2:24]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:32]([N:31]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21]([C@H:11]1[CH2:10][CH2:9][C@H:8]2[C@H:7]3[C@H:16]([CH2:15][CH2:14][C@:12]12[CH3:13])[C@:17]1([CH3:20])[C:4]([NH:3][C:2](=[O:1])[CH2:19][CH2:18]1)=[CH:5][CH2:6]3)=[O:23])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reactant: c1ccc(CNCc2ccccc2)cc1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)N(Cc1ccccc1)Cc1ccccc1
Yield: 71 %

Procedure:
The title compound was prepared in a yield of 71% in a similar manner to that described in Example 1 by reacting 3-oxo-4-azaandrost-5-ene-17β-carboxylic acid and N,N-dibenzylamine.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[NH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][OH:19].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:16][C:17]([CH2:18][OH:19])([CH3:21])[CH3:20])=[O:5]
Reactant: CC(C)(N)CO
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(CO)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
In a DMF solution containing 0.20 g of Boc-Pro-OH, 0.09 ml of 2-amino-2-methyl-1-propanol, 0.14 g of HOBt and 0.21 g of EDC hydrochloride were added and the resultant mixture was stirred for 14 hrs. The reaction mixture was treated similarly to that in Example 46 to give 80 mg of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:29][CH:30]=C)[C:13]([N:15]([CH2:25][CH2:26][O:27][CH3:28])[C@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:17]=C)=[O:14].CS(C)=O>C1(C)C=CC=CC=1.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[CH3:28][O:27][CH2:26][CH2:25][N:15]1[C@H:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:17]=[CH:30][CH2:29][CH:12]([N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[C:13]1=[O:14]
Reactant: C=CCC(C(=O)N(CCOC)[C@@H](C=C)c1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: COCCN1C(=O)C(N2C(=O)c3ccccc3C2=O)CC=C[C@H]1c1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-(2-methoxyethyl)-N-[(1S)-1-phenylprop-2-en-1-yl]pent-4-enamide (6b) (524 mg) dissolved in Toluene (50 mL) at 80° C. under N2 was added Grubbs catalyst (2nd generation) (53 mg) and the reaction mixture was stirred at 80° C. for 1 h, then cooled to RT. DMSO (0.2 mL) was added to the reaction and the mixture stirred for 1 h, then concentrated. The crude product was directly purified via flash chromatography (gradient—5%, 10%, 20%, 30% EtOAc/hexanes) to give a diastereomeric mixture (1:1) of the title compound. (426 mg, 87%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:26]([C:35]4[CH:39]=[CH:38][O:37][N:36]=4)C(OCC(Cl)(Cl)Cl)=O)[O:22][C:21]3=[O:40])=[CH:16][C:15]=2[F:41])[CH2:10]1)=[O:7]>C(O)(=O)C.O.[Zn]>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:35]4[CH:39]=[CH:38][O:37][N:36]=4)[O:22][C:21]3=[O:40])=[CH:16][C:15]=2[F:41])[CH2:10]1)=[O:7]
Reactant: COCCOC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c4ccon4)OC3=O)cc2F)C1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: COCCOC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
3-(4-(3(S)-(2-Methoxyethoxycarbonylamino)pyrrolidin-1-yl)-3-fluorophenyl)-5(R)-(N-(2,2,2-trichloroethyloxycarbonyl)isoxazol-3-ylaminomethyl)oxazolidin-2-one (400 mg, 0.5 mM) was stirred in a mixture of acetic acid (10 ml) and water (2 ml). Zinc dust (203 mg, 3.1 mM) was added, and the mixture stirred 30 minutes at ambient temperature. The mixture was filtered through celite, and the residue after evaporation partitioned between ethyl acetate (10 ml) and aqueous sodium bicarbonate (15 ml). The organic phase was washed with sodium bicarbonate (2×15 ml), water (15 ml), dried (magnesium sulfate), and evaporated. The crude product was purified by chromatography on a 10 g Biotage silica column, eluting with a gradient from dichloromethane to ethyl acetate. Relevant fractions were combined to give the desired product (141 mg ). NMR (DMSO-d6) δ: 1.83 (hextet, 1H); 2.09 (hextet, 1H); 3.13 (m, 1H); 3.26 (s, 3H); 3.40, 3.47 (t overlapping m, 7H); 3.73 (dd, 1H); 4.04 (overlapping m, 4H); 4.82 (m, 1H); 6.01 (d, 1H); 6.52 (t, 1H); 6.72 (t, 1H); 7.08 (dd, 1H); 7.39 (dd, 1H); 7.52 (d, 1H); 8.37 (d, 1H). MS (ESP): 464 (MH+) for C21H26FN5O6
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH:13]C(OC(C)(C)C)=O)=[CH:8][CH:9]=1)=[O:4].Cl>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(CCCNC(=O)OC(C)(C)C)s1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(CCCN)s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 400.5 %

