Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][C:13]=2[F:20])(=[O:11])=[O:10])[CH:5]=[N:6][CH:7]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[F:20])(=[O:10])=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cncc(Br)c2)c(F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=S(=O)(Nc1cncc(Br)c1)c1ccc(O)cc1F
Reaction time: 8 h
Yield: 62.1 %

Procedure:
N-(5-Bromopyridin-3-yl)-2-fluoro-4-methoxybenzenesulfonamide (692 mg, 1.92 mmol) was dissolved in DCM (10 ml), the reaction flask was sealed and boron tribromide (5 ml, 1M solution in DCM) was added dropwise under an argon atmosphere. After stirring overnight at reflux, more boron tribromide was added (5 ml) and the mixture was refluxed for 18 h. After cooling in an ice bath, methanol was added dropwise and evaporated under reduced pressure. The mixture was poured into ice and extracted with ethyl acetate. The resulting organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by flash chromatography (0% to 5% DCM/MeOH) to give 414 mg (62% yield) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]([NH:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)[CH:9]=[C:8]([Cl:19])[CH:7]=1)=[O:4].C(O)(=O)C.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]=O.C([BH3-])#N.[Na+].Cl>C(OC)(OC)OC.O>[Cl:19][C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:37][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=2)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)[CH:9]=1
Reactant: O=Cc1ccccn1
Reactant: Cc1cc(-c2cc(Cl)cc(NC(=O)[C@@H](N)Cc3ccccc3)c2)ccn1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: COC(OC)OC
Product: Cc1cc(-c2cc(Cl)cc(NC(=O)[C@H](Cc3ccccc3)NCc3ccccn3)c2)ccn1
Yield: 75.5 %

Procedure:
(2S)-2-amino-N-(3-chloro-5-(2-methylpyridin-4-yl)phenyl)-3-phenylpropanamide (32 mg, 87 μmol) was dissolved in trimethyl thoformate (1 ml) and acetic acid (0.25 ml, 4367 μmol). To this was added picolinaldehyde (94 mg, 875 mmol). After 30 min sodium cyanoborohydride (82 mg, 1312 μmol) dissolved in trimethyl orthoformate (1 ml). After 1 h the reaction mixture was poured onto 1N HCl and water was added, the mixture was concentrated under reduced pressure. The resulting crude solid was dissolved in AcOH/DMSO and purified on Phenomenex Geminni C18 HPLC 50 mm×250 mm running ACN/Water/0.1% TFA in a linear gradient. The fractions containing the desired product were combined and concentrated to afford (2S)—N-(3-chloro-5-(2-methylpyridin-4-yl)phenyl)-3-phenyl-2-(pyridin-2-ylmethylamino)propanamide (46) (30 mg, 75% yield). MS ESI (pos.) m/e: 457.1 (M+H). 1H NMR (500 MHz) (CDCl3) δ 10.13 (1H, s), 8.68 (1H, d, J=6.1 Hz), 8.50 (1H, d, J=5.4 Hz), 7.99 (1H, dt, J=1.2, 9.0 Hz), 7.88 (1H, s), 7.72-7.77 (3H, m), 7.47-7.53 (2H, m), 7.34 (1H, m), 7.16-7.24 (6H, m), 4.28-4.36 (3H, m), 3.30 (1H, dd, J=5.8, 13.9 Hz), 3.14 (1H, dd, J=7.8, 13.7 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9][CH3:10].[CH:11]1([CH2:16][C:17](Cl)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([S:9][CH3:10])[CH:4]=[CH:5][C:6]=1[C:17](=[O:18])[CH2:16][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CSc1cccc(Cl)c1Cl
Reactant: O=C(Cl)CC1CCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CSc1ccc(C(=O)CC2CCCC2)c(Cl)c1Cl

Procedure:
2',3'-Dichloro-4'-methylthio-2-cyclopentylacetophenone is prepared following substantially the same procedure described in Example 10, Step A, using the following substances: 2,3-dichlorothioanisole (63.1 g., 0.327 mole), methylene chloride (300 ml.), cyclopentylacetyl chloride (52.7 g., 0.367 mole) and aluminum chloride (48.0 g., 0.36 mole).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[F:35])(=[O:27])=[O:26].[OH-].[NH4+:37]>>[NH2:37][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([CH3:22])([CH3:21])[CH3:23])=[N:9][C:8]=2[C:7]2[C:2]([Cl:1])=[C:3]([NH:24][S:25]([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[F:35])(=[O:26])=[O:27])[CH:4]=[CH:5][CH:6]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2Cl)c(-c2ccnc(Cl)n2)s1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2Cl)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide (100 mg, 0.180 mmol) and ammonium hydroxide (3 mL, 77 mmol), the title compound was obtained as an off white solid (88 mg, 87% yield). MS (ESI): 536 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15](S(O)(=O)=O)=[CH:14][CH:13]=1.C(O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:22]([O:10][C:9]([C@H:6]1[CH2:5][CH2:4][C@H:3]([CH2:2][NH2:1])[CH2:8][CH2:7]1)=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCc1ccccc1
Solvent: Cc1ccccc1
Product: NC[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1
Temperature: 25 °C

