Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[CH:8]([N:11]1[C:15]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=4[C:24]=3[N:25]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].[CH:36]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH2:37].C(Cl)Cl.CO>O.C(O)C>[CH:8]([N:11]1[C:15]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][N:33]([CH2:37][CH2:36][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=4[C:24]=3[N:25]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCNCC3)ccc1-2
Reactant: C=CS(C)(=O)=O
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCN(CCS(C)(=O)=O)CC3)ccc1-2
Yield: 71 %

Procedure:
Following the procedure for 320, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 375 and methyl vinyl sulfone were reacted, with added DCM to aid dissolution. Addition of a mixture of methanol, ethanol and water followed by removal in vacuo of the DCM precipitated the product from the reaction mixture. The resulting solid was collected by filtration to give 476 as an off-white solid (175 mg, 71%). LCMS: RT=3.30 min, [M+H]+=502. 1H NMR δ (ppm) (DMSO-d6): 8.23 (1H, d, J=8.20 Hz), 8.05 (1H, s), 7.05 (1H, dd, J=8.25, 1.78 Hz), 6.89 (1H, d, J=1.74 Hz), 5.82-5.72 (1H, m), 4.33-4.27 (2H, m), 3.37 (2H, t, J=5.06 Hz), 3.02 (3H, s), 2.97 (2H, s), 2.70 (2H, s), 2.03 (2H, s), 1.75 (2H, d, J=12.38 Hz), 1.67-1.55 (2H, m), 1.50 (6H, d, J=6.59 Hz). 3 Protons obscured by solvent peaks
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:21]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[CH:22][CH2:23][CH2:24][C:25]([O:27]C)=[O:26])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:21]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[CH:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CCC=C(c1cccnc1)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCC=C(c1cccnc1)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2

Procedure:
Prepared from methyl 5-(2-(4-chlorobenzenesulphonylamino) indan-5-yl)-5-(3-pyridyl)pent-4-enoate by hydrolysis with sodium hydroxide solution.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH:21]2[N:25]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C:24](=[O:35])[NH:23][CH2:22]2)=[C:4]([O:36][CH3:37])[CH:3]=1.[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:38]([N:23]1[CH2:22][CH:21]([C:12]2[CH:13]=[C:14]([C:17]([F:20])([F:18])[F:19])[CH:15]=[CH:16][C:11]=2[C:5]2[CH:6]=[C:7]([CH:8]([CH3:9])[CH3:10])[C:2]([F:1])=[CH:3][C:4]=2[O:36][CH3:37])[N:25]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[C:24]1=[O:35])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(CN2C(=O)NCC2c2cc(C(F)(F)F)ccc2-c2cc(C(C)C)c(F)cc2OC)cc1
Product: COc1ccc(CN2C(=O)N(Cc3ccccc3)CC2c2cc(C(F)(F)F)ccc2-c2cc(C(C)C)c(F)cc2OC)cc1

Procedure:
Following the procedure described in EXAMPLE 379, Step A, 31 mg of 5-[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1-(4-methoxybenzyl)imidazolidin-2-one (INTERMEDIATE 32) and 9 μL of benzyl bromide gave the title compound. Mass spectrum (ESI) 607.5 (M+1).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]([OH:19])[C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([C:7]([C@H:8]2[CH2:9][CH2:10][C@H:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:13]2)=[O:19])=[N:4][CH:3]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](C(O)c2ncc(Br)s2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@H](C(=O)c2ncc(Br)s2)CC1
Reaction time: 0.5 h

Procedure:
Ethyl trans-4-[(5-bromo-1,3-thiazol-2-yl)(hydroxy)methyl]cyclohexanecarboxylate (11.5 g, 33 mmol) was diluted with CH2Cl2 (115 mL) and immersed in a room temperature water bath. To this was added Dess-Martin periodinane (15.4 g, 36.3 mmol) resulting in a noticeable exotherm. After 30 min, an aqueous solution of 5% NaHCO3 and 5% sodium sulfite was added and the resulting biphasic mixture stirred until both layers were clear. The layers were separated, the aqueous layer back extracted with CH2Cl2 and the combined organics dried with MgSO4, filtered and concentrated in vacuo. The crude residue was absorbed on silica and purified by flash chromatography to afford ethyl trans-4-[(5-bromo-1,3-thiazol-2-yl)carbonyl]cyclohexane-carboxylate (11.1 g, 32 mmol) as a yellow oil. MS ESI calc'd. for C13H17BrNO3S [M+H]+ 346, 348. found 346, 348. 1H NMR (600 MHz, CDCl3) δ 7.82 (s, 1H), 4.14-4.03 (m, 2H), 3.53-3.41 (m, 1H), 2.35-2.21 (m, 1H), 2.15-1.96 (m, 4H), 1.61-1.43 (m, 4H), 1.21 (t, J=7.1, 3H).
Reaction SMILES: [C:1]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:10])[C@H:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)O.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.N1C(C)=CC=CC=1C.CCN(C(C)C)C(C)C.[Si:51]([O:58][CH2:59][C@@H:60]1[C@@H:64]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH2:63][NH:62][CH2:61]1)([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52]>C(Cl)Cl>[Si:51]([O:58][CH2:59][C@@H:60]1[C@@H:64]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH2:63][N:62]([C@H:2]([CH:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[C:1]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:61]1)([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1ccccc1
Reactant: O=C(OCc1ccccc1)[C@@H](O)C1CCCCC1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CN([C@@H](C(=O)OCc2ccccc2)C2CCCCC2)C[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 42.4 %

Procedure:
A solution of 330 mg (1.3 mmol) of benzyl (S)-hexahydromandelate (from EXAMPLE 1, Step F) in 6.5 mL of CH2Cl2 at −78° C. was treated with 0.26 mL (1.5 mmol) of trifluoromethanesulfonic anhydride. The resulting mixture was stirred cold for 5 min and then treated with 0.30 mL (2.6 mmol) of 2,6-lutidine maintaining the internal temperature below −70° C. The resulting mixture was stirred cold for 15 min and then was treated with 0.46 mL (2.6 mmol) of DIEA. The resulting mixture was stirred cold for 15 min and then was treated with a solution of 300 mg (1.0 mmol) of 3-(R)-(t-butyldimethylsilyloxymethyl)-4-(S)-phenylpyrrolidine (from EXAMPLE 1, Step E) in 1.0 mL CH2Cl2. The reaction was warmed to 0° C. and stirred for 5 h. The reaction was partitioned between 50 mL of ether and 25 ml of H2O and the layers were separated. The aqueous layer was extracted with 25 mL of ether. The combined organic phases were dried over MgSO4 and concentrated. Flash chromatography using 9:1 v/v hexanes/EtOAc as the eluant afforded 221 mg (31%) of the title compound: RF: 0.72 (4:1 v/v hexanes/EtOAc); 1H NMR (500 MHz) δ 0.002 (s, 3H), 0.005 (s, 3H), 0.87 (s, 9H), 0.98-1.80 (9H), 2.01-2.07 (m, 2H), 2.33-2.37 (m, 1H), 2.70-2.74 (m, 2H), 2.90 (q, J=8.0, 1H), 3.12 (t, J=8.0, 1H), 3.20-3.24 (m, 2H), 3.49 (dd, J=7.5, 8.5, 1H), 3.58 (dd, J=5.0, 10.0), 5.18 (s, 2H), 7.18-7.41 (10H).
Reaction SMILES: [CH2:1]=[O:2].[C:3]1([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(=O)(O)[O-].[Na+].CS(C)=O>[C:10]([O:12][CH3:13])(=[O:11])[CH:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:1][OH:2]
Reactant: COC(=O)Cc1ccccc1
Reactant: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(CO)c1ccccc1
Reaction time: 0.67 h
Yield: 65.6 %

Procedure:
A nitrogen purged 500 mL three-neck flask was charged with sodium bicarbonate (1.05 g; 0.013 mole), paraformaldehyde (17.37 g; 0.55 mole) and dimethyl sulfoxide (100 mL). Methyl phenylacetate (75.09 g; 0.5 mole) was added and rinsed in with dimethylsulfoxide (50 mL). The slurry was stirred magnetically and the temperature rose from 22° C. to 34° C. over 40 minutes. The temperature remained at 33°-35° C. for about one hour, after which the temperature was raised to 45°-46° C. and held for 12 hours. The reaction mixture was allowed to cool with stirring for about seven hours. A solution of tartaric acid (1.88 g) in dimethylsulfoxide (6 mL) was added, and the solvent was distilled at pot temperature 45° C. to 88° C. at 0.25 mm Hg. The distillate g) was retained. The pale yellow oily residue (97.79 g) which contained a small amount of white solid(sodium hydrogen tartrate) was filtered, then fractionally distilled to give a main cut (59.1 g) of methyl tropate b.p. 106°-112° C. (0.2 mm. Hg).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]=[N+:13]=[N-:14])=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:15][N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[F:28])[CH3:2].[C:29]([O:33][CH2:34][CH3:35])(=[O:32])[C:30]#[CH:31]>C(O)C>[CH2:34]([O:33][C:29]([C:30]1[N:14]=[N:13][N:12]([C:10]2[CH:9]=[CH:8][C:7]3[N:3]([CH2:1][CH3:2])[C:4]([CH2:15][N:16]4[CH:20]=[CH:19][N:18]=[C:17]4[C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[F:28])=[N:5][C:6]=3[CH:11]=2)[CH:31]=1)=[O:32])[CH3:35]
Reactant: CCn1c(Cn2ccnc2-c2cc(F)ccc2F)nc2cc(N=[N+]=[N-])ccc21
Reactant: C#CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cn(-c2ccc3c(c2)nc(Cn2ccnc2-c2cc(F)ccc2F)n3CC)nn1

Procedure:
A mixture of crude 1-ethyl-2-{[2-(2,5-difluorophenyl)-1H-imidazol-1-yl]methyl}-5-azido-1H-benzimidazole (143 mg) and ethyl propiolate (1 eq.) in ethanol (10 mL) is heated at reflux for 6 h. The mixture is cooled, concentrated, and the residue purified by preparative silica gel chromatography to give 1-{2-[2-(2,5-Difluoro-phenyl)-imidazol-1-ylmethyl]-1-ethyl-1H-benzoimidazol-5-yl}-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester. 1H NMR (CDCl3): δ 8.51 s, (1H), 8.05 (s, 1H), 7.74 (m, 1H), 7.50-7.39 (m, 4H), 7.21-7.17 (m, 2H), 7.06 (s, 1H), 5.54 (s, 2H), 4.47 (q, 2H), 3.86 (q, 2H), 1.43 (t, 3H), 1.04 (t, 3H), LCMS MH+ 460.6.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O-:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-]>>[C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cc1ccccc1

Procedure:
Using the procedure in Example 2, methyl 3-chloro-4-(3-(2-phenylethyl)-7-propyl-6-benz[4,5]isoxazoloxy)propylthio)-phenylacetate was saponified with LiOH to form 3-chloro-4-(3-(2-phenylethyl)-7-propyl-6-benz[4,5]isoxazoloxy)propylthio)phenylacetic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[C:7]1([B:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[B:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)O)[OH:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:30]1([B:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[O:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[B:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:14][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: OB(c1ccccc1)c1ccccc1Oc1ccccc1B(O)c1ccccc1
Reactant: CN(C)CCO
Product: CN(C)CCOB(c1ccccc1)c1ccccc1Oc1ccccc1B(OCCN(C)C)c1ccccc1

Procedure:
The entitled compound (60 mg) was obtained by allowing 50 mg of dimethylethanolamine to act on 95 mg of bis(4,4′-(phenylhydroxyboryl)phenyl) ether.
Reaction SMILES: C(N(CC)CC)C.Br[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=[O:12])[O:10]1>CC(C)=O>[C:11]1([C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][O:10]1)=[O:12]
Reactant: O=C1OC(Br)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C1OCc2ccccc21
Reaction time: 1 h

Procedure:
A solution of 6-tritylaminopenicillanic acid (9.8 g; 0.02M) in dry acetone (100 ml.) was cooled to 0°C, triethylamine (2.9 mg. 0.02 M) was added, followed by 3-bromophthalide (4.1 g; 0.02M) in dry acetone (20 ml.), and the reaction mixture kept at 0°C with stirring for 2 hours and finally at ambient temperatures for 1 hour. The triethylammonium bromide which precipitated was removed by filtration, the evaporated filtrate was dissolved in ethyl acetate (150 ml.) and after two washings with cold 2% aqueous sodium bicarbonate (2 × 150 ml.) and with ice-water (2 × 100 ml.) the ethyl acetate layer was dried over anhydrous magnesium sulphate to yield, on removal of solvent in vacuo, phthalide 6-tritylaminopenicillanate as a white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Br[C:45]1[CH:50]=[CH:49][C:48]([N:51]=[S:52]([CH3:56])([NH:54][CH3:55])=[O:53])=[CH:47][CH:46]=1>>[OH:35][C@H:34]1[C@H:30]2[O:29][CH2:28][C@@H:27]([O:26][C:24]3[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:41])[CH3:42])[C:5]4=[N:6][C:7]([C:8]5[CH:13]=[CH:12][C:11]([C:45]6[CH:46]=[CH:47][C:48]([N:51]=[S:52]([CH3:56])([NH:54][CH3:55])=[O:53])=[CH:49][CH:50]=6)=[CH:10][CH:9]=5)=[C:2]([Cl:1])[CH:3]=[C:4]4[N:25]=3)[C@H:31]2[O:32][CH2:33]1
Reactant: CNS(C)(=O)=Nc1ccc(Br)cc1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Product: CNS(C)(=O)=Nc1ccc(-c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)cc1

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and N′-(4-bromophenyl)-N-methyl-methanesulfonimidamide following a procedure analogous to that described for Intermediate 3 (Step 3). LC (method 1): tR=1.07 min; Mass spectrum (ESI+): m/z=686 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]([NH:33][C:34](=[O:37])[CH:35]=[CH2:36])([CH3:32])[CH3:31].C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:36]=[CH:35]/[C:34]([NH:33][CH:30]([CH3:32])[CH3:31])=[O:37])[CH:12]=[CH:11][C:10]=1[N:16]1[CH2:17][C:18](=[O:29])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[S:20]1(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)NC(C)C
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)NC(=O)/C=C/c1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Temperature: 100 °C

Procedure:
To a mixture of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (240 mg, 0.44 mmol), N-isopropylacrylamide (60 mg, 0.53 mmol) and triethylamine (445 mg, 0.44 mmol) in MeCN (5 mL) in a pressure vessel is added Pd(OAc)2 (5 mg) and the mixture is heated at 100° C. for 8 h. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using hexane/EtOAc (86:15) as eluent to give the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:10][CH2:11][C:12]([OH:14])=O)=[N:4][C:5]([F:9])=[C:6]([Cl:8])[CH:7]=1.S(Cl)([Cl:17])=O>>[Cl:1][C:2]1[C:3]([O:10][CH2:11][C:12]([Cl:17])=[O:14])=[N:4][C:5]([F:9])=[C:6]([Cl:8])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)COc1nc(F)c(Cl)cc1Cl
Product: O=C(Cl)COc1nc(F)c(Cl)cc1Cl

Procedure:
A solution was prepared by admixing 8.6 grams (0.036 mole) of 3,5-dichloro-6-fluoro-2-pyridyloxy acetic acid in 15 milliliters of thionyl chloride. The mixture was refluxed for about 50 minutes. At the completion of the reaction, the excess thionyl chloride was removed by distillation. The liquid residue was cooled and the crystals which formed were separated. The (3,5-dichloro-6-fluoro-2-pyridyloxy)acetyl chloride product was recovered in a yield of 8.4 grams (92 percent of theoretical). Upon analysis, the product was found to have carbon, hydrogen, chlorine and nitrogen contents of 32.9, 0.9, 41.9 and 5.3 percent, respectively as compared with the theoretical contents of 32.8, 0.4, 41.4 and 5.5 percent, respectively, as calculated for the above-named compound.
Reaction SMILES: C([N:11]1[CH2:18][C:17]([F:20])([F:19])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O.[BrH:21].CCOCC>C(O)(=O)C>[BrH:21].[F:19][C:17]1([F:20])[CH2:18][NH:11][C@H:12]([C:13]([OH:15])=[O:14])[CH2:16]1
Reactant: O=C(O)[C@@H]1CC(F)(F)CN1C(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C(O)[C@@H]1CC(F)(F)CN1

Procedure:
A mixture of 2.4 grams of N-carbobenzyloxy-4, 4-difluoro-L-proline and 12 ml. of hydrogen bromide in acetic acid (30-32%) is stirred for 30 minutes at room temperature and then 300 ml. of anhydrous ether is added. The mixture is cooled and the precipitated solid is filtered and dried under reduced pressure. The desired 4,4-difluoro-L-proline, hydrobromide melts at 163°-165° (s. 160°); [α]D26 -14° (c=1%; methanol).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(N(CC)CC)C.[S:12]1[CH:16]=[CH:15][C:14]2[CH2:17][CH2:18][CH2:19][CH:20]([N:21]=[C:22]=[O:23])[C:13]1=2>C(Cl)Cl>[CH3:2][O:3][NH:4][C:22]([NH:21][CH:20]1[C:13]2[S:12][CH:16]=[CH:15][C:14]=2[CH2:17][CH2:18][CH2:19]1)=[O:23]
Reactant: CON
Reactant: O=C=NC1CCCc2ccsc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CONC(=O)NC1CCCc2ccsc21

Procedure:
A mixture of methoxyamine hydrochloride (5 g.) in 60 ml. of methylene chloride is stirred and 6 g. of triethylamine in 15 ml. of methylene chloride is added slowly. After half an hour of stirring, 5.4 g. of 4,5,6,7-tetrahydrobenzo[b]thien-7-yl isocyanate is added dropwise. The mixture is stirred at room temperature for an hour and filtered. The filter cake is washed with water and dried to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:11]([O:22][Si:23]([CH3:27])([CH3:26])[CH2:24][CH3:25])(=[O:21])[CH2:12][C:13]([O:15][Si:16]([CH3:20])([CH3:19])[CH2:17][CH3:18])=[O:14].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[C:12]([C:11]([O:22][Si:23]([CH3:27])([CH3:26])[CH2:24][CH3:25])=[O:21])[C:13]([O:15][Si:16]([CH3:19])([CH3:20])[CH2:17][CH3:18])=[O:14]
Reactant: COc1ccccc1C=O
Reactant: CC[Si](C)(C)OC(=O)CC(=O)O[Si](C)(C)CC
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCNCC1
Product: CC[Si](C)(C)OC(=O)C(=Cc1ccccc1OC)C(=O)O[Si](C)(C)CC
Yield: 74 %

Procedure:
2-Methoxybenzaldehyde (0.98 g, 7.2×10−3 mol) and di(methyltrimethylsilyl) malonate (2 g, 7.23×10−3 mol) in 8 ml of dry toluene in the presence of 6 mg of piperidine and 5 mg of acetic acid are refluxed for 5 hours in a reactor equipped with Dean-Stark apparatus. The water formed is removed azeotropically. The mixture is cooled and the toluene is removed by distillation. The reaction mixture is taken up in diisopropyl ether. The organic phase is washed twice with water, dried over sodium sulfate and filtered, and the solvent is evaporated off under vacuum. The brown oil obtained is purified by chromatography on a column of silica (eluent: 95/5 heptane/EtOAc). 2.1 g of clean fractions (yield: 74%) of the derivative of Example 12 are recovered in the form of a colorless viscous oil:
Reaction SMILES: C([O:4][CH:5]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:6][CH2:7][CH2:8][N:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])[S:10]([CH3:13])(=[O:12])=[O:11])(=O)C.[OH-].[Na+].O>C(O)C>[OH:4][CH:5]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:6][CH2:7][CH2:8][N:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[S:10]([CH3:13])(=[O:11])=[O:12]
Reactant: CCCCCC(CCCN(CCCCCCC(=O)OCC)S(C)(=O)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCC(O)CCCN(CCCCCCC(=O)O)S(C)(=O)=O
Reaction time: 20 h

Procedure:
A solution composed of ethyl 7-[N-(4-acetoxynonyl)methanesulfonamido]heptanoate (6.0 g., 0.0134 mole), sodium hydroxide (1.66 g., 0.0414 mole), water (9 ml.), and ethanol (81 ml.) is kept at room temperature for 20 hours. Most of the solvent is removed in vacuo, water (150 ml.) is added and the solution extracted with ethyl acetate (100 ml.). Then the aqueous layer is acidified (hydrochloric acid) and extracted again with ethyl acetate (2 × 75 ml.). The organic layer is dried over sodium sulfate then concentrated in vacuo to yield 7-[N-(4-hydroxynonyl)methanesulfonamido]heptanoic acid. The yield is 4.3 g. (88%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([O:21][C:22](=[O:39])[C@H:23]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([OH:38])[CH:33]=1)[NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH3:20]>C(C(C)=O)C.[I-].[K+]>[CH2:19]([O:21][C:22](=[O:39])[C@H:23]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH2:2][C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=2)[CH:33]=1)[NH:24][C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])[CH3:20]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCOC(=O)[C@H](Cc1cccc(O)c1)NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)[C@H](Cc1cccc(OCc2ccc3ccccc3c2)c1)NC(=O)C(F)(F)F
Temperature: 60 °C
Reaction time: 14 h
Yield: 78.8 %

Procedure:
2-(Bromomethyl)naphthalene (453 mg, 1.97 mmol), potassium carbonate (340 mg, 2.46 mmol) and potassium iodide (14 mg, 0.084 mmol) were added in turn to a solution of N-trifluoroacetyl-3-hydroxy-L-phenylalanine ethyl ester (500 mg, 1.64 mmol) in methyl ethyl ketone (20 ml) and the mixture was stirred under argon atmosphere at 60° C. for 14 hrs. The reaction mixture was cooled to room temperature and the insoluble materials were filtered off and washed with ethyl acetate. The filtrate and washings were combined and washed with water and brine and then dried. The solvent was distilled off under reduced pressure. The residue was purified, by column chromatography on silica gel (n-hexane/ethyl acetate=12) to give N-trifluoroacetyl-3-[(2-naphthyl)methoxy]-L-phenylalanine ethyl ester (576 mg, 79%) as colorless crystals.
Reaction SMILES: C([O:5][C:6](=[O:13])[C:7]([C:11]#[N:12])([CH3:10])[CH:8]=[CH2:9])(C)(C)C>Cl.O1CCOCC1>[C:11]([C:7]([CH3:10])([CH:8]=[CH2:9])[C:6]([OH:13])=[O:5])#[N:12]
Reactant: C=CC(C)(C#N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C=CC(C)(C#N)C(=O)O
Reaction time: 38 h

Procedure:
2-Cyano-2-methyl-but-3-enoic acid tert-butyl ester (362 mg, 2 mmol) was suspended in 4 M hydrochloric acid in dioxane (10 mL) and the reaction mixture stirred for 38 h and then evaporated. The residue was used directly in the next reaction.