Procedure:
A solution of 5-(3-tert-butoxycarbonylamino-propyl)-thiophene-2-carboxylic acid methyl ester (0.118 g, 0.5 mmol) in 50 mL MeOH was cooled to 0° C. and was saturated with HCl (g). The reaction was stirred at room temperature for 90 minutes. The solution was concentrated to a solid which was partitioned between EtOAc and saturated NaHCO3. The layers were separated, and the organic solution was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as an oil (399 mg). MS 200 (M+1).
Reaction SMILES: [CH:1]([C:3]1[O:4][C:5](B(O)O)=[CH:6][CH:7]=1)=[O:2].[CH3:11][CH:12]([NH:14][CH2:15][CH2:16][CH2:17][N:18]1[C:27]([S:28][C:29]2[CH:34]=[C:33]3[O:35][CH2:36][O:37][C:32]3=[CH:31][C:30]=2I)=[N:26][C:20]2[C:21]([NH2:25])=[N:22][CH:23]=[N:24][C:19]1=2)[CH3:13].C([O-])(O)=O.[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:25][C:21]1[N:22]=[CH:23][N:24]=[C:19]2[C:20]=1[N:26]=[C:27]([S:28][C:29]1[C:30]([C:5]3[O:4][C:3]([CH:1]=[O:2])=[CH:7][CH:6]=3)=[CH:31][C:32]3[O:37][CH2:36][O:35][C:33]=3[CH:34]=1)[N:18]2[CH2:17][CH2:16][CH2:15][NH:14][CH:12]([CH3:11])[CH3:13]
Reactant: CC(C)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Reactant: O=Cc1ccc(B(O)O)o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NCCCn1c(Sc2cc3c(cc2-c2ccc(C=O)o2)OCO3)nc2c(N)ncnc21
Temperature: 90 °C
Yield: 33.8 %

Procedure:
2-Formyl-5-furanylboronic acid (12.3 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H2O (0.1 mL) and Pd(PPh3)2Cl2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90° C. for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH2Cl2:EtOAc:MeOH—NH3 (7N), 2:2:1:0.5) to give 9.5 mg (34%) of DZ3-33. 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 9.57 (s, 1H), 8.18 (s, 1H), 7.36 (d, J=3.8 Hz, 1H), 7.32 (s, 1H), 7.07 (s, 1H), 6.98 (d, J=3.8 Hz, 1H), 6.12 (s, 2H), 4.32 (t, J=6.7 Hz, 2H), 3.31 (septet, J=6.6 Hz, 1H), 2.93 (t, J=6.8 Hz, 2H), 2.30 (m, 2H), 1.42 (d, J=6.6 Hz, 6H); 13C NMR (125 MHz, CDCl3/MeOH-d4) δ 177.5, 156.8, 154.5, 152.2, 151.9, 151.4, 150.1, 149.7, 148.1, 127.5, 124.3, 119.2, 118.7, 115.7, 112.7, 109.9, 102.9, 51.3, 41.8, 40.4, 26.4, 19.2; HRMS (ESI) m/z [M+H]+ calcd. for C23H25N6O4S, 481.1658; found. 481.1657; HPLC: method A Rt=5.87, method B Rt=5.93.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:17][C@@H:16]([CH3:18])[C@@H:14]([OH:15])[C@H:12]1[OH:13].CC1N=CN=C2C=1N=CN2[C@@H]1O[C@H](CI)[C@@H](O)[C@H]1O.CC(N=NC(C#N)(C)C)(C#N)C.C([SnH](CCCC)CCCC)CCC>O1CCCC1>[CH3:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:17][C@H:16]([CH3:18])[C@@H:14]([OH:15])[C@H:12]1[OH:13]
Reactant: Cc1ncnc2c1ncn2[C@@H]1O[C@@H](C)[C@@H](O)[C@H]1O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Agent: Cc1ncnc2c1ncn2[C@@H]1O[C@H](CI)[C@@H](O)[C@H]1O
Solvent: C1CCOC1
Product: Cc1ncnc2c1ncn2[C@@H]1O[C@H](C)[C@@H](O)[C@H]1O

Procedure:
The reaction is carried out according to the procedure for the preparation of 1f starting from 2b (68 mg, 0.18 mmol), AIBN (26 mg, 0.16 mmol), and tributyltin hydride (176 μl, 0.63 mmol) in tetrahydrofuran (THF) (10 ml). After a 2 h reflux followed by isolation and purification as described in Example 6, pure 2c crystallized from THF in two crops as a white solid.