Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][C:3]=1[F:10].[Li]CCCC.[B:16](OC)([O:19]C)[O:17]C.Cl>C1COCC1.CCOCC>[F:10][C:3]1[CH:4]=[C:5]([S:8][CH3:9])[CH:6]=[CH:7][C:2]=1[B:16]([OH:19])[OH:17]
Reactant: CSc1ccc(Br)c(F)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CSc1ccc(B(O)O)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 16.3 %

Procedure:
A stirred solution of 1-bromo-2-fluoro-4-(methylthio)benzene (180 g, 814 mmol) at −78° C. in THF (500 mL) was treated with n-BuLi (358 mL, 2.5M in hexanes, 895 mmol) over 1.5 h. After 15 min at −78° C., B(OMe)3 (254 g, 244 mol) was added over 1.5 h, and the reaction mixture was slowly warmed to ambient temperature. 10% Aqueous HCl (100 mL) was added and the mixture was stirred for 5 min. Et2O (500 mL) was added and the organic layer was separated and washed with 2M NaOH (300 mL). The aqueous phase was rinsed one more time with Et2O. The aqueous phase was then acidified with 10% aqueous HCl to pH ˜4 and the resulting solid was collected to give [2-fluoro-4-(methylthio)phenyl]boronic acid (24.7 g). 1H NMR (400 MHz, CDCl3): δ 7.70 (t, 1H, J=7.6 Hz), 7.03 (dd, 1H, Ja=8.1 Hz, Jb=1.6 Hz), 6.88 (dd, 1H, Ja=11.7 Hz, Jb=1.6 Hz), 2.49 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([O:11][CH2:12][C:13]2[C:14]([C:19]3[N:23](COCC[Si](C)(C)C)[N:22]=[CH:21][CH:20]=3)=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:9][N:10]=1)[CH:6]=[O:7].[ClH:32]>CCO>[ClH:32].[ClH:32].[NH:23]1[C:19]([C:14]2[C:13]([CH2:12][O:11][C:8]3[C:5]([CH:6]=[O:7])=[CH:4][C:3]([O:2][CH3:1])=[N:10][CH:9]=3)=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:20][CH:21]=[N:22]1
Reactant: COc1cc(C=O)c(OCc2cccnc2-c2ccnn2COCC[Si](C)(C)C)cn1
Agent: Cl
Solvent: CCO
Product: COc1cc(C=O)c(OCc2cccnc2-c2ccn[nH]2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To 2-methoxy-5-((2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (120 mg, 0.27 mmol, 1 equiv) suspended in EtOH (1 mL) was added HCl (1.0 mL, 3 N). The solution turned homogeneous and the mixture was stirred at rt overnight. The EtOH was partially removed by blowing in N2 gas and the precipitate was collected. The solid was washed with acetonitrile and EtOAc and dried under high vacuo to give 5-((2-(1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde dihydrochloride (100 mg, 96%) as a white solid. 1H NMR (400 MHz; DMSO, 80° C.) δ=10.27 (s, 1H), 8.68 (br, 1H), 8.32 (br, 1H), 8.22 (s, 1H), 7.82 (br, 1H), 7.57 (br, 1H), 7.00 (br, 2H), 5.75 (s, 2H), 3.89 (s, 3H). LRMS (M+H+) m/z 311.1.
Reaction SMILES: [Si]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][C:10]=1[CH2:17][CH:18]=[CH2:19])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][C:10]=1[CH2:17][CH:18]=[CH2:19]
Reactant: C=CCc1cc(CO)ccc1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCc1cc(CO)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 793.1 %

Procedure:
To a solution of approximately 7.26 g (2.6 mmol) of crude 4-tert-butyldimethylsilyloxy-3-(2-propen-1-yl)benzyl alcohol, from Step D, dissolved in 50 mL of anhydrous THF was added 26 mL (2.6 mmol) of tetra-n-butylammonium fluoride and the reaction mixture was stirred at room temperature for 16 hours. The mixture was then evaporated in vacuo and the residual oil was purified on a silica gel flash chromatography column eluted with 5% methanol/chloroform to afford 3.386 g (79%) of the title compound as a colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[C:31]([OH:38])[C:30]=2[CH2:39][CH2:40][CH3:41])[C:8]=1[CH2:42][CH2:43][CH3:44])C.[OH-].[Na+]>CO>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:45])=[O:3])=[C:8]([CH2:42][CH2:43][CH3:44])[C:9]=1[O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[C:31]([OH:38])[C:30]=1[CH2:39][CH2:40][CH3:41])(=[O:15])[CH3:14]
Reactant: CCCc1c(OCCOCCOCCOCCOc2c(C(C)=O)ccc(OCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCOCCOCCOCCOc2c(C(C)=O)ccc(OCC(=O)O)c2CCC)ccc(C(C)=O)c1O
Yield: 65.3 %

