Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].C/[C:12](=[CH:17]\[CH2:18][CH2:19]/[C:20](/C)=[CH:21]/[CH2:22][O:23]C1CCCCO1)/[CH2:13][CH2:14][CH:15]=O.CC(=CC)C>O.C(O)(C)(C)C>[C:22]([OH:23])(=[O:6])[CH2:21][CH2:20][CH:19]=[CH:18][CH2:17][CH2:12][CH:13]=[CH:14][CH3:15]
Reactant: O=P([O-])(O)O
Reactant: C/C(=C\CC/C(C)=C/COC1CCCCO1)CCC=O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC=CCCC=CCCC(=O)O

Procedure:
A.a) A solution of 105 g of 80% sodium chlorite and 100 g of sodium dihydrogen phosphate in 1 l of water is added within 30 min. to 50 g of (4E,8E)-(RS)-4,8-dimethyl-10-(tetrahydro-pyran-2-yloxy)-deca-4,8-dienal in 1.5 l of tert-butanol and 1.5 1 of 2-methyl-2-butene. After 2 1/2 hrs. at room temperature the mixture is concentrated and the residue is taken up in methylene chloride, washed with ice-water and 10% potassium hydrogen sulphate solution and dried. 46.5 g of (4E,8E)-(RS)-4,8-dimethyl-10-(tetrahydro-pyran-2-yloxy])-deca-4,8-dienoic acid are obtained. The acid obtained is dissolved in 590 ml of methylene chloride and treated at 0° C. with 14.9 ml of N-allyl-methyl-amine, 32.0 g of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and 1.88 g of dimethylaminopyridine. After 3 hrs. at room temperature and working up with methylene chloride/10% potassium hydrogen sulphate and subsequently saturated sodium hydrogen carbonate solution the organic phase is dried and concentrated. 52.3 g of crude (4E,8E)-(RS)-4,8-dimethyl-1 0-(tetrahydro-pyran-2-yloxy)-deca-4,8-dienoic acid allyl-methylamide are obtained.
Reaction SMILES: [Br:1][C:2]1[C:12]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[C:11]([Br:19])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>C1COCC1.O>[Br:1][C:2]1[C:12]([O:13][CH2:14][C:15]([F:16])([F:17])[F:18])=[C:11]([Br:19])[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1ccc(Br)c(OCC(F)(F)F)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Br)c(OCC(F)(F)F)c1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.380 g (3.40 mmol) of ethyl 2,4-dibromo-3-(2,2,2-trifluoroethoxy)benzoate were dissolved in a mixture of 15 ml of THF and 15 ml of water, and 0.150 g (3.47 mmol) of NaOH was added. The mixture was stirred at RT for 12 h and concentrated to completion. The residue was taken up in water, and 6 N HCl was added. The precipitate was filtered off with suction and dried. This gave 2-chloro-2,4-dibromo-3-(2,2,2-trifluoroethoxy)benzoic acid in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[N+:17]([O-])=O)=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl.[OH-].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH2:17])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
N-(4-Chlorophenyl)-5-chloro-2-nitrobenzamide (13.2 g, 42.4 mmol) and tin(II) chloride dihydrate (48 g, 213 mmol) were combined in ethyl acetate (90 mL) and the mixture was heated at 70° C. under a nitrogen atmosphere. After 15 minutes, the mixture was cooled to ambient temperature, then poured onto water (750 mL) and ethyl acetate (750 mL). The aqueous layer was adjusted to pH 8 with by addition of 1 N NaOH and a saturated NaHCO3 solution, and the layers were separated. The aqueous layer was further extracted with 500 mL of ethyl acetate. The combined organic extracts were washed with water (1 L), then brine (500 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford 11.6 g (97% yield) of N-(4-chlorophenyl)-2-amino-5-chlorobenzamide as an bite solid; NMR (CDCl3) 7.7 (br s, 1), 7.2-7.5 (m, 6), 6.7 (d, 1), 5.5 (br s, 2) ppm.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[N:5]12[CH2:12][CH2:11][CH:8]([CH2:9][CH2:10]1)[CH:7]([C:13]1[C:21]3[C:16](=[CH:17][CH:18]=[C:19](O)[CH:20]=3)[NH:15][CH:14]=1)[CH2:6]2.OC1C=C2C(=CC=1)NC=C2.N12CCC(CC1)C(=O)C2>CN(C=O)C.O=[Mn]=O>[N:5]12[CH2:12][CH2:11][CH:8]([CH2:9][CH2:10]1)[CH:7]([C:13]1[C:21]3[C:20]4[N:3]=[CH:2][CH:1]=[N:4][C:19]=4[CH:18]=[CH:17][C:16]=3[NH:15][CH:14]=1)[CH2:6]2
Reactant: Oc1ccc2[nH]cc(C3CN4CCC3CC4)c2c1
Reactant: NCCN
Agent: O=[Mn]=O
Agent: O=C1CN2CCC1CC2
Agent: Oc1ccc2[nH]ccc2c1
Solvent: CN(C)C=O
Product: c1cnc2c(ccc3[nH]cc(C4CN5CCC4CC5)c32)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.2 mmol of ethane-1,2-diamine and 1 mmol of MnO2 are added to a solution of 0.1 mmol of 3-(1-azabicyclo[2.2.2]oct-3-yl)-1H-indol-5-ol (prepared analogously to Example 1.1 to 1.2 by reaction of 5-hydroxy-1H-indole with 3-quinuclidinone followed by hydrogenation) in 2 ml of DMF, and the mixture is stirred at room temperature for 18 hours. The suspension is filtered through Celite and subjected to conventional work-up, giving 9-(1-azabicyclo[2.2.2]oct-3-yl)-7H-pyrrolo[3,2-f]quinoxaline; ESI 279.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[Cl:13])[CH:2]=[CH2:3].[OH2:14].C[N+]1([O-])CC[O:19]CC1>CC(C)=O.CC(=O)OCC.O=[Os](=O)(=O)=O.C(O)(C)(C)C>[OH:14][CH:2]([CH2:3][OH:19])[CH2:1][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[Cl:13]
Reactant: O
Reactant: C=CCOc1ccc(C=O)cc1Cl
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CC(C)(C)O
Product: O=Cc1ccc(OCC(O)CO)c(Cl)c1
Reaction time: 20 h

Procedure:
To a solution of 3-chloro-4-hydroxybenzaldehyde (5.0 g, 31.9 mmol) in DMF/THF 1:3 (120 mL) is added NaH (1.67 g of a 55% dispersion in mineral oil, 38.3 mmol) in four portions. The mixture is stirred at it for 1 h before allylbromide (9.66 g, 79.8 mmol) is added. The reaction mixture is heated to 65° C. for 18 h, diluted with water (250 mL) and extracted with diethyl ether (3×250 mL). The organic extracts are washed with water (250 mL), combined and concentrated. The remaining oil is chromatographed on silic gel with heptane/EA 4:1 to afford 4-allyloxy-3-chlorobenzaldehyde (5.37 g) as an almost colourless oil. LC: tR=0.95 min. The above 4-allyloxy-3-chloro-benzaldehyde (5.37 g, 27.3 mmol) is dissolved in acetone (100 mL) and water (10 mL) and treated with a 2.5% solution of OsO4 in tert.-butanol (1.71 mL, 0.137 mmol OsO4). N-methyl morpholine-N-oxide (3.87 g, 32.8 mmol) is added and the reaction mixture is stirred at it for 20 h before it is diluted with EA (300 mL) and washed with 10% aq. citric acid solution (200 mL) and water (2×150 mL). The washings are extracted with EA (300 mL) and the combined organic extracts are dried over MgSO4, filtered and concentrated to furnish the title compound (6.02 g) as beige foam which was used in the following steps without further purification. LC: tR=0.67 min.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:3]=1[C:17]([OH:19])=O.Cl.C(N=C=NCCCN(C)C)C.[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>ClCCl>[F:32][C:33]1[CH:34]=[CH:35][C:36]([N:39]2[CH2:44][CH2:43][N:42]([C:17]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[O:19])[CH2:41][CH2:40]2)=[CH:37][CH:38]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Cc1onc(-c2cccc(C(F)(F)F)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1onc(-c2cccc(C(F)(F)F)c2)c1C(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 71.2 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-methyl-3-(3-(trifluoromethyl)phenyl)isoxazol-4-carboxylic acid (500 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(4-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (566 mg, 1.31 mmol, 71%) was obtained.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[N:11]1[CH:16]=[C:15]([C:17](O)=O)[CH:14]=[N:13][CH:12]=1.N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[N:10]=[C:17]([C:15]3[CH:16]=[N:11][CH:12]=[N:13][CH:14]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: O=C(O)c1cncnc1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: c1cncc(-c2noc(-c3cncnc3)n2)c1

Procedure:
The titled compound was prepared according to the procedure of Method C using N′-hydroxynicotinimidamide (Tyger) and pyrimidine-5-carboxylic acid (Maybridge). 1H NMR (300 MHz, DMSO-d6) δ 7.68 (ddd, J=8.0, 4.9, 1.0 Hz, 1 H), 8.48 (dt, J=7.7, 2.1 Hz, 1 H), 8.84 (dd, J=4.7, 1.7 Hz, 1 H), 9.29 (dd, J=2.4, 1.0 Hz, 1 H), 9.51 (s, 1 H), 9.56 (s, 2 H) ppm; MS (DCI/NH3) m/z=226 (M+H)+, 243 (M+NH4)+.
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCO>[CH2:20]([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:2]([OH:1])[C:3]([OH:5])=[O:4])=[CH:12][CH:11]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCc1ccccc1
Reactant: O=C(O)[C@@H](O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(O)[C@@H](O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
(S)-2-Hydroxy-3-(4-hydroxy-phenyl)-propionic acid (121 g, 0.664 mol) (Wang et al. Tetrahedron Lett. 1998, 39, 5501) in absolute EtOH (2 L) was treated with potassium carbonate (184 g, 1.33 mol) and benzyl chloride 169 g, 1.34 mol). The mixture was heated at reflux overnight and concentrated to about half the volume under vacuum. Aqueous 5N NaOH (100 mL) was added, and the mixture was stirred at ambient temperature overnight and then concentrated. The residue was acidified with concentrated HCl. The yellow sold was collected by filtration and dried overnight under vacuum at 50° C. The crude product in isopropanol (1.8 L) was heated at reflux for about 30 minutes, cooled to ambient temperature, and stirred for about 16 hours. The slurry was filtered and dried under vacuum at 70° C. overnight to give the title compound as a white solid (137 g, 76%).
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[C:5]([O:9][C:10]([C:12]1[CH:28]=[C:27]([OH:29])[C:15]2[CH2:16][CH:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:14]=2[CH:13]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:5]([O:9][C:10]([C:12]1[CH:28]=[C:27]([O:29][CH:2]([CH3:4])[CH3:3])[C:15]2[CH2:16][CH:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:14]=2[CH:13]=1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)c1cc(O)c2c(c1)OC(COc1ccccc1)C2
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(C(=O)OC(C)(C)C)cc2c1CC(COc1ccccc1)O2
Temperature: 60 °C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
2-Iodopropane (174 mg, 1.02 mmol)) was added to a mixture of 4-hydroxy-2-phenoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (214b) (350 mg, 1.02 mmol) and K2CO3 (141 mg, 1.02 mmol) in DMF (5 mL). The reaction mixture was stirred at 60° C. overnight. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (2×50 mL). The organic layers were washed with H2O (2×70 mL), dried over MgSO4 and concentrated. The residue was purified by flash column chromatograph eluting with 5% EtOAc in hexanes to give a white solid (182 mg, 46% yield). 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J=1.26 Hz, 1 H) 7.22-7.26 (m, 1 H) 7.13 (s, 1 H) 7.07 (s, 1 H) 6.91-7.00 (m, 3 H) 6.85 (d, J=7.58 Hz, 1 H) 5.17-5.25 (m, 1 H) 4.59-4.68 (m, 1 H) 4.07-4.17 (m, 1 H) 3.34 (dd, J=16.55, 9.47 Hz, 1 H) 3.09 (dd, J=16.55, 6.95 Hz, 1 H) 1.58 (s, 9 H) 1.35 (d, J=6.06 Hz, 6 H); LCMS for C23H28O5 m/z 385.20 (M+H)+.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([O:17][C:18](=[O:28])[CH2:19][CH:20]1[NH:23][C:22](=[O:24])[CH:21]1[CH:25](O)[CH3:26])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(O)=O.[Na+]>ClCCl>[CH2:10]([O:17][C:18](=[O:28])[CH2:19][CH:20]1[NH:23][C:22](=[O:24])[CH:21]1[CH:25]([F:7])[CH3:26])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(O)C1C(=O)NC1CC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(F)C1C(=O)NC1CC(=O)OCc1ccccc1
Reaction time: 0.08 h

Procedure:
To a -78° cooled solution of 1.5 ml of diethylaminosulphurtrifluoride in 4 ml abs. dichloromethane is added a solution of 2.52 g of (3SR,4RS)-3-[1(SR)-hydroxyethyl]-2-oxoazetidine-4-yl-acetic acid benzyl ester (prepared analogously to D. G. Melillo et. al., Tetrahedron Letters 21, 2783 [1980]) in 4 ml abs. dichloromethane. The mixture is stirred for 5 minutes at -78° and mixed with excess cold saturated NaHCO3. After addition of further dichloromethane the phases are separated, the organic phase dried over magnesium sulphate and evaporated to dryness. Chromatography of the residue over silica gel (cyclohexane/ethylacetate=2/1) yields the title compound m.p. 40°-43°.
Reaction SMILES: C(OC([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH2:21][N:22]([C@H:30]([CH3:40])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]=[O:39])[CH:33]=2)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)=O)(C)(C)C.N>CO>[Si:42]([O:41][C@H:20]([C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:19])[NH:17]2)[CH2:21][N:22]([C@H:30]([CH3:40])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]=[O:39])[CH:33]=1)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])([C:45]([CH3:46])([CH3:47])[CH3:48])([CH3:44])[CH3:43]
Reactant: C[C@H](Cc1cccc(C=O)c1)N(C[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OC(=O)OC(C)(C)C)c2[nH]c(=O)ccc12)C(=O)OC(C)(C)C
Agent: N
Solvent: CO
Product: C[C@H](Cc1cccc(C=O)c1)N(C[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl (R)-2-(8-(tert-butoxycarbonyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-(tert-butyldimethylsilyloxy)ethyl((R)-1-(3-formylphenyl)propan-2-yl)carbamate (Example 276, step h) (0.521 g) was suspended in methanol (20 mL) and treated with ‘880’ aqueous ammonia (2.5 mL) to give a suspension that was stirred at room temperature for 3 hours. The mixture was concentrated by blowing with a stream of nitrogen, and the residue was partitioned between ethyl acetate, water and brine, and the phases separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the subtitled compound. Yield 0.476 g. Material used immediately in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20])[C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][CH2:8][N:7]=2)[CH:16]=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20]
Reactant: O=C(NCCc1ccccc1)c1ccc(C(F)(F)F)c(F)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1cc(C2=NCCc3ccccc32)ccc1C(F)(F)F
Temperature: 25 °C
Yield: 74.1 %

Procedure:
To a stirred mixture of 3-fluoro-N-phenethyl-4-(trifluoromethyl)benzamide (1.27 g, 4.08 mmol) in 30 mL of toluene, phosphorus pentoxide (1.751 g, 12.3 mmol) and phosphorus oxychloride (1.90 mL, 20.4 mmol) were added. The mixture was refluxed for overnight. The reaction mixture was cooled to RT. Supernatant was removed and the ice-water was added to the flask containing the residue. The mixture was stirred to break the chunks into powder. EtOAc was added and the pH was adjusted to ˜12 with 3N aqueous potassium hydroxide. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with water and saturated aqueous sodium chloride. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford 0.887 g of yellow viscous oil. The crude product was purified by silica gel chromatography (0-30% EtOAc in hexanes) to afford the title compound as a clear oil. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.63-7.73 (m, 1H) 7.39-7.54 (m, 3H) 7.31 (d, J=7.60 Hz, 2H) 7.16-7.24 (m, 1H) 3.84-3.96 (m, 2H) 2.77-2.89 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17](F)=[C:16]([CH3:21])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:32]([SH:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([S:39][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[C:16]([CH3:21])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: SCc1ccccc1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1SCc1ccccc1
Temperature: 90 °C
Yield: 80 %

Procedure:
To a solution of 5-(3,5-dichlorophenyl)-3-(4-fluoro-3-methylphenyl)-4,5-dihydro-5-(trifluoromethyl)isoxazole (i.e. the product from Step B of Example 2) (2.6 g, 6.65 mmol) and potassium carbonate (2.3 g, 16.6 mmol) in N,N-dimethylformamide (25 mL) was added benzyl mercaptan (0.782 mL, 6.65 mmol). The reaction mixture was heated at 90° C. for 4 h. The reaction mixture was then cooled and excess water was added, and the mixture was extracted with ethyl acetate (2×100 mL). The organic extracts were dried (MgSO4) and concentrated under reduced pressure to provide a solid residue. The elude product was partially purified by silica gel column chromatography eluted with mixtures of hexane and ethyl acetate to afford a product containing the title compound (about 80% purity, 2.8 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH:17]=[CH:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.[H][H]>C(O)C.[Pd]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=2)=[CH:15][CH:14]=1
Reactant: [H][H]
Reactant: N#Cc1ccc(C=Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: N#Cc1ccc(CCc2ccc(OCc3ccc4ccccc4n3)cc2)cc1

Procedure:
A mixture of 0.75 g (2.07 mmol) of (4-(4-(2-quinolinylmethyloxy)styryl)benzonitrile and 0.08 g of 10% Pd on carbon in 75 ml of ethanol is shaken for 1.5 hours under 30 PSI of hydrogen. The mixture is filtered through a bed of celite and the filtrate concentrated in vacuo. Trituration with ether gives a precipitate which is filtered off and recrystallized from methylene chloride-ether to give 4-(4-(2-quinolinylmethyloxy)phenethyl)benzonitrile. (M.P. 156° C.-158° C.)
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: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
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: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13]Br)=[C:9]([Cl:15])[CH:8]=2)[CH:6]=1.[C-:16]#[N:17].[Na+].O>CS(C)=O>[Cl:15][C:9]1[CH:8]=[C:7]([N:5]2[CH:6]=[C:2]([Cl:1])[CH:3]=[N:4]2)[CH:12]=[CH:11][C:10]=1[CH2:13][C:16]#[N:17]
Reactant: Clc1cnn(-c2ccc(CBr)c(Cl)c2)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1ccc(-n2cc(Cl)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 99.5 %

Procedure:
15 g of 4-chloro-1-(4-bromomethyl-3-chlorophenyl)pyrazole are added to 2.8 g of sodium cyanide in 67 ml of dimethylsulfoxide and stirred for 6.5 hours at room temperature. 300 ml of water are added dropwise and 12.3 g of 2-chloro-4-(4-chloropyrazol-1-yl)phenylacetonitrile are thus obtained. Chromatographing the latter with a mixture of cyclohexane/ethanol/ethyl acetate on silica gel, yields a product with a m.p. 139.5° to 140° C. (As by-product, 1,2-bis-[2-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionic acid nitrile has formed; from this by-product the appropriate amide with m.p. 248° to 249.5° C. is obtained by saponification with concentrated sulfuric acid.)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[H-].[Na+].I[CH2:21][CH3:22]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:21][CH3:22])[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: CCI
Reactant: Cn1cc(Br)cc(NC(=O)OC(C)(C)C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)(C)C)c1cc(Br)cn(C)c1=O
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
To a solution of the title compound from Example 110, step 1 (150.0 mg, crude) in DMF (10 mL) was added NaH (60.0 mg, 1.5 mmol, 60% in oil) in portions at 0° C. and stirred for 30 min. Then iodoethane (234.0 mg, 1.5 mmol) was added dropwise at 0° C. The reaction mixture was stirred for 2 h at 30° C. It was then quenched with saturated aqueous NH4Cl (15 mL), extracted with ethyl acetate (20 mL), washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give the title compound (120.0 mg, crude) as a light green solid which was carried forward without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:63][N:64]([CH3:73])[CH2:65][CH2:66][CH:67]1[CH2:72][CH2:71][CH2:70][CH2:69][NH:68]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:68]1[CH2:69][CH2:70][CH2:71][CH2:72][CH:67]1[CH2:66][CH2:65][N:64]([CH3:63])[CH3:73])=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CN(C)CCC1CCCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCCCC3CCN(C)C)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-(2-dimethylamino-ethyl)-piperidine in DMSO at ambient temperature.