Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.[F-].[K+].[C:15]([OH:23])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[C:15]([O:23][C:11]1[CH:12]=[CH:2][CH:3]=[C:4]2[C:9]([O:8][C:6](=[O:7])[C:5]=12)=[O:10])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH:22][C:11]1[CH:12]=[CH:2][CH:3]=[C:4]2[C:9]([O:8][C:6](=[O:7])[C:5]=12)=[O:10]
Reactant: O=C1OC(=O)c2cc(F)ccc21
Reactant: O=C(O)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Oc1cccc2c1C(=O)OC2=O)c1ccccc1
Product: O=C1OC(=O)c2c(O)cccc21

Procedure:
4-Fluorophthalic anhydride (0.44 g, 2.6 mmol shown as FPAN in table below), potassium fluoride (Aldrich, 0.18 g, 3.1 mmol), benzoic acid (Aldrich, 0.28 g, 2.3 mmol shown as BzOH in table below) and dimethyl formamide (Aldrich, 3 ml) were heated in a 160° C. oil bath. The reaction was monitored by GC and showed the following results (BOPAN=benzoyloxyphthalic anhydride; ODPAN=oxydiphthalic anhydride; and HOPAN=hydroxyphthalic anhydride):
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:12][C:13]([N:15]1[CH2:20][C@H:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]3[O:31][CH2:30][CH2:29][N:28]([CH2:32][CH2:33][CH2:34][O:35][CH3:36])[C:27]=3[CH:37]=2)[C@@H:18]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][O:45][CH2:46][C@@H:47]([CH3:51])[CH2:48][O:49][CH3:50])=[CH:40][CH:39]=2)[C@H:17]([CH2:52][NH2:53])[CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>ClCCl>[CH2:5]([O:12][C:13]([N:15]1[CH2:20][C@H:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]3[O:31][CH2:30][CH2:29][N:28]([CH2:32][CH2:33][CH2:34][O:35][CH3:36])[C:27]=3[CH:37]=2)[C@@H:18]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][O:45][CH2:46][C@@H:47]([CH3:51])[CH2:48][O:49][CH3:50])=[CH:40][CH:39]=2)[C@H:17]([CH2:52][NH:53][C:1](=[O:3])[CH3:2])[CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](CN)[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](CNC(C)=O)[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Reaction time: 0.5 h

Procedure:
5.936 mmol of acetyl chloride are added to a solution of 5.396 mmol of (3R,4R,5R)-3-aminomethyl-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy -propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester and 6.475 mmol of triethylamine in 80 ml of dichloromethane under argon at 0° C. After 30 minutes, the reaction mixture is quenched with saturated aqueous sodium bicarbonate solution and extracted with tert-butyl methyl ether (2×). The combined organic layers are washed successively with water and brine, dried with sodium sulfate and evaporated. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound as a yellow oil. Rt=4.98 (gradient I).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:12][CH:11]2[C:13](=O)[CH:7]([CH2:8][CH2:9][CH2:10]2)[CH2:6]1)=[O:4].C([O-])(=O)C.[NH4+].[BH3-]C#[N:22].[Na+]>CO>[CH3:1][O:2][C:3]([CH:5]1[CH2:12][CH:11]2[CH:13]([NH2:22])[CH:7]([CH2:8][CH2:9][CH2:10]2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CC2CCCC(C1)C2=O
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CC2CCCC(C1)C2N

Procedure:
The product of Example 7A (2.03 g, 10.38 mmol) was stirred at room temperature in the presence of ammonium acetate (8 g, 103.8 mmol) and NaBH3CN (3.3 g, 51.9 mmol) in methanol (30 mL) for twelve hours at 23° C. The solvent was then evaporated and the residue was dissolved in dichloromethane; washed with water, NaHCO3 solution, and brine; and dried (Na2SO4). After filtration and evaporation of the solvent, the amine was used without further purification.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[N:12]1([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1>CS(C)=O.O.C(OCC)(=O)C>[N:12]1([CH:17]2[CH2:22][CH2:21][N:20]([C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=3)[CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: COC(=O)c1ccc(F)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N2CCC(N3CCCC3)CC2)cc1
Temperature: 150 °C
Reaction time: 4 h
Yield: 73.4 %