Procedure:
Trans-4-(aminomethyl)-cyclohexane carboxylic acid (50 g, 0.318 moles), p-toluenesulfonic acid monhydrate (61.7 g, 0.324 moles), benzyl alcohol (250 mL, 2.4 moles) and 250 mL of toluene were combined and stirred. The mixture was refluxed for 24 hours and the liberated water was removed by means of a Dean-Stark apparatus. A clear solution was obtained after 5 hours of refluxing. The solution was allowed to cool to room temperature whereupon the product crystallized. The mixture was vacuum filtered, washed with ether and dried in a vacuum oven to give 128.12 g (96% yield). Greenstein, J. P. and Winitz, M., "Chemistry of the Amino Acids", Robert E. Krieger Publishing Company, Malabar, Fla., Vol. 2, p942 (1986). 1H NMR (CD3OD) 8 1.05 (m, 2H), 1.43 (m, 2H), 1.59 (m, 1H), 1.85 (m, 2H), 2.03 (m, 2H), 2.33 (m, 1H), 2.35 (s, 3H), 2.75 (d, 2H), 5.09 (s, 2H), 7.23 (d, 2H), 7.32 (m, 5H), 7.69 (d, 2H). M.P. 154°-156° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>C(#N)C>[N:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:24][CH2:25][N:26]([CH2:2][C:3]([C:5]3[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:27][CH2:28]2)=[CH:19][CH:18]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: COC(=O)COc1ccc(C(=O)CBr)cc1
Solvent: CC#N
Product: COC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 1.5 h

Procedure:
A solution of methyl 4-bromoacetylphenoxyacetate (4.3 g) in acetonitrile (50 ml) was added dropwise over 40 minutes to a stirred solution of 1-(4-pyridyl)piperazine (4.9 g) in acetonitrile (100 ml). Stirring was continued for a further 1.5 hours, then the solution was filtered and the filtrate evaporated in vacuo. The solid residue was triturated with water (50 ml), then dried and suspended in methylene chloride (50 ml). The suspension was then filtered and the filtrate concentrated to a small volume. Purification by flash chromatography on neutral alumina eluting first with dichloromethane, then 0.5% v/v methanol/dichloromethane and finally 1% v/v methanol/dichloromethane gave the title compound, 1.93 g, as a solid: m.p. 150°-152° C.; NMR(d6DMSO) δ 8.14(2H,d), 7.98(2H,d), 7.03(2H,d), 6.78(2H,d), 4.90(2H,s), 3.83(2H,s), 3.72(3H,s), 3.34(4H,bt), 2.65(4H,bt); m/e 370 (M+H)+ ; calculated for C20H23N3O4 : C, 65.0; H, 6.3; N, 11.4. found: C, 65.2; H, 6.4; N, 11.3%.
Reaction SMILES: [C:1]1([N:7]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[C:8]([C:10]2[CH:11]=[C:12]3[N:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=4)[N:16]([CH3:30])[C:13]3=[N:14][CH:15]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C.O>[C:1]1([N:7]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:8]([C:10]2[CH:11]=[C:12]3[N:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([C:27](=[NH:28])[NH2:29])=[CH:25][CH:26]=4)[N:16]([CH3:30])[C:13]3=[N:14][CH:15]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCN(C(=O)c1cnc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1c(CCc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccc3)cnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 535 mg (1.0 mmol) of 3-methyl-2-[2-(4-amidinophenyl)ethyl]imidazo[4,5-b]pyridine-6-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide in 10 mL ethanol was mixed with 5 mL of 2N sodium hydroxide solution and stirred for 2 hours at room temperature. Then the mixture was diluted with 10 mL water, the alcohol was distilled off, the aqueous phase was washed with 20 mL ethyl acetate and acidified with concentrated hydrochloric acid, whereupon the desired compound was precipitated in the form of white crystals. Yield: 375 mg (74% of theory), C26H26N6O3 (470.54); Rf value: 0.23 (silica gel; ethyl acetate/ethanol/ammonia=90:5:5); mass spectrum: (M+H)+=471.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[C:13]2[N:14]=[CH:15][O:16][C:12]=2[CH:11]=[CH:10][CH:9]=1.C1(=O)O[CH2:20][CH2:19][O:18]1>CN(C=O)C.O.CO>[O:16]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([O:7][CH2:20][CH2:19][OH:18])[C:13]=2[N:14]=[CH:15]1
Reactant: Oc1cccc2ocnc12
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: OCCOc1cccc2ocnc12
Temperature: 90 °C
Reaction time: 2 h

Procedure:
K2CO3 (254 mg, 1.84 mmol) was added to a stirred solution of 4-hydroxybenzoxazole* (248 mg, 1.84 mmol) in DMF (5 mL) at room temperature. The mixture was heated at 90° C. for 15 min and ethylene carbonate (176 mg, 2.00 mmol) was added. The mixture was stirred at 150° C. for 2 h and allowed to attain room temperature. The mixture was diluted with water (2 mL) and MeOH (2 mL), and concentrated. The residue was partitioned between water and CH2Cl2. The aqueous layer was separated and extracted with CH2Cl2 (2×10 mL). The organic phases were pooled and washed with water and brine, and dried over MgSO4. The filtrate was concentrated to give the product as a brown oil that slowly solidified: yield 278 mg (84%), mp 47-49° C. Anal (C9H9NO3) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([B:8]2[O:12][CH2:11][CH2:10]O2)[CH:5]=[CH:6][CH:7]=1.Br[C:14]1C=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1COCOC>>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]2[B:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[O:12][CH2:11][C:10]=2[CH:18]=1
Reactant: COCOCc1cc(Cl)ccc1Br
Reactant: Fc1cccc(B2OCCO2)c1
Product: Fc1cccc(B2OCc3cc(Cl)ccc32)c1

Procedure:
This was prepared as per the procedure in Example 11, from 2-(3-fluorophenyl)-[1,3,2]-dioxaborolane and 1-bromo4-chloro-2-((methoxymethoxy)methyl)-benzene to afford white crystalline product.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.C(OC([N:31]1[CH2:35][CH2:34][C@H:33]([N:36]2[CH:40]=[C:39](B3OC(C)(C)C(C)(C)O3)[CH:38]=[N:37]2)[CH2:32]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C@H:12]([O:11][C:10]1[C:5]2[O:4][CH:3]=[C:2]([C:39]3[CH:38]=[N:37][N:36]([C@H:33]4[CH2:34][CH2:35][NH:31][CH2:32]4)[CH:40]=3)[C:6]=2[CH:7]=[N:8][C:9]=1[NH2:23])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](Oc1c(N)ncc2c(-c3cnn([C@H]4CCNC4)c3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]furo[3,2-c]pyridin-6-ylamine (20 mg, 0.048 mmol), (S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (26 mg, 0.071 mmol) and potassium carbonate (20 mg, 0.10 mmol) in 1,4-dioxane (2 mL) and H2O (0.5 mL) was stirred at 100° C. for 30 min in the microwave reactor. Then, the mixture was passed through PL-Thiol MP SPE+ resin and concentrated in vacuo. The resulting solid was left to stir in DCM (0.2 mL) and TFA (0.2 mL) at rt for 30 min. Purification via MDP afforded the title compound as a white solid. MS (ES+): m/z: 475.96/477.94 (70/50) [MH+]. HPLC: tR=2.35 min (ZQ3, polar—5 min). 1H NMR (400 MHz, CD3OD): δ 1.89 (d, J=6.6 Hz, 3H), 2.40 (ddd, J=13.9, 7.6, 3.3 Hz, 1H), 2.50-2.62 (m, 1H), 3.50 (ddd, J=11.5, 8.8, 4.4 Hz, 1H), 3.63-3.73 (m, 2H), 3.75-3.82 (m, 1H), 5.28 (q, J=6.4 Hz, 1H), 6.53 (q, J=6.8 Hz, 1H), 7.21 (t, J=8.6 Hz, 1H), 7.39 (dd, J=8.9, 4.9 Hz, 1H), 7.79 (s, 1H), 7.89 (s, 1H), 8.14 (d, J=4.8 Hz, 2H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[Br:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[C:18]([C:20]1[NH:21][CH:22]=[CH:23][N:24]=1)=[O:19]>C1COCC1.C(OCC)(=O)C.O.[Cl-].[NH4+].[Cu]I>[Br:14][C:15]1[CH:16]=[C:17]([C:18]([C:20]2[NH:24][CH:23]=[CH:22][N:21]=2)([C:3]2[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=2)[OH:19])[CH:25]=[CH:26][CH:27]=1
Reactant: O=C(c1cccc(Br)c1)c1ncc[nH]1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: [Cu]I
Agent: [Cl-]
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(c1ccc(OC(F)(F)F)cc1)(c1cccc(Br)c1)c1ncc[nH]1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
A mixture of magnesium (0.644 g, 87.7 mmol) in THF (13 mL) at 50° C. is treated dropwise with a solution of 1-bromo-4-(trifluoromethoxy)benzene (6.32 g, 26.2 mmol) in THF over a period of 5 min, stirred at 50° C. for an additional 1.5 h, cooled to room temperature, treated with copper(I) iodide (0.041 g, 0.215 mmol) and a solution of 2-(3-bromobenzoyl)-1H-imidazole (2.60 g, 10.4 mmol) in THF, heated at 65° C. overnight, cooled to room temperature and diluted with a 1:1:1 mixture of ethyl acetate, water and saturated aqueous ammonium chloride. The phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate, filtered and concentrated. The resultant residue is purified by flash chromatography (silica, 85:15 to 75:25 hexanes/ethyl acetate as eluent) affords the title product as a yellow solid, 3.47 g (81% yield), identified by NMR and mass spectral analyses. 1H NMR (500 MHz, CDCl3) δ 8.98 (br s, 1H), 7.55 (t, J=1.6 Hz, 1H), 7.45 (dt, J=8.1, 1.9 Hz, 1H), 7.37-7.34 (m, 2H), 7.24-7.20 (m, 2H), 7.18 (d, J=8.1 Hz, 2H), 7.07 (br s, 1H), 6.98 (br s, 1H), 4.30 (br s, 1H); ESI MS m/z 412 [C17H12BrF3N2O2+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C([O-])(O)=O.[Na+].[NH:13]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C@H:14]([C:18](ON1C(=O)CCC1=O)=[O:19])[CH:15]([CH3:17])[CH3:16].Cl.[Na+].[Cl-]>O.O1CCOCC1.CCOC(C)=O.CO>[NH:13]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C@H:14]([C:18]([NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])=[O:19])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: N[C@@H](CO)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 120.5 %

Procedure:
L-Serine (104.19 g, 991 mmol) was dissolved in water (1440 mL) in a 4-L Erlenmeyer flask. Solid NaHCO3 (83.25 g, 991 mmol was added and the mixture was stirred at room temperature to give a clear solution. Cbz-Val-OSu (300.0 g, 861 mmol) was added as a solution in 1,4-dioxane (1500 mL), with additional 1,4-dioxane (220 mL) used to rinse. The resulting cloudy mixture became clear after 1.5 h of stirring at 25° C. After 44 h, the mixture was divided into two equal portions. Methanol (700 mL) and 12 N aqueous HCl (42 mL, 504 mmol) was added to each portion, followed by EtOAc (1000 mL) and a solution of NaCl (100 g) dissolved in water (600 mL). The layers were separated and the organic layer was washed with saturated aqueous NaCl (350 mL). The aqueous layers were extracted in succession with EtOAc (1000 mL). The organic layers resulting from work-up of both portions of the reaction were combined, dried (Na2SO4), filtered, and evaporated to give a white solid (351 g). This material was suspended in CH2Cl2 (1500 mL) and stirred for 2 h. The mixture was filtered and the crystals were washed with CH2Cl2 (1000 mL) to give compound 2b as white crystals (262.3 g, 90% yield). 1H NMR (300 MHz, DMSO-d6): consistent with proposed structure for compound 2b. MS: m/z=339.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:16][NH2:17]>C1COCC1>[Br:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][C:5]([NH:16][NH2:17])=[N:6][CH:7]=1
Reactant: NN
Reactant: Clc1ccc(-c2cc(Cl)ncc2Br)cc1
Solvent: C1CCOC1
Product: NNc1cc(-c2ccc(Cl)cc2)c(Br)cn1
Temperature: 20 °C
Yield: 63.9 %

Procedure:
To a solution of 5-bromo-2-chloro-4-(4-chlorophenyl)pyridine (1.3 g, 4.3 mmol) in THF (10 mL) was added hydrazine (1.4 g, 43 mmol). The reaction mixture was refluxed under argon for 4 days, then allowed to cool to 20° C. and concentrated in vacuo. The residue was purified by using reverse phase preparative HPLC (Conditions: Phenomenex Luna 5μ C18 30×100 mm; Eluted with 0% to 100% B, 10 min gradient, 100% B hold for 5 min, (A=90% H2O, 10% CH3CN, 0.1% trifluoroacetic acid and B=10% H2O, 90% CH3CN, 0.1% trifluoroacetic acid); Flow rate at 40 mL/min, UV detection at 220 nm), followed by basification with 1N aqueous NaOH to pH 12 and extraction with CHCl3 to afford 0.82 g (63%) of the title compound as an off-white solid. LC/MS (method B): retention time=1.47 min, [M+H]+=298.0.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]([CH3:33])[C:6]([C:8]1[S:20][C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH2:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:11](=[O:30])[C:10]=2[C:9]=1[O:31][CH3:32])=[O:7].C(N(CC)CC)C.[C:41]([O:44][CH2:45][C:46](Cl)=[O:47])(=[O:43])[CH3:42]>C1COCC1.C(=O)([O-])O.[Na+]>[C:41]([O:44][CH2:45][C:46]([NH:2][CH2:3][CH2:4][N:5]([C:6]([C:8]1[S:20][C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH2:21][C:22](=[O:29])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:11](=[O:30])[C:10]=2[C:9]=1[O:31][CH3:32])=[O:7])[CH3:33])=[O:47])(=[O:43])[CH3:42]
Reactant: COc1c(C(=O)N(C)CCN)sc2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1c(C(=O)N(C)CCNC(=O)COC(C)=O)sc2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a solution of the compound of Example 103 (150 mg, 0.31 mmol) and triethylamine (69 mg, 0.68 mmol) in THF (10 mL) was added acetoxyacetyl chloride (46 mg, 0.34 mmol) under ice-cooling. After stirring at room temperature for 1 hr, the reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluate; ethyl acetate to ethyl acetate/methanol=50/1) to give a white solid. Recrystallization of the white solid from ethyl acetate-hexane gave the title compound (140 mg, 82%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:42]2[CH2:47][CH2:46][C:45]([CH3:49])([CH3:48])[CH2:44][CH2:43]2)=[CH:8][C:9]=1[N:10]([CH:20]([CH2:33][O:34][SiH](C(C)C)C(C)C)[CH2:21][O:22][Si](C(C)C)(C(C)C)C(C)C)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:42]2[CH2:43][CH2:44][C:45]([CH3:48])([CH3:49])[CH2:46][CH2:47]2)=[CH:8][C:9]=1[N:10]([CH:20]([CH2:33][OH:34])[CH2:21][OH:22])[C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(C2CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C(CO[SiH](C(C)C)C(C)C)CO[Si](C(C)C)(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1sc(C2CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C(CO)CO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-[(1-diisopropylsilanyloxymethyl-2-triisopropylsilanyloxy-ethyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(4,4-dimethyl-cyclohexyl)-thiophene-2-carboxylic acid methyl ester (60 mg, 0.078 mmol) in THF (1 mL) was treated with HF.pyridine (0.1 mL). The mixture was stirred at room temperature for 16 h. The mixture was diluted with EtOAc and added to solid NaHCO3. It was stirred at room temperature for 2 h, filtered and evaporated. Pure 5-(4,4-dimethyl-cyclohexyl)-3-[(2-hydroxy-1-hydroxymethyl-ethyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester was obtained on chromatography over silica gel (EtOAc as eluent) (32 mg, 89%).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][NH2:22])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]1(=O)[O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][N:22]1[C:31](=[O:32])[CH2:30][CH2:29][CH2:28][C:27]1=[O:33])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](C(=O)NN)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C1CCCC(=O)O1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H](C(=O)NN1C(=O)CCCC1=O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 49.2 %

Procedure:
A solution of 1.0 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvalerohydrazide, 0.35 g of glutaric anhydride and 0.85 ml of triethylamine in 30 ml of dry toluene was heated at reflux under a nitrogen atmosphere for 7 hours. The mixture was cooled to room temperature and washed with 2M aqueous hydrochloric acid, 5% aqueous sodium hydrogen carbonate and brine. The organic phase was dried over anhydrous magnesium sulphate and the solvent was then evaporated. The residue was triturated with diethyl ether to give 0.623 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methyl-N-(2,6-dioxopiperidino)valeramide in the form of a white solid.