Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22](O)=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[O:33][NH2:34].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O.CCN=C=NCCCN(C)C.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:34][O:33][CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32][O:27]4)=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:25][CH:26]=1
Reactant: O=C(O)/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)nc1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)nc1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.4 %

Procedure:
To a solution of (2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylic acid (1.58 g) in DMF (16 mL) was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (546 mg), HOBt (744 mg), and EDCI.HCl (1.06 mg) and the resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was diluted with water and extracted with AcOEt. The organic phase was washed with sat NH4Cl aq solution and sat NaHCO3 aq solution, and brine, and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography eluted with chloroform:methanol=97.5:2.5 to give (2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (1.89 g) as colorless oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].CCN(CC)CC.[OH:12][C:13]1[CH:14]=[CH:15][C:16]2[CH:20]=[C:19]([CH3:21])[S:18][C:17]=2[CH:22]=1>C1COCC1.CCOC(C)=O>[C:1]([O:12][C:13]1[CH:14]=[CH:15][C:16]2[CH:20]=[C:19]([CH3:21])[S:18][C:17]=2[CH:22]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1cc2ccc(O)cc2s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc2cc(C)sc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 126.1 %

Procedure:
Acetyl chloride (1.5 ml, 1.66 g, 21 mmole) and Et3N (3 ml, 2.18 g, 21.5 mmole) were added, sequentially, to a solution of 6-hydroxy-2-methylbenzo[b]thiophene 8a (2.51 g, 15 mmole) in THF (120 ml) at 0°. The reaction was left stirring for 14 hours, gradually warming to ambient temperature, then diluted with EtOAc (100 ml) and washed with H2O (100 ml) and brine (100 ml). The combined aqueous layers were extracted with EtOAc (100 ml). The combined organic extracts were subsequently dried over Na2SO4 and concentrated, in vacuo, to give 3.9 g of a yellow solid which was purified by silica gel chromatography. Elution with hexane: Et2O (90:10) and evaporation of the appropriate fractions gave 2.93 g (93%) of a white solid. 1H NMR (DMSO-d6) δ 7.70 (1H, d, J=8.6 Hz), 7.66 (1H, d, J=2.2 Hz), 7.12 (1H, s), 7.07 (1H, dd, J=2.2, 8.6 Hz), 2.54 (3H, s), 2.27 (3H, s). Anal. Calcd. for C, 11H10O2S: C, 64.05; H, 4.89; S, 15.55. Found: C, 63.84; H, 4.93; S, 15.57.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[C:8](=[N:10]/[OH:11])/[CH3:9].C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][CH2:20][CH2:21][OH:22]>C(#N)C>[OH:22][CH2:21][CH2:20][CH2:19][O:11]/[N:10]=[C:8](/[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1])\[CH3:9]
Reactant: C/C(=N\O)c1ccccc1N
Reactant: OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C/C(=N\OCCCO)c1ccccc1N
Yield: 81 %

Procedure:
(E)-1-(2-aminophenyl)ethanone oxime (0.2 mmol) was added into anhydrous acetonitrile (MeCN) (10 mL), followed by adding K2CO3 (1.1 equivalent weights) and 3-chloropropan-1-ol (5 equivalent weights) therein to obtain a mixture. The mixture was heated under reflux for 36 hours and was purified using a silica gel column (n-hexane/acetone=2:1), thereby obtaining (E)-1-(2-aminophenyl)ethanone O-3-hydroxypropyl oxime (168 mg, yield 81%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:16][CH:15]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[Mn]([O-])(=O)(=O)=[O:34].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH:20]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32]3)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:18][CH:19]=2)[C:7]([C:11]([OH:34])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(C(C(=O)OC(C)(C)C)C2CCCC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(C(C(=O)OC(C)(C)C)C2CCCC2)cc1

Procedure:
6.9 g (15 mmol) of the compound from Example I are oxidised with tetrabutylammonium permanganate analogously to Example XCV. The product is recrystallised from ethyl acetate/petroleum ether (1:1).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](Cl)[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-:13].[Na+].Cl>>[Cl:1][C:2]1[NH:10][C:9](=[O:13])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: [OH-]
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1cc(F)c(=O)[nH]c1Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 46.8 %

Procedure:
A mixture of 2,6-dichloro-5-fluoronicotinic acid (15.00 g, 71.43 mmol, Lancaster Synthesis) and 2 N NaOH (178.6 ml, 357.2 mmol) was stirred at reflux for 2 hours and then at room temperature for 16 hours. The reaction mixture was cooled to 0° C. and acidified with 12 N HCl (32.74 ml, 392.9 mmol). The mixture was cooled for 30 minutes in an ice bath, the solid filtered and washed with H2O. The isolated solid was slurried in warm EtOH, filtered and then washed with warm EtOH. The solids were collected and dried under vacuum overnight to yield the desired product (6.4 g, 47%) as a beige solid.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C@@H:13]([NH2:14])[C:11](=[O:12])[S:10][CH2:9]1.Cl.[CH:16](=O)[CH:17]([CH3:19])[CH3:18].[BH3-]C#N.[Na+]>CO>[CH2:16]([NH:14][CH:13]1[CH2:8][CH2:9][S:10][C:11]1=[O:12])[CH:17]([CH3:19])[CH3:18]
Reactant: N[C@@H]1CCSC1=O
Reactant: CC(C)C=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)CNC1CCSC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4.6 mmol of triethylamine are added at 0° C., under an inert atmosphere, to a solution of 4.23 mmol of D-homocysteine thiolactone hydrochloride and 8.46 mmol of isobutyraldehyde in 20 ml of methanol. After stirring for 4 hours at ambient temperature, the reaction mixture is cooled to 0° C. and 8.8 mmol of NaCNBH3 are slowly added in the course of 40 minutes. After stirring for 30 minutes at 0° C., the reaction mixture is hydrolysed and then extracted with ether. The combined organic phases are then washed with a saturated NaCl solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. Chromatography on silica gel (dichloromethane/methanol: 99/1) allows the expected product to be isolated in the form of syrup.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][CH:13]=[N:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.[Sn].Cl>C(O)C>[O:14]1[C:10]([C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)=[CH:11][N:12]=[CH:13]1
Reactant: O=[N+]([O-])c1ccc(-c2cnco2)cc1
Agent: Cl
Agent: [Sn]
Solvent: CCO
Product: Nc1ccc(-c2cnco2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a solution of 5-(4-nitro-phenyl)-oxazole (500 mg, 2.6 mmol) in ethanol (10 ml) was added tin (620 mg, 5.2 mmol), followed by dropwise addition of concentrated hydrochloric acid (1 ml) and then the reaction was stirred at room temperature for 2 hr. The reaction mixture was filtered and the filtrate evaporated to dryness. The resultant residue was diluted with water (10 ml), basified with saturated bicarbonate solution, then extracted with ethyl acetate. The organic layer was separated, washed with water, dried and concentrated to dryness to yield 4-oxazol-5-yl-phenylamine (380 mg, 90%) as solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])[CH2:4]1.C(N(C(C)C)CC)(C)C.[C:36](=O)([O:46]C1C=CC([N+]([O-])=O)=CC=1)[O:37][CH2:38][C@@H:39]1[CH2:43][O:42][C:41]([CH3:45])([CH3:44])[O:40]1>O1CCCC1.ClCCl>[CH3:44][C:41]1([CH3:45])[O:40][C@H:39]([CH2:38][O:37][C:36]([NH:2][C@@H:3]2[CH2:7][CH2:6][N:5]([C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH2:18][C@H:17]([CH2:19][N:20]5[CH:24]=[CH:23][N:22]=[N:21]5)[O:16][C:15]4=[O:25])=[CH:10][C:9]=3[F:26])[CH2:4]2)=[O:46])[CH2:43][O:42]1
Reactant: CC1(C)OC[C@@H](COC(=O)Oc2ccc([N+](=O)[O-])cc2)O1
Reactant: N[C@@H]1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)OC[C@@H](COC(=O)N[C@@H]2CCN(c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)C2)O1
Yield: 51.8 %

Procedure:
(5R)-3-(4-((3R)-3-Aminopyrrolidin-1-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)-oxazolidin-2-one hydrochloride (400 mg, 1.05 mM) was suspended in tetrahydrofuran (10 ml) and treated with diisopropylethylamine (176 mg, 1.36 mM) and (4S)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl 4-nitrophenyl carbonate (429 mg, 1.44 mM) dissolved in dichloromethane (5 ml). The mixture was stirred vigorously at ambient temperature for 18 hours, with the addition of two further portions of diisopropylethylamine (137 mg, 1.06 mM). Solvent was evaporated, the residue redissolved in ethyl acetate (20 ml), washed with water (3×20 ml), and dried (magnesium sulfate). After removal of the solvent, the residue was purified by chromatography on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 5% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (273 mg).
Reaction SMILES: I[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Br:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:3]3[C:8]([C:9]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[C:10]4[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:25][CH:24]=1
Reactant: Ic1c2ccccc2c(-c2ccccc2)c2ccccc12
Reactant: OB(O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2c3ccccc3c(-c3ccccc3)c3ccccc23)cc1
Temperature: 80 °C
Reaction time: 9 h
Yield: 52 %

Procedure:
Into a 50 mL three-neck flask were put 1.0 g (2.63 mmol) of 9-iodo-10-phenylanthracene and 542 mg (2.70 mmol) of p-bromophenyl boronic acid. The atmosphere in the flask was replaced with nitrogen. After that, 10 mL of toluene and 3 mL of potassium carbonate aqueous solution (2.0 M) were added to the flask. This mixture was degassed under reduced pressure, then 46 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium(0) was added to the mixture. The mixture was stirred under a nitrogen stream at 80° C. for 9 hours. After the stirring, about 20 mL of toluene was added to this mixture. Then, the mixture was subjected to suction filtration through Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135), Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), and alumina. The obtained filtrate was washed with water and a saturated saline, and then dried with magnesium sulfate. This mixture was gravity filtered, and the obtained filtrate was concentrated to give a solid. The obtained solid was recrystallized with chloroform/hexane to give 0.56 g of a light-brown solid, which was the object of the synthesis, in a yield of 45%.
Reaction SMILES: [P:1]([CH2:5][NH:6]CC(O)=O)([OH:4])([OH:3])=[O:2].C[Si](C)(C)N[Si](C)(C)C.N.Cl[C:22]([O:24][CH2:25][O:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[O:23]>C(Cl)Cl>[C:27]([CH2:28][O:4][P:1]([CH2:5][NH:6][C:22]([O:24][CH2:25][O:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[O:23])([OH:3])=[O:2])([OH:31])=[O:26]
Reactant: O=C(O)CNCP(=O)(O)O
Reactant: CC(C)C(=O)OCOC(=O)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: N
Solvent: ClCCl
Product: CC(C)C(=O)OCOC(=O)NCP(=O)(O)OCC(=O)O
Temperature: 125 °C
Reaction time: 12 h

Procedure:
A stirred solution of phosphonomethyl glycine (9.49 g, 56.2 mmol) in hexamethyldisilazane (25.5 mL, 121 mmol) was slowly heated to 90° C. (at this temperature it was noted out gassing of ammonia occurred). The reaction temperature was increased to 125° C. for 150 min at which time the reaction became homogeneous. The solution was allowed to cool to room temperature at which time, dry methylene chloride (60 mL) was added. The material (34.0 g, 74.5 mmol) was syringed into a flask and placed under a N2 atm. Methylene chloride (120 mL) was added and the solution cooled in a dry ice acetone bath. A solution of 2-methylpropanoic acid chlorocarbonyloxymethyl ester (10.7 g, 59.1 mmol) in 5 mL of methylene chloride was added dropwise over two minutes through a 3 mL syringe. After 10 minutes the cooling bath was removed and the reaction was allowed to warm to room temperature and stir for 12 h. The reaction solution was concentrated under reduced pressure and dissolved in 200 mL of methanol and allowed to stand for 4 h. The reaction was vacuum filtered and concentrated under reduced pressure. The oil was dissolved with 120 mL of dry acetone and allowed to stand for one hour, vacuum filtered, and concentrated under vacuum. The solid was triterated with 60 mL of warm hexanes and then placed under vacuum. Yield 14.0 grams. 1H-NMR (300 MHz, D2O) δ (ppm): 1.01 (dd, 6H), 2.51 (m, 1H), 3.47 (d, 2H), 4.09 (d, 2H), 5.63 (d, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)([CH3:12])[CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][NH:31][CH:32]=2)O1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:29]=[N:30][NH:31][CH:32]=3)=[CH:3][CH:4]=2)([CH3:12])[CH2:9][NH:10][CH3:11])=[CH:14][CH:15]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CNCC(C)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: CNCC(C)(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1

Procedure:
[2,2-Bis-(4-chloro-phenyl)-propyl]-methyl-amine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LCMS (PS-A3) Rt 6.94 min [M+H]+ 326. 1H NMR (Me-d3-OD) δ 1.86 (3H, s), 2.77 (3H, s), 3.89 (2H, s), 7.26-7.33 (4H, m), 7.37-7.40 (2H, m), 7.68 (2H, d), 8.35 (2H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.CN(C)C=O.C1(C)C=CC=CC=1>O>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([O:1][C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc([N+](=O)[O-])cc2)cc(C(=O)OC)c1
Yield: 68 %

Procedure:
Into a 2 liter four-necked flask equipped with a thermometer, a stirrer and a Dean Stark distillation apparatus, 133.24 g (0.63 moles) of dimethyl 5-hydroxyisophthalate, 107.33 g (0.76 moles) of 4-fluoronitrobenzene, 60 ml of N,N-dimethylformamide and 190 ml of toluene were placed. The resultant mixture was stirred at 165° C. for 4 hours while water formed as the byproduct was removed by azeotropic distillation. After cooling, the obtained reaction mixture was poured into 3 liters of ion-exchanged water and the product was precipitated. The formed precipitates were separated by filtration and washed with ion-exchanged water and ethanol. The obtained light yellow solid substance was dried under a reduced pressure at 50° C. for 1 day and 142.01 g of a product was obtained (the yield: 68%).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Na].O1CCCC1.[Cl:13][C:14]1[C:18]([F:20])([F:19])[C:17]([F:22])([F:21])[C:16]([F:24])([F:23])[C:15]=1Cl>CCOCC>[CH:1]1([O:6][C:15]2[C:16]([F:24])([F:23])[C:17]([F:21])([F:22])[C:18]([F:19])([F:20])[C:14]=2[Cl:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCC1
Reactant: FC1(F)C(Cl)=C(Cl)C(F)(F)C1(F)F
Agent: [Na]
Solvent: CCOCC
Solvent: C1CCOC1
Product: FC1(F)C(Cl)=C(OC2CCCC2)C(F)(F)C1(F)F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 79 %

Procedure:
Cyclopentanol (23 g, 0.27 mol) and sodium metal (5.6 g, 0.24 mol) were refluxed with 25 ml dry tetrahydrofuran (THF) overnight. The reaction mixture was diluted with 200 ml of dry ether and then added to 1,2-dichlorohexafluorocyclopentene (49 g, 0.2 mol) in 100 ml of dry ether at room temperature with stirring over 20 minutes. After the completion of the addition, the reaction mixture was heated to reflux for 2 hours. The reaction mixture was poured into ice water (150 ml) and the organic layer was separated. Then the aqueous layer was extracted with 4 portions of 100 ml of ether. Next, the organic layer and the ether extracts were combined and dried over CaCl2 overnight. Thereafter, the solvent was distilled out at atmospheric pressure. That which remained was distilled under reduced pressure to give the desired 2-chlorohexafluorocyclopentenyl cyclopentyl ether in 79% yield based on the 1,2-dichlorohexafluorocyclopentene used.
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:14])[CH3:13])([O-:5])=[O:4]>CO.O1CCOCC1.C(OCC)(=O)C>[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([OH:14])[CH3:13])([O-:5])=[O:4]
Reactant: CC(=O)c1ccccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaBH4 (3.24 g, 85.60 mmol) was slowly added to a solution of 2′-nitroacetophenone NAP (3.74 g, 22.65 mmol) in a mixture of methanol (34 mL) and dioxane (22 mL). The reaction mixture was stirred at room temperature for one hour and then diluted with ethyl acetate (100 mL) and washed with water (25 mL). The organic layer was dried with Na2SO4, filtered, and concentrated in vacuo to yield 1-(2-nitrophenyl)ethanol dC.13a (3.49 g, 92%) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19](OC)=[O:20])[C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH3:23]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([NH2:23])=[O:20])[C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N
Reactant: COC(=O)c1cccc2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc12
Product: NC(=O)c1cccc2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc12

Procedure:
Following standard procedure C, methyl 2-(4'-nitrophenyl)-1-H-benzimidazole-4-carboxylate was dissolved in liquid ammonia and heated under constant volume in a pressure vessel. The product was purified by column chromatography from dichloromethane/methanol 99:1 and recrystallised from methanol.
Reaction SMILES: [CH3:1][CH:2]1[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:3]1.Cl.[CH3:18][C:19]1[C:20]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1>>[CH3:18][C:19]1[C:20]([N:26]2[CH2:27][CH2:28][N:29]([C:12]([C:11]3[CH:10]=[CH:9][C:8]([N:4]4[CH2:3][CH:2]([CH3:1])[O:6][C:5]4=[O:7])=[CH:16][CH:15]=3)=[O:14])[CH2:30][CH2:31]2)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1
Reactant: CC1CN(c2ccc(C(=O)O)cc2)C(=O)O1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)OC4=O)cc3)CC2)c(C)c1
Yield: 34.5 %

Procedure:
By reaction and treatment in the same manner as in Example 49 and using 4-(5-methyl-2-oxooxazolidin-3-yl)benzoic acid (442 mg) described in Preparation Example 40 and 1-(3,5-dimethylpyridin-2-yl)piperazine hydrochloride (455 mg) described in Preparation Example 64, the title compound (272 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1>O1CCCC1>[F:1][C:2]([F:19])([F:20])[C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Solvent: C1CCOC1
Product: OCc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2.0 g commercially available 4-(4-Trifluoromethyl-phenoxy)-benzoic acid in 180 ml tetrahydrofuran 269 mg lithium aluminum hydride were added at −20° C. portionwise. The reaction temperature was maintained between −5° C. and −20° C. After completion of the addition the cooling bath was removed and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for two hours. Then the reaction mixture was cooled again to −40° C. and 3 ml water were added. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for four hours. Then the reaction mixture was dried over MgSO4. The solvent was removed in vacuo and the residue purified by flash chromatography on silica gel with the eluents n-heptane:ethyl acetate=9:1=>2:1 to obtain 600 mg [4-(4-Trifluoromethyl-phenoxy)-phenyl]-methanol.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([F:22])=[C:8]([F:21])[CH:9]=2)[N:4]=1.O.[SH:24][C:25]1[N:33]=[CH:32][N:31]=[C:30]2[C:26]=1[NH:27][CH:28]=[N:29]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([F:22])=[C:8]([F:21])[CH:9]=2)[N:4]=[C:3]1[CH2:2][S:24][C:25]1[N:33]=[CH:32][N:31]=[C:30]2[C:26]=1[N:27]=[CH:28][NH:29]2
Reactant: Sc1ncnc2nc[nH]c12
Reactant: O=c1c2cc(F)c(F)cc2nc(CCl)n1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2cc(F)c(F)cc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1Cl
Yield: 53.4 %

Procedure:
Prepared according to Procedure C using Intermediate 2q (200 mg, 0.586 mmol), 6-mercaptopurine monohydrate (110 mg, 0.645 mmol), K2CO3 (89 mg, 0.645 mmol), and DMF (4 mL). The crude product was recrystallized from EtOH to provide 143 mg of a pale yellow crystalline solid (53%), mp 207.8° C. (discolors; sweats at 136(C). 1H NMR (DMSO-d6) δ: 13.57 (br s, 1H); 8.49 (s, 1H); 8.46 (s, 1H); 8.11 (t, J=9.4 Hz, 1H); 7.88 (dd, J=7.3, 11 Hz, 1H); 7.77 (dd, J=1.7, 7.3 Hz, 1H); 7.67 (d, J=7.4 Hz, 1H); 7.42-7.55 (m, 2H); 4.48 (s, 2H). 13C NMR (DMSO-d6) ppm: 159.5 (d, J=2.5 Hz), 154.6 (dd, J=14, 255 Hz), 154.0 (d, J=1.5 Hz), 151.5, 149.3 (dd, J=14, 250 Hz), 145.1 (d, J=12 Hz), 143.9, 133.9, 132.1, 131.8, 131.4, 130.5, 128.9, 118.0 (d, J=4.9 Hz), 115.8 (d, J=18 Hz), 114.6 (d, J=20 Hz), 32.0. MS (ES): m/z 457.0 (M+). Anal. calcd. for C20H11ClF2N6OS: C, 52.58; H, 2.43; Cl, 7.76; N, 18.40; S, 7.02. Found: C, 51.81; H, 2.37; Cl, 7.49; N, 18.04; S, 7.55.
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].Cl.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][NH2:33]>>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:2]2[C:3](=[CH:14][CH:15]=[C:16]([OH:18])[CH:17]=2)[C:4]([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=2[OH:13])=[N:33]1
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Reactant: NNc1ccccc1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: Oc1ccc(-c2nn(-c3ccccc3F)c3cc(O)ccc23)c(O)c1
Yield: 9.3 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (0.400 g, 1.60 mmol), sodium acetate (0.267 g, 3.3 mmol) and 2-fluorophenylhydrazine hydrochloride (0.400 g, 2.5 mmol) to give 0.050 g of product as a pink solid.