Procedure:
Commercially available methyl 4-fluorobenzoate (1.5 g, 9.73 mmol) was added to a solution of commercially available 4-(1-pyrrolidinyl)piperidine (3.0 g, 19.5 mmol) in dimethylsulfoxide (15 mL) at room temperature and then the mixture was stirred under nitrogen atmosphere and under irradiation with microwave at 150° C. for 4 hours. The reaction liquid was allowed to stand to cool to room temperature and then diluted with water and ethyl acetate. The organic layer was washed with water and then dried by a conventional method. The drying agent was separated by filtration and then the filtrate was concentrated under vacuum. The residue was purified with NH silica gel column chromatography (n-heptane:ethyl acetate=1:1) to obtain the title compound (2.06 g, 73%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:24]3[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=3)([C:14]3[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([C:30]([F:33])([F:32])[F:31])[C:3]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41].C[O-].[Na+].CO>>[CH3:40][O:41][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:24]3[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=3)([C:14]3[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([C:30]([F:33])([F:32])[F:31])[C:3]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(C(F)(F)F)c(-c3ccccc3)c(Cl)c2c1
Agent: C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1c(-c2ccccc2)c(C(F)(F)F)nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc12
Temperature: 70 °C

Procedure:
A mixture of (4-chloro-3-phenyl-2-(trifluoromethyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol•TFA (78 mg, 0.099 mmol, Example 172) and 0.5 M NaOMe in MeOH (0.46 mL, 0.23 mmol) in a sealed tube was heated at 70° C. for 7 hours. More 0.5 M NaOMe in MeOH (0.33 mL, 0.17 mmol) was added and the mixture was heated at the same temperature for another hour. The solvent was evaporated, and DMSO was added. After filtering through a syringe filter, the filtrate was purified by reverse phase HPLC (water/acetonitrile/0.1% TFA) to give the title compound as a white solid. 1H NMR (400 MHz, MeOD-d4) δ 9.07 (s, 1H), 8.86 (d, J=2.02 Hz, 1H), 8.34 (d, J=2.53 Hz, 1H), 8.27 (d, J=8.59 Hz, 1H), 8.13 (dd, J=2.02, 8.08 Hz, 1H), 7.84-7.95 (m, 2H), 7.46-7.56 (m, 3H), 7.35-7.45 (m, 2H), 7.15 (s, 1H), 3.72 (s, 3H), 3.55 (s, 3H); MS m/e 559.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH:42]=[CH:41][N:40]=[CH:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:38]3[CH:42]=[CH:41][N:40]=[CH:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: c1c[nH]cn1
Product: O=C(Nc1ccc(Oc2ccnc(-n3ccnc3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and imidazole according to conditions described in general procedure C. Mp: 175-176° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.58-1.60 (m, 6 H), 3.28-3.31 (m, 4 H), 6.96 (d, J=12.4, 1 H), 7.03-7.04 (m, 1 H), 7.10-7.12 (m, 1 H), 7.17 (d, J=8.8 Hz, 1 H), 7.47 (s, 1 H), 7.55-7.67 (m, 5 H), 7.88-7.90 (m, 1 H), 8.03 (d, J=8.4 Hz, 1 H), 8.18-8.19 (m, 1 H), 8.73-8.75 (m, 1 H), 10.49 (s, 1H).
Reaction SMILES: [CH:1](=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[C:7]([O:11][C:12]([NH:14][CH:15](P(OC)(OC)=O)[C:16]([O:18][CH3:19])=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8]>O1CCCC1>[C:7]([O:11][C:12]([NH:14]/[C:15](=[CH:1]\[C:2]([CH3:5])([CH3:4])[CH3:3])/[C:16]([O:18][CH3:19])=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)C=O
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Solvent: C1CCOC1
Product: COC(=O)/C(=C/C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 4 h

