Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1.[F:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[C@@H:25]([NH2:27])[CH3:26].CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O>CS(C)=O>[F:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[C@@H:25]([NH:27][C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1)[CH3:26]
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Reactant: C[C@H](N)c1cccc(F)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2cccc(F)c2F)n1
Temperature: 110 °C
Yield: 20.4 %

Procedure:
To a microwave vial with stir bar was added (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (24.96 mg, 0.103 mmol) in DMSO (1653 μL). To this reaction mixture was added (S)-1-(2,3-difluorophenyl)ethanamine (40 mg, 0.207 mmol) and DIEA (144 μL, 0.826 mmol). The vial capped and heated at 110° C. over the weekend. The solution was filtered, then purified by reverse phase HPLC. Product fractions combined, frozen and lyopholyzed to afford ((S)-3-(2-((S)-1-(2,3-difluorophenyl)ethylamino) pyrimidin-4-yl)-4-isopropyloxazolidin-2-one (10.2 mg, 0.021 mmol, 10.26% yield) as a TFA salt. 1H NMR (400 MHz, CD3OD) δ ppm 0.59 (br. s., 3H) 0.75 (br. s., 3H) 1.59 (d, J=6.99 Hz, 3H) 1.69 (br. s., 1H) 4.37 (d, J=5.67 Hz, 2H) 4.66 (br. s., 1H) 5.40 (d, J=7.38 Hz, 1H) 7.06-7.23 (m, 3H) 7.70 (d, J=6.90 Hz, 1H) 8.14 (d, J=6.46 Hz, 1H); LCMS m/z 363.3 (M+H)+, Rt 0.77 min.; HRMS(A) m/z 363.1642 (M+H)+, Rt 1.89 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=O)[C:15]([NH:17][C@H:18]2[C@@H:21]([CH2:22][N:23]3[CH2:27][CH2:26][O:25][C:24]3=[O:28])[N:20]([S:29]([OH:32])(=[O:31])=[O:30])[C:19]2=[O:33])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:35][O:36][C@H:37]([C:62]([O:64][CH:65]([C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)=[O:63])[CH2:38][O:39][C:40]1[CH:61]=[CH:60][C:43]([C:44](=[NH:59])[NH:45][CH:46]2[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]2)=[CH:42][CH:41]=1.CC(O)=O>C(Cl)(Cl)Cl.CCO>[CH:65]([O:64][C:62](=[O:63])[C@@H:37]([O:36]/[N:35]=[C:14](/[C:12]1[N:13]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[S:10][CH:11]=1)\[C:15]([NH:17][C@H:18]1[C@@H:21]([CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[N:20]([S:29]([OH:32])(=[O:30])=[O:31])[C:19]1=[O:33])=[O:16])[CH2:38][O:39][C:40]1[CH:61]=[CH:60][C:43]([C:44](=[NH:59])[NH:45][CH:46]2[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:56])([CH3:57])[CH3:58])=[O:53])[CH2:48][CH2:47]2)=[CH:42][CH:41]=1)([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:72]1[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2CN2CCOC2=O)cs1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=N)c2ccc(OC[C@H](ON)C(=O)OC(c3ccccc3)c3ccccc3)cc2)CC1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/O[C@@H](COc2ccc(C(=N)NC3CCN(C(=O)OC(C)(C)C)CC3)cc2)C(=O)OC(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2CN2CCOC2=O)cs1
Reaction time: 2 h
Yield: 32.7 %

