Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH:3]1[CH2:7][CH2:6][NH:5][C:4]1([CH3:9])[CH3:8].C(N(CC)C(C)C)(C)C.[CH3:20][C:21]([O:24][C:25]([N:27]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[N:28]([C:36]1[C:41]([F:42])=[C:40](Cl)[N:39]=[C:38]([Cl:44])[N:37]=1)[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:26])([CH3:23])[CH3:22]>CN(C=O)C>[CH3:23][C:21]([O:24][C:25]([N:27]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[N:28]([C:36]1[C:41]([F:42])=[C:40]([N:5]2[CH2:6][CH2:7][CH:3]([N:2]([CH3:10])[CH3:1])[C:4]2([CH3:9])[CH3:8])[N:39]=[C:38]([Cl:44])[N:37]=1)[C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[O:26])([CH3:20])[CH3:22]
Reactant: CN(C)C1CCNC1(C)C
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C1CCN(c2nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2F)C1(C)C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
To a solution of racemic N,N,2,2-tetramethyl-3-pyrrolidinamine (0.1466 g, 1.031 mmol) in DMF (6 mL) was added N,N-diisopropylethylamine (0.220 mL, 1.263 mmol) and tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (0.513 g, 1.031 mmol), and the solution was stirred overnight. The solution was partitioned between Et2O (100 mL) and water (20 mL), and the organic phase was washed with a fresh portion of water (20 mL). The combined aqueous phase was extracted with a fresh portion of Et2O (50 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by gradient silica gel chromatography (0% to 100% EtOAc in hexanes) to give racemic tris(1,1-dimethylethyl)2-{2-chloro-6-[3-(dimethylamino)-2,2-dimethyl-1-pyrrolidinyl]-5-fluoro-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (0.4647 g, 75% yield) as a white foam. LCMS: (M+H)+: 603.3.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(O)(=O)=[O:18].OO>>[C:1]1([NH:7][C:8]([NH:10][CH:11]([CH3:15])[C:12]([O:14][OH:18])=[O:13])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(NC(=O)Nc1ccccc1)C(=O)O
Reactant: CS(=O)(=O)O
Agent: OO
Product: CC(NC(=O)Nc1ccccc1)C(=O)OO

Procedure:
20.8 g (0.01 mol) of N-(N'-phenylcarbamoyl)-2-aminopropanoic acid, 35 g of methanesulfonic acid and 12 g (0.3 mol) of hydrogen peroxide (85% strength by weight) are reacted and worked up as described in Example 3.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9]1.Cl>>[CH3:9][N:8]([CH2:3][CH2:2][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:9]1)[CH3:12]
Reactant: Oc1ccccc1-n1ccc(-c2ccccc2)c1
Agent: Cl
Product: CN(C)CCOc1ccccc1-n1ccc(-c2ccccc2)c1

Procedure:
This is prepared from 1-(2-hydroxyphenyl)-3-phenyl-pyrrole analogously to Example 12 (step b). Melting point: 116-121° C. (hydrochloride);
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[C@H:6]([CH2:7][OH:8])[C:5]1([CH3:23])[C:9]1[CH:18]=[CH:17][C:16]2[C:15]([CH3:20])([CH3:19])[CH2:14][CH2:13][C:12]([CH3:22])([CH3:21])[C:11]=2[CH:10]=1.[CH2:24](I)C>>[CH2:1]([O:2][CH2:3][CH:4]1[C@H:6]([CH2:7][OH:8])[C:5]1([CH3:23])[C:9]1[CH:18]=[CH:17][C:16]2[C:15]([CH3:20])([CH3:19])[CH2:14][CH2:13][C:12]([CH3:22])([CH3:21])[C:11]=2[CH:10]=1)[CH3:24]
Reactant: CCI
Reactant: COCC1[C@H](CO)C1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: CCOCC1[C@H](CO)C1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 78 %

Procedure:
Following a procedure similar to that for the preparation of Intermediate 6a using Intermediate 4 as the starting material and ethyl iodide as alkylating reagent yielded the title compound as a colorless oil (69 mg, 78% yield):
Reaction SMILES: CS([O:5][CH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[N:11]=1)(=O)=O>ClCCl.[O-2].[O-2].[Mn+4]>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH:6]=[O:5])[S:8][CH:9]=1
Reactant: CS(=O)(=O)OCc1nc(-c2ccccc2Cl)cs1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1nc(-c2ccccc2Cl)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(4-(2-Chlorophenyl)thiazol-2-yl)methyl methane-sulfonate 4 from Step C above (0.10 g, 0.51 mmol) is dissolved in dichloromethane (4.0 mL), followed by addition of manganese dioxide (0.18 g, 2 mmol). The suspension is vigorously stirred at room temperature overnight. Filtration and concentration yielded 4-(2-chlorophenyl)thiazole-2-carbaldehyde 5 as a light-brown oil: MS calcd. for C10H7ClNOS (M+H+) 224.0. found 224.0.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[OH-].[Na+].[F:12][C:13]1[CH:22]=[CH:21][C:16]([CH2:17][CH2:18][CH:19]=[O:20])=[CH:15][CH:14]=1.S(=O)(=O)(O)O>CO>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:18]([CH:19]=[O:20])[CH2:17][C:16]1[CH:21]=[CH:22][C:13]([F:12])=[CH:14][CH:15]=1
Reactant: O=CCCc1ccc(F)cc1
Reactant: O=Cc1ccccc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=CC(=Cc1ccccc1Cl)Cc1ccc(F)cc1
Reaction time: 1 h

Procedure:
71.7 g (0.51 mol) of 2-chlorobenzaldehyde are added to a solution of 4 g of 50% strength sodium hydroxide solution in 300 ml of methanol while cooling, at a rate such that the temperature does not exceed 20° C. 70.0 g (0.46 mol) of p-fluorodihydrocinnamaldehyde are then added dropwise at 25°-30° C. in the course of 4 hours. Stirring is continued for one hour at 30° C., the mixture is neutralized with dilute sulfuric acid and evaporated down and the residue is distilled.
Reaction SMILES: O=[C:2]1[NH:7][CH2:6][C:5](=O)[N:4]2[CH2:9][CH2:10][CH2:11][CH2:12][C@H:3]12.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:2]1[NH:7][CH2:6][CH2:5][N:4]2[CH2:9][CH2:10][CH2:11][CH2:12][C@H:3]12
Reactant: O=C1NCC(=O)N2CCCC[C@H]12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C1CCN2CCNC[C@H]2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
(R)-Octahydro-1,4-dioxo-2H-pyrido[1,2-a]pyrazine (0.5 g, 2.98 mmol) was added portionwise to a stirred solution of lithium aluminium hydride (1M in tetrahydrofuran; 11.9 ml, 11.9 mmol). The resulting mixture was heated under reflux for 0.5 h. The solution was then cooled to 0° C. and treated dropwise with water (1.35 ml), 1 M sodium hydroxide solution (0.45 ml), then water (1.35 ml). Tetrahydrofuran (10 ml) was added and the solution stirred for 0.5 h, before filtration. The filter cake was washed with tetrahydrofuran (2×5 ml) and the combined filtrate and washings concentrated to yield (R)-octahydro-2H-pyrido[1,2-a]pyrazine as a yellow oil (0.29 g, 2.07 mmol).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]2)=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Reactant: NCc1ccc(F)cc1
Product: O=C(O)c1ccnc(-c2cn(CCNCc3ccc(F)cc3)cn2)c1
Yield: 20 %

Procedure:
The title compound was prepared in 20% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 4-fluorobenzylamine according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 2.86 (2H, t, J=6.0 Hz), 3.70 (2H, s), 4.09 (2H, t, J=6.0 Hz), 7.08 (2H, t, J=8.9 Hz), 7.33 (2H, dd, J=7.1 Hz and 2.6 Hz), 7.55 (1H, dd, J=3.2 Hz and 1.5 Hz), 7.75 (1H, d, J=1.0 Hz), 7.81 (1H, s), 8.27 (1H, s), 8.59 (1H, d, J=4.9 Hz). [M+H] Calc'd for C18H17FN4O2, 341. Found, 341.
Reaction SMILES: [C:1]([NH:18][C:19]1[CH:31]=[CH:30][N:22]([C@@H:23]2[O:29][C@H:26]([CH2:27][OH:28])[CH2:25][CH2:24]2)[C:21](=[O:32])[N:20]=1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].C[O:41][P:42](OC)([O:44]C)=[O:43]>>[P:42]([O:28][CH2:27][C@H:26]1[O:29][C@@H:23]([N:22]2[CH:30]=[CH:31][C:19]([NH:18][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N:20][C:21]2=[O:32])[CH2:24][CH2:25]1)([OH:44])([OH:43])=[O:41]
Reactant: COP(=O)(OC)OC
Reactant: CCCCCCCCCCCCCCCC(=O)Nc1ccn([C@H]2CC[C@@H](CO)O2)c(=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCCCCCC(=O)Nc1ccn([C@H]2CC[C@@H](COP(=O)(O)O)O2)c(=O)n1
Temperature: 0 °C

Procedure:
2.7 g (6 mmol) N4 -palmitoyl-2',3'-dideoxycytidine is added gradually to a mixture of 1.09 ml (12 mmol) phosphorylchloride and 20 ml trimethylphosphate that is stirred at 0° C. The batch is stirred for a further 2 hours when cold and then slowly neutralized with 0.5N NaOH during cooling. The precipitate that is formed is centrifuged off, absorbed in chloroform/methanol; 7/3; V/V, filtered over sodium sulphate and freed of solvent in a vacuum. The residue so obtained is crystallized several times from ethanol. When this is done, 2.5 g of N4 -palmitoyl-2',3'-dideoxycytidine-5'-phosphate is obtained and this displays an Rf value of 0.35 on the silica gel plate in the chloroform/methanol; 1/1; V/V system.
Reaction SMILES: [Na].[OH:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]([CH2:17][C:18]([OH:20])=O)[NH:13][C:14](=[O:16])[CH:15]=2)[CH2:5]1.Cl.CN(C)CCCN=C=NCC.[CH3:33][C@H:34]1[CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35]1>N1C=CC=CC=1.O.CN(C=O)C>[OH:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]([CH2:17][C:18]([N:35]3[C:36]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:42][C@@H:34]3[CH3:33])=[O:20])[NH:13][C:14](=[O:16])[CH:15]=2)[CH2:5]1
Reactant: O=C(O)Cc1nc(N2CCOC(CO)C2)cc(=O)[nH]1
Reactant: C[C@H]1Cc2ccccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1Cc2ccccc2N1C(=O)Cc1nc(N2CCOC(CO)C2)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In a three-necked flask under argon, 0.35 g of the sodium salt of (−)-[4-(2-hydroxymethylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetic acid (example 31b, step 2b) is placed in 5 ml of pyridine and 5 ml of DMF whitish heterogeneous solution. N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride is added at ambient temperature, 0.18 g of (S)-2-methylindoline (CAS 22160-09-4) is added, and the mixture is stirred at ambient temperature for 72 hours. 25 ml of water are added, extraction is carried out with 3 times approximately 25 ml of dichloromethane, washing is carried out with 25 ml of water, washing is carried out with twice approximately 15 ml of 1M hydrochloric acid solution, washing is carried out with 25 ml of water, washing is carried out with 25 ml of saturated NaCl solution, drying is carried out over MgSO4, filtration is carried out through a VF filter, and the resulting product is concentrated under vacuum. The compound obtained is chromatographed on silica gel (40-63 μm), elution being carried out with a mixture of dichloromethane and ethanol (95/5, v/v). The fractions containing the expected compound are combined and evaporated. The compound obtained is triturated from dichloromethane and diisopropyl ether, filtered, and dried at ambient temperature (20° C.). (+)-6-(2-Hydroxymethylmorpholin-4-yl)-2-[2-((S)-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-3H-pyrimidin-4-one is isolated (0.11 g).
Reaction SMILES: C(N(CC)CC)C.ClC(OCC)=O.[C:14]1([N:20]2[C:28]3[CH2:27][CH2:26][CH2:25][C:24](=[CH:29][C:30]([OH:32])=O)[C:23]=3[CH:22]=[N:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>C(Cl)Cl>[C:14]1([N:20]2[C:28]3[CH2:27][CH2:26][CH2:25][C:24](=[CH:29][C:30]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[O:32])[C:23]=3[CH:22]=[N:21]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)C=C1CCCc2c1cnn2-c1ccccc1
Reactant: C1COCCN1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C=C1CCCc2c1cnn2-c1ccccc1)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 30.8 %

Procedure:
Triethylamine (0.054 mL, 0.39 mmol) and ethyl chloroformate (0.037 mL, 0.30 mmol) are added to a solution of a mixture of E/Z of 2-(1,5,6,7-tetrahydro-1-phenyl-4H-indazol-4-ylidene)acetic acid (100 mg, 0.39 mmol) in CH2Cl2 (5 mL) cooled to 0° C. and is stirred for 45 minutes at 0° C. Then morpholine (0.034 mL, 0.39 mmol) is added following the reaction by means of TLC. The solution is washed with diluted NaOH, the organic phase is separated, dried and evaporated under reduced pressure. The resulting crude product is purified by means of silica gel chromatography giving an E/Z mixture (80/20) of 4-(2-(1-phenyl-6,7-dihydro-1H-indazol-4(5H)-ylidene)acetyl)morpholine (40 mg, 0.12 mmol, 32%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]4[CH:25]=[CH:24]C([N+]([O-])=O)=C[CH:21]=4)=[O:18])[CH2:13][CH2:12]3)=[N:7][C:6]=12.[O:29]1CC[C@H](O)C1.[H-].[Na+]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]4[CH2:25][CH2:24][O:29][CH2:21]4)=[O:18])[CH2:13][CH2:12]3)=[N:7][C:6]=12
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Reactant: O[C@H]1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O[C@H]1CCOC1)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 151.9 %

Procedure:
To 224 mg (0.50 mmol) of 4-nitrophenyl 4-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate dissolved in 18 mL of THF, was added (S)-tetrahydrofuran-3-ol (88 mg, 1.0 mmol), followed by 60% NaH (80 mg, 2.0 mmol) and stirred at RT for 2 hr. After 2 hr it was diluted with 30 mL of EtOAc and slowly quench with brine. The organic layer was dried over MgSO4 and concentrated, it was purified using a 40 g silica gel column eluting with 0-10% MeOH/DCM to obtain 301 mg (76% yield) of the desired product. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.01-2.13 (m, 1 H) 2.17-2.29 (m, 1 H) 3.57-3.70 (m, 4 H) 3.74-3.84 (m, 4 H) 3.86-4.01 (m, 4 H) 5.27-5.38 (m, 1 H) 6.37 (d, J=7.83 Hz, 1 H) 7.87 (s, 1 H) 8.28 (d, J=7.83 Hz, 1 H)
Reaction SMILES: C(O[C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([OH:24])=[CH:21]2)=[CH:16][CH:15]=1)CCCCCCCCCCC>C1C2C(=CC=CC=2)C=CC=1O.C(Cl)(Cl)(Cl)Cl>[CH:15]1[CH:16]=[C:17]2[CH:18]=[CH:19][C:20]([OH:24])=[C:21]([C:21]3[C:22]4[C:17](=[CH:16][CH:15]=[CH:14][CH:23]=4)[CH:18]=[CH:19][C:20]=3[OH:24])[C:22]2=[CH:23][CH:14]=1
Reactant: CCCCCCCCCCCCOc1ccc2ccc(O)cc2c1
Agent: Oc1ccc2ccccc2c1
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Reaction time: 0.17 h
Yield: 94 %

Procedure:
A reaction flask described in example 9 was charged with a solution of catalyst 1c (12.2 mg, 0.02 mmol) in anhydrous CCl4 (1 mL). The solution was stirred for 10 min under an oxygen atmosphere and then treated with a solution of 7-dodecyloxy-2-naphthol (66 mg, 0.2 mmol) in anhydrous CCl4 (1 mL) under 0° C. The reaction mixture was stirred at 0° C. until the reaction was complete (monitored by TLC). The crude mixture was concentrated under reduced pressure, and purified by column chromatography (Ethyl acetate/Petroleum ether=⅓) to give (R)-BINOL 3k, Yield 94%. [α]D25=−86.3 (c=0.2 in EtOAc), 1HNMR (300 MHz, CDCl3) δ (ppm) 7.86 (d, J=9.0 Hz, 2H, 2×HC (5)), 7.78 (d, J=9.0 Hz, 2H, 2×HC (4)), 7.21 (d, J=9.0 Hz, 2H, 2×HC (3)), 7.03 (dd, J=9.0 Hz, 2.1 Hz, 2H, 2×HC (6)), 6.49 (d, J=2.1 Hz, 2H, 2×HC (8)), 5.08 (s, 2H, 2×OH), 3.65–3.79 (m, 4H, 4×OCH2), 1.59–1.67 (m, 4H, 4×OCH2CH2), 1.25–1.27 (m, 36H, 36 ×CH2), 0.88–0.92 (t, 6H, 6×CH3). e.e. 97%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[OH:17])=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:20]\[OH:21])/[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[OH:17])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2ccc(Cl)cc2)c(O)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(/C(=N/O)c2ccc(Cl)cc2)c(O)c1

Procedure:
A mixture of 382 g of 4'-chloro-2-hydroxy-4-methoxybenzophenone, 230 g hydroxylamine hydrochloride and 1.5 liters of pyridine is heated under reflux for 3 hr. The solvent is evaporated and the residue is partitioned between hydrochloric acid and ethyl acetate. The organic extracts are combined and washed with saturated sodium chloride solution. The solvent is removed to afford a mixture of E- and Z-oxime isomers which is separated on a Waters Prep LC System 500 using 5% ethyl acetate/toluene as the eluting system to afford E-4'-chloro-2-hydroxy-4-methoxybenzophenone oxime, mp 159° C.
Reaction SMILES: [CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH:18]([CH:22]([CH3:24])[CH3:23])[C:19]([OH:21])=O)[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1N=NN(CC(O)=O)N=1)CCCCCCCCC.[CH3:44][O:45][C:46]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[C:49]([O:55][CH3:56])[C:47]=1[NH2:48].C(C1C=CC=C(C(C)C)C=1N)(C)C>>[CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH:18]([CH:22]([CH3:24])[CH3:23])[C:19]([NH:48][C:47]2[C:49]([O:55][CH3:56])=[CH:50][C:51]([O:53][CH3:54])=[CH:52][C:46]=2[O:45][CH3:44])=[O:21])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1nnn(C(C(=O)O)C(C)C)n1
Reactant: COc1cc(OC)c(N)c(OC)c1
Agent: CC(C)c1cccc(C(C)C)c1N
Agent: CCCCCCCCCCc1nnn(CC(=O)O)n1
Product: CCCCCCCCCCCCc1nnn(C(C(=O)Nc2c(OC)cc(OC)cc2OC)C(C)C)n1

Procedure:
When in the general procedure of Example 88 an appropriate amount of 5-dodecyl-α-(1-methylethyl)-2H-tetrazole-2-acetic acid was substituted for 5-decyl-2H-tetrazole-2-acetic acid and 2,4,6-trimethoxyaniline was substituted for 2,6-diisopropylaniline, the title compound was obtained, mp 135°-137° C.
Reaction SMILES: C([O:3][P:4]([C:9]([C:12]1[C:21]([Br:22])=[CH:20][C:19]2[C:14](=[CH:15][C:16]([C:23]#[N:24])=[CH:17][CH:18]=2)[CH:13]=1)([F:11])[F:10])(=[O:8])[O:5]CC)C>ClCCl.C[Si](Br)(C)C>[Br:22][C:21]1[C:12]([C:9]([P:4](=[O:3])([OH:8])[OH:5])([F:10])[F:11])=[CH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([C:23]#[N:24])[CH:15]=2
Reactant: CCOP(=O)(OCC)C(F)(F)c1cc2cc(C#N)ccc2cc1Br
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: N#Cc1ccc2cc(Br)c(C(F)(F)P(=O)(O)O)cc2c1

Procedure:
A solution of diethyl[(3-bromo-7-cyano-2-naphthyl)(difluoro)methyl]phosphonate (2.2 g) in dichloromethane (5 mL) and TMSBr (7 mL) was stirred overnight and concentrated. The residue was co-evaporated with dichloromethane (2×), ethanol/water (2×) and then dissolved in 20 mL of methanol. Ammonia (30%) was then added with vigorous stirring and the mixture was concentrated and co-evaporated with methanol (3×). The solid residue was washed with ether to give the desired product as a white powder. MS (-ESI): m/z 360.0 and 361.9 (M-1)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)=[CH:11][C:10]([C:28](=[N:30][OH:31])[CH3:29])=[N:9]1.[OH-].[K+].Cl.[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38]Cl.CS(C)=O>O>[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38][O:31][N:30]=[C:28]([C:10]1[CH:11]=[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:9]=1)[CH3:29]
Reactant: CN(C)CCCl
Reactant: CC(=NO)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(=NOCCN(C)C)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 22.2 %

Procedure:
A mixture of 1-[1-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]ethanone oxime (196 mg, 0.415 mmol), KOH (142 mg, 2.3 mmol), 2-(dimethylamino)ethyl chloride hydrochloride (185 mg, 1.3 mmol), and anhydrous DMSO (5 mL) was stirred at 60° C. in a sealed vial for 3 h. The reaction mixture was diluted with water, extracted with ether. The combined extracts were washed with brine, dried over Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography (0-30% MeOH/DCM) to give the title compound as a white solid (50 mg, 22%). 1HNMR (CDCl3): δ8.04 (d, 1H), 7.83-7.81 (m, 1H), 7.74-7.71 (m, 1H), 7.57-7.43 (m, 5H), 7.21 (d, 1H), 7.00 (s, 1H), 6.76 (d, 1H), 4.38 (t, 2H), 3.07 9s, 3H), 2.78 (m, 2H), 2.40 (brs, 6H), 2.31 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=[O:7].[CH2:17]([Mg]Br)[CH3:18].Cl>O1CCCC1>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:6]([OH:7])[CH2:17][CH3:18])[CH:8]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:10]=1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCC(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 48.9 %

Procedure:
A solution of 3,5-bis(trifluoromethyl)benzaldehyde (300 mg, 1.24 mmol) in anhydrous tetrahydrofuran (3 mL) was added with ethylmagnesium bromide (1.00 M solution in anhydrous tetrahydrofuran, 1.86 mL, 1.86 mmol) with stirring on an ice bath, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was added with 1 M hydrochloric acid on an ice bath (pH<7), and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 1-[3,5-bis(trifluoromethyl)phenyl]-1-propanol (165 mg, 49%) as colorless solid.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.[C:15]([O:19][C:20]([N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1B(O)O)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[C:15]([O:19][C:20]([N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC1(C)OC(=O)Nc2ccc(Br)cc21
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
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: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Temperature: 80 °C
Yield: 60.1 %

Procedure:
A solution of 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.87 g, 3.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (96 mg, 0.08 mmol) in toluene (40 mL) was stirred under a flow of nitrogen for 25 min. To the solution was added sequentially 1-t-butoxycarbonylpyrrole-2-boronic acid (1.4 g, 7.0 mmol) in absolute ethanol (10 mL) and potassium carbonate (0.94 g, 7.0 mmol) in water (10 mL). The mixture was heated at 80° C. for 16 h and allowed to cool to rt. The reaction mixture was poured into aqueous saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (3×100 mL). The organic layers were combined, washed with water (100 mL) and brine (50 mL) and dried over magnesium sulfate. The solution was filtered, concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (30% ethyl acetate/hexane) to give the title compound as an off-white powder (0.7 g, 62%): mp 176° C. 1H NMR (CDCl3) δ 1.40 (s, 9H), 1.73 (s, 6 H), 6.17 (dd, 1H, J=1.8, 3.3 Hz), 6.22 (dd, 1H, J=3.3, 3.3 Hz), 6.77 (d, 1H, J=8.1 Hz), 7.13 (d, 1H, J=1.8 Hz), 7.23 (dd, 1H, J=1.8, 8.1 Hz), 7.33 (dd, 1H, J1.8, 3.3 Hz), 7.69 (bs, 1H). MS ((−) ESI) m/z 341 [M−H]−. Anal. Calcd for C19H22N2O4: C, 66.65; H, 6.48; N, 8.18. Found: C, 65.46; H, 6.51; N, 7.74.