Procedure:
Pivalaldehyde (303.2 g, 3.41 mol, 10 equivalents) and methyl {[tert-butoxycarbonyl]amino}-(dimethoxyphosphoryl)acetate (101.5 g, 0.341 mol, 1.0 equivalent) are dissolved in tetrahydrofuran (800 ml) and cooled to −70° C. At −70° C., N,N,N,N-tetramethylguanidine (78.7 g, 0.683 mmol, 6.95 ml, 2.0 equivalents) is slowly added dropwise and the mixture is then stirred at −70° C. for 4 h, subsequently, the mixture is stirred at RT for 4 days. The reaction mixture is concentrated, then extracted with ethyl acetate (2×500 ml) against water, and the combined organic phases are washed with a saturated sodium chloride solution (100 ml) and dried over sodium sulfate. After concentration, the crude product is chromatographed (1.5 kg of silica gel, eluent: cyclohexane/ethyl acetate 5:1). 67 g (76% of theory) of the title compound are obtained.
Reaction SMILES: CC1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/[CH2:18][OH:19].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1.C[C:33]1[CH:49]=[CH:48][C:47](C)=[CH:46][C:34]=1[CH2:35][O:36]CC1C=C(C)C=CC=1C>>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][O:36][CH2:35][C:34]2[CH:46]=[CH:47][C:48]([O:19][CH3:18])=[CH:49][CH:33]=2)=[CH:26][CH:25]=1
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/CO)C(C)(C)CCC1
Reactant: Cc1ccc(C)c(COCc2cc(C)ccc2C)c1
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(COCc2ccc(OC)cc2)cc1

Procedure:
Retinyl 4-Methoxybenzyl Ether (3e) was prepared from retinol and 4-methoxybenzyl chloride by the method described for 3c. The ether extract was washed successively with saturated sodium bicarbonate solution and with brine. The crude product was purified by successive chromatographic operations with the column absorbent and eluting solvent as follows: deactivated alumina, pentane and then 95:5 pentane-ethyl acetate; silica gel 60, chloroform; silica gel 60, 4:1 chloroform-pentane; repetition of the last method. The purified product was a yellow syrup: HPLC, 99.3% (340 nm), 100% (254 nm); MS m/z 406 (M), 285 (C20H29O), 269 (C20H29), 255 (C19H27), 121 (4-methoxybenzyl); UV λmax326 nm (ε 51 300), 226 nm (ε 14 000); 1H NMR (CDCl3) δ 7.27 (m, 2H, H2′), 6.88 (m, 2H, H3′), 6.59(dd, 1H, H11, J10,11=11.3 Hz, J11,12=15.0Hz), 6.29 (d, 1H, H12), 6.15 (bd, 1H, H8,J7,8=16.0Hz), 6.11 (d, 1H, H7), 6.09 (d, 11H, H10), 5.68 (t, 1H, H14), 4.45 (s, 2H, H21), 4.15 (d, 2H, H15, J14,15=6.8 Hz), 3.80 (s, 3H, OCH3), 2.01 (t, 2H, H4), 1.95 (s, 3H, H17), 1.82 (s, 3H, H20), 1.71 (s, 3H, H18), 1.65-1.57 (m, 2H, H3), 1.48-1.44 (m, 3H, H2), 1.02 (s, 6H, H16, H17). Anal. Calcd. for C28H38O2.½H2O:C, 80.92; H, 9.46. Found: C, 80.93; H, 9.38.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[NH2:14][C@H:15]1[CH2:19][CH2:18][N:17]([C:20](=[O:33])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)[CH2:16]1.C(N(CC)C(C)C)(C)C.C(O)CCC>C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>[CH3:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([NH:14][C@H:15]2[CH2:19][CH2:18][N:17]([C:20](=[O:33])[CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:26][CH:27]=3)[CH2:16]2)[CH:11]=1
Reactant: Cc1cc(Cl)nc2ccccc12
Reactant: N[C@H]1CCN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N[C@H]2CCN(C(=O)Cc3ccc(OC(F)(F)F)cc3)C2)nc2ccccc12
Temperature: 140 °C
Yield: 33.1 %