Procedure:
To a soln of (3S,4R)-3-(2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetamido)-2-oxo-4-((2-oxooxazolidin-3-yl)methyl)azetidine-1-sulfonic acid (170 mg, 0.328 mmol) in CHCl3 (2 mL, ratio: 1) and EtOH (6 mL, ratio: 3) was added (S)-tert-butyl 4-(4-(2-(aminooxy)-3-(benzhydryloxy)-3-oxopropoxy)benzimidamido)piperidine-1-carboxylate (prepared according to WO2013110643, 193 mg, 0.328 mmol). After stirring for 2 h, AcOH (19 μL, 0.328 mmol) was added. After 12 h, more solution of (3S,4R)-3-(2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetamido)-2-oxo-4-((2-oxooxazolidin-3-yl)methyl)azetidine-1-sulfonic acid (170 mg, 0.328 mmol) in 3:1 CHCl3:EtOH was added. After stirring for 45 h, it was concentrated in vacuo, and the crude residue was purified with HP21 resin (10-100% ACN-water), affording the title compound (117 mg, 33%) as an off white solid. LCMS: Rt=0.96 min, m/z=1091.1 (M+1) Method 2m_acidic.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:54])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH2:29][CH2:30]CS(C)(=O)=O)[CH2:25][CH2:24]3)=[O:22])[C:10]([C:36]3[C:37]([O:51][CH2:52][CH3:53])=[CH:38][C:39]([Cl:50])=[C:40]([S:42]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])(=[O:44])=[O:43])[CH:41]=3)=[N:9]2)=[CH:4][CH:3]=1.N1(CC[OH:63])CCNCC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:54])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][OH:63])[CH2:27][CH2:28]3)=[O:22])[C:10]([C:36]3[C:37]([O:51][CH2:52][CH3:53])=[CH:38][C:39]([Cl:50])=[C:40]([S:42]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])(=[O:43])=[O:44])[CH:41]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: OCCN1CCNCC1
Reactant: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1
Product: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCO)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(5-tert-butylsulfamoyl-4-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 45) was reacted with 2-piperazin-1-yl-ethanol (Chemical Dynamics) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 25% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C36H45N5O5SCl3 [(M+H)+] 764.2202, observed 764.2198.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([Br:15])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Cl-].[F:17][CH:18]([F:24])[C:19](OCC)=[O:20].[Cl-].[NH4+]>O1CCCC1.CO>[Br:15][C:13]1[CH:12]=[C:4]([CH:3]=[C:2]([CH:19]([OH:20])[CH:18]([F:24])[F:17])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(Br)c1
Reactant: CCOC(=O)C(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(Br)cc(C(O)C(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.8 %

Procedure:
To a solution of tert-butyl 3,5-dibromobenzoate (18.43 g, 54.9 mmol) in tetrahydrofuran (137 mL) at 0° C. was added isopropylmagnessium chloride (2.0 M in THF; 46.6 mL, 93 mmol). The reaction mixture was warmed to ambient temperature. The reaction was monitor by LC-MS for disappearance of tert-butyl 3,5-dibromobenzoate. The mixture was cooled back to 0° C. and ethyl difluoroacetate (13.7 mL, 137 mmol) was added. The mixture was stirred at 0° C. for 1 h, then warmed to ambient temperature. After 18 h, methanol and saturated ammonium chloride were added and the mixture was concentrated to remove organic solvents. Water was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→75% hexanes/ethyl acetate) gave the title compound (4.04 g).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][P:24]([O:29][CH2:30][CH3:31])(=[O:28])[O:25][CH2:26][CH3:27]>>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:21][CH2:22][CH2:23][P:24](=[O:28])([O:29][CH2:30][CH3:31])[O:25][CH2:26][CH3:27])[C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(CCCBr)OCC
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Product: CCOP(=O)(CCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O)OCC