Procedure:
A solution of 1.25 g (0.002 mole) of [4-acetyl-3-[2-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester in 30 ml of methanol and 10 ml (0.01 mole) of 1.0N sodium hydroxide was stirred at reflux for 5 hours. Most of the solvent was removed in vacuo and the pH of the residue was adjusted to 2.0 with 6N hydrochloric acid. The product was extracted with methyl acetate and the dried (magnesium sulfate) extract was concentrated in vacuo to an oil which was purified by chromatography on 75 g of silica gel. Elution with toluene-ethyl acetate-acetic acid (65:25:10) gave 0.79 g (66% yield) of [4-acetyl-3-[2-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]acetic acid as an oil.
Reaction SMILES: FC1C=CC=C(F)C=1CN1C2C=CC=CC=2N=C1C1C(F)=CC=CC=1F.FC1C=CC=C(F)C=1C(Cl)=O.Cl[Sn]Cl.Cl.CC(OC(C)=O)=O.[BH4-].[Na+].OS(O)(=O)=O.N([O-])=O.[Na+].Br.[F:61][C:62]1[CH:88]=[CH:87][CH:86]=[C:85]([F:89])[C:63]=1[CH2:64][N:65]1[C:69]2[CH:70]=[CH:71][CH:72]=[C:73]([N+:74]([O-])=O)[C:68]=2[N:67]=[C:66]1[C:77]1[C:82]([F:83])=[CH:81][CH:80]=[CH:79][C:78]=1[F:84]>C1COCC1.CC(O)=O.N1C=CC=CC=1.C1COCC1>[NH2:74][C:73]1[C:68]2[N:67]=[C:66]([C:77]3[C:82]([F:83])=[CH:81][CH:80]=[CH:79][C:78]=3[F:84])[N:65]([CH2:64][C:63]3[C:62]([F:61])=[CH:88][CH:87]=[CH:86][C:85]=3[F:89])[C:69]=2[CH:70]=[CH:71][CH:72]=1
Reactant: O=[N+]([O-])c1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Agent: Br
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: Nc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F

Procedure:
FIG. 9 provides a schematic approach for the preparation of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole substituted with chloro, bromo, nitro, amino, acetylamino, dimethylamino groups at the C-4 position of the benzimidazole ring. In this Figure, “a” comprises 2,6-difluorobenzoyl chloride, pyridine:THF (1:1); “b” comprises AcOH reflux; “c” comprises 2,6-F2-BnBr, NaH,THF; “d” comprises SnCl2, AcOH, HCl; “e” comprises Ac2O, THF; “f” comprises H2CO, NaBH4, H2SO4; and “g” comprises NaNO2, HBr or HCl. As shown in this Figure, reduction of the 4-nitro group of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-nitrobenzimidazole (Example 83) was accomplished with tin (II) chloride, which gives 4-amino-1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole 3300 (Example 85). Compound 3300 was used to prepare 4-bromo-1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole (Example 86) and 4-chloro-1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole (Example 87) via the Sandmeyer reactions (i.e., methods known in the art). Monoacylation of compound 3300 with acetic anhydride gave 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-acetamidobenzimidazole (Example 88), while treatment of 3300 with formaldehyde and sodium borohydride yielded the dimethylamino compound 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-N,N-dimethylaminobenzimidazole (Example 89).
Reaction SMILES: [NH2:1][C:2]([C@@H:4]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[N:5]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:3].[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.N1C=CC=CC=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[NH2:1][C:2]([C@@H:4]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)=[CH:11][CH:10]=2)[N:5]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(O)cc2)CC[C@H]1C(N)=O
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(Oc3ccc(F)cc3)cc2)CC[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 112.8 %

Procedure:
This compound was prepared in two batches under different conditions (Conditions A and B). In a closed vial 1,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-5-(4-hydroxyphenyl)-1-pyrrolidinecarboxylate (D13, 19 mg, 0.062 mmol), copper-(II)-acetate (11 mg, 0.062 mmol), (4-fluorophenyl)boronic acid (17 mg, 0.124 mmol) and molecular sieves were suspended in DCM. Then either pyridine (Condition A, 24.5 mg, 0.31 mmol) or triethylamine (Condition B, 31.3 mg, 0.31 mmol) was added and the reaction was shaken at room temperature for 24 h. The crude reaction products from Conditions A and B were combined, filtered and evaporated. The crude residue was purified by chromatography on silica gel using cyclohexanes/ethyl acetate (7:3) to afford the title compound (28 mg, 56%); Rt (HPLC): 5.61 min; MS: (ES/+) m/z: 423 [M+Na+], C22H25N2O4 requires 400; 1H NMR (400 MHz, DMSO-d6) δ ppm: 1.08 (s, 9H); 1.73-1.84 (m, 1H); 1.86-1.96 (m, 1H); 2.00-2.11 (m, 1H); 2.17-2.27 (m, 1H); 4.56-4.73 (m, 1H); 4.74-4.86 (m, 1H); 6.92 (br. s., 2H); 6.95 (br. s., 1H); 7.02 (br. s., 2H); 7.21 (t, 2H); 7.38 (s, 1H); 7.64 (br. s., 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([C:21](O)=[O:22])=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([CH3:27])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.C([N:38](CC)CC)C.N>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[C:20]([C:21](=[O:22])[NH2:38])=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([CH3:27])[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(C(=O)O)cc1[N+](=O)[O-]
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: ClCCl
Product: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(C(N)=O)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-5-carboxy-2-methylnitrobenzene (4.8 g) in dichloromethane (100 ml) were added isobutyl chloroformate (1.7 ml) and triethylamine (1.8 ml) in an ice bath and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added 28% aqueous ammonia (0.8 ml) and the resulting mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using dichloromethane/methanol=19/1 as an eluant to give the desired compound (4.7 g, yield 97%) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:21]=[C:20]([F:22])[C:19]([N+:23]([O-:25])=[O:24])=[C:18]([F:26])[CH:17]=2)[CH2:11][S:10](=[O:28])(=[O:27])[CH2:9]1)(C)(C)C.[ClH:30]>O1CCOCC1>[ClH:30].[NH2:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:17]=[C:18]([F:26])[C:19]([N+:23]([O-:25])=[O:24])=[C:20]([F:22])[CH:21]=2)[CH2:11][S:10](=[O:27])(=[O:28])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CS(=O)(=O)C[C@@H](Cc2cc(F)c([N+](=O)[O-])c(F)c2)[C@@H]1O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CS(=O)(=O)C[C@@H](Cc2cc(F)c([N+](=O)[O-])c(F)c2)[C@@H]1O
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To [(3R,4S,5S)-5-(3,5-difluoro-4-nitro-benzyl)-4-hydroxy-1,1-dioxo-hexahydro-1lambda*6*-thiopyran-3-yl]-carbamic acid tert-butyl ester (0.873 g, 2 mmol) was added 4N HCl in dioxane (5 mL) and the reaction mixture was stirred for 3 h at 40° C. After evaporation the residue was stirred with Et2O, filtered and dried to provide the title compound as a beige solid: TLC (CH2Cl2-MeOH-AcOH-H2O 180:20:2:1) Rf=0.13; HPLC RtA=1.22 min; ESIMS [M+H]+=337; 1H NMR (600 MHz, DMSO-d6): δ 8.34 (s, 3H), 7.37 (d, 2H), 6.14 (d, 1H), 3.3-3.5 (m, 4H), 3.31 (d, 1H), 3.22 (d, 1H), 3.12 (m, 1H), 2.74 (dd, 1H), 2.26 (m, 1H).
Reaction SMILES: Br[Si](C)(C)C.CS(C)=O.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C@H:17]1[C@H:22]([C:23]([OH:25])=[O:24])[CH2:21][CH:20]=[CH:19][CH2:18]1.C=CC=C.[Br:30]C1C=CC=CC=1C=CC(O)=O.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:30][C@H:19]1[C@@H:20]2[CH2:21][C@@H:22]([C:23](=[O:25])[O:24]2)[C@H:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[Br:10])[CH2:18]1
Reactant: O=C(O)[C@@H]1CC=CC[C@H]1c1ccccc1Br
Reactant: O=C(O)C=Cc1ccccc1Br
Agent: C=CC=C
Agent: C[Si](C)(C)Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C1O[C@H]2C[C@@H]1[C@H](c1ccccc1Br)C[C@H]2Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Bromotrimethylsilane (1.96 mL, 15.1 mmol) was added dropwise to a 0° C. solution of dimethyl sulfoxide (1.10 mL, 15.5 mmol) in chloroform (15 mL) with stirring at this temperature for 30 minutes. (−)-(1R,6R)-6-(2-bromophenyl)cyclohex-3-ene-1-carboxylic acid (4.24 g, 15.1 mmol; prepared in 93% ee, [α]D=62° (c=1.0, CHCl3), by resolution of the racemic Diels-Alder adduct between 1,3-butadiene and 2-bromocinnamic acid [see Morn, R.; Manuel, C.; Mazmanian, C. Eur. J. Med. Chem. 1976, 11, 493-499]with (R)-phenethyl amine) was added as a solid with stirring at rt for 1 h prior to the addition of diisopropylethylamine (2.65 mL, 15.2 mmol) at 0° C. followed by reflux for 24 hours. The reaction vessel contents were then cooled to rt, diluted with ethyl acetate and washed in succession with water, 5% HCl, water and brine, and the organic phase was dried over sodium sulfate. Concentration in vacuo afforded (1R,2R,4R,5S)-4-bromo-2-(2-bromophenyl)-6-oxabicyclo[3.2.1]octan-7-one as an oily solid.
Reaction SMILES: C(O[C:4]([CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]=2)[N:8]([CH2:23][CH3:24])[C:7]1=[O:25])=[O:5])C.[NH2:26][C:27]1[CH:28]=[C:29]([CH:40]=[CH:41][CH:42]=1)[C:30]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([Br:39])=[CH:35][CH:34]=1)=[O:31]>>[Br:39][C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:30]([C:29]2[CH:28]=[C:27]([NH:26][C:4]([CH:6]3[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([C:15](=[O:22])[C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=5)[CH:13]=4)[N:8]([CH2:23][CH3:24])[C:7]3=[O:25])=[O:5])[CH:42]=[CH:41][CH:40]=2)=[O:31])=[CH:34][CH:35]=1
Reactant: Nc1cccc(C(=O)Nc2ccc(Br)cc2)c1
Reactant: CCOC(=O)C1C(=O)N(CC)c2ccc(C(=O)c3ccccc3)cc21
Product: CCN1C(=O)C(C(=O)Nc2cccc(C(=O)Nc3ccc(Br)cc3)c2)c2cc(C(=O)c3ccccc3)ccc21

Procedure:
Prepared as in Example 1, Step A, from 5-benzoyl-1-ethyl-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid ethyl ester (U.S. Pat. No. 4,686,224) and 3-amino-N-(4-bromo-phenyl)-benzamide. Purified by flash-chromatography (hexanes/acetone, 1:1) followed by trituration in ethyl acetate/hexanes. mp 139-142° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.CN(C=O)C.C(Cl)Cl.[H-].[Na+].[C:20]([C:24]1[C:25]([Cl:33])=[C:26]([C:30](Cl)=[O:31])[N:27]([CH3:29])[N:28]=1)([CH3:23])([CH3:22])[CH3:21]>CCOC(C)=O>[NH2:9][C:4]1[C:5]([NH:8][C:30]([C:26]2[N:27]([CH3:29])[N:28]=[C:24]([C:20]([CH3:22])([CH3:21])[CH3:23])[C:25]=2[Cl:33])=[O:31])=[N:6][CH:7]=[C:2]([Br:1])[N:3]=1
Reactant: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)Cl
Reactant: Nc1ncc(Br)nc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)Nc1ncc(Br)nc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-bromo-pyrazine-2,3-diamine (250 mg, 1.32 mmol) in 1:1 DMF/DCM (8 mL) was added NaH (159 mg, 3.97 mmol, 60% dispersion in mineral oil) slowly. After stirring at room temperature for 1 h, the resulting mixture was cooled to 0° C. Solid 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carbonyl chloride (373 mg, 1.59 mmol, prepared as described in Example 1, STEP C) was added slowly. The resulting mixture was warmed to room temperature and then stirred for 18 h. The resulting mixture was treated with 50 mL of EtOAc and washed with aqueous saturated NH4Cl (20 mL), H2O (2×10 mL) and brine (10 mL). After drying with Na2SO4, the resulting solution was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (0:100-20:80 EtOAc/hexanes) to yield 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (3-amino-5-bromo-pyrazin-2-yl)-amide as a light brown solid. 1H-NMR (400 MHz, CDCl3) δ: 8.88 (s, 1H), 8.12 (s, 1H), 5.34 (br. s., 2H), 4.14 (s, 3H), 1.42 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calculated For C13H16BrClN6O: 387.0 (M+H). Measured: 387.0.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(=N[OH:16])CCCCC1.Cl>>[C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:16]
Reactant: ON=C1CCCCC1
Agent: Cl
Agent: O=C1CCCCCN1
Product: NCCCCCC(=O)O
Yield: 3.5 %