Procedure:
A mixture of 2-chloro-4-methylquinoline (0.30 g), 1-((S)-3-aminopyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone mono hydrochloride (0.60 g), N,N-diisopropylethylamine (0.74 mL), and n-butanol (1.5 mL) was heated at 140° C. in a sealed tube for 23 h. The reaction mixture was diluted with chloroform and saturated aqueous sodium hydrogencarbonate, and then the aqueous layer was extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate, the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=1:1) to obtain 1-((S)-3-(4-methylquinolin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.24 g). (2) 1-((S)-3-(4-Methylquinolin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.24 g) was dissolved in ethyl acetate (2.5 mL), followed by addition of a solution (0.28 mL) of 4 M HCl in ethyl acetate, the mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, and then solidified with diethyl ether to obtain the title compound (0.24 g).
Reaction SMILES: Br[C:2]([CH3:25])([CH3:24])[C:3]([NH:5][C:6](=[O:23])[NH:7][C:8]1[S:9][C:10]2[CH2:16][CH2:15][O:14][C:13]3[CH:17]=[C:18]([Br:21])[CH:19]=[CH:20][C:12]=3[C:11]=2[N:22]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:21][C:18]1[CH:19]=[CH:20][C:12]2[C:11]3[N:22]=[C:8]([N:7]4[C:2]([CH3:25])([CH3:24])[C:3](=[O:4])[NH:5][C:6]4=[O:23])[S:9][C:10]=3[CH2:16][CH2:15][O:14][C:13]=2[CH:17]=1
Reactant: CC(C)(Br)C(=O)NC(=O)Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)NC(=O)N1c1nc2c(s1)CCOc1cc(Br)ccc1-2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 1.002 g (2.048 mmol) of 2-bromo-2-methyl-N-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)carbamoylpropanamide and 1.660 g (5.11 mmol) of cesium carbonate in 100 ml of N,N-Dimethylformamide was stirred at 60° C. for 2 hours. The mixture was filtered, the filtrate concentrated in high vacuum, the residue partitioned between ethyl acetate and water. pH was adjusted to 5 by addition of 5% aq citric acid. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated in vacuum to give 1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2,4-dione as an off-white powder which was used in the next steps without further purification. Yield 0.812 g (97%). MS (ESI+): 408.1
Reaction SMILES: [C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6])([CH3:4])([CH3:3])[CH3:2].[Cl:15]C1C=CC(C(Cl)=O)=CC=1>>[C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:9]=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=1)[NH2:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N(N)C(=O)c1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: CC(C)(C)N(N)C(=O)c1ccc(Cl)cc1

Procedure:
N'-t-butyl-N'-(4-chlorobenzoyl)hydrazine was prepared substantially according to the procedure for preparing N'-t-butyl-N'-benzoylhydrazine described for Example 220, Step 3, except 4-chlorobenzoyl chloride was used in place of benzoyl chloride.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[CH:5][NH:4][N:3]=1.[P:8](=[O:12])([OH:11])([OH:10])[OH:9]>O>[P:8]([O-:12])([OH:11])([OH:10])=[O:9].[CH3:1][C:2]1[NH:3][NH+:4]=[CH:5][C:6]=1[CH3:7]
Reactant: O=P(O)(O)O
Reactant: Cc1c[nH]nc1C
Solvent: O
Product: Cc1c[nH+][nH]c1C
Product: O=P([O-])(O)O
Yield: 98 %

Procedure:
96 g (1.0 mol) of 3,4-dimethylpyrazole were dissolved in 115 g (1.0 mol) of phosphoric acid (85%) at room temperature. The water contained in the phosphoric acid was evaporated. After a few hours, the title compound crystallized out from the oil initially present (yield 98%).
Reaction SMILES: [S:1]([OH:5])(O)(=O)=[O:2].[C:6]1([C:13]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=2)[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1>S(=O)(=O)(O)O>[NH2:10][C:9]1[CH:8]=[CH:7][C:6]2[C:13]3[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=3[S:1](=[O:5])(=[O:2])[C:12]=2[CH:11]=1
Reactant: Nc1ccc(-c2ccc(N)cc2)cc1
Reactant: O=S(=O)(O)O
Product: Nc1ccc2c(c1)S(=O)(=O)c1cc(N)ccc1-2
Temperature: 70 °C
Yield: 86.6 %