Procedure:
The title substance was prepared from 7-benzyl-3-methylxanthine, (0.04 mol) and diethyl 3-bromopropanphosphonate (0.046 mol) analogously to Example 23.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10](Cl)([Cl:11])[C:9](=O)[CH2:8][CH:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[NH:6]1)=[O:4].Cl.[NH2:25][OH:26].N1C=CC=CC=1>CO>[CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[CH2:8][C:9](=[N:25][OH:26])[C:10]=1[Cl:11])=[O:4]
Reactant: COC(=O)C1NC(c2ccc(Cl)c(OC)c2F)CC(=O)C1(Cl)Cl
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: COC(=O)C1=C(Cl)C(=NO)CC(c2ccc(Cl)c(OC)c2F)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
3-Chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-chloro-4-oxo-1,4,5,6-tetrahydropyridine-2-carboxylic acid methyl ester (33; 1.612 g, 4.63 mmol) was suspended in MeOH (20 mL). Hydroxylamine hydrochloride (966 mg, 13.9 mmol) was added followed by pyridine (3 mL). The reaction mixture was stirred for 18 h at room temperature and then for 4 h at 40° C. The solvent was removed by rotary evaporation. H2O (100 mL) was added, and the resulting solid was filtered, washed with H2O followed by MeOH to give 3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-hydroxyimino-1,4,5,6-tetrahydropyridine-2-carboxylic acid methyl ester (34; 1.353 g, 81%) as a white powder: mp 174-176° C.; 1H NMR (300 MHz, DMSO-d6) δ 11.23 (s, 1H, NOH), 7.35 (dd, JF-H=1.5 Hz, JH-H=8.7 Hz, 1H, aromatic), 7.17 (dd, JF-H=JH-H=8.7 Hz, 1H, aromatic), 6.93 (br s, 1H, NH), 4.69 (m, 1H, H6), 3.88 (s, 3H), 3.79 (s, 3H), 3.03 (dd, J=4.5, 16 Hz, 1H, H5a), 2.74 (dd, J=9.0, 16 Hz, 1H, H5b); Anal. Calcd for C14H13Cl2FN2O4: C, 46.30; H, 3.61; N, 7.71. Found: C, 46.77; H, 3.64; N, 7.42.
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])(=O)=O.[Br:16][C:17]1[N:21]2[CH:22]=[CH:23][C:24]([C:26](O)([CH3:28])[CH3:27])=[N:25][C:20]2=[N:19][CH:18]=1.C(N(C(C)C)CC)(C)C>ClCCl>[Br:16][C:17]1[N:21]2[CH:22]=[CH:23][C:24]([C:26]([CH3:28])([O:6][Si:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])[CH3:27])=[N:25][C:20]2=[N:19][CH:18]=1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(Br)cnc2n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Triethylsilyl trifluoromethanesulfonate (4.85 ml, 21.5 mmol) was added dropwise over 15 min to a cooled (−50° C.) solution of 2-(3-bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol (5.0 g, 19.5 mmol) and diisopropylethylamine (4.76 ml, 27.5 mmol) in dichloromethane (150 ml). The mixture was stirred for 20 min then allowed to warm to ambient temperature overnight. The reaction mixture was diluted with dichloromethane (100 ml) and washed with 1N hydrochloric acid (100 ml) and water (100 ml), dried over anhydrous magnesium sulfate, filtered and evaporated. The red oil was purified by dry flash column chromatography on silica eluting with dichloromethane on a gradient of methanol (0-3%). Collecting the appropriate fractions gave 3-bromo-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine as a pale yellow oil which crystallised on standing (6.21 g, 86%): δH (400 MHz, CDCl3) 0.64 (6H, q, J 8), 0.97 (9H, t, J 8), 7.50 (1H, d, J 7), 7.72 (1H, s), 8.35 (1H, d, J 7).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:20][CH2:19]2)=[N:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]/[C:43]([OH:45])=[O:44]>C1COCC1.CO.CCOCC.C(Cl)Cl.O>[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]/[C:43]([OH:45])=[O:44].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:20][CH2:19]2)[NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CN=C(c2ccc(F)cc2)C2CCN(CCc3ccccc3)CC2)cc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(CNC(c2ccc(F)cc2)C2CCN(CCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 73.8 %

Procedure:
A mixture of 7.85 g (0.0188 mol) of α-(4-fluorophenyl)-N-[(4-fluorophenyl)methyl]-1-(2-phenylethyl)-4-piperidinemethanimine and 1.30 g (0.034 mol) of lithium aluminum hydride in 200 mL of dry THF (distilled from sodium-benzophenone ketyl) and under an atmosphere of nitrogen was stirred at room temp for 14 h. A solution of 5% NaOH was added dropwise to the mixture and 20 mL of water was added. Methylene chloride was added and the mixture was filtered through Celite. The filtrate was extracted with water and was dried (Na2SO4). The solvent was removed in vacuo to give an oil. This was dissolved in methanol, treated with 4.41 g (0.038 mol) of fumaric acid, and anhydrous ether was added. A precipitate formed to give 7.45 g (65.4%) of the title compound as a white solid, mp 177°-179° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][C:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[O:53])[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:72])[CH3:2].N1C=CC=CC=1.F>O1CCCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][C:52]([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)=[O:53])[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([OH:64])[CH2:5][C:4]1=[O:72])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(=O)c4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: *CC(*)C
Agent: F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(=O)c4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2"'-phenyl-2"'-oxo-ethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (10 mg in 0.4 mL tetrahydrofuran contained in a polypropylene vial) was added 20 μL of a solution of hydrogen fluoride-pyridine complex (40% in (2:1) tetrahydrofuran:pyridine) and the mixture stirred at room temperature. After 96 hours, the reaction was quenched by the careful addition of saturated sodium bicarbonate and extracted with ethyl acetate. The combined organics were dried by passage through a magnesium sulfate plug, concentrated in vacuo and purified by flash chromatography (ethyl acetate:hexane (1:1)+1% methanol) to give the title compound (5.2 mg).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:14])[F:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH:12]([F:13])[F:14])=[C:6]([O:9][CH3:10])[C:7]=1[O:8][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: COc1c(OC(F)F)ccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1c(OC(F)F)ccc(Br)c1OCc1ccc(S(C)(=O)=O)cc1
Temperature: 80 °C
Yield: 92.3 %

Procedure:
To a stirring solution of 6-bromo-3-(difluoromethoxy)-2-methoxyphenol (200 mg, 0.743 mmol) in acetonitrile (10 mL) was added potassium carbonate (307 mg, 2.228 mmol) and 1-(bromomethyl)-4-(methylsulfonyl)benzene (368.6 mg, 1.48 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure to afford 300 mg of 1-Bromo-4-(difluoromethoxy)-3-methoxy-2-(4-(methylsulfonyl)benzyloxy)benzene crude product as a solid.
Reaction SMILES: [OH-].[K+].II.CC(CC(C)(C)C)CC([O:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][O:19]C(=O)CC(C)CC(C)(C)C)[CH2:14][CH2:13]1)=O>>[CH:15]1([CH2:18][OH:19])[CH2:16][CH2:17][CH:12]([CH2:11][OH:10])[CH2:13][CH2:14]1
Reactant: CC(CC(=O)OCC1CCC(COC(=O)CC(C)CC(C)(C)C)CC1)CC(C)(C)C
Agent: II
Agent: [K+]
Agent: [OH-]
Product: OCC1CCC(CO)CC1

Procedure:
A 1 L four-necked flask equipped with a stirrer, a thermometer and a water-fractionating receiver with a cooling tube was charged with 483.5 g (3.06 mol) of 3,5,5-trimethylhexanoic acid, 216 g (1.5 mol) of 1,4-cyclohexane dimethanol (produced by hydrogenating a nucleus of dimethyl terephthalate in the presence of a ruthenium-supporting molded catalyst to obtain dimethyl 1,4-cyclohexanedicarboxylate, and then hydrogenating the thus obtained dimethyl 1,4-cyclohexanedicarboxylate in the presence of a copper-chromium molded catalyst), xylene (5% by weight on the basis of a total weight of the raw materials), and tin oxide as a catalyst (0.2% by weight on the basis of a total weight of the raw materials), and the contents of the flask were gradually heated to 220° C. under a nitrogen atmosphere. Then, the contents of the flask were subjected to esterification reaction under reduced pressure for about 8 h while removing water distilled off by the water-fractionating receiver until reaching a theoretical amount (72 g) thereof. After completion of the reaction, an excess amount of the acid was removed by distillation. Next, the resultant esterification reaction product was neutralized with an aqueous sodium hydroxide solution which was used in an excess amount relative to a total acid value of the esterification reaction product, and then washed with water until reaching a neutrality, thereby obtaining a crude esterification reaction product. Further, the thus obtained crude esterification reaction product was treated with activated carbon, and then filtered to obtain 568 g of 1,4-cyclohexane dimethanol di(3,5,5-trimethylhexanoate) (Compound 4). It was confirmed that the resultant ester had a total acid value of 0.01 mg KOH/g, an iodine number of less than 0.1 I2g/100 g and a molar ratio of cis-isomer to trans-isomer of 29/71. Various properties of the thus obtained compound 4 such as coefficient of traction, kinematic viscosity, viscosity index (VI), flash point and pour point thereof, are shown in Table 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH:15]=[C:14]([C:16](OC)=[O:17])[C:13]([CH3:20])=[N:12]2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([N:11]2[CH:15]=[C:14]([CH:16]=[O:17])[C:13]([CH3:20])=[N:12]2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COC(=O)c1cn(-c2cc(OC)cc(OC)c2)nc1C
Agent: [Mn+4]
Agent: [Al+3]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc(OC)cc(-n2cc(C=O)c(C)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
A solution (15 mL) of methyl 1-(3,5-dimethoxyphenyl)-3-methyl-1H-pyrazole-4-carboxylate (3.0 g) synthesized in the above-mentioned (1) in tetrahydrofuran was added to an ice-cooled solution (35 mL) of lithium aluminum hydride (0.42 g) in tetrahydrofuran. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr, ice-cooled again, and water (1.1 mL), 1N aqueous sodium hydroxide solution (5.5 mL), water (1.1 mL) were successively added dropwise to quench the reaction. The residue was filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude product (2.7 g) of 1-(3,5-dimethoxyphenyl)-3-methyl-1H-pyrazole-4-methanol as a pale-yellow oil. This was dissolved in toluene (30 mL), manganese dioxide (2.0 g) was added, and the mixture was heated under reflux with a Dean-Stark trap for 1 hr. The reaction mixture was allowed to cool to room temperature, manganese dioxide was collected by filtration, and the solvent was evaporated under reduced pressure to give the title object compound (2.0 g, 74%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([C:20]([C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][C:23]=3[O:31][CH2:32][CH3:33])=[O:21])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>CCOC(C)=O.[Pd]>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]([N:13]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:19]3[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:12]2)=[O:21])=[C:23]([O:31][CH2:32][CH3:33])[CH:24]=1
Reactant: CCOc1cc([N+](=O)[O-])ccc1C(=O)n1cc(-c2ccc(OC)c(OC)c2)c2cccnc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1cc(N)ccc1C(=O)n1cc(-c2ccc(OC)c(OC)c2)c2cccnc21
Reaction time: 8 h

