Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH2:7][O:8][C:9]([C:11]1[N:15]2[C:16](=[O:28])[C@H:17]([C@H:18]([O:20][Si](C(C)(C)C)(C)C)[CH3:19])[C@H:14]2[C@@H:13]([CH3:29])[C:12]=1[S:30][C@H:31]1[CH2:35][NH:34][C:33](=[S:36])[CH2:32]1)=[O:10])(=[O:5])[CH:2]([CH3:4])[CH3:3].CN(C)C=O.F.[NH4+].P([O-])([O-])([O-])=O>CN1CCCC1=O>[C:1]([O:6][CH2:7][O:8][C:9]([C:11]1[N:15]2[C:16](=[O:28])[C@H:17]([C@H:18]([OH:20])[CH3:19])[C@H:14]2[C@@H:13]([CH3:29])[C:12]=1[S:30][C@H:31]1[CH2:35][NH:34][C:33](=[S:36])[CH2:32]1)=[O:10])(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)C(=O)OCOC(=O)C1=C(S[C@H]2CNC(=S)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: F
Agent: O=P([O-])([O-])[O-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: CC(C)C(=O)OCOC(=O)C1=C(S[C@H]2CNC(=S)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 20 °C
Reaction time: 72 h
Yield: 91 %

Procedure:
A mixture of (1R,5S,6S)-2-[(4R)-pyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid isobutyryloxymethyl ester (3 g), dimethylformamide (20 ml), N-methylpyrrolidone (7 ml) and ammonium hydrogenfluoride (1.21 g) is stirred at 20° C. for three days. The reaction mixture is poured into a phosphate buffer (pH 7.0), and the mixture is extracted with ethyl acetate. The aqueous layer is extracted with ethyl acetate, and the organic layers are combined, washed with water, dried, and concentrated under reduced pressure. The resulting residue is crystallized from a mixture of ethyl acetate and diisopropyl ether. To the resultant is added diisopropyl ether, and the precipitate is collected by filtration, and washed to give (1R,5S,6S)-2-[(4R)-pyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid isobutyryloxymethyl ester (2.17 g) as crystals.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[C:6]([O:7][CH2:8][CH2:9][OH:10])=[C:5]([O:15][CH3:16])[CH:4]=1>C(Cl)Cl.O=[Mn]=O>[OH:10][CH2:9][CH2:8][O:7][C:6]1[C:11]([O:13][CH3:14])=[CH:12][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:15][CH3:16]
Reactant: COc1cc(CO)cc(OC)c1OCCO
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1cc(C=O)cc(OC)c1OCCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
To a solution of 2-(4-hydroxymethyl-2,6-dimethoxyphenoxy)ethanol (1.78 g, 7.8 mmol) in methylene chloride (39 mL, 0.2 M) was added MnO2 (6.8 g, 78 mmol). The reaction mixture was stirred for 3 hours at room temperature, then subjected to celite filtration, and evaporated under reduced pressure. Recrystallization of the residue from diethyl ether gave a colorless granular crystal (1.586 g, 89.8%, m.p. 69 to 70° C.).
Reaction SMILES: COC[O:4][C:5]1[CH:44]=[CH:43][C:8]2[CH:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][S:32][CH2:33][CH2:34][CH2:35][C:36]([F:42])([F:41])[C:37]([F:40])([F:39])[F:38])[C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20]COC)=[CH:16][CH:15]=3)([CH3:13])[CH2:11][O:12][C:7]=2[CH:6]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CO>[OH:4][C:5]1[CH:44]=[CH:43][C:8]2[CH:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][S:32][CH2:33][CH2:34][CH2:35][C:36]([F:42])([F:41])[C:37]([F:38])([F:39])[F:40])[C:10]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)([CH3:13])[CH2:11][O:12][C:7]=2[CH:6]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCSCCCC(F)(F)C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CO
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCSCCCC(F)(F)C(F)(F)F
Temperature: 25 °C
Yield: 60.1 %

Procedure:
(3RS,4RS)-7-Methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-4-[8-(4,4,5,5,5-pentafluoropentylthio)octyl]-2,3-dihydro-4H-benzopyran (120 mg, 0.19 mmol) and pyridinium p-toluenesulfonate (580 mg, 2.3 mmol) were dissolved in methanol (8 ml) and then refluxed for 7 hours. The reaction solution was cooled to room temperature and, after adding water, extracted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and then concentrated. The residue was subjected to column chromatography (n-hexane:ethyl acetate=4:1) to obtain 64 mg (yield: 69%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([Li])[CH:15]=[CH:14][CH:13]=[CH:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-:17].[Cl-].[Cl-].[Cl-].[Zr+4:21]>O1CCCC1.C1(C)C=CC=CC=1.ClCCl>[Cl-:17].[Cl-:17].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([Zr+2:21][C:11]3([C:8]4[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=4)[CH:15]=[CH:14][CH:13]=[CH:12]3)[CH:15]=[CH:14][CH:13]=[CH:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]C1(c2ccc(C(C)(C)C)cc2)C=CC=C1
Reactant: [Zr+4]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C2([Zr+2]C3(c4ccc(C(C)(C)C)cc4)C=CC=C3)C=CC=C2)cc1
Reaction time: 2 h

Procedure:
A solution of 1.2 g of 4-t-butylphenylcyclopentadienyllithium (0.0059 mole) in 20 ml tetrahydrofuran was slowly added at room temperature to a solution of 0.685 g of zirconium tetrachloride (0.0029 mole) in 50 ml tetrahydrofuran. After stirring the solution for 2 hours, the tetrahydrofuran was removed by evaporation leaving a residue. The resulting residue was taken up in hot toluene. Any undissolved material was removed by filtration and a resultant clear solution was evaporated to dryness. The solid residue obtained from the evaporation to dryness was taken up in dichloromethane. Undissolved, off-white solids were removed by centrifugation and decantation. The clear solution was once again evaporated to dryness yielding bis[(4-t-butylphenyl)cyclopentadienyl]zirconium dichloride as a yellow solid material. Spectral data from a proton-NMR is consistent with the product obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]=[CH:12][N:13](C)C)=[CH:6][C:5]=1[Cl:16].[NH2:18]N>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][NH:13][N:18]=2)=[CH:6][C:5]=1[Cl:16]
Reactant: COC(=O)c1ccc(CC=CN(C)C)cc1Cl
Reactant: NN
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2cc[nH]n2)cc1Cl
Yield: 94.1 %

Procedure:
A solution of 2-chloro-4-(3-dimethylamino-2-propen-1-yl)-benzoic acid methyl ester of Step B (6.13 g, 22.9 mmol) and anhydrous hydrazine (1.44 mL, 45.8 mmol) in 15 mL of glacial acetic acid was heated at 90° C. for 30 minutes. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over sodium sulfate. The solvent was evaporated and the residual solid triturated with diethyl ether-hexane to give the title compound (5.1 g) as an orange solid.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].Cl[CH2:33][CH2:34][CH2:35][N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][C:37]1=[O:45].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC.CO.ClCCl>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:33][CH2:34][CH2:35][N:36]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH2:38][C:37]3=[O:45])[CH2:8][CH2:7]2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23]
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Reactant: O=C1Cc2ccccc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCN4C(=O)Cc5ccccc54)CC3)C2=O)c1
Yield: 35.4 %

Procedure:
tert-Butyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.30 g, 0.712 mmol), 1-(3-chloropropyl)indolin-2-one (0.15 g, 0.712 mmol), sodium iodide (0.032 g, 0.214 mmol), and potassium carbonate (0.15 g, 1.07 mmol) in 2-butanone (8 mL) were heated at 78° C. for 4 hours. The reaction was diluted with 10% methanol/dichloromethane, filtered, and evaporated. The residue was purified by PTLC (5% methanol/dichloromethane) to give product as an oil (0.15 g, 35%); NMR (DMSO-d6); δ1.52 (s, 9H); 1.55-1.70 (m, 2H); 1.70-1.83 (m, 2H); 2.33-2.45 (m, 2H); 2.51-2.63 (m, 2H); 2.63-2.80 (m, 4H); 3.55 (s, 2H); 3.74 (t, J=6.8 Hz, 2H); 4.59 (s, 2H); 4.61 (s, 2H); 6.78 (t, J=7.2 Hz, 1H); 6.86 (d, J=8 Hz, 2H); 6.99 (t, J=7.6 Hz, 1H); 7.09 (d, J=8 Hz, 1H); 7.21-7.27 (m, 4H); 7.48-7.55 (m, 2H); 7.79 (s, 1H); 7.82-7.85 (m, 1H); MS for C36H42N4O4 m/z 595 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([C@H:7]2[CH2:12][CH2:11][N:10](C(OC)=O)[C@@H:9]([CH2:17][C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=3)[CH2:8]2)[O:4][NH:3]1.Br>>[F:26][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([F:24])[C:21]=1[F:25])[CH2:17][C@H:9]1[CH2:8][C@@H:7]([C:5]2[O:4][NH:3][C:2](=[O:1])[CH:6]=2)[CH2:12][CH2:11][NH:10]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(F)c(F)c(F)c1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](Cc3cc(F)c(F)c(F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.9 %

Procedure:
(2R,4S)-Methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3,4,5-trifluorobenzyl)piperidine-1-carboxylate (584 mg, 1.58 mmol) was dissolved in hydrogen bromide (33% in AcOH, 7 mL, 302.80 mmol) and stirred at room temperature for 20 h. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(3,4,5-trifluorobenzyl)piperidin-4-yl)isoxazol-3(2H)-one (325 mg, 66%). 1H NMR (600 MHz, dmso) δ 1.05 (q, 1H), 1.31 (dq, 1H), 1.71-1.78 (m, 2H), 2.34-3.78 (m, 6H), 5.68 (s, 1H), 7.12-7.20 (m, 2H). HRMS Calculated for [C15H15F3N2O2+H]+: 313.1164. Found: 313.1172
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+:11]([O-])=O)[CH:3]=1.[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19](N)=[CH:18][CH:17]=1.CC1C=CC(C)=C(C)C=1C>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][C:19]2[CH:21]=[CH:22][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: COc1ccc(N)cc1
Solvent: Cc1ccc(C)c(C)c1C
Solvent: O
Product: COc1ccc(Nc2cc(Cl)ccc2[N+](=O)[O-])cc1
Yield: 33.4 %

Procedure:
A mixture of 10 g of 4-chloro-1,2-dinitrobenzene, 6.5 g of 4-methoxyaniline and 16 g of 1,2,3,4-tetramethylbenzene is refluxed for 15 hours. After cooling, water is added, the mixture is extracted with AcOEt, washed with a 1N solution of HCl , with a 1N solution of NaOH and with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is taken up with iso ether, a gummy insoluble material is separated off and the filtrate is chromatographed on alumina using iso ether as the eluent to give 4.6 g of the expected product after crystallization from isopropanol. M.p.=98° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:32]=[C:33](Cl)[N:34]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([N:18]2[C:25]3[N:21]([N:22]=[C:23]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:24]=3)[CH:20]=[CH:19]2)[CH:12]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.[CH3:65][N:66](C)C(=O)C>C(OCC)(=O)C.FC(F)(F)C([O-])=O.[Pd+2].FC(F)(F)C([O-])=O.[Zn].[C-]#N.[Zn+2].[C-]#N>[C:1]([C:5]1[CH:6]=[C:7]([CH:32]=[C:33]([C:65]#[N:66])[N:34]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([N:18]2[C:25]3[N:21]([N:22]=[C:23]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:24]=3)[CH:20]=[CH:19]2)[CH:12]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(NC(=O)c2cc(Cl)nc(C(C)(C)C)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Reactant: CC(=O)N(C)C
Agent: [Pd+2]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Agent: O=C([O-])C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2cc(C#N)nc(C(C)(C)C)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Temperature: 95 °C
Reaction time: 20 h

Procedure:
Under argon, a mixture of 137 mg (0.28 mmol) of the compound of Example 65, 4.04 mg (0.012 mmol) of palladium(II) trifluoroacetate, 9.91 mg (0.025 mmol) of racemic 2-di-tert-butylphosphino-1,1′-binaphthyl, 3.51 mg (0.054 mmol) of zinc flakes and 18.6 mg (0.16 mmol) of zinc cyanide in 1.5 ml N,N-dimethylacetamide was stirred at 95° C. for 20 hours. After cooling, the mixture was diluted with 80 ml of ethyl acetate and the mixture was washed in each case once with 10 ml of water and 10 ml saturated sodium chloride solution. The organic phase was dried over sodium sulphate and, after filtration, concentrated under reduced pressure. The residue obtained in this manner was purified by chromatography on a Biotage system (25 g Snap column; mobile phase gradient ethyl acetate/hexane, starting with 70% ethyl acetate, then increasing rapidly to 100% ethyl acetate). Further purification was by preparative thick-layer chromatography (2 mm layer thickness with concentration zone, mobile phase ethyl acetate, elution with methylene chloride/methanol 7:3). This gave 56 mg (38% of theory) of the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[C:7]([CH:10]=1)[C:8]#[N:9])=O.C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].N1CCCCC1>N1C=CC=CC=1>[C:8]([C:7]1[CH:10]=[C:3](/[CH:1]=[CH:17]/[C:18]([OH:20])=[O:19])[CH:4]=[CH:5][C:6]=1[N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)#[N:9]
Reactant: O=C(O)CC(=O)O
Reactant: N#Cc1cc(C=O)ccc1-n1cncn1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: N#Cc1cc(/C=C/C(=O)O)ccc1-n1cncn1

Procedure:
2.05 g (10.3 mmol) of 5-formyl-2-(1H-1,2,4-triazol-1-yl)benzonitrile (lit.: WO-A-2008/019760), 1.60 g (16.6 mmol) of malonic acid and 176 mg (2.07 mmol) of piperidine were stirred in 20 ml of pyridine at 80° C., for 48 hours. The pyridine was distilled off under reduced pressure. The residue was added to ice-water and adjusted to pH 1 with concentrated hydrochloric acid. The aqueous phase was extracted repeatedly with ethyl acetate and dried over sodium sulphate, and the solvent was distilled off under reduced pressure.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:10]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:18][C@H:19]([CH3:33])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:23]=1.C([BH3-])#N.[Na+]>CO>[CH3:32][O:31][C:29]([CH2:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C@H:19]([NH:18][CH2:10][C@@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:33])=[CH:23][CH:24]=1)=[O:30]
Reactant: COC(=O)Cc1ccc(OC[C@@H](C)N)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H](C=O)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(OC[C@@H](C)NC[C@@H](O[Si](C)(C)C(C)(C)C)c2ccccc2)cc1

Procedure:
Following a procedure similar to that described in Preparation 29, but using 1.5 g of (S)-α-(t-butyldimethylsilyloxy)-α-phenylacetaldehyde (prepared as described in Preparation 26), 1.1 g of methyl 4-[2(R)-amino-1-propoxy]phenylacetate (prepared as described in Preparation 27), 10 ml of absolute methanol and 950 mg of sodium cyanoborohydride, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18](=O)C(F)(F)F)[CH2:14][C@H:13]2[O:24][CH2:25][CH:26]([F:28])[F:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].Cl.C(N(C(C)C)CC)(C)C.BrC1[S:43][C:44]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:45][N:46]=1>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:43][C:44]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:45][N:46]=3)[CH2:14][C@H:13]2[O:24][CH2:25][CH:26]([F:28])[F:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cnc(Br)s1
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)C(F)(F)F)C[C@H]2OCC(F)F)nc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCOC(=O)c1cnc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC(F)F)C2)s1
Temperature: 40 °C
Reaction time: 0.67 h
Yield: 73.9 %

Procedure:
cis(±)-4-Chloro-N-{3-(2,2-difluoroethoxy)-1-(trifluoroacetyl)piperidin-4-yl}-5-ethyl-1H-imidazole-2-carboxamide obtained in Example (121f) (144 mg, 0.33 mmol) was dissolved in methanol (4 mL). A 2 N aqueous lithium hydroxide solution (0.4 mL) was added, and the mixture was stirred at 40° C. for 40 minutes. The pH was adjusted to 4 by adding a 1 N aqueous hydrochloric acid solution, and the solvent was evaporated under reduced pressure. The residue was dissolved in DMA (5 mL). Diisopropylethylamine (130 mg, 1 mmol) and ethyl 2-bromo-1,3-thiazole-5-carboxylate (155 mg, 0.66 mmol) were added, and the mixture was stirred at 75° C. for one hour. Dilution with ethyl acetate, washing with water and brine, drying over anhydrous magnesium sulfate, and concentration under reduced pressure gave a residue, which was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 3/2, 4/1) to obtain 0.12 g of the title compound as a colorless amorphous solid (74%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)O1>>[F:15][C:14]([F:17])([F:16])[C:12]1[CH:11]=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:36]3[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=3)[CH:7]=[CH:6][CH:5]=2)[N:13]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: Nc1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)cc1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.3) (0.22 g, 0.5 mmol) and commercially available 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.13 g, 0.59 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.174 g, 76%). MS (ISP) 460.3 [(M+H)+]; mp 186° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:11](=[O:13])[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K]>CN(C)C=O>[C:14]1(=[O:24])[N:18]([CH2:2][C:3]2[CH:4]=[C:5]([C:11](=[O:13])[CH3:12])[CH:6]=[CH:7][C:8]=2[O:9][CH3:10])[C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc(C(C)=O)cc1CCl
Agent: [K]
Solvent: CN(C)C=O
Product: COc1ccc(C(C)=O)cc1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 9 h
Yield: 76.7 %

Procedure:
A solution of 3'-chloromethyl-4'-methoxyacetophenone (10.0 g) in N,N-dimethylformamide (30 ml) was added slowly to a suspension of potassium phthalimide (9.4 g) in N,N-dimethylformamide (70 ml) at room temperature and then the mixture was stirred for 9 hours at room temperature. After removed of the insoluble material, the solvent was removed under reduced pressure. The residue was suspended in water (100 ml). The mixture was extracted with ethyl acetate (300 ml). The extract was dried with magnesium sulfate. The solvent was removed under reduced pressure to afford 3'-phthalimidomethyl-4'-methoxyacetophenone (11.94 g).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[OH-:13].[K+:14].[OH-:15].[Na+]>>[O:1]=[C:2]([O-:15])[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([C:11]([O-:13])=[O:12])[OH:10])[OH:8])[OH:6])[OH:4].[K+:14].[K+:14]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: [OH-]
Agent: [K+]
Agent: [Na+]
Product: O=C([O-])[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(=O)[O-]

Procedure:
The oxidation of D-glucose was carried out as in Examples 1 and 2. However, potassium hydroxide was substituted for sodium hydroxide in the neutralization process to give crude D-glucaric acid dipotassium salt (151.25 g, 70.4% based on pure dipotassium D-glucarate). The salt was precipitated from methanol as described to give an off white solid (145.75 g, 67.9% based on pure dipotassium D-glucarate).
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([F:25])[CH:19]=3)=[CH:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+].[CH2:28](I)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(O)CCC>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[C:20]([F:25])[CH:19]=3)=[CH:16][N:17]=2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCI
Reactant: CCCCCCc1ccc(-c2ncc(-c3ccc(O)c(F)c3)s2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCCCCOc1ccc(-c2cnc(-c3ccc(CCCCCC)cc3)s2)cc1F
Yield: 68 %

Procedure:
In a 30 ml-round-bottomed flask, 1.07 g (3.01 mM) of 2-(4-hexylphenyl)-5-(3-fluoro-4-hydroxyphenyl)thiazole prepared in Example 29, 0.23 g (3.48 mM) of potassium hydroxide and 5 ml of butanol were placed and heated. To the solution, 0.74 g (3.49 mM) of hexyl iodide was gradually added under heat-stirring, followed by heat-stirring for 5 hours about 90° C. After the reaction, the solvent was removed from the reaction mixture and water was added to the resultant residue to precipitate a crystal. The crystal was recovered by filtration and washed with water. The resultant crystal was purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent of toluene-methanol to obtain 0.90 g of 2-(4-hexylphenyl)-5-(3-fluoro-4-hexyloxyphenyl)thiazole (Yield: 68.0%). ##STR205##
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C:12]1[CH:17]=[C:16]([CH2:18][P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[CH:15]=[CH:14][N:13]=1.O.NN>ClCl>[NH2:3][C:12]1[CH:17]=[C:16]([CH2:18][P:19](=[O:26])([O:20][CH2:21][CH3:22])[O:23][CH2:24][CH3:25])[CH:15]=[CH:14][N:13]=1
Reactant: CCOP(=O)(Cc1ccnc(N2C(=O)c3ccccc3C2=O)c1)OCC
Agent: ClCl
Agent: NN
Solvent: O
Product: CCOP(=O)(Cc1ccnc(N)c1)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
The product from Example 15 (1.4 g, 3.7 mmol) was dissolved in CH2 Cl2 (10 mL) and placed in a 25 mL flask. Hydrazine monohydrate (0.187 g, 3.7 mmol) was added to the flask, and the reaction was allowed to stir at room temperature for 2 h. Two additional equivalents of hydrazine monohydrate were added to drive the reaction to completion. Filtering and solvent removal under reduced pressure gave 0.87 g of crude title compound which was used without further purification.
Reaction SMILES: Cl[C:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9](Cl)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>C(#N)C>[N:29]1([C:2]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9]([N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]3[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: ClC1(c2ccccc2)c2ccccc2C(Cl)(c2ccccc2)c2ccccc21
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: c1ccc(C2(n3ccnc3)c3ccccc3C(c3ccccc3)(n3ccnc3)c3ccccc32)cc1
Yield: 53.8 %

Procedure:
15 g (0.04 mol) of 9,10-dichloro-9,10-dihydro-9,10-diphenyl-anthracene and 17.7 g (0.24 mol) of imidazole in 250 ml of absolute acetonitrile are heated under reflux for 6 hours. Thereafter, the solvent is distilled off in vacuo and the residue is taken up in 500 ml of methylene chloride. The methylene chloride solution is washed twice with 500 ml of water each time and the organic phase is separated off, dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. The residue is heated in 300 ml of methanol and filtered. The filtrate is concentrated and the oil which remains is triturated with 50 ml of diisopropyl ether, whereupon it crystallises. 10 g (54% of theory) of 9,10-diimidazol-1-yl-9,10-dihydro-9,10-diphenyl-anthracene of melting point 258°-260° C. are obtained.