Procedure:
According to the present invention, the oxime that is the substrate can be put into a prescribed high-temperature high-pressure state within a short time, and hence hydrolysis of the oxime can be suppressed, and moreover by making an acid be present in the reaction zone, the lactam can be produced efficiently. Note, however, that a small amount of an amino acid may also be produced through the present reaction. For example, in the case of synthesizing ε-caprolactam from cyclohexanone oxime by reacting for 0.728 seconds under a high temperature of 375° C. and high pressure of 40 MPa, in the case that hydrochloric acid was made to be present at a concentration of 1.4 mol % relative to the reaction substrate, an ε-caprolactam yield of 96.2% and a 6-aminocaproic acid yield of 3.5% were obtained. In the case that such an acid was not present, the ε-caprolactam yield was 41.4% and the 6-aminocaproic acid yield was 0.3%. Conversion of 6-aminocaproic acid into ε-caprolactam is relatively easy, and this reaction also proceeds readily in high-temperature high-pressure water. In the above two reactions, only a very small amount of the hydrolysis product cyclohexanone was detected.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].Br[C:14]1[CH:35]=[CH:34][C:17]2[N:18]=[C:19]([CH2:21][C:22]3[O:26][C:25]([NH:27][C@H:28]4[CH2:32][CH2:31][NH:30][C:29]4=[O:33])=[N:24][N:23]=3)[S:20][C:16]=2[CH:15]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.CO.[Pd]>[O:33]=[C:29]1[C@@H:28]([NH:27][C:25]2[O:26][C:22]([CH2:21][C:19]3[S:20][C:16]4[CH:15]=[C:14]([C:7]5[CH:8]=[CH:9][C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=5)[CH:35]=[CH:34][C:17]=4[N:18]=3)=[N:23][N:24]=2)[CH2:32][CH2:31][NH:30]1
Reactant: O=C1NCC[C@@H]1Nc1nnc(Cc2nc3ccc(Br)cc3s2)o1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1ccc(-c2ccc3nc(Cc4nnc(N[C@H]5CCNC5=O)o4)sc3c2)cc1
Temperature: 125 °C
Yield: 31.9 %

Procedure:
To a microwave vial containing SiliaCat DPP-Pd (150 mg, 0.041 mmol) and (4-carbamoylphenyl)boronic acid (65 mg, 0.40 mmol) were added Compound 51b (104 mg, 0.260 mmol) dissolved in dioxane (2.5 mL) followed by K3PO4 (138 mg, 0.79 mmol) dissolved in water (0.3 mL) and the reaction mixture was heated in a microwave reactor at 125° C. for 1.5 h. The reaction mixture was allowed to cool to rt then diluted with a mixture of DCM and MeOH, filtered and concentrated under reduced pressure. The residue was purified on silica gel eluting with 0 to 15% MeOH/DCM to give Compound 51c (36 mg, 31% yield) as a pale brown solid. LCMS=1.33 min using analytical method (B), 435.1 (M+H). 1H NMR (400 MHz CDCl3 containing CD3OD) δ 8.05 (d, J=1.5 Hz, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.89 (d, J=8.5 Hz, 2H), 7.69 (dd, J=8.5, 1.8 Hz, 1H), 7.65 (d, J=8.5 Hz, 2H), 4.54 (s, 1H), 4.23 (dd, J=10.5, 8.3 Hz, 1H), 3.36-3.31 (m, 1H), 2.68-2.59 (m, 1H), 2.03 (dq, J=12.5, 9.8 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:18][CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N+:19]([O-])=O)[CH:14]=3)[NH:9][C:8]=2[CH2:7]1)=[O:5])[CH3:2].[H][H]>[Ni].C(O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:18][CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([NH2:19])[CH:14]=3)[NH:9][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCc2c([nH]c3ccc([N+](=O)[O-])cc23)C1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)C1CCc2c([nH]c3ccc(N)cc23)C1

Procedure:
A mixture of 1.3 g. of 6-nitro-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid ethyl ester, 0.5 teaspoonful of Raney nickel and 100 ml. of ethanol was shaken in a Parr hydrogenation apparatus under 3.7 atmospheres of hydrogen at room temperature. After 2 hours of shaking the uptake of hydrogen had stopped. The catalyst was removed by filtration and the filtrate was concentrated to dryness, yielding 1.2 g. of product. Following recrystallization from a mixture of hexane and ethyl acetate, a yield of 0.8 g. of 6-amino-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid ethyl ester, m.p. 123°-124° was obtained.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][S:5][C:6](SC)=[CH:7][C:8]([C:10]1[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=1[Cl:21])=O>C(O)C>[Cl:21][C:11]1[CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:15]([Cl:16])[C:10]=1[C:8]1[CH:7]=[C:6]([S:5][CH3:4])[NH:3][N:2]=1
Reactant: CSC(=CC(=O)c1c(Cl)cc(C(F)(F)F)cc1Cl)SC
Reactant: NN
Solvent: CCO
Solvent: O
Product: CSc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n[nH]1
Reaction time: 0.75 h

Procedure:
Hydrazine monohydrate (0.51 ml) was added dropwise to a solution of 3.6 g of 3,3-bis[methylthio]-1-(2,6-dichloro-4-trifluoromethylphenyl)-2-propen-1-one (17) in 40 ml of ethanol at room temperature, and the mixture was stirred for 45 minutes and then refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel (eluent: ether/hexane=2/5) to afford 3.3 g of the desired compound in the form of white crystals.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH2:4]1)=O.[OH:31][C:32]1([CH2:38][CH2:39][CH2:40][C:41]2[CH:50]=[CH:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[OH:31][C:32]1([CH2:38][CH2:39][CH2:40][C:41]2[CH:50]=[CH:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=2)[CH2:33][CH2:34][N:35]([CH2:1][C@@H:3]2[C@@H:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:6][N:5]([C@H:14]([CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)[C:15]([OH:17])=[O:16])[CH2:4]2)[CH2:36][CH2:37]1
Reactant: OC1(CCCc2ccc3ccccc3c2)CCNCC1
Reactant: O=C[C@H]1CN([C@@H](C(=O)OCc2ccccc2)C2CCCCC2)C[C@@H]1c1ccccc1
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(O)(CCCc3ccc4ccccc4c3)CC2)[C@@H](c2ccccc2)C1

Procedure:
The title compound was prepared from 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, benzyl ester (from EXAMPLE 1, Step I) and 4-hydroxy-4-(3-(2-naphthyl)propyl)piperidine.HCl (from EXAMPLE 82, Step A) using procedures analogous to those described in EXAMPLE 71, Steps A and B. For the title compound: 1H NMR (500 MHz) δ 0.89-3.88 (35H), 7.22-7.77 (12H); ESI-MS 569.6 (M+H).
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[F:22][C:23]1[CH:24]=[C:25]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36](O)=[O:37])[CH:26]=[CH:27][C:28]=1[F:29]>>[F:22][C:23]1[CH:24]=[C:25]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:37])[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)c(F)c2)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Product: Cc1nc(C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2ccc(F)c(F)c2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(3,4-difluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid.