Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][NH:3]1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[F:19]>C(#N)C>[F:19][C:11]1[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=1[N:3]1[CH2:4][C@@H:5]([CH3:8])[NH:6][CH2:7][C@@H:2]1[CH3:1]
Reactant: C[C@@H]1CN[C@@H](C)CN1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CC#N
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2F)[C@@H](C)CN1
Yield: 40.4 %

Procedure:
trans-2,5-Dimethylpiperazine (4.81 g, 42.1 mmol) and 1,2-difluoro-4-nitrobenzene (10.00 g, 62.9 mmol) are dissolved in 60 mL of dry acetonitrile and refluxed for 3 h, upon which a yellow precipitate forms on the bottom of the flask. The crude reaction mixture is concentrated in vacuo and the residue is chromatographed (silica gel, 10% MeOH in CH2Cl2) to give 4.32 g (17.0 mmol, 40%) of racemic-1-(2-fluoro-4-nitrophenyl)-trans-2,5-dimethylpiperazine as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 1.01 (d, J=6.0 Hz, 3H), 1.09 (d, J=6.3 Hz, 3H), 2.45 (dd, J=11.5, 9.0 Hz, 1H), 2.72 (dd, J=12.1, 9.0 Hz, 1H), 3.05-3.12 (m, 1H), 3.15 (dd, J=12.1, 3.3 Hz, 1H), 3.26 (dd, 2H), 7.12 (t, J=8.5 Hz, 1H), 7.91 (dd, J=11.2, 2.4 Hz, 1H), 7.95-8.01 (m, 1H). LCMS-ESI (m/z): calcd for C12H16FN3O2, 253.1; [M+H]+ found, 254.4.
Reaction SMILES: [S:1]1[C:5]([CH2:6][OH:7])=[CH:4][N:3]=[CH:2]1.[C:8]([Si:12](Cl)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:11])([CH3:10])[CH3:9].N1C=CN=C1.O>ClCCl>[C:8]([Si:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[O:7][CH2:6][C:5]1[S:1][CH:2]=[N:3][CH:4]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1cncs1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](OCc1cncs1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2.12 g of 1,3-thiazol-5-ylmethanol in 48 ml of dichloromethane were added 5.2 ml of tert-butyl (chloro)diphenylsilane and 2.5 g of imidazole at 0° C., followed by stirring at room temperature for 15 hours. To the reaction mixture was added water, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 6.47 g of 5-({[tert-butyl (diphenyl)silyl]oxy}methyl)-1,3-thiazole.
Reaction SMILES: F[C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([OH:14])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+]>>[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:2]2[C:3]([C@H:8]3[CH2:13][CH2:12][CH2:11][C@H:10]([OH:14])[CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:28][CH:27]=1)=[O:25]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: O[C@H]1CCC[C@H](c2nccnc2F)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(c1ccc(Oc2nccnc2[C@H]2CCC[C@H](O)C2)cc1)c1nc2ccccc2[nH]1
Temperature: 150 °C

Procedure:
A mixture of (rac)-trans-3-(3-fluoropyrazin-2-yl)cyclohexanol (106 mg, 0.540 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (257 mg, 1.080 mmol), and cesium carbonate (352 mg, 1.080 mmol) was heated in a Biotage™ microwave reactor at 150° C. for 30 min. The mixture was partitioned between H2O (10 ml) and CH2Cl2 (20 ml), the layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×20 ml). The combined organic layers were dried (MgSO4), concentrated under reduced pressure, and the resulting brown oil was purified by reversed phase HPLC (Gilson Gemini-NX 10u C18 110A, 100×50.0 mm, 10% to 95% H2O/MeCN, 0.1% TFA). The product containing fractions were combined, neutralized by the addition of solid Na2CO3, and extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to deliver (rac)-trans-(1H-benzo[d]imidazol-2-yl)(4-(3-(3-hydroxycyclohexyl)pyrazin-2-yloxy)phenyl)methanone as a light yellow solid. MS (ESI, pos. ion) m/z: 415.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[N+:10]([O-])([O-:12])=[O:11].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:10]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[C:3]=1[OH:9])([O-:12])=[O:11]
Reactant: Oc1cccc(Cl)c1Cl
Reactant: O=[N+]([O-])[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Cl)c(Cl)c1O
Reaction time: 24 h
Yield: 43.3 %

Procedure:
2,3-dichlorophenol (3.26 g, 20 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (1.88 g, 22 mmol). The addition of sulfuric acid (20 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(1.8 g, 44%). 1H NMR (CD3COCD3): d 8.04 (d,1H), 7.15 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.[S:26]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27]1>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:21][CH2:22][N:23]([S:31]([C:28]3[CH:29]=[CH:30][S:26][CH:27]=3)(=[O:33])=[O:32])[CH2:24][CH2:25]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: O=S(=O)(Cl)c1ccsc1
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)c3ccsc3)CC2)nc1N

Procedure:
The title compound was prepared from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone, Example 59, and 3-thiophenesulfonyl chloride (Maybridge) by the procedure described in Example 152. HR-MS (ES, m/z) calculated for C21H23FN5O4S2 [(M+H)+] 492.1170, observed 492.1175.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15](Cl)=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1.[NH:22]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[N:22]1([C:15]([C:9]2[C:8]([CH3:18])=[C:7]([N+:19]([O-:21])=[O:20])[CH:6]=[C:5]3[C:10]=2[N:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[N:4]3)=[O:16])[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: C1CNCCNC1
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC
Product: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)N3CCCNCC3)c2nc1OC
Reaction time: 30 h

Procedure:
Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13) 250 mg (0.80 mmol) and homopiperazine 160 mg (1.60 mmol). Reaction was continued for 30 hours, and the crude product was eluted through a flash column (8% methanol in chloroform), 260 mg (87%), mp 141-143° C.; 1H NMR (CDCl3): δ 8.29 (s, 1H), 4.03 (s, 3H), 3.93 (br s, 7H), 3.02 (br s, 2H), 2.82 (t, 2H, J=5.4, J=5.6 Hz), 2.54 (s, 3H), 1.88 (t, 2H, J=5.6, 5.4 Hz), 1.79 (bs, 1H); MS (APCI): m/z 376 (M+H). Anal. Calcd. for C17H21N5O5: C, 54.39; H, 5.64; N, 18.66. Found: C, 54.07; H, 5.57; N, 18.24.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]=[CH:10][C:9]3[CH:12]=[N:13][N:14]([C:15]4[N:20]=[C:19]([N:21]5[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]5)[CH:18]=[CH:17][CH:16]=4)[C:8]=3[CH:7]=2)[CH:3]=[N:2]1.Br[CH2:36][C:37]#[N:38]>>[N:21]1([C:19]2[N:20]=[C:15]([N:14]3[C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][N:2]([CH2:36][C:37]#[N:38])[CH:3]=5)[N:11]=[CH:10][C:9]=4[CH:12]=[N:13]3)[CH:16]=[CH:17][CH:18]=2)[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(-n3ncc4cnc(-c5cn[nH]c5)cc43)n2)CC1
Reactant: N#CCBr
Product: N#CCn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCNCC3)n2)cn1
Yield: 18.5 %

Procedure:
Following the procedures as described in Example 61 and starting with tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and 2-bromoacetonitrile, 155 was obtained as a white solid (25 mg, 18.5%) over two steps. 1H NMR (500 MHz, CDCl3) δ (ppm) 9.064-9.065 (d, J=0.5 Hz, 1H), 8.75 (s, 1H), 8.25 (s, 1H), 8.19 (s, 1H), 8.05 (s, 1H), 7.61-7.64 (t, J=16.5 Hz, 1H), 7.28 (s, 1H), 6.43-6.45 (d, J=8.5 Hz, 1H), 5.15 (s, 2H), 3.88-3.92 (m, 4H), 3.17-3.19 (t, J=11 Hz, 2H), 2.92-2.94 (t, J=11 Hz, 2H), 2.02-2.05 (t, J=12 Hz, 2H); MS (ESI) m/z: 400 [M+H]+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:20])=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:20][Br:1])=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Br)cc1C(F)(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(Br)ccc1CBr
Yield: 83.1 %

Procedure:
N-Bromosuccinimide (2.6 g) and 2,2′-azobis(isobutyronitrile) (35 mg) were added to a solution of 5-bromo-2-methylbenzotrifluoride (CAS #86845-27-4, 3.5 g) in carbon tetrachloride (35 mL), and the mixture was heated under reflux for five hours. The reaction solution was ice-cooled and then the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Wakogel C-200; elution solvent: heptane) to obtain 3.86 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[O:12][C:13]1[C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=[C:15]([S:22][CH3:23])[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:26]=[CH:25][CH:24]=[C:11]([O:12][C:13]2[C:18]([C:19](=[O:21])[NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:17][N:16]=[C:15]([S:22][CH3:23])[N:14]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1ccccc1
Reactant: CSc1ncc(C(=O)O)c(Oc2cccc(NC(=O)OC(C)(C)C)c2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CSc1ncc(C(=O)Nc2ccccc2)c(Oc2cccc(NC(=O)OC(C)(C)C)c2)n1
Temperature: 110 °C
Yield: 65 %

Procedure:
A solution of 4 (0.275 g, 1.19 mmol), 5 (0.403 g, 1.19 mmol), prepared according to Step-1 of Example 20, Pd(OAc)2 (0.0026 g, 0.11 mmol), BINAP (0.0037 g, 0.059 mmol) and Cs2CO3 (0.969 g, 2.95 mmol) in degassed toluene (toluene was purged with N2 for 30 min) was heated at 110° C. for 16 h under N2 atmosphere. The reaction mixture was cooled, diluted with EtOAc (20 mL), washed with water (10 mL), brine (10 mL) and dried over Na2SO4. Filtration followed by concentration under reduced pressure offered a residue which was further purified by column chromatography (SiO2, 60-120, pet ether/ethyl acetate 5/5) to give 6 (0.350 g, 55%) as a yellow solid.
Reaction SMILES: C(OC([N:8]1[C@H:12]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][C@H:12]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][OH:10]
Reactant: CC(C)(C)OC(=O)N1[C@H](COc2ccccc2)COC1(C)C
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](CO)COc1ccccc1
Reaction time: 16 h
Yield: 66.2 %

Procedure:
To a stirred solution of (R)-2,2-dimethyl-4-phenoxymethyl-oxazolidine-3-carboxylic acid tert-butyl ester (300 mg) at r.t. in dioxane (5 ml) under an argon atmosphere was added 4 M HCl solution in dioxane (2.44 ml). The mixture was stirred for 16 h. The mixture was concentrated. The residue was resuspended in saturated aq sodium carbonate solution and the mixture was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated in vacuo. The crude product was purified by column chromatography (SiO2; gradient: CH2Cl2->CH2Cl2/MeOH 9:1) to give (S)-2-amino-3-phenoxy-propan-1-ol (108 mg, 66%) as a white solid. MS (ISP): 168.3 ([M+H]+)).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:13]([CH3:16])=[CH:14][N:15]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([CH3:12])[CH:6]=2.C(Cl)(Cl)Cl>C(N)CN>[NH2:4][CH2:3][CH2:2][NH:11][C:2]1[C:3]2[N:4]([C:13]([CH3:16])=[CH:14][N:15]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([CH3:12])[CH:6]=2
Reactant: Cc1ccc2nc(Cl)c3ncc(C)n3c2c1
Solvent: ClC(Cl)Cl
Solvent: NCCN
Product: Cc1ccc2nc(NCCN)c3ncc(C)n3c2c1
Yield: 174.2 %

Procedure:
A solution of 4-chloro-1,8-dimethylimidazo(1,2-a)quinoxaline (compound 5) (4.8 g, 21 mmol) in ethylenediamine (300 mL) was heated at 60° C. under nitrogen gas (N2) for 16 hours. The solvent was evaporated under vacuum. The residue was diluted with EtOAc (200 mL), washed with saturated Na2CO3 and brine, dried over MgSO4, filtered and concentrated. Flash chromatography using methanol (MeOH) provided a solid, which was then dissolved with CHCl3 and filtered to remove any dissolved silica gel. The filtrate was concentrated under vacuum, providing the title compound 6 as a white solid (4.67 g). 1H NMR (500 MHz, CDCl3) δ 7.88 (s, 1H), 7.63 (d, J=8.3 Hz, 1H), 7.26 (s, 1H), 7.22 (d, J=8.3 Hz, 1H), 6.31 (s, 1H), 3.63 (apparent q, J=5.9 Hz, 2H), 2.96 (t, J=6.0 Hz, 2H), 2.88 (s, 3H), 1.38 (br, 2H); MS (ESI), m/z 256.15 [(M+H)+; calculated for compound 6, C14H17N5:255.15].
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1>ClCCl>[C:1]([O:6][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: C1=COCCC1
Solvent: ClCCl
Product: C=C(C)C(=O)OC1CCCCO1
Yield: 3.7 %

Procedure:
a solution of 25.0 g (290 mmol) methacrylic acid and 27.8 g (330 mmol) dihydropyran in 80 ml of dichloromethane was stirred for 14 hr at room temperature. The reaction mixture was thoroughly extracted with saturated aqueous sodium bicarbonate, dried (MgSO4) and concentrated in vacuo. The residue was distilled to give 1.84 g (10.8 mmol; 3.7% yield) tetrahydropyran-2-yl methacrylate, bp 53° C. at 0.2 torr.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[NH2:21][CH:22]1[CH2:29][CH:28]2[N:30]([CH3:31])[CH:24]([CH2:25][CH2:26][CH2:27]2)[CH2:23]1>>[CH3:31][N:30]1[CH:24]2[CH2:25][CH2:26][CH2:27][CH:28]1[CH2:29][CH:22]([NH:21][C:16]([C:15]1[C:9]3[O:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:11][C:10]=3[CH:12]=[CH:13][CH:14]=1)=[O:18])[CH2:23]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1cccc2nc(-c3ccccc3)oc12
Agent: Cl
Product: CN1C2CCCC1CC(NC(=O)c1cccc3nc(-c4ccccc4)oc13)C2
Yield: 43 %

Procedure:
N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-phenylbenzoxazole-7-carboxamide was prepared from 2-phenylbenzoxazole-7-carboxylic acid and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride using the method outlined in Step C of Example 7. This compound was obtained in 43% yield and obtained as an off-white solid: mp 208-210° C.; 1H NMR (500 MHz, CDCl3) δ 8.95 (br s, 1H), 8.23 (d, J=6.9 Hz, 2H), 8.20 (d, J=2.0 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.57-7.65 (m, 3H), 4.58 (q, J=7.1 Hz, 1H), 3.18 (br s, 2H), 2.58 (m, 5H), 2.02-2.25 (m, 3H), 1.55 (s, 3H), 1.23 (m, 3H); MS (APCI) m/z 411 [M+H]+
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O)C.[NH3:30]>C(O)C>[CH3:21][O:20][C:18]1[C:17]([O:22][CH3:23])=[CH:16][C:15]2[N:11]([C:9]3[S:10][C:6]([C:4]([NH2:30])=[O:3])=[C:7]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:8]=3)[CH:12]=[N:13][C:14]=2[CH:19]=1
Reactant: CCOC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1-c1ccccc1
Reactant: N
Solvent: CCO
Product: COc1cc2ncn(-c3nc(-c4ccccc4)c(C(N)=O)s3)c2cc1OC
Yield: 36 %

Procedure:
2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-phenyl-thiazole-5-carboxylic acid amide was prepared from 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-phenyl-thiazole-5-carboxylic acid ethyl ester (80 mg, 0.20 mmol) and ammonia in ethanol (29 molar) as described above in the general amide formation procedure. The product was isolated by preparative HPCL: 7.7 mg, 36% yield. 1H-NMR (DMSO-D6) 8.78 (s, 1H); 7.80-7.90 (m, 4H); 7.789s, 1H); 7.40-7.55 (m, 3H); 7.38 (s, 1H); 3.84 (s, 3H); 3.83 (s, 3H). MS M/z 381 (M+1).
Reaction SMILES: C1COCC1.[CH3:6][N:7]1[CH:12]=[C:11]([O:13][CH2:14][O:15][CH3:16])[C:10]([C@@H:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][C@H:18]2[C:30]([O:32]CC)=[O:31])=[CH:9][C:8]1=[O:35].[OH-].[Li+]>CO>[CH3:29][C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][C@@H:17]([C:10]2[C:11]([O:13][CH2:14][O:15][CH3:16])=[CH:12][N:7]([CH3:6])[C:8](=[O:35])[CH:9]=2)[C@H:18]([C:30]([OH:32])=[O:31])[CH2:19]1)=[O:24])([CH3:27])[CH3:28]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1cc(=O)n(C)cc1OCOC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCOc1cn(C)c(=O)cc1[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 3:2 (v/v) THF:MeOH solution (0.04 M) of trans-1-(1,1-dimethylethyl) 3-ethyl 4-(1-methyl-5-{[(methyloxy)methyl]oxy}-2-oxo-1,2-dihydro-4-pyridinyl)-1,3-piperidinedicarboxylate (1 eq.) from the previous step was added lithium hydroxide (1 M aq. solution, 3 eq.). The resulting cloudy solution was stirred vigorously at RT for 24 h. The volatiles were then removed in vacuo and the residue was partitioned between EtOAc and 10% aq. HCl. The aqueous layer was separated and back-extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a pink solid.
Reaction SMILES: [C:1]([C:4]1[S:18][C:7]2[O:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[NH:11][C:12](=[O:13])[C:6]=2[CH:5]=1)(=O)[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([C:4]1[S:18][C:7]2[O:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[NH:11][C:12](=[O:13])[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CC(=O)c1cc2c(s1)Oc1ccccc1NC2=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc2c(s1)Oc1ccccc1NC2=O
Temperature: 25 °C
Reaction time: 42 h
Yield: 77.5 %

Procedure:
2-Acetylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.5 g) was dissolved in trifluoroacetic acid (20 ml) and triethylsilane (2 g) was added. The mixture was stirred at room temperature for 42 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in chloroform. The mixture was washed with water and saturated aqueous sodium hydrogencarbonate solution, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. To the residue were added chloroform and ethyl acetate and the precipitated crystals were collected by filtration. The obtained crystals were washed with diisopropyl ether to give 2-ethylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.1 g).
Reaction SMILES: C(C(C)=O)C.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:13]1([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])=[CH:12][CH:11]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: OCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: OCCCCCCOc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
To 80 mL of methyl ethyl ketone, 9.05 g (50 mmol) of 4-hydroxybiphenyl, 10.20 g (60 mmol) of 6-bromo-1-hexanol, and 20.7 g (150 mmol) of potassium carbonate were added. This solution was refluxed for 24 hours and then cooled to room temperature. This solution was diluted with 200 mL of methylene chloride and rinsed with water three times. The organic phase was then separated and dried over magnesium sulfate, and the solvent was distilled off. The residue was dissolved in toluene and purified by recrystallization to provide 10.25 g of 6-(4-phenylphenoxy)hexane-1-ol.
Reaction SMILES: O[N:2]1[C:6]2[CH:7]=[C:8]([N+:14]([O-:16])=[O:15])[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]=2[N:4]=[C:3]1[C:17]([F:20])([F:19])[F:18].S(Cl)([Cl:23])=O>CN(C)C=O.O>[Cl:23][C:7]1[C:6]2[N:2]=[C:3]([C:17]([F:20])([F:19])[F:18])[NH:4][C:5]=2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c2nc(C(F)(F)F)n(O)c2c1
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c2[nH]c(C(F)(F)F)nc2c1Cl
Reaction time: 8 h

Procedure:
Crude 1-hydroxy-4,6-dinitro-2 -(trifluoromethyl)-benzimidazole (about 5 grams) was mixed with about 50 milliliters of thionyl chloride and several drops of dimethylformamide added. The reaction mixture was stirred overnight, then poured slowly into water and filtered. The solid was dissolved in benzene and eluted off a silica column with benzene. As a result of the foregoing operations, the desired 7-chloro-4,6-dinitro-2-(trifluoromethyl) benzimidazole product was obtained, m.p., 189° -91° C.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][C:12]([C:16](=[O:22])[NH:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:11][C:10]=1[F:23])[O:6][CH2:7][CH3:8])C.CO.O.O[Li].O>C1COCC1.CCOC(C)=O>[F:15][C:14]1[CH:13]=[C:12]([C:16](=[O:22])[NH:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH:11]=[C:10]([F:23])[C:9]=1[CH:5]([O:6][CH2:7][CH3:8])[C:4]([OH:24])=[O:3]
Reactant: CCOC(=O)C(OCC)c1c(F)cc(C(=O)NCC(C)C)cc1F
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(C(=O)O)c1c(F)cc(C(=O)NCC(C)C)cc1F
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 66.2 %

Procedure:
To a solution of (RS)-(2,6-difluoro-4-isobutylcarbamoyl-phenyl)-ethoxy-acetic acid ethyl ester (125 mg) in a mixture of THF (1 ml), MeOH (1 ml) and H2O (0.5 ml) was added LiOH.H2O (31 mg). After stirring 1.5 h at 60° C. AcOEt was added (10 ml) and the product was extracted with H2O (10 ml). The aqueous layer was collected, acidified with 1 N HCl and extracted with AcOEt (2×15 ml). The combined organic layers were dried (Na2SO4) and the solvent is evaporated to obtain 76 mg (66%) of (RS)-(2,6-difluoro-4-isobutylcarbamoyl-phenyl)-ethoxy-acetic acid. Off-white solid. MS 333.4 ([M+H]+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[CH3:17])[O:9]CCO1.[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22]([C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH3:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:5]([CH2:4][CH2:3][CH2:2][N:29]1[CH2:28][CH2:27][C:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:18])([F:33])[F:34])[CH:21]=2)([OH:32])[CH2:31][CH2:30]1)=[O:9]
Reactant: Cc1cc(F)ccc1C1(CCCCl)OCCO1
Reactant: OC1(c2cccc(C(F)(F)F)c2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1C(=O)CCCN1CCC(O)(c2cccc(C(F)(F)F)c2)CC1
Temperature: 0 °C

Procedure:
A mixture of 3 g of 4-chloro-1-(2-methyl-4-fluorophenyl)-1,1-ethylenedioxybutane, 2.5 g of 4-(3-trifluoromethylphenyl)-4-hydroxypiperidine, 1.4 g of anhydrous potassium carbonate, 0.05 g of potassium iodide and 30 ml of dimethylformamide was refluxed for 3 hours. The resulting mixture was poured into ice water and was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. To the residual oil were added 60 ml of methanol, 21 ml of water and 10.5 ml of concentrated hydrochloric acid. The mixture was refluxed for 50 minutes and concentrated in vacuo. The residual oil was made alkaline with 28% aqueous ammonia and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated. The residual solid was recrystallized from isopropyl ether to give 1-[γ-(2-methyl-4-fluorobenzoyl)-propyl]-4-(3-trifluoromethylphenyl)-4-hydroxypiperidine, melting at about 63.5°-64.5° C.