Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:6])(=[S:5])[CH:2]([CH3:4])[CH3:3].Cl[CH2:8][C:9]([CH2:11]Cl)=O.ClC[C:15]1SC=C[N:19]=1.CN>C1COCC1>[CH:2]([C:1]1[S:5][CH:8]=[C:9]([CH2:11][NH:19][CH3:15])[N:6]=1)([CH3:4])[CH3:3]
Reactant: ClCc1nccs1
Reactant: O=C(CCl)CCl
Reactant: CC(C)C(N)=S
Agent: CN
Solvent: C1CCOC1
Product: CNCc1csc(C(C)C)n1
Reaction time: 1 h

Procedure:
The thioisobutyramide resulting from Example 73A was dissolved in 70 mls THF and added slowly to a solution of (34.1 g, 0.27 mols) 1,3-dichloracetone in 40 mls THF. A 10 ml rinse of THF was used to completely transfer the thioamide. The reaction was carried out in a 250 ml flask with mechanical stirring under nitrogen atmosphere. The reaction temperature was maintained below 25° C. during addition with a 15°±5 C. bath. The bath was kept in place for 1 hour after which it was removed and the reaction stirred for 18 hours. Next this stirred chloromethyl-thiazole solution was added to 376 mls (4.37 mols) 40 % aqueous methylamine solution at 15° C. in a 1 liter flask. The temperature was maintained below 25° C. during addition. After half an hour the bath was removed and the reaction stirred for 3 hours at ambient temperature. The solvent was removed under vacuum with a 50° C. bath to an end volume of 310 mls. The residue was then basified with 50 g 10 % NaOH to pH 12 and extracted into methylene chloride (2×160 mls). The combined organics were then washed with 1×150 g of 20% ammonium chloride followed by 1×90 g of 20% ammonium chloride. The combined aqueous washes were then back extracted with 150 mls methylene chloride. The combined product methylene chloride layers were then extracted with 100 g of a solution of 25 g conc. HCl and 75 g water. This acidic product solution was then washed with 135 mls methylene chloride. Next the acidic product solution was cooled, then neutralized with 100 g 20% NaOH solution. The product was extracted from this mixture with methylene chloride (2×135 mls). The solvent was removed under vacuum to afford the desired product as an amber oil. (yield approx. 28 grams)
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].[CH3:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=[S:21]>>[CH3:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]1[NH:8][C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:21]1
Reactant: CC(C)C[C@H](N)CO
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Product: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](CC(C)C)CS1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with 1-bromo-2-ethylbutane according to Method D2a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-3-(2-ethyl-1-butyl)-1,3-thiazolidine HCl salt.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=O.[CH3:12][N:13]1[C:17]([C@@H:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[N:16][C:15]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][N:28]=[C:27]3[C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)=[N:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl.O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH2:4][N:20]1[CH2:21][CH2:22][CH2:23][C@@H:18]([C:17]2[N:13]([CH3:12])[N:14]=[C:15]([C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[NH:29][N:28]=[C:27]4[C:33]3[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=3)[N:16]=2)[CH2:19]1
Reactant: COc1cccc(F)c1C=O
Reactant: Cn1nc(-c2ccc3[nH]nc(-c4ccncc4)c3c2)nc1[C@@H]1CCCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COc1cccc(F)c1CN1CCC[C@@H](c2nc(-c3ccc4[nH]nc(-c5ccncc5)c4c3)nn2C)C1
Reaction time: 2 h
Yield: 63.6 %

Procedure:
Added 2-Fluoro-6-methoxy benzaldehyde (20 mg, 0.129 mmol) to a solution of (R)-5-(1-methyl-5-(piperidin-3-yl)-1H-1,2,4-triazol-3-yl)-3-(pyridin-4-yl)-1H-indazole (15 mg, 0.0379 mmol) and sodium triacetoxyborohydride (25 mg, 0.118 mmol) in MeOH (4 ml) at room temperature, then stirred for 2 hours. Reaction was diluted with CH2Cl2 (50 ml) and H2O (25 ml), organic layer was separated, dried over Na2SO4, filtered and solvent evaporated. The residue was chromatographed on silica gel eluting with 5% v/v MeOH/CH2Cl2/NH4OH to yield (R)-5-(5-(1-(2-fluoro-6-methoxybenzyl)piperidin-3-yl)-1-methyl-1H-1,2,4-triazol-3-yl)-3-(pyridin-4-yl)-1H-indazole as a white solid (12 mg).
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:12]=[C:11]([CH2:13][CH:14]=O)[CH:10]=[CH:9][C:6]=2[C:7]#[N:8])[CH2:3][CH2:2]1.[N:16]1([CH2:22][CH2:23][C:24]2[CH:33]=[CH:32][C:27]3[C:28](=[O:31])[O:29][CH2:30][C:26]=3[CH:25]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH:1]1([O:4][C:5]2[CH:12]=[C:11]([CH2:13][CH2:14][N:19]3[CH2:20][CH2:21][N:16]([CH2:22][CH2:23][C:24]4[CH:33]=[CH:32][C:27]5[C:28](=[O:31])[O:29][CH2:30][C:26]=5[CH:25]=4)[CH2:17][CH2:18]3)[CH:10]=[CH:9][C:6]=2[C:7]#[N:8])[CH2:2][CH2:3]1
Reactant: N#Cc1ccc(CC=O)cc1OC1CC1
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc(CCN2CCN(CCc3ccc4c(c3)COC4=O)CC2)cc1OC1CC1

Procedure:
A solution of crude 2-(cyclopropyloxy)-4-(2-oxoethyl)benzonitrile (80 mg, 0.4 mmol), 5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one (150 mg, 0.6 mmol) and NaBH(OAc)3 (400 mg, 2 mmol) in 10 mL of anhydrous DCM was stirred at ambient temperature overnight. The reaction mixture was added 50 mL of DCM and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified with prep-TLC to afford 2-(cyclopropyloxy)-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H-NMR (400 MHz, CDCl3) δ ppm 7.77 (d, J=7.8 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.27 (s, 1H), 7.11 (s, 1H), 6.78˜6.80 (m, 1H), 5.22 (s, 2H), 2.42˜2.93 (m, 17H), 0.77˜0.80 (m, 4H). (0.28 μM)
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][C@H:16]([CH2:20]OS(C4C=CC(C)=CC=4)(=O)=O)[O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][NH2:33].[OH-].[Na+]>>[C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][C@H:16]([CH2:20][NH:33][CH3:32])[O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccc(S(=O)(=O)c4ccccc4)cc3O2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CNC[C@H]1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Temperature: 100 °C

Procedure:
A solution of toluene-4-sulfonic acid (R)-7-benzenesulfonyl-chroman-2-ylmethyl ester (274 mg, 0.6 mmol) and MeNH2 (2M in THF, 5 mL) was heated at 100° C. under microwave conditions for 6 hours. MeNH2 (40% in water, 2 mL) was then added and the mixture was heated at 100° C. under microwave conditions overnight. NaOH (10%) was added and the mixture was extracted 3 times with DCM. The combined organic extracts were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography to afford the desired product (172 mg). The product was recrystallized from DCM affording 8 mg ((R)-7-benzenesulfonyl-chroman-2-ylmethyl)-methyl-amine with 79% ee and from the evaporation of the mother liquors were recovered an additional 164 mg. Recrystallation from ethanolic HCl yielded the corresponding hydrochloride salt, Mp 271.8-273.0° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:37])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:17][CH:16]2[C:34]([OH:36])=O)[CH:12]=[CH:13][CH:14]=1.[C:38]([NH:41][CH2:42][CH2:43][NH2:44])(=[O:40])[CH3:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:38]([NH:41][CH2:42][CH2:43][NH:44][C:34]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:37])[C:19]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:31])[CH3:32])[NH:17]1)=[O:36])(=[O:40])[CH3:39]
Reactant: CC(=O)NCCN
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NCCNC(=O)C1NC(CC(C)(C)C)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1F
Yield: 83.3 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 26c (0.3 g, 0.54 mmol) was reacted with N-acetylethylenediamine (Aldrich) (0.15 g, 1.5 mmol), HATU (0.3 g, 0.75 mmol) and iPr2NEt (0.6 g, 4.8 mmol) in CH2Cl2 (20 mL) at room temperature for 24 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-acetylamino-ethyl)-amide as a white solid (0.24 g, 83%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)=[CH:12][CH:11]=[CH:10][C:4]=2[NH:5][S:6](=[O:9])(=[O:8])[N:7]=1.[ClH:29]>O1CCOCC1>[Cl-:29].[NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH3+:21])=[CH:12][CH:11]=[CH:10][C:4]=2[NH:5][S:6](=[O:9])(=[O:8])[N:7]=1
Reactant: Cl
Reactant: CC(C)(C)OC(=O)NCCCCCCOc1cccc2c1C(N)=NS(=O)(=O)N2
Solvent: C1COCCO1
Product: NC1=NS(=O)(=O)Nc2cccc(OCCCCCC[NH3+])c21
Product: [Cl-]
Temperature: 25 °C
Yield: 62.9 %

Procedure:
To a solution of tert-butyl 6-(4-amino-2,2-dioxo-1H-benzo[c][1,2,6]thiadiazin-5-yloxy)hexylcarbamate (118 mg, 286 μmol) (Example 281) in dioxane (2 mL) was added con. HCl (1 mL) and the solution stirred at room temperature for 15 minutes. The solvents were removed in vacuo and the residue triturated with hot ethanol. After cooling to room temperature, the precipitated was collected, washed with hot ethanol, and dried in vacuo to give the desired product 56 mg (62.9%) as an off-white powder. 1H NMR (400 MHz, DMSO-d6) δ 1.367 (m, 4H), 1.529 (pentet, J=7 Hz, 2H), 1.795 (pentet, J=7 Hz, 2H), 2.741 (br m, 2H), 4.144 (t, J=7 Hz, 2H), 6.596 (d, J=8 Hz, 1H), 6.733 (d, J=8 Hz, 1H), 7.440 (t, J=8 Hz, 1H), 7.725 (br. s, 3H), 7.795 (br. s, 1H), 8.350 (br. s, 1H), 10.954 (s, 1H). MS 313 (MH+).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:10]=3[N:9]=2)=[CH:6][C:5]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[N:4][NH:3]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH2:57]([N:59]([CH2:62][CH2:63][NH2:64])[CH2:60][CH3:61])[CH3:58]>O.CN(C)C=O>[CH2:57]([N:59]([CH2:60][CH3:61])[CH2:62][CH2:63][NH:64][C:17]([C:15]1[CH:14]=[CH:13][C:11]2[NH:12][C:8]([C:7]3[C:2](=[O:1])[NH:3][N:4]=[C:5]([C:20]4[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=4)[CH:6]=3)=[N:9][C:10]=2[CH:16]=1)=[O:19])[CH3:58]
Reactant: CCN(CC)CCN
Reactant: O=C(O)c1ccc2[nH]c(-c3cc(-c4ccncc4)n[nH]c3=O)nc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCNC(=O)c1ccc2[nH]c(-c3cc(-c4ccncc4)n[nH]c3=O)nc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture consisting of 50 mg of 2-(3-oxo-6-pyridin-4-yl-2,3-dihydropyridazin-4-yl)-1H-benzoimidazole-5-carboxylic acid, 0.065 ml of triethylamine and 1.5 ml of dimethylformamide (DMF) is stirred at room temperature for 10 minutes, mixed with 68.4 mg of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (Hatu) and stirred at room temperature for a further 30 minutes. Then 21 mg of diethylaminoethylamine are added, and the mixture is stirred at 50° C. for 3 hours. After cooling, it is diluted with 5 ml of water, and the precipitate is filtered off with suction and stirred with isopropanol at 60° C., filtered off with suction and dried in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].[CH2:19]([O:21][C:22](=[O:25])[CH2:23]Br)[CH3:20].C(O)C>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[O:10][CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:25]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(C=O)cc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)=O
Product: CCOC(=O)COc1c(F)cc(C=O)cc1OC
Yield: 78.3 %

Procedure:
The compound was prepared according to general procedure E with 3-fluoro-4-hydroxy-5-methoxybenzaldehyde (1.8 mmol) in dry acetone (20 ml), anhydrous K2CO3 (2.4 mmol), and ethylbromoacetate (2.7 mmol) at reflux for 1 h. Ethanol was added and evaporated by azeotropic distillation with ethylbromoacetate. 395 mg of crude product were obtained and purified by silica gel chromatography (eluent dichloromethane). 361 mg of purified compound were obtained (79% yield). 1H NMR (500 MHz, CD3COCD3): δ 1.25 (t, J=, 3H), 3.98 (s, 3H), 4.21 (q, J=, 2H), 4.89 (s, 2H), 7.34 (dd, J=10.3 and 1.6 Hz, 1H), 7.40 (t, J=1.6 Hz, 1H), 9.88 (d, J=1.6 Hz, 1H) 13C NMR (126 MHz, CD3COCD3): δ 15.0, 57.6, 62.1, 70.3, 110.0, 111.8 (d, J=20.6 Hz), 133.1 (d, J=7.2 Hz), 141.8 (d, J=12.7 Hz), 154.5 (d, J=4.5 Hz), 156.0 (d, J=246 Hz), 169.7, 191.3. MS (ESI): m/z 256.9 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]([O:13]C)=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.CO.[OH-].[K+].Cl>C1COCC1.O>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COC(=O)c1ccc2nc(C)oc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1nc2ccc(C(=O)O)cc2o1
Temperature: 25 °C
Reaction time: 1.08 h
Yield: 110.2 %

Procedure:
A solution of compound 138 (920 mg, 4.815 mmol) in THF:MeOH (30 mL of a 1:1 solution) was treated with a solution of potassium hydroxide (0.698 g, 17.86 mmol) in H2O (15 mL). The reaction mixture was stirred for 65 min at room temperature then quenched with 1N HCl (18 mL, 18.6 mmol) (final pH of 2.5), THF was removed under reduced pressure and the remaining aqueous solution was cooled to −78° C. and lyophilized to give compound 139 (940 mg, quantitative).
Reaction SMILES: [CH:1]1([N:4]2[CH:8]=[CH:7][CH:6]=[C:5]2[CH:9]=O)[CH2:3][CH2:2]1.[C:11]([O:20][CH2:21][CH3:22])(=O)[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl.CC([O-])=[O:26].[K+]>CCO.C(OC(=O)C)(=O)C>[C:21]([O:20][C:11]1[CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=[C:5]2[C:6]=1[CH:7]=[CH:8][N:4]2[CH:1]1[CH2:2][CH2:3]1)(=[O:26])[CH3:22]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: O=Cc1cccn1C1CC1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc(OC(C)=O)c2ccn(C3CC3)c2c1
Temperature: 25 °C

Procedure:
Na (14.6 g) was added portion wise to EtOH (400 ml) with stirring at room temperature. To the mixture was added a solution of 1-cyclopropyl-1H-pyrrole-2-carbaldehyde (38.9 g) and diethyl succinate (48.2 ml) in EtOH (100 ml) at 50° C., then the mixture was refluxed overnight. 140 ml of aqueous 5N HCl was added to the mixture at 0° C. and EtOH was evaporated. The residue was extracted with CHCl3, the organic layer was dried over Na2SO4 and concentrated to give red oil. The material was dissolved in 400 ml of acetic anhydride and KOAc (47.4 g) was added thereto. The mixture was refluxed for 30 min. and allowed to cool to room temperature. The mixture was filtrated and the filtrate was concentrated. The residue was purified by silicagel column chromatography (hexane/EtOAc) to give intended compound a red oil.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][NH:8][C:7](=[O:11])[C:6]1=[O:12])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18]>CN(C=O)C>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([O:19][CH3:20])=[O:18])[C:7](=[O:11])[C:6]1=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: CCCCN1CCNC(=O)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN1CCN(C(C(=O)OC)c2ccccc2)C(=O)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
To a solution of 1-butylpiperazine-2,3-dione (1.6 g, 9.1 mmol) in DMF (12 ml) at 0° C. was added sodium hydride (0.25 g, 10.4 mmol). After stirring for 20 min, methyl α-bromophenylacetate (1.6 ml, 10.0 mmol) was added to the reaction. The reaction was warmed to rt and allowed to stir for 18 h. The reaction was quenched with water, diluted with EtOAc, washed with 3M LiCl, water, and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified via flash chromatography (silica) to yield methyl (4-butyl-2,3-dioxopiperazin-1-yl)(phenyl)acetate (86%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[H][H]>C(O)C.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1ccc(O)cc1-c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(O)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution (E)-ethyl 3-(5-hydroxy-[1,1′-biphenyl]-2-yl)acrylate (652) (420 mg, 1.57 mmol) in ethanol (6 mL) was added Pd/C (42 mg, 10% Degussa type). A balloon of hydrogen gas was added and the reaction was evacuated and back-filled with hydrogen three times. The reaction was stirred overnight at room temperature, was filtered through a pad of celite and concentrated in vacuo to give ethyl 3-(5-hydroxy-[1,1′-biphenyl]-2-yl)propanoate (653).
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[Na+].[Na+].[C:7]([N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])(OCC)=O>O>[C:13]1(=[O:22])[N:12]([C@@H:7]([CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[C:1]([OH:2])=[O:4])[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (+)-L-ε-hydroxynorleucine [prepared according to the procedure of Bodanszky et al., J. Med Chem., 1978, 21, 1030-1035] (1,030 g., 7.0 mmol. ) and sodium carbonate (745 mg., 7.0 mmol. ) in water (12 ml. ) was treated with N-carbethoxyphthalimide (1.495 g., 7.0 mmol.) and the mixture was stirred at room temperature for 2 hours. The solution was filtered, cooled to 0° C., and acidified with 6N hydrochloric acid to afford a white precipitate. The solid was collected by filtration and dried in vacuo at 80° C. for one hour to give 1.297 g. of the title compound; m.p. 162°-163° C.; [α]D =-35.7° (c=1.3, methanol).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH3:9].[CH3:10][S:11][C:12]1[CH:13]=[CH:14][C:15]([OH:21])=[C:16]([CH:20]=1)[C:17]([OH:19])=[O:18].[CH3:22][C:23](=O)CC>>[CH3:10][S:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:8][CH3:9])=[C:16]([CH:20]=1)[C:17]([O:19][CH2:22][CH3:23])=[O:18]
Reactant: CCI
Reactant: CSc1ccc(O)c(C(=O)O)c1
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cc(SC)ccc1OCC
Temperature: 80 °C
Yield: 85 %

Procedure:
Potassium carbonate (22.0 g, 159 mmol) and iodoethane (9.0 mL, 112 mmol) were added to a stirred solution of 5-methylthio-2-hydroxy-benzoic acid (5.00 g, 27 mmol) in 2-butanone (125 mL). The resulting mixture was heated in an oil bath (80° C.) for 16 h and then allowed to cool. The solution was concentrated and redissolved in methylene chloride. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 5-15% ethyl acetate in hexanes) gave ethyl 5-methylthio-2-ethoxybenzoate as a yellow oil (5.5 g, 85%).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:11]1[CH:15]=[CH:14][N:13]=[N:12]1.CN[C@@H]1CCCC[C@H]1NC>CN(C=O)C.CCOC(C)=O.[Cu]I>[N:11]1[N:12]([C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[N:13]=[CH:14][CH:15]=1
Reactant: c1c[nH]nn1
Reactant: O=C(O)c1ccccc1I
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1-n1nccn1
Temperature: 120 °C

Procedure:
A solution of 2-iodobenzoic acid (3.0 g, 12.09 mmol) in DMF was treated with (1.5 g, 21.7 mmol) 1,2,3-triazole, 7.08 g (21.7 mmol) CsCO3, 114 mg (0.60 mmol) CuI and 310 mg (2.17 mmol) trans-N,N′-dimethylcyclohexane-1,2-diamine. The mixture was heated at 120° C. for 10 min in a microwave reactor. The reaction was cooled to rt, diluted with EtOAc, and filtered through Celite. The residue was purified by gradient elution on SiO2 (0 to 10% MeOH in DCM with 0.1% AcOH) to give the faster eluting desired 2-(2H-1,2,3-triazol-2-yl)benzoyl acid, B-1. Data for B-1: 1HNMR (500 MHz, DMSO-d6) δ 13.05 (br s, 1H), 8.12 (s, 2H), 7.81-7.52 (m, 4H) ppm. The undesired 2-(1H-1,2,3-triazol-2-yl)benzoic acid (B-2) eluted second.
Reaction SMILES: C([N:11]1[CH2:29][CH2:28][CH2:27][C@H:12]1[C:13]([NH:15][C:16]([C:24]([OH:26])=[O:25])=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])(OCC1C=CC=CC=1)=O.CCOCC.[BrH:35].CC(O)=O>>[BrH:35].[NH:11]1[CH2:29][CH2:28][CH2:27][C@H:12]1[C:13]([NH:15][C:16]([C:24]([OH:26])=[O:25])=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14]
Reactant: O=C(O)C(=Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C(O)C(=Cc1ccccc1)NC(=O)[C@@H]1CCCN1
Yield: 74 %

Procedure:
A solution of 0.5 g (0.00125 mole) of N-carbobenzoxy-L-prolyl-dehydrophenylalanine in 3 ml of 32% HBr/HOAc was treated as N-carbobenzoxy-L-prolyl-dehydrohpenylalanine azlactone was treated in Example 7(a) except that the ether precipitated product was allowed to stand two days at room temperature before filtration and crystallization from methanol/ethyl acetate to yield 0.313 g (74%) of L-prolyldehydrophenylalanine hydrobromide, m.p. 227°-228.5° (dec.), RfA 0.45.
Reaction SMILES: [CH2:1]([O:3][N:4]=[CH:5][C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([Cl:13])=[CH:8][C:7]=1[Cl:14])[CH3:2].[O:15]=[C:16](Cl)OC(Cl)(Cl)Cl>>[CH2:1]([O:3][N:4]=[CH:5][C:6]1[CH:11]=[C:10]([N:12]=[C:16]=[O:15])[C:9]([Cl:13])=[CH:8][C:7]=1[Cl:14])[CH3:2]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCON=Cc1cc(N)c(Cl)cc1Cl
Product: CCON=Cc1cc(N=C=O)c(Cl)cc1Cl

Procedure:
65.3 g (0.28 mol) of 5-amino-2,4-dichlorobenzaldehyde (O-ethyl)-oxime (obtainable by the process given for precursors 28.1-28.3) and 60.9 g (0.31 mol) of diphosgene were reacted in the manner described for precursor 3.1. Yield: 72.9 g.
Reaction SMILES: [K].[N+:2]([C:5]1[CH:6]=[C:7]([OH:13])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)([O-:4])=[O:3].Cl[CH2:15][C:16](=[O:18])C.[CH3:19]N(C=O)C>O>[CH3:19][O:13][C:7]1[CH:6]=[C:5]([N+:2]([O-:4])=[O:3])[CH:10]=[CH:9][C:8]=1[O:11][CH2:12][C:16](=[O:18])[CH3:15]
Reactant: CC(=O)CCl
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: CN(C)C=O
Agent: [K]
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1OCC(C)=O
Temperature: 80 °C

Procedure:
A mixture of the potassium salt of 4-nitroguaiacol (2.00 g, 9.65 mmol) and chloroacetone (1.15 mL, 14.5 mmol) in 20 mL of DMF was heated at 80° C. for 3 h. The suspension was cooled to rt and diluted with water. A precipitate formed which was filtered, washed with water and dried under vacuum to afford the title compound (1.63 g) as an off-white solid. 1H NMR (CDCl3) δ 2.29 (s, 3H), 3.96 (s, 3H), 4.71 (s, 2H), 6.74 (d, J=8.80 Hz, 1H), 7.76 (d, J=2.20 Hz, 1H), 7.84 (dd, J=8.79 Hz, 2.20 Hz, 1H); 13C NMR (CDCl3) δ 26.37, 56.33, 73.62, 107.11, 111.88, 117.36, 142.33, 149.23, 152.49, 203.40; HPLC (Method #1): 1.98 min, (100%); LCMS (ES): m/z 226 [M+H]+.