Procedure:
[3-(3,4-dimethoxy-phenyl)-pyrrolo[2,3-b]pyridine-1-yl]-(2-ethoxy-4-nitro-phenyl)-methanone, 54, (100 mg, 0.22 mmol) was dissolved in EtOAc (30 mL). A catalytic amount of 10% Pd/C (7 mg) was added and the flask capped with rubber septa. The flask was evacuated and back filled with hydrogen twice. Finally, the reaction was stirred overnight under a hydrogen gas atmosphere (balloon). The reaction mixture was filtered over Celite®, rinsed generously with EtOAc (2×75 mL) and concentrated under reduced pressure to give the titled compound. (56 mg, 60%) MS(ESI) [M+H+]+=418.24
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3=[N:14][C:15]([CH3:22])=[C:16]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:11]3[N:10]=2)=[CH:5][CH:4]=1.[Br-].[H-].[Na+].O.[CH:27]([O:29][CH3:30])=O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3=[N:14][C:15]([CH3:22])=[C:16]([C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:27][O:29][CH3:30])[N:11]3[N:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)Cc1c(C)nc2sc(-c3ccc(OC)cc3)nn12
Reactant: COC=O
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC=C(C(=O)OC)c1c(C)nc2sc(-c3ccc(OC)cc3)nn12
Reaction time: 8 h

Procedure:
A solution of 10 g of 2-(4-methoxyphenyl)-5-methoxycarbonylmethyl-6-methylimidazolo-[2,1-b]-1,3,4-thiadiazole in 50 cm3 of methyl formate is dripped into a solution of 1.8 g of sodium hydride bromide in 10 cm3 of anhydrous dimethylformamide (DMF). The solution is left under agitation overnight at ambient temperature and is then poured into water and extracted twice with ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([NH2:25])[C:23]#[CH:24].C1C=CC=CC=1>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([NH:25][CH2:22][C:23]#[CH:24])=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)cc2)C1
Reactant: C#CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: C#CCNC(=O)N1CC(Oc2ccc(Cl)cc2)C1
Reaction time: 16 h

Procedure:
A stirred mixture of 7.4 g (0.03 mole) of 3-(4-chlorophenoxy)-1-azetidinecarbonyl chloride and 4.5 g (0.03 mole) of potassium carbonate in 20 ml of tetrahydrofuran was treated with 1.7 g (0.03 mole) of 2-propynylamine added dropwise from a needle and syringe. After stirring for 16 hr, the reaction mixture was diluted with 400 ml of water and the resulting tan solid was collected by filtration, yielding 7.7 g of crude product. Repeated triturations of the crude product with hot benzene gave upon combining and cooling 1.2 g (15.2%) of tan powder, m.p. 120°-122° C.