Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](OCC=O)CC(CCC=C(C)C)C.[CH3:15][C:16]1([CH3:31])[C:24]2[CH:23]=[C:22]3[O:25][CH2:26][C:27](=[O:30])[CH2:28][O:29][C:21]3=[CH:20][C:19]=2[CH2:18][CH2:17]1>>[CH3:31][CH:16]([CH2:15][CH3:1])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH2:26][C:27](=[O:30])[CH2:28][O:29][C:21]=2[CH:20]=1
Reactant: CC(C)=CCCC(C)CCOCC=O
Reactant: CC1(C)CCc2cc3c(cc21)OCC(=O)CO3
Product: CCC(C)CCc1ccc2c(c1)OCC(=O)CO2

Procedure:
Odor: Marine, animalic, civet-like, floral-aldehyde odor, also somewhat reminiscent of citronelloxyacetaldehyde ([3,7-dimethyl-6-octenyl]oxy-acetaldehyde). -IR (film): ν=1502/1435/1460/1580 cm−1 (ν C═C, Ar), 1265/1304/1202 cm−1 (ν ring), 1051 cm−(ν C—O—C), 1741 cm−1 (ν C═O). -1H-NMR (CDCl3): δ=0.87 (t, J=7.2 Hz, 3H, 5′-H3), 0.91 (d, J=6.4 Hz, 3H, 3′-Me), 1.18 (mc1 1H, 2′-Hb), 1.34-1.43 (m, 3H, 2′-Ha, 4′-H2), 1.56-1.62 (m, 1H, 3′-H), 2.48 (ddd, J=14.0, 10.0, 6.4 Hz, 1H, 1′-Ha), 2.56 (ddd, J=14.0, 10.4, 5.2 Hz, 1H, 1′-Hb), 4.67 (d, J=2.4 Hz, 4H, 2-,4-H2), 6.78 (dd, J=8.2, 2.4 Hz, 1H, 8-H), 6.82 (d, J=2.0 Hz, 1H, 6-H), 6.90 (d, J=8.4 Hz, 1H, 9-H). -13C-NMR (CDCl3): δ=11.14 (q, C-5′), 18.93 (q, 3′-Me), 29.18 (t, C-4′), 32.42 (t, C-1′), 33.84 (d, C-3′), 38.23 (t, C-2′), 22.38 (t, C-4′), 30.90/31.26 (2t, C-2′,-3′), 75.35/75.64 (2t, C-2,-4), 120.27/120.51 (2d, C-6,-9), 123.45 (d, C-8), 139.11 (s, C-7), 146.00/147.86 (2s, C-5a,-9a), 204.72 (s, C-3). -MS (EI): m/z (%)=77 (21) [C8H5+], 92 (14) [C7H8+], 135 (11) [M+-C5H11—C2H2O], 149 (16) [M+-C5H11—CO], 177 (100) [M+-C5H11], 191 (4) [M+-C4H9], 205 (7) [M+-C3H7], 248 (45) [M+].
Reaction SMILES: [C:1]([O-:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[CH:4][CH:3]=1.[Na+].[Na+].Cl>>[C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccc(C(=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1ccc(C(=O)O)cc1

Procedure:
An aqueous solution of disodium terephthalate, passed through adsorption tower (4), was transferred to neutralization tank (5). Then, the solution was stirred by agitator (5a) in neutralization tank and added slowly with hydrochloric acid and incessantly until the pH of solution became 4.0. As a result of monitoring by SEM, the particle size of terephthalic acid formed from said neutralization process, its particle size (10 to 15 μm) was very small.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:6]([CH2:7][C:8]([OH:10])=O)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:11]=[C:6]2[CH2:7][C:8]([O:14][C:12](=[O:13])[C:5]2=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C(O)Cc1cc(Cl)ccc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1Cc2cc(Cl)ccc2C(=O)O1

Procedure:
The starting material is prepared as follows. The mixture of 6.2 g of 5-chlorohomophthalic acid and 70 ml of acetic anhydride is refluxed for 1/2 hour and evaporated. The residue is washed with chloroform, carbon tetrachloride and dryed to yield the 5-chlorohomophthalic anhydride melting at 170°-173°.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:36][O:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])[C:5]([NH:7][CH:8]1[C:34](=[O:35])[N:10]2[C:11]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:12](/[CH:15]=[CH:16]/[Cl:17])[CH2:13][S:14][C@H:9]12)=[O:6].[NH2:44][C:45]([NH2:47])=[S:46].C([O-])(=O)C.[Na+]>O1CCCC1.O>[CH3:42][O:41][C:39]([CH2:38][O:37][N:36]=[C:4]([C:3]1[N:44]=[C:45]([NH2:47])[S:46][CH:2]=1)[C:5]([NH:7][CH:8]1[C:34](=[O:35])[N:10]2[C:11]([C:18]([O:20][CH:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:19])=[C:12](/[CH:15]=[CH:16]/[Cl:17])[CH2:13][S:14][C@H:9]12)=[O:6])=[O:40]
Reactant: COC(=O)CON=C(C(=O)CCl)C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/Cl)CS[C@H]12
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/Cl)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of benzhydryl 7-(4-chloro-2-methoxycarbonylmethoxyimino-3-oxobutyramido)-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate (1.65 g) in a mixture of tetrahydrofuran (10 ml) and water (10 ml) were added thiourea (0.39 g) and sodium acetate (1.05 g). The mixture was stirred at ambient temperature for 2 hours and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was triturated with diisopropyl ether and collected by filtration to give benzhydryl 7-[2-methoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate (syn isomer) (1.45 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:11]([F:23])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:24]([CH:26]1[CH2:29][CH:28]([C:30](Cl)=[O:31])[CH2:27]1)[CH3:25].C(C1CC(C(Cl)=O)C1)CCCCCCC>>[CH2:24]([CH:26]1[CH2:29][CH:28]([C:30]([O:8][C:7]2[CH:6]=[CH:5][C:4]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:11]([F:23])[CH:10]=3)=[CH:3][C:2]=2[F:1])=[O:31])[CH2:27]1)[CH3:25]
Reactant: CCC1CC(C(=O)Cl)C1
Reactant: CCCCCCCOc1ccc(-c2ccc(O)c(F)c2)cc1F
Agent: CCCCCCCCC1CC(C(=O)Cl)C1
Product: CCCCCCCOc1ccc(-c2ccc(OC(=O)C3CC(CC)C3)c(F)c2)cc1F
Yield: 91.8 %

Procedure:
Except that 0.60 g of the crude 3,3'-difluoro-4-hydroxy-4'-heptyloxybiphenyl obtained in Example 6-(c) was used in place of 0.7 g of the crude 3,3'-difluoro-4-hydroxy-4'-decyloxybiphenyl and 0.3 g of 3-ethylcyclobutanecarboxylic acid chloride obtained in Example 13-(d) in place of 0.5 g of the 3-octylcyclobutanecarboxylic acid chloride used in Example 9-(g) and purification was carried out by way of column chromatography on silica gel (eluent: hexane/benzene=2/1), the operation was performed in the same manner as in Example 9-(g) to obtain 0.74 g (yield 90.6%) of 3,3'-difluoro-4-heptyloxybiphenyl-4'-yl 3-ethylcyclobutanecarboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][C:5](Br)=[C:6]([F:8])[CH:7]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]=1B(O)O>>[NH2:1][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][C:5]([C:19]2[CH:18]=[C:17]([O:20][CH2:21][CH2:22][CH3:23])[CH:16]=[CH:15][C:14]=2[F:13])=[C:6]([F:8])[CH:7]=1
Reactant: CCCOc1ccc(F)c(B(O)O)c1
Reactant: Nc1cc(F)c(Br)nc1C(=O)O
Product: CCCOc1ccc(F)c(-c2nc(C(=O)O)c(N)cc2F)c1
Yield: 28 %

Procedure:
Method 1 was followed using 3-amino-6-bromo-5-fluoropicolinic acid (1.0 equiv.) and 2-fluoro-5-propoxyphenylboronic acid (1.3 equiv.) and Pd(dppf)C12-DCM (0.05 equiv.) to give 3-amino-5-fluoro-6-(2-fluoro-5-propoxyphenyl)picolinic acid in 28% yield. LC/MS=309.1 (M+H), Rt=1.00 min.
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16](C)[C:17](=O)OC(C)(C)C)[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[CH:29]=[C:30]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:31]=[CH:32][C:33]=2[O:34][CH3:35])[C:6]2[CH:42]=[CH:43][C:44]([C:46]#[N:47])=[CH:45][C:5]1=2)(=[O:3])[CH3:2].[ClH:48]>O1CCOCC1.CCOCC>[ClH:48].[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([NH:16][CH3:17])[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[CH:29]=[C:30]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:31]=[CH:32][C:33]=2[O:34][CH3:35])[C:6]2[CH:42]=[CH:43][C:44]([C:46]#[N:47])=[CH:45][C:5]1=2)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2ccccc2)cc1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(C)=O)c2cc(C#N)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2cc(-c3ccccc3)ccc2OC)c2ccc(C#N)cc2N(C(C)=O)[C@H]1C
Yield: 87 %

Procedure:
A rt solution of tert-butyl(S)-1-((3S,4S)-5-acetyl-7-cyano-1-((4-methoxybiphenyl-3-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (37 mg, 57.8 μmol) in 4 M HCl in dioxane (289 μl) was stirred for 1 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((3S,4S)-5-acetyl-7-cyano-1-((4-methoxybiphenyl-3-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (29.0 mg, 87%) as a white solid. MS m/z 540 (MH)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(=O)=O.[Li]CCCC.Cl[SiH:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21]>C1COCC1.CC(C)=O>[CH:20]([SiH:19]([CH:23]([CH3:25])[CH3:24])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)([CH3:22])[CH3:21]
Reactant: CC(C)[SiH](Cl)C(C)C
Reactant: COc1ccc(Br)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1ccc([SiH](C(C)C)C(C)C)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 94.1 %

Procedure:
A solution of p-bromoanisole (28.6 mL, 228 mmol, 1 equiv.) in THF (550 mL) was chilled to −78° C. (CO2(s), acetone). n-BuLi (91.2 mL, 228 mmol, 2.5M in hexanes, 1 equiv.) was added via cannula over a 5 min period. After 5 min a white precipitate begins to form. The mixture was stirred for 30 min at −78° C., after which chlorodiisopropylsilane (34.6 g, 228 mmol, 1 equiv.) was slowly added via syringe. After 1 h the ice bath was removed and the solution was allowed to come to 23° C. with stirring overnight. The reaction was quenched with NH4Cl(sat'd) (50 mL) and extracted with ether (3×500 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to yield a light yellow oil. Filtration through SiO2 (gradient: 3-5% EtOAc/hexanes) yielded 47.7 g (94%) of a colorless oil. This material could also be purified by distillation bp=76-85° C. @ 275 mTorr (40 g, 63%). TLC Rf=0.61 (9:1 Hexanes/EtOAc). IR (film) 2393, 1853, 1710, 1691, 1658, 1584, 1482, 1346 cm−1. 1H NMR (500 MHz, CDCl3) δ7.48 (d, 2H, J=8.10, C3-H, C7-H), 6.95 (d, 2H, J=8.10, C4-H, C6-H), 3.97 (s, 1H, Si—H), 3.85 (s, 3H, C1-H), 1.39 (q, 2H, J=3.0, C8-H, C11-H), 1.10 (d, 6H, J=6.5, C9-H, C10-H), 1.03 (d, 6H, J=7.5, C12-H, C13-H). 13C NMR (125 MHz, CDCl3) δ137.13, 113.73, 113.62, 55.18, 18.95, 18.72, 11.08. Anal. Calcd for C13H22OSi: C, 70.21; H, 9.97; Si, 12.63. Found: C, 70.43; H, 9.83; Si, 12.39.
Reaction SMILES: FC1C=C(F)C=CC=1CCC1(C=CC=CC1)C(N)=O.N1SN=C2C(S(NC3C=CC=CC=3C(O)=O)(=O)=O)=CC=CC=12.[N:42]1[S:46][N:45]=[C:44]2[C:47]([S:51]([NH:54][C:55]3[CH:73]=[C:72](C(F)(F)F)[CH:71]=[CH:70][C:56]=3[C:57]([NH:59][C@@H:60]([C:62]3[CH:67]=[CH:66][C:65]([F:68])=[CH:64][C:63]=3[F:69])[CH3:61])=[O:58])(=[O:53])=[O:52])=[CH:48][CH:49]=[CH:50][C:43]=12>>[N:42]1[S:46][N:45]=[C:44]2[C:47]([S:51]([NH:54][C:55]3[CH:73]=[CH:72][CH:71]=[CH:70][C:56]=3[C:57]([NH:59][C@@H:60]([C:62]3[CH:67]=[CH:66][C:65]([F:68])=[CH:64][C:63]=3[F:69])[CH3:61])=[O:58])(=[O:53])=[O:52])=[CH:48][CH:49]=[CH:50][C:43]=12
Reactant: C[C@@H](NC(=O)c1ccc(C(F)(F)F)cc1NS(=O)(=O)c1cccc2nsnc12)c1ccc(F)cc1F
Agent: NC(=O)C1(CCc2ccc(F)cc2F)C=CC=CC1
Agent: O=C(O)c1ccccc1NS(=O)(=O)c1cccc2nsnc12
Product: C[C@@H](NC(=O)c1ccccc1NS(=O)(=O)c1cccc2nsnc12)c1ccc(F)cc1F

Procedure:
(R)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-N-[1-(2,4-difluorophenyl-ethyl]benzamide. 2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)benzoic acid was coupled with (R) 1-(2,4-difluorophenyl)-ethylamine (see EXAMPLE 39), and the product was purified, as described in EXAMPLE 7 to provide the title compound. MS (ESI): neg. ion m/z 473 [M−H]−. HPLC (reversed-phase): RT=9.64 min). 1H NMR (400 MHz, CDCl3): 11.38 (s, 1H), 8.32 (dd, J=7.1, 1.0 Hz, 1H), 8.16 (dd, J=8.8, 1.0 Hz, 1H), 7.68 (m, 1H), 7.65 (dd, J=8.8, 7.0 Hz, 1H), 7.30 (m, 3H), 6.98 (m, 1H), 6.88 (m, 1H), 6.85 (m, 1H), 6.40 (bd, J=7.6 Hz, 1H), 5.32 (m, 1H), 1.54 (d, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]([CH:10]=[N:11][C@H:12]([CH3:16])[C:13]([NH2:15])=[O:14])=[CH:8][CH:7]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][NH:11][C@H:12]([CH3:16])[C:13]([NH2:15])=[O:14])=[CH:17][CH:18]=1
Reactant: C[C@@H](N=Cc1ccc(OCc2ccccc2F)cc1)C(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H](NCc1ccc(OCc2ccccc2F)cc1)C(N)=O
Temperature: 3.5 °C
Yield: 94 %

Procedure:
A mixture of (R)-2-[4-(2-fluorobenzyloxy)benzylideneamino]propanamide (III′b) (30 g) and of methanol (180 mL) is cooled under stirring to 2-5° C. Sodium borohydride (3.8 g) is added in twenty small portions in 90 min to the previously prepared cold mixture keeping the temperature below 5° C. The mixture is then stirred for additional 10 min at 5° C. The reaction mixture is concentrated under vacuum and worked up as described in Example 2 to provide 28.44 g (94% yield of (R)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide (I′b) with a HPLC purity of 99.8 (area %) determined according to the method of Example 25A and a C,O-dialkylated (R)-2-[3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)-benzylamino]propanamide content less than 0.005% by weight determined by HPLC, according to the method of Example 25B.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([N:6]1[CH2:11][CH:10]=[CH:9][C@H:8]2[NH:12][C:13]([NH2:15])=[N:14][C@@H:7]12)=[O:5].[OH-].[Na+]>P([O-])([O-])([O-])=O>[CH3:2][O:3][C:4](=[O:5])[NH:6][CH2:11][CH:10]=[CH:9][C:8]1[NH:12][CH:13]([NH2:15])[NH:14][CH:7]=1
Reactant: COC(=O)N1CC=C[C@H]2NC(N)=N[C@H]21
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: COC(=O)NCC=CC1=CNC(N)N1
Reaction time: 0.08 h
Yield: 85 %

Procedure:
0.111 g (0.47 mmol) of the methyl ester of 2-amino-1,3a,5,7a-tetrahydroimidazo[4,5-b]pyridine-4-carboxylic acid 4 is added to 4 ml of a NaOH solution (1 ml). The reaction mixture is brought to reflux with stirring for 5 minutes (reaction monitored by TLC). After cooling, a phosphate buffer solution (pH=7) (20 ml) is added and the mixture is extracted with BuOH until exhausted. The organic phases are combined and evaporated to dryness to give 0.079 g of allyl amine 16 in the form of a brown solid with a yield of 85%.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[S:15]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16]1>>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][CH2:20][C:17]2[CH:18]=[CH:19][S:15][CH:16]=2)[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=Cc1ccsc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccsc2)CC1
Yield: 70.4 %

Procedure:
Using general procedure A, 4-amino-1-Boc-piperidine (481 mg, 2.40 mmol) and 3-thiophenecarboxaldehyde (228 mg, 2.03 mmol) gave 4-[(thiophen-3-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil (425 mg, 1.43 mmol, 71%). 1H NMR (CDCl3) δ 1.22-1.36 (m, 3H), 1.45 (s, 9H), 1.80-1.90 (m, 2H), 2.67 (tt, 1H, J=10.1, 3.9 Hz), 2.74-2.86 (m, 2H), 3.85 (s, 2H), 3.95-4.10 (m, 2H), 7.04 (dd, 1H, J=4.8, 1.5 Hz), 7.11-7.14 (m, 1H), 7.29 (dd, 1H, J=5.0, 2.9 Hz).
Reaction SMILES: [CH2:1]([C@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:46])[CH3:45])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:9][C@H:10]([OH:29])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:51]([S:55][CH2:56][CH:57]([CH3:59])[CH3:58])[CH:52]([CH3:54])[CH3:53].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[CH2:1]([C@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:45])[CH3:46])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:9][C@H:10]([O:29][CH:51]([S:55][CH2:56][CH:57]([CH3:59])[CH3:58])[CH:52]([CH3:54])[CH3:53])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Reactant: CC(C)CSCC(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)CSC(O[C@@H](C[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(C(C)C)n1)C(C)C)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of the compound of Example 1 (1.0 g, 1.38 mmol) and diisobutyl sulfide (6.2 mL) in acetonitrile (10 mL) at 0° C. was added benzoyl peroxide (2.0 g) in three portions over 30 minutes, and the reaction was stirred at 0° C. for 1 hour. The reaction was diluted with ethyl acetate and washed with 10% Na2CO3 and brine. The organic phase was dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel eluting with a gradient starting with 0-100% ethyl acetate/dichloromethane to provide the title product (0.890 g, 75% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: Oc1cc(F)ccc1Br
Reactant: Fc1ccccn1
Product: Fc1ccc(Br)c(Oc2ccccn2)c1

Procedure:
2-Bromo-5-fluoro-phenol was reacted with 2-fluoro-pyridine according to the method of Example 101A to provide the title compound. MS (DCI/NH3) m/z 268 (M)+, 270 (M+2)+.
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[CH:5][C:4]2[C:7]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]4[C:28]([O:29][CH3:30])=[CH:27][C:26]([N:31]5[CH2:35][CH2:34][O:33][C:32]5=[O:36])=[CH:25][C:22]=4[CH:23]=[O:24])[CH2:13][CH2:12]3)=[CH:8][CH:9]=[CH:10][C:3]1=2.Cl.[K].[BH4-].[Na+].Cl.[OH-].[Na+]>>[ClH:1].[S:2]1[CH:6]=[CH:5][C:4]2[C:7]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]4[C:28]([O:29][CH3:30])=[CH:27][C:26]([N:31]5[CH2:35][CH2:34][O:33][C:32]5=[O:36])=[CH:25][C:22]=4[CH2:23][OH:24])[CH2:13][CH2:12]3)=[CH:8][CH:9]=[CH:10][C:3]1=2
Reactant: COc1cc(N2CCOC2=O)cc(C=O)c1OCCCN1CCN(c2cccc3sccc23)CC1
Agent: Cl
Agent: [BH4-]
Agent: [K]
Product: COc1cc(N2CCOC2=O)cc(CO)c1OCCCN1CCN(c2cccc3sccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.6 %

Procedure:
First, 2-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-(2-oxo-oxazolidin-3-yl)benzaldehyde hydrochloride (1.28 g. 2.4 mmol)) was added to an aqueous potassium hydrochloride solution. The mixture was extracted with dichloromethane. The extracted solution was concentrated under reduced pressure and the residue was dissolved in THF (15 ml). To the solution, sodium borohydride (0.05 g, 1.2 mmol) was added under ice cooling and the mixture was stirred at room temperature for 3 hours. Then, 10% hydrochloric acid was added to the mixture under ice cooling to decompose the reagent excessively present. After an aqueous 6N sodium hydroxide solution was added to the solution to make it an alkaline solution, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and thereafter concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate=3:7→dichloromethane:methanol=100:3). The purified product was concentrated under reduced pressure and the residue was dissolved in ethanol. A 1N hydrochloric acid/ethanol solution was added to this. The crystal produced was recrystallized from ethanol to obtain 3-{4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-propoxy]-3-hydroxymethyl-5-methoxy-phenyl}oxazolidin-2-one hydrochloride (0.52 g, 41% yield) as white powder.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:12](=[O:13])[CH2:11][CH2:10][N:9]([C:14](=[O:24])/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[CH2:8][CH2:7]1)C.[BH4-].[Na+].OS([O-])(=O)=O.[K+]>C(O)C>[Cl:23][C:19]1[CH:18]=[C:17](/[CH:16]=[CH:15]/[C:14]([N:9]2[CH2:10][CH2:11][C:12](=[O:13])[N:6]([CH2:5][CH2:4][OH:3])[CH2:7][CH2:8]2)=[O:24])[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)CN1CCN(C(=O)/C=C/c2cccc(Cl)c2)CCC1=O
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Agent: [K+]
Solvent: CCO
Product: O=C(/C=C/c1cccc(Cl)c1)N1CCC(=O)N(CCO)CC1
Temperature: 25 °C
Reaction time: 21 h
Yield: 78.6 %

Procedure:
A solution of 2.16 g (5.91 mmol) of {4-[(E)-3-(3-chloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-acetic acid ethyl ester in 30 ml of ethanol was treated at 0° C. with 0.45 g (11.81 mmol) of sodium borohydride in 30 ml of ethanol during 20 min. The reaction was stirred for 21 h at RT, cooled (0° C.) and treated again with 0.45 g (11.81 mmol) of sodium borohydride. After 22 h at RT the reaction neutralized with cold aqueous 10% KHSO4 and extracted with EtOAc (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na2SO4 evaporated and purified by flash silica gel column (EtOAc and then EtOAc/EtOH 1 to 7.5%) to yield 1.50 g (79%) of the title compound as light white foam. MS: 323.1 (MH+, Cl).
Reaction SMILES: [O:1]=[C:2]([CH3:7])[CH2:3][C:4]([NH2:6])=[O:5].[OH-].[Na+].[Cl-].[C:11]1([N+:17]#[N:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[C:11]1([NH:17][N:18]=[C:3]([C:2](=[O:1])[CH3:7])[C:4]([NH2:6])=[O:5])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)CC(N)=O
Reactant: N#[N+]c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C(=NNc1ccccc1)C(N)=O

Procedure:
5.0 g (0.049 mol) of 3-oxobutyramide, a solution of 6.9 g (0.171 mol) of NaOH in 75 ml of water and 0.051 mol of phenyldiazonium chloride were treated as described in preparation 8. The crude reaction mixture was purified by chromatography on silica gel(EtOAc) obtaining 3 g of the title compound which was used as such in the subsequent step. M.p.=146°-147° C.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:28])([F:27])[CH2:6][N:7]([C:17]1[C:22]([N+:23]([O-])=O)=[CH:21][N:20]=[C:19]([Cl:26])[N:18]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)C>C(O)(=O)C.[Fe]>[Cl:26][C:19]1[N:20]=[CH:21][C:22]2[NH:23][C:4](=[O:3])[C:5]([F:28])([F:27])[CH2:6][N:7]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[C:17]=2[N:18]=1
Reactant: CCOC(=O)C(F)(F)CN(Cc1ccc(OC)cc1)c1nc(Cl)ncc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1ccc(CN2CC(F)(F)C(=O)Nc3cnc(Cl)nc32)cc1
Reaction time: 0.17 h
Yield: 41.6 %

Procedure:
To a solution of 1.9 g (0.0044 mole) of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(4-methoxy-benzyl)-amino]-2,2-difluoro-propionic acid ethyl ester (IV-291) in 40 mL of acetic acid was added 1.9 g (0.034 g-atom) of iron powder. The mixture was heated to 80 degrees for 2 hours and then filtered while hot. Water and ethyl acetate were added to the filtrate and the mixture was stirred for 10 minutes and then filtered. The layers were separated. The organic layer was washed successively with ammonium hydroxide and water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure and recrystallized from ethyl acetate to give 0.65 g of 2-chloro-7,7-difluoro-9-(4-methoxy-benzyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-291) as a white solid.