Procedure:
The title compound was prepared as described in U.S. Pat. Nos. 2,590,632 and 2,620,343. At 10° C., 30 g of benzidine sulfate was added, in portions, to 100 ml of fuming sulfuric acid. After the addition, the reaction was maintained at 70° C. for 18 hours, cooled and poured into 250 g of cracked ice. The beige solid was collected, washed with water and saturated sodium bicarbonate yielding a yellow solid. The yellow solid was stirred with bicarbonate solution 2×, collected, washed with large volumes of water, and dried in vacuo to give 22.66 g (87%) of the desired product.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[S:3]([O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[C:10]([CH:17]([OH:20])[CH2:18][OH:19])[CH:11]=[CH:12][CH:13]=2)[N:8]=1)(=[O:5])=[O:4].N1C=CN=C1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].O>CN(C=O)C>[F:22][C:2]([F:1])([F:21])[S:3]([O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[C:10]([CH:17]([OH:20])[CH2:18][O:19][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:11]=[CH:12][CH:13]=2)[N:8]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(Oc1ccc2cccc(C(O)CO)c2n1)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(O)c1cccc2ccc(OS(=O)(=O)C(F)(F)F)nc12
Yield: 87.3 %

Procedure:
A solution of 12 g (35 mmol) of 2-trifluoromethanesulfonyloxy-8-(1,2-dihydroxyethyl)quinoline, of 5.33 g (78.3 mmol) of imidazole and of 5.63 g of tert-butyldimethylsilyl chloride in 280 ml of DMF is stirred at ambient temperature for 16 h. 800 ml of water are added and extraction is carried out with ethyl acetate (3×250 ml). The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by silica chromatographic column (eluent: cyclohexane/ethyl acetate 8/2) to provide 13.8 g of 2-trifluoromethanesulfonyloxy-8-(1-hydroxy-2-tert-butyldimethylsilyloxyethyl)quinoline in the form of a yellow oil. (Yield: 91%)
Reaction SMILES: O[N:2]1C(=O)[CH2:5][CH2:4][C:3]1=[O:8].C1([N:15]=C=NC2CCCCC2)CCCCC1.C(O[C:29]([C@@H:31]1[CH2:35][CH2:34][CH2:33][N:32]1[S:36]([C:39]1[N:43]2[C@:44]([CH3:69])([CH2:56][C:57]3[CH:62]=[CH:61][C:60]([C:63]4[CH:64]=[N:65][CH:66]=[N:67][CH:68]=4)=[CH:59][CH:58]=3)[C:45](=[O:55])[N:46]([C:47]3[CH:52]=[C:51]([Cl:53])[CH:50]=[C:49]([Cl:54])[CH:48]=3)[C:42]2=[N:41][CH:40]=1)(=[O:38])=[O:37])=[O:30])(C)(C)C>C(Cl)Cl>[C:3]([C@H:4]([NH:15][C:29]([C@@H:31]1[CH2:35][CH2:34][CH2:33][N:32]1[S:36]([C:39]1[N:43]2[C@:44]([CH3:69])([CH2:56][C:57]3[CH:62]=[CH:61][C:60]([C:63]4[CH:64]=[N:65][CH:66]=[N:67][CH:68]=4)=[CH:59][CH:58]=3)[C:45](=[O:55])[N:46]([C:47]3[CH:52]=[C:51]([Cl:53])[CH:50]=[C:49]([Cl:54])[CH:48]=3)[C:42]2=[N:41][CH:40]=1)(=[O:38])=[O:37])=[O:30])[CH3:5])(=[O:8])[NH2:2]
Reactant: O=C1CCC(=O)N1O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(-c3cncnc3)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Product: C[C@@H](NC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(-c3cncnc3)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
N-Hydroxysuccinimide (0.035 g), followed by 1,3-dicyclohexylcarbodiimide (DCC, 0.064 g), were added to a solution of (S)-1-[(R)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-5-(4-pyrimidin-5-yl-benzyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl]-pyrrolidine-2-carboxylic acid (Example 14) (0.16 g) in CH2Cl2 (20 mL). The reaction was stirred at room temperature for 1 h, then was filtered through a pad of diatomaceous earth, concentrated and re-dissolved in 2N NH3—CH3OH (10 mL). The solution was stirred at room temperature for 1 h. The volatiles were then removed and the resultant residue was re-dissolved in CH2Cl2 and washed with H2O. The combined organic layers were concentrated and the resultant residue was purified by silica gel chromatography to afford the title compound (0.128 g) as a foam (697.2, M+1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(OC([NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[CH:17][N:18]2[CH:23]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:24]([O:26][CH3:27])=[O:25])=O)(C)(C)C.C(N(CC)CC)C.O>C(Cl)Cl>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([CH:23]([N:18]2[C:19]3[C:15](=[C:14]([NH:13][S:2]([CH3:1])(=[O:4])=[O:3])[CH:22]=[CH:21][CH:20]=3)[CH:16]=[CH:17]2)[C:24]([O:26][CH3:27])=[O:25])=[CH:33][CH:32]=1
Reactant: COC(=O)C(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (159 μL, 2.04 mmol) was added to a stirred solution of 2b (320 mg, 1.02 mmol) and triethylamine (213 μL, 1.53 mmol) in DCM (3 mL) at rt. After 1 h, the reaction mixture was poured into water and extracted with DCM. The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC on YMC Pack Pro C18 stationary phase (CH3CN/H2O as eluent, 0.05% TFA as modifier), followed by lyophilization of the purified fractions to afford the title compound 17. m/z (ES) 393 (MH)+ IP=C rating.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7]([C:9](Cl)(Cl)Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C([O-])(=O)C.[NH4+:26]>C(#N)C.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7]([C:9](=[NH:26])[N:19]3[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]3)=[N:8][C:4]=2[CH:3]=1
Reactant: [NH4+]
Reactant: CN1CCNCC1
Reactant: Clc1ccc2[nH]c(C(Cl)(Cl)Cl)nc2c1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN1CCN(C(=N)c2nc3cc(Cl)ccc3[nH]2)CC1
Reaction time: 0.17 h
Yield: 22.4 %

