Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:14]1([C:20]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]3[CH:24]([CH2:25][NH:26][CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH2:9][C:10]([N:26]1[CH2:25][CH:24]2[CH:28]([C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:21][CH2:22][C:23]2=[O:29])[CH2:27]1)=[O:12]
Reactant: O=C(O)Cc1c(F)cccc1F
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3c(F)cccc3F)CC12
Reaction time: 0.75 h
Yield: 67.6 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 2-(2,6-difluorophenyl)acetic acid (1.2 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 45 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.3 g) and triethylamine (0.98 cc) in dichloromethane (40 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with distilled water (2×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from ethyl acetate (10 cc). The crystals obtained are drained, washed with isopropyl ether (10 cc) and dried. (3aRS,7aRS)-2-[(2,6-difluorophenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (2.1 g) melting at 218° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([C:17]2[C:21]([Cl:22])=[C:20]([C:23]([F:26])([F:25])[F:24])[N:19]([CH3:27])[N:18]=2)=[CH:12][C:3]=1[O:4][CH:5]([CH3:11])[C:6]([O:8]CC)=[O:7].[OH-].[Na+].Cl>O.O1CCOCC1>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([C:17]2[C:21]([Cl:22])=[C:20]([C:23]([F:25])([F:26])[F:24])[N:19]([CH3:27])[N:18]=2)=[CH:12][C:3]=1[O:4][CH:5]([CH3:11])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(C)Oc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(Oc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1Cl)C(=O)O
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
To a slurry of 1.4 g (3.3 mmole) 2-(2-chloro-5-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4 -fluorophenoxy)-propanoic acid, ethyl ester in 50 mL water and 30 mL 1,4-dioxane was added 1.3 mL (3.3 mmole) of a 10% NaOH solution. After 30 minutes, the solution was cooled and the pH adjusted to 3 with concentrated HCl. The reaction mixture was extracted with diethyl ether. The ether solution was washed with water, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was recrystallized from methylcyclohexane to give 1.3 g (100%) of 2-(2-chloro-5-(4-chloro-1-methyl-5-(tri-fluoromethyl)-1H-pyrazol-3-yl)-4-fluorophenoxy)-propanoic acid as a white solid, mp 150°-151° C.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][CH:35]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:22][CH2:21]N(C(OCC3C=CC=CC=3)=O)[CH2:19]2)[CH2:14]1)=[O:11])=[O:7].[S:38]1CCC(=O)C1.O=C1CCN(C(OCC2C=CC=CC=2)=O)C1>>[O:11]=[C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:22][CH2:21][S:38][CH2:19]2)[CH2:14]1)[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:33]=[CH:34][CH:35]=[C:3]([C:2]([F:37])([F:36])[F:1])[CH:4]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCN(C(=O)OCc3ccccc3)C2)C1
Reactant: O=C1CCSC1
Agent: O=C1CCN(C(=O)OCc2ccccc2)C1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCSC2)C1

Procedure:
The title compound was synthesized in similar fashion to benzyl (3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3′-bipyrrolidine-1′-carboxylate, whereby dihydrothiophen-3(2H)-one was substituted for benzyl 3-oxopyrrolidine-1-carboxylate, and was isolated, as a mixture of diastereomers, as a white solid. 1H-NMR (CDCl3) δ: 1.55-1.66 (m, 1H), 1.71-1.81 (m, 1H), 2.03-2.14 (m, 1H), 2.15-2.26 (m, 1H), 2.33-2.39 (m, 1H), 2.52-2.58 (m, 1H), 2.63-2.73 (m, 3H), 2.74-2.81 (m, 4H), 4.07 (d, J=4.8 Hz, 2H), 4.36-4.38 (m, 1H), 7.04 (d, J=7.8 Hz, 1H), 7.46 (t, J=7.9 Hz, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.81 (t, J=4.9 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 8.03 (s, 1H). MS m/z: 402 (M+1)
Reaction SMILES: [NH:1]([C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([N:10]2[CH2:13][CH:12]([C:14]3[N:18]([CH3:19])[C:17]4[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=4[N:15]=3)[CH2:11]2)[CH:4]=1)[NH2:2]>C(O)(=O)C>[CH2:4]([C:5]1[N:1]([C:3]2[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([N:10]3[CH2:11][CH:12]([C:14]4[N:18]([CH3:19])[C:17]5[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=5[N:15]=4)[CH2:13]3)[CH:4]=2)[N:2]=[C:7]([CH3:9])[N:6]=1)[CH3:3]
Reactant: Cc1nc(NN)cc(N2CC(c3nc4ccccc4n3C)C2)n1
Solvent: CC(=O)O
Product: CCc1nc(C)nn1-c1cc(N2CC(c3nc4ccccc4n3C)C2)nc(C)n1

Procedure:
A solution of Intermediate 11 (50 mg, 0.16 mmol) and A (46 mg, 0.32 mmol) in acetic acid (1.6 mL) was heated at 100° C. for 30 min. The solvent was removed in vacuo and the residue was purified by reverse phase chromatography (MeCN/H2O/0.1% TFA). The fractions containing the product were partitioned between EtOAc and saturated NaHCO3. The organic layer was washed with 50% saturated brine solution, dried over Na2SO4 and concentrated to provide Example 35 as an off-white solid. 1H NMR: (500 MHz, DMSO-d6) δ 7.60 (d, J=8 Hz, 1H), 7.53 (d, J=8 Hz, 1H), 7.21 (m, 2H), 6.52 (s, 1H), 4.58 (m, 2H), 4.45 (m, 3H), 3.74 (s, 3H), 3.22 (q, J=7.5 Hz, 2H), 2.44 (s, 3H), 2.30 (s, 3H) 1.25 (t, J=7.5 Hz, 3H). MS: m/z=389.5 (M+H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:24])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)O1>>[OH:21][CH2:20][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[N:7]=3)=[O:24])=[CH:14][CH:15]=1)([CH3:23])[CH3:22]
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Product: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(-c4ccncc4)nc3s2)cc1
Yield: 63 %

Procedure:
The titled compound (yield=63%, white solid) was prepared using a procedure analogous to that described in connection with 10 (Example 10) except 2F (Example 2) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (s, 6H) 3.49 (s, 2H) 7.59 (d, J=8.59 Hz, 2H) 8.10-8.12 (d, J=8.59 Hz, 2H) 8.31-8.36 (m, 1H) 8.37-8.44 (m, 3H) 8.85 (d, J=5.31 Hz, 2H) 13.15 (s, 1H); ESI-MS: m/z 405.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3C=CC(CCC(O)=O)=CC=3)[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4]([O:31][CH2:32]C2CCCC2)[CH:3]=1.ClC1C=CC(C2N(CC3C=C(C=CC=3)C(O)=O)C3C=C(F)C(F)=CC=3N=2)=C(OCC2CCCC2)C=1.[CH2:73]([O:75][C:76](=[O:83])[CH2:77][CH2:78][CH2:79]CCBr)C>>[CH3:73][O:75][C:76](=[O:83])[CH2:77][CH2:78][CH2:79][CH2:14][CH2:13][N:12]1[C:11]2[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=2[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[O:31][CH3:32]
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Reactant: CCOC(=O)CCCCCBr
Agent: O=C(O)c1cccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)c1
Product: COC(=O)CCCCCn1c(-c2ccc(Cl)cc2OC)nc2cc(F)c(F)cc21

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-chloro-2-methoxy-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 19, intermediate c) and (6-bromo-hexanoic acid ethyl ester (CAS Reg. No. 25542-62-5). Brown solid (67%). MS (Turbo Spray): m/z=437.2 (M+H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:38]([C:40]([CH3:47])([CH2:44][CH2:45][CH3:46])[C:41](Cl)=[O:42])[CH3:39]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:41](=[O:42])[C:40]([CH2:38][CH3:39])([CH3:47])[CH2:44][CH2:45][CH3:46])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCCC(C)(CC)C(=O)Cl
Product: CCCC(C)(CC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 78.4 %

Procedure:
A procedure similar to that described in Example 6, above, was followed, but using 1.0 g (1.8 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] and 1.18 g (7.3 mmol) of 2-ethyl-2-methylvaleryl chloride, to provide 956 mg of the title compound.
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][N:4]([CH3:13])[C:3]1=[O:14].[C:15]1([CH3:42])[CH:20]=[CH:19][C:18]([C:21]([C@@:23]([C:39]([OH:41])=[O:40])([OH:38])[C@@:24]([C:29]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)=[O:30])([OH:28])[C:25]([OH:27])=[O:26])=[O:22])=[CH:17][CH:16]=1>CO>[C:15]1([CH3:42])[CH:20]=[CH:19][C:18]([C:21]([C@@:23]([C:39]([OH:41])=[O:40])([OH:38])[C@@:24]([C:29]([C:31]2[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=2)=[O:30])([OH:28])[C:25]([OH:27])=[O:26])=[O:22])=[CH:17][CH:16]=1.[NH2:1][C@H:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][N:4]([CH3:13])[C:3]1=[O:14]
Reactant: CN1CCc2ccccc2C(N)C1=O
Agent: Cc1ccc(C(=O)[C@](O)(C(=O)O)[C@@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Solvent: CO
Product: CN1CCc2ccccc2[C@H](N)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 22 L vessel, under nitrogen, 1-amino-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one (438 g, 2.3 mol) was heated (about 40° C.) to provide a solution in methanol (4.38 mL). In another flask, di-p-toluoyl-l-tartaric acid (889.7 g, 2.3 mol) was dissolved in 4.38 L of methanol and heated to about 40° C. before the solution of 1-amino-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one was added. The heating was continued and an additional 6.13 L of methanol was added before the mixture was refluxed for about 45 minutes and then slowly cooled to ambient temperature to give a solid. After stirring for about 18 hours, the solid was collected by filtration and rinsed with a small amount of mother liquors, and after air drying, with about 2 L of ethyl acetate to give 561.6 g of (S)-1-amino-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one di-p-toluoyl-L-tartaric acid salt. Combine (S)-1-amino-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one di-p-toluoyl-L-tartaric acid salt, dichloromethane (6.57 L) and 1N aqueous sodium hydroxide solution (6.57 L) and agitate. Separate the layers and extract the organic layer twice with and 1N aqueous sodium hydroxide solution (3.28 L), once with brine (2.46 L) before drying over magnesium sulfate, filtering, and evaporating on a rotary evaporator to give the title compound 250g (57.4%, 94.1% ee).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[N:22]=[C:23]=[S:24].Cl.[NH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].C(N(CC)CC)C.O>CC(C)=O.C(Cl)Cl.C(Cl)Cl.C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[NH:22][C:23]([NH:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[S:24]
Reactant: COC(=O)CCN
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N=C=S)c(Cl)cc2F)c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)CCNC(=S)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
A solution of 2-chloro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-4-fluorophenyl isothiocyanate (6.0 g, 15.8 mmol) and β-alanine, methyl ester, hydrochloride salt (2.65 g, 19.0 mmol) in acetone is cooled to 0° C., treated dropwise with a solution of triethylamine (1.92 g, 19.0 mmol) in methylene chloride, stirred overnight at room temperature, and poured into water. The resultant aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with 5% hydrochloric acid and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a brown foam. Flash column chromatography of the foam using silica gel and a (9:1) methylene chloride/diethyl ether solution gives the title product as an off-white foam (5.68 g, 74.4% yield, mp 110° C.) which is identified by 1H NMR spectral analysis.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(OC=3C3C=CC=CC=3)=C3C(=CC=4)NN=C3)=CC=2)CCC1.C(OC(=O)[NH:38][C:39]1([C:43]2[CH:48]=[CH:47][C:46]([C:49]3[C:54](=[O:55])[C:53]4[CH:56]=[CH:57][C:58]5[N:59]=[C:60]([CH:63]([F:65])[F:64])[NH:61][C:62]=5[C:52]=4[O:51][C:50]=3[C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)=[CH:45][CH:44]=2)[CH2:42][CH2:41][CH2:40]1)(C)(C)C>>[NH2:38][C:39]1([C:43]2[CH:48]=[CH:47][C:46]([C:49]3[C:54](=[O:55])[C:53]4[CH:56]=[CH:57][C:58]5[N:59]=[C:60]([CH:63]([F:65])[F:64])[NH:61][C:62]=5[C:52]=4[O:51][C:50]=3[C:66]3[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=3)=[CH:45][CH:44]=2)[CH2:40][CH2:41][CH2:42]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5nc(C(F)F)[nH]c54)c3=O)cc2)CCC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5[nH]ncc54)c3=O)cc2)CCC1
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5nc(C(F)F)[nH]c54)c3=O)cc2)CCC1
Yield: 58 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-2-phenyl-7H-pyrano[2,3-e]indazol-4-one, {1-[4-(2-difluoromethyl-6-oxo-8-phenyl-1,6-dihydro-chromeno[7,8-d]imidazol-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a white solid (29 mg, 58%). 1H NMR (400 MHz, DMSO-d6): δ 7.78 (d, J=8.7 Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.50-7.46 (m, 2H), 7.45-7.34 (m, 5H), 7.27-7.23 (m, 2H), 7.12 (t, J=53.8 Hz, 1H), 2.55-2.46 (m, 2H), 2.34-2.25 (m, 2H), 2.13-2.03 (m, 1H), 1.80-1.70 (m, 1H). LCMS (Method E): RT=3.14 min, [M+H]+=458.
Reaction SMILES: [CH2:1]([C:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)C1C=CC=CC=1.[CH:17]1C(Cl)=CC=C(Cl)C=1>CCCCCC>[CH2:10]1[CH:11]2[CH:12]3[CH:13]=[CH:14][CH:15]([CH:16]2[CH:1]=[CH:8]1)[CH2:17]3
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Reactant: Clc1ccc(Cl)cc1
Solvent: CCCCCC
Product: C1=CC2C3C=CC(C3)C2C1

Procedure:
A one mole equivalent sample of product II and two mole equivalent of dibenzylketone is heated for 4 hours in a mechanically stirred dichlorobenzene solution. The mixture is diluted with addition of hexane and the solid product is filtered, washed with hexane and dried. Purification of this product may be carried out by recrystallization from acetone or methyl ethyl ketone. ##STR41## where: Ph=phenyl rings.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:29]=[CH:28][C:27]([NH:30][C:31](=[O:52])[C:32]4[CH:37]=[C:36]([NH:38][C:39](=[O:50])[C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=5)[CH:35]=[CH:34][C:33]=4[Cl:51])=[CH:26][N:25]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:53]([OH:59])([C:55]([F:58])([F:57])[F:56])=[O:54]>C(Cl)Cl>[Cl:51][C:33]1[CH:34]=[CH:35][C:36]([NH:38][C:39](=[O:50])[C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:47])([F:48])[F:49])[CH:41]=2)=[CH:37][C:32]=1[C:31]([NH:30][C:27]1[CH:26]=[N:25][C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([S:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)(=[O:16])=[O:15])=[CH:18][CH:19]=2)=[N:29][CH:28]=1)=[O:52].[C:53]([OH:59])([C:55]([F:58])([F:57])[F:56])=[O:54]
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(Nc3ncc(NC(=O)c4cc(NC(=O)c5cccc(C(F)(F)F)c5)ccc4Cl)cn3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Cl)c(C(=O)Nc2cnc(Nc3ccc(S(=O)(=O)C4CCNCC4)cc3)nc2)c1)c1cccc(C(F)(F)F)c1
Reaction time: 3 h

Procedure:
A stirred suspension of intermediate 14 (Example 21) (0.058 g, 0.076 mmol) in DCM (8 mL) was treated with TFA (0.100 mL) and stirred for 3 h. Solvents were then removed yielding desired product as TFA salt (0.05 g, 99%). 1H NMR (DMSO-d6): δ 1.62-1.70 (m, 2H), 2.01-2.08 (m, 4H), 2.8-2.9 (m, 2H), 3.3-3.6 (m, 2H), 3.45-3.49 (m, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.81 (t, J=15.7 Hz, J=7.8 Hz, 1H), 7.93 (dd, J=8.8 Hz, J=2.5 Hz, 1H), 8.00 (d, J=7.6 Hz, 1H), 8.05 (d, J=8.9 Hz, 2H), 8.10 (d, J=2.5 Hz, 1H), 8.20-8.32 (m, 3H), 8.65-8.69 (m, 1H), 8.90 (s, 2H), 10.37 (s, 1H), 10.76 (s, 1H), 10.80 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[Si](C=[N+]=[N-])(C)(C)[CH3:15].CC(O)=O>CO.C(#N)C>[Cl:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:15])=[O:6]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cccc(Cl)c1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CO
Product: COC(=O)c1cccc(Cl)c1[N+](=O)[O-]
Reaction time: 0.33 h
Yield: 74.3 %

Procedure:
To 3-chloro-2-nitrobenzoic acid (3.15 g, 15.6 mmol) in methanol/acetonitrile (20 mL/20 mL) was dropwise added TMSCHN2 (2N in hexanes, 11.7 mL, and 23.4 mmol) at 0° C. under N2 over 10 min until the yellow color persist. The mixture was continued stirring for 20 min, followed by dropwise addition of HOAc until the yellow color disappeared to kill excessive TMSCHN2. Partial of the solvent was removed on rotary vacuum, the product came out solution as a light yellow solid, which was filtered and washed with Et2O (2×2 mL) to afford the expected product as a white solid (2.5 g, 74% yield); 1H NMR (400 MHz, CDCl3) δ ppm 3.91 (s, 3 H), 7.51 (t, J=8.06 Hz, 1 H), 7.70 (dd, J=8.06, 1.26 Hz, 1 H), 7.97 (dd, J=7.81, 1.26 Hz, 1 H); Mass spec. 216.02 (MH+), Calc. for C8H6ClNO4 215.00.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[NH:7][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.Cl.[NH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[F:30][C:27]([F:28])([F:29])[C:4]1[CH:3]=[C:2]([C:37]2[CH:38]=[CH:39][C:34]([CH2:33][NH2:32])=[CH:35][CH:36]=2)[C:10]2[NH:9][C:8]([N:11]3[CH2:12][CH2:13][N:14]([C:17]4[C:22]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:15][CH2:16]3)=[N:7][C:6]=2[CH:5]=1
Reactant: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1
Reactant: NCc1ccc(B(O)O)cc1
Agent: Cl
Product: NCc1ccc(-c2cc(C(F)(F)F)cc3nc(N4CCN(c5ncccc5C(F)(F)F)CC4)[nH]c23)cc1

Procedure:
The title compound was prepared from 4-bromo-6-trifluoromethyl-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-1H-benzoimidazole (Example 7) and 4-aminomethylphenylboronic acid hydrochloride (Acros) under the conditions of Example 51a and isolated as a white amorphous solid. MS (ESI, pos. ion) m/z: 521 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([S:10]([N:13]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[CH3:25])[CH2:14][CH:15]([CH3:17])[CH3:16])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[CH:8]=[CH2:9].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[OH-].[K+].[O:58]1CCOCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:25][C:19]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=1[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:10]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH2:9])=[C:2]([OH:58])[CH:3]=1)(=[O:12])=[O:11]
Reactant: C1COCCO1
Reactant: C=Cc1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)cc1Cl
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: C=Cc1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)cc1O
Temperature: 150 °C

Procedure:
3-chloro-N-(2,4-dimethylphenyl)-N-isobutyl-4-vinylbenzenesulfonamide (250 mg, 0.662 mmol), tris(dibenzylideneacetone)dipalladium(0) (6.06 mg, 6.62 μmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (2.81 mg, 6.62 μmol) and potassium hydroxide (111 mg, 1.985 mmol) were added to a microwave vial. 1,4-dioxane (1 mL) and water (1.000 mL) were then added. The reaction vessel was sealed and heated by microwaves (Biotage Initiator) to 150° C. for 2 hours. LCMS analysis showed the desired product and several side-products. The crude material was purified by silica (Si) chromatography (0-100% ethyl acetate-cyclohexane gradient). The appropriate fractions were combined and evaporated in vacuo to give the required product, 100.8 mg, as a yellow gum. LCMS [LCMS2] Rt 1.42 min, m/z (ES+) 360 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([CH3:17])=[C:5]([O:13]C(=O)C)[C:6]([CH3:12])=[N:7][C:8]=1[CH2:9][CH2:10][CH3:11]>Cl>[OH:1][CH2:2][C:3]1[C:4]([CH3:17])=[C:5]([OH:13])[C:6]([CH3:12])=[N:7][C:8]=1[CH2:9][CH2:10][CH3:11]
Reactant: CCCc1nc(C)c(OC(C)=O)c(C)c1CO
Agent: Cl
Product: CCCc1nc(C)c(O)c(C)c1CO
Yield: 105.9 %

Procedure:
A solution of acetic acid 5-hydroxymethyl-2,4-dimethyl-6-propyl-pyridin-3-yl ester (176) (7.8 g, 32.9 mmol) in hydrochloric acid (100 mL, 1N) was refluxed for 90 minutes. The reaction mixture was evaporated to give 5-hydroxymethyl-2,4-dimethyl-6-propyl-pyridin-3-ol (177) (6.8 g, 97% yield).
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][C:6]=1[F:14].[Al+3].[Cl-].[Cl-].[Cl-].[C:19]1([O:25][CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>ClCCl>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([C:22]2[CH:23]=[CH:24][C:19]([O:25][CH3:26])=[CH:20][CH:21]=2)=[O:10])=[CH:7][C:6]=1[F:14]
Reactant: O=C(Cl)c1ccc(OCCBr)c(F)c1
Reactant: COc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(OCCBr)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.2 %

Procedure:
To a solution of 4-(2-bromoethoxy)-3-fluorobenzoyl chloride (1.07 g, 3.80 mmol) and anhydrous AlCl3 (1.01 g, 7.60 mmol) in dry dichloromethane (18 mL) was added anisole (822 mg, 7.60 mmol) in 2 mL dichloromethane at 0° C. After stirring at rt for 6 h, the mixture was poured into 3 N HCl and extracted with dichloromethane twice. The extracts were combined, washed with sat. NaHCO3 and brine, dried over Na2SO4, filtered, concentrated, and purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate=10/1 to 5/1) to give 1.05 g (77% yield) of the subtitle compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=8.8 Hz, 2H), 7.58 (d, J=11.6 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.03 (dd, J=8.0 Hz, 8.4 Hz, 1H), 6.98 (d, J=9.2 Hz, 2H), 4.44 (t, J=6.4 Hz, 2H), 3.90 (s, 3H), 3.70 (t, J=6.4 Hz, 2H).
Reaction SMILES: O=C[C@H]([C@@H]([C@@H](CO)O)O)O.[O:11]=[CH:12][C@H:13]([C@@H:15]([C@@H:17]([C@H:19]([CH3:21])[OH:20])[OH:18])[OH:16])[OH:14].OCC([C@@H]([C@@H]([C@H](C)O)O)O)=O.OCC([C@H]([C@H]([C@@H](CO)O)O)O)=O>>[OH:11][CH2:12][C:13]([C@H:15]([C@@H:17]([C@H:19]([CH3:21])[OH:20])[OH:18])[OH:16])=[O:14]
Reactant: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Agent: C[C@H](O)[C@@H](O)[C@@H](O)C(=O)CO
Agent: O=C(CO)[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Product: C[C@H](O)[C@@H](O)[C@H](O)C(=O)CO

Procedure:
With D-arabinose isomerase, L-fucose (6-deoxy L-galactose) was isomerized to 6-deoxy L-tagatose, which was further epimerized with D-tagatose 3-epimerase, to produce 6-deoxy L-sorbose.