Procedure:
To a suspension of 5-chloro-2-trichloromethyl-1H-benzoimidazole (100 mg, 0.37 mmol) in acetonitrile (4 mL) was added N-methylpiperazine (0.04 mL, 0.4 mmol). The mixture was stirred for 10 min then ammonium acetate (29 mg, 0.38 mmol) was added. After 18 h the reaction mixture was diluted with satd aq NaHCO3 (10 mL), and then extracted with dichloromethane (3×10 mL). The combined extracts were dried (Na2SO4) and then concentrated under reduced pressure. The crude product was purified on silica gel (10 g; 0-10% methanol (2 M NH3)/dichloromethane) to afford 23 mg (22%) of the title compound. MS (ESI): mass calculated for C13H16N4O, 277.11; m/z found, 278.2 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.79-7.74 (m, 2H)1 7.45 (dd, J=8.6, 2.0 Hz, 1H), 4.23-4.17 (m, 4H), 3.63-3.58 (m, 4H), 3.01 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:3]=1[CH2:4][N:5]1[C@@H:9]([CH3:10])[C@@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:7][C:6]1=[O:17].[CH3:26][O:27][C:28](=[O:47])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[CH3:26][O:27][C:28](=[O:47])[CH2:29][C:30]1[CH:31]=[C:32]([C:2]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:3]=2[CH2:4][N:5]2[C@@H:9]([CH3:10])[C@@H:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]2=[O:17])[C:33]([O:36][CH3:37])=[CH:34][CH:35]=1
Reactant: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1Br
Reactant: COC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (4S,5R)-3-(2-bromo-5-trifluoromethyl-benzyl)-4-methyl-5-phenyl-oxazolidin-2-one and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester.