Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[C:17]2[N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[CH:12][CH:11]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CSC.B.Cl.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([NH:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[C:17]2[N:20]2[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]2)=[CH:12][CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(c2cccc3ccc(NC(=O)c4ccccc4)cc23)CC1
Agent: B
Agent: Cl
Solvent: CSC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN1CCN(c2cccc3ccc(NCc4ccccc4)cc23)CC1
Yield: 45.9 %

Procedure:
The title product of example 1 (0.12 g, 0.348 mmol) was dissolved in toluene (4 mL) and borane-dimethyl sulfide (0.3 mL, 3 mmol) was added. The mixture was refluxed 3 hours and cooled. 6N HCl and ethyl acetate were added and the mixture was refluxed until all the solids had dissolved. The organic phase was separated and discarded. The aqueous phase was made basic with 4N NaOH and extracted with methylene chloride. This organic phase was washed with brine, dried over calcium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel (0.5×4 inches). Elution with 50% and then 75% ethyl acetate/hexane gave 0.053 g of product. This material was further purified by trituration with hexane to provide 0.03 g, (26%) of the title product as a tan powder: mp 115°-117° C.; 1H NMR δ 7.64 (d, J=8.5 Hz, 1H), 7.46-7.24 (m, 6H), 7.14 (t, J=7.5 Hz, 1H), 7.0 (d, J=2.5 Hz, 1H), 7.00 (ss, J=1, 7.5 Hz, 1H), 6.94 (dd, J=2.5, 8.5 Hz, 1H), 4.50 (br s, 2H), 4.34 (br m, 1H), 3.01 (br s, 4H), 2.53 (br s, 4H), 2.38 (s, 3H). Analysis calculated for C22H25N3 ·0.5 H2O: C, 77.61; H, 7.70; N, 12.34. Found: C, 77.78; H, 7.48; N, 12.07.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]3[CH2:33][CH2:34][C:35](=[O:38])[NH:36][N:37]=3)=[CH:31][C:26]=2[N:25]=[CH:24]1>>[CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][CH2:22][N:23]2[C:27]3[CH:28]=[CH:29][C:30]([C:32]4[CH2:33][CH2:34][C:35](=[O:38])[NH:36][N:37]=4)=[CH:31][C:26]=3[N:25]=[CH:24]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: NCCCn1cnc2cc(C3=NNC(=O)CC3)ccc21
Reactant: CC(C)COCCc1ccc(OCC2CO2)cc1
Product: CC(C)COCCc1ccc(OCC(O)CNCCCn2cnc3cc(C4=NNC(=O)CC4)ccc32)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isobutoxyethyl)-phenoxy]-2,3-epoxypropane and 6-[1-(3-aminopropyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2(C(O)=O)[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([OH:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:3].C([N:36]([CH2:39]C)CC)C.P(N=[N+]=[N-])(=O)(OC1C=CC=CC=1)[O:42]C1C=CC=CC=1>O1CCOCC1>[N:36]([C@:7]12[CH2:6][CH2:5][C@@H:4]([C:2]([CH3:1])=[CH2:3])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:30])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:28])([CH3:27])[C@@H:16]([OH:29])[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)=[C:39]=[O:42]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CCN(CC)CC
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(N=C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Yield: 78.1 %

Procedure:
To a suspension of betulinic acid (10 g, 21.90 mmol) in 1,4-dioxane (100 mL) was added triethylamine (9.16 mL, 65.7 mmol) and diphenyl phosphorazidate (7.08 mL, 32.8 mmol). The mixture was heated to reflux. Upon heating, all solids dissolved. After heating the mixture for 26 h, the mixture was cooled to rt and was concentrated under reduced pressure. The residue was diluted with 100 mL of water and was extracted with dichloromethane (3×100 mL). The combined organic layers were dried with sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography using a 0-15% EtOAc in hexanes gradient and a Thomson 240 g silica gel column. The fractions containing the expected product were combined and concentrated under reduced pressure. A second batch of less-pure product was concentrated and was repurified using a Thomson 240 g column and the same gradient. The fractions containing the expected product were combined with the first batch to give the title compound as a white solid (7.76 g, 17.10 mmol, 78% yield). 1H NMR (400 MHz, chloroform-d) δ=4.75 (s, 1H), 4.67-4.62 (m, 1H), 3.20 (dt, J=11.3, 5.6 Hz, 1H), 2.55 (td, J=10.9, 5.9 Hz, 1H), 2.17-2.03 (m, 1H), 1.92-1.76 (m, 5H), 1.69 (s, 3H), 1.06 (s, 3H), 0.98 (s, 3H), 0.95 (s, 3H), 0.85 (s, 3H), 0.78 (s, 3H), 1.74-0.66 (m, 19H).
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12](CO)[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(O)C=CC=CC=1.[Br:23]C1C=CC=C(Br)N=1>CS(C)=O>[Br:23][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:13]=1
Reactant: Brc1cccc(Br)n1
Reactant: OCc1cccc(Oc2ccccc2)n1
Solvent: CS(C)=O
Solvent: Oc1ccccc1
Product: Brc1cccc(Oc2ccccc2)n1

Procedure:
The 6-phenoxy-2-pyridinylmethanol may be prepared by first reacting phenol with 2,6-dibromopyridine in dimethyl sulfoxide under basic conditions to give 2-bromo-6-phenoxypyridine. This compound is then reacted at -70° C. with n-butyllithium in diethyl ether and then with dimethylformamide at -30° C. to give 2-formyl-6-phenoxypyridine. This aldehyde is in turn reacted with sodium borohydride in methanol, yielding the corresponding 6-phenoxy-2-pyridinylmethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7](F)=[CH:8][CH:9]=1)[C:5]#[N:6].CC[N:13]([CH:17]([CH3:19])[CH3:18])C(C)C.C1(N)CC1>CN1CCCC1=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([NH:13][CH:17]2[CH2:19][CH2:18]2)=[C:4]([CH:3]=1)[C:5]#[N:6]
Reactant: CCN(C(C)C)C(C)C
Reactant: N#Cc1cc(Cl)ccc1F
Agent: NC1CC1
Solvent: CN1CCCC1=O
Product: N#Cc1cc(Cl)ccc1NC1CC1
Temperature: 25 °C
Yield: 75 %

Procedure:
A solution of 3-chloro-6-fluorobenzonitrile (5 g), Hunig's base (5.60 mL, 1 eq), and cyclopropylamine (3.34 mL, 1.5 eq) in anhydrous N-methylpyrrolidinone (16 mL) was heated to 110° C. for 18 h in a sealed tube. The mixture was then cooled to room temperature and partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer was washed once with water, then brine, then concentrated and the residue was washed with hexanes delivering the product as a crystalline white solid (4.66 g, 75% yield). 1H-NMR (300 MHz, DMSO-d6) δ 7.58 (s, 1H), 7.46 (dd, 1H), 7.02 (d, 1H), 6.70 (s, 1H), 2.40 (m, 1H), 0.75 (m, 2H), 0.50 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5].C[Si](Cl)(C)C.C(N(CC)CC)C.CO[C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1.[OH-].[Na+].[ClH:42]>C(Cl)Cl>[Cl:42][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:1][C:2]2[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=2[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5])=[O:36])=[CH:33][CH:32]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cl
Reactant: Nc1ccccc1C(=O)NCCCC(=O)O
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CCCNC(=O)c1ccccc1NC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 2.00 g (9.01 mmol) of 4-(2-aminobenzoylamino)butanoic acid in 20 ml of dry methylene chloride, add 8.36 g (77.00 mmol) of trimethylsilyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 1.17 g (11.55 mmol) of triethylamine and a solution of 1.35 g (7.70 mmol) of 4-methoxybenzoyl chloride dissolved 10 ml of dry methylene chloride. Allow the reaction to stir for 30 minutes in an ice bath and 24 hours at room temperature. Eliminate the solvent at low pressure, add 30 ml of 10% NaOH to the crude product and continue stirring the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCl, filter the resulting solid and wash several times with water and with ether. Purify the reaction product by recrystallization (EtOH/H2O). This yields 1.79 g (65%) of 4-[2-(4-chlorobenzoylamino)benzoylamino]butanoic acid as a cream-coloured solid.
Reaction SMILES: [C:1]([C:9]1[N:13]([CH3:14])[C:12]([CH2:15][C:16]#N)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:18].[Na+].[OH2:20]>C(O)C>[C:1]([C:9]1[N:13]([CH3:14])[C:12]([CH2:15][C:16]([OH:20])=[O:18])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O
Reactant: Cn1c(CC#N)ccc1C(=O)c1ccccc1
Agent: [Na+]
Solvent: CCO
Product: Cn1c(CC(=O)O)ccc1C(=O)c1ccccc1

Procedure:
A suspension of 2.42 g. (0.11 mole) of 5-benzoyl-1-methylpyrrole-2-acetonitrile, 0.9 g. (0.22 mole) sodium hydroxide, 6 ml. water, and 0.5 ml. ethanol, is stirred and refluxed for one hour. The resulting solution is cooled and extracted in water and chloroform. The aqueous fraction is made acidic with 3N hydrochloric acid. A white solid, 5-benzoyl-1-methylpyrrole-2-acetic acid, precipitates which is filtered and washed with a hexane-ether solution, m.p. 144°-145°C.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[CH:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(#N)C>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:30]([C:26]2[N:27]=[CH:28][O:29][C:25]=2[CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)=[O:31])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(O)c1ncoc1C1CCCCC1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ncoc2C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.8 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride (Reference Example 1, 0.30 g, 1.03 mmol), 5-cyclohexyl-1,3-oxazole-4-carboxylic acid (Reference Example 14, 0.22 g, 1.13 mmol), triethylamine (0.23 g, 2.26 mmol), EDCI (0.22 g, 1.13 mmol) and HOBt (0.17 g, 1.13 mmol) in acetonitrile (10 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and 10% sodium hydrogen carbonate solution. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate 80:20 to 50:50) and the resulting white solid was triturated with hexane to give the title compound (0.15 g, 37%) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([CH3:19])=[C:11]([Cl:18])[C:12]([F:17])=[CH:13]2)=[C:8]([CH:20]2[CH2:22][CH2:21]2)[CH:7]=1)=[O:5])C.C([O-])(O)=O.[Na+].C(OC([NH:35][C@@H:36]([C@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1)[CH3:37])=O)(C)(C)C>C(#N)C>[ClH:18].[NH2:35][C@@H:36]([C@H:38]1[CH2:42][CH2:41][N:40]([C:11]2[C:12]([F:17])=[CH:13][N:14]3[C:9]([C:10]=2[CH3:19])=[C:8]([CH:20]2[CH2:21][CH2:22]2)[CH:7]=[C:6]([C:4]([OH:3])=[O:5])[C:15]3=[O:16])[CH2:39]1)[CH3:37]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)[C@H]1CCNC1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1c(N2CC[C@H]([C@@H](C)N)C2)c(F)cn2c(=O)c(C(=O)O)cc(C3CC3)c12
Product: Cl

Procedure:
A 0.44 g sample of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, and 1.51 g of NaHCO3 were dissolved in 40 mL of anhydrous acetonitrile, reacted with (3S,1R)-3-(1-(t-butoxycarbonylamino)ethyl)pyrrolidine (1.06 g, prepared as described by Schroeder et al., J. Heterocyclic Chem., 29:1481-1498 (1992)), and carried forward as described in Example 253k-l to give the title product. mp 235°-240° C. (dec.). MS 374 (M+H)+ ; 1H NMR (D6 -DMSO) ∂: 0.59 (m, 2H), 1.00 (m, 2H), 1.29 (d, 3H, J=6 Hz), 1.76 (m, 1H), 2.13 (m, 1H), 2.28 (m, 1H), 2.41 (m, 1H), 2.63 (s, 3H), 3.30 (m, 1H), 3.74 (m, 3H), 3.94 (m, 1H), 7.90 (s, 1H), 8.16 (br s, 3H), 9.07 (d, 1H, J=11 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14](/[CH:17]=[CH:18]/[C:19]#[C:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:28][OH:29]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH:18]([NH:28][OH:29])[C:19]#[C:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(/C=C/C#CCc1ccccc1)N1CCN(c2ccc(F)cc2)CC1
Reactant: NO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(CC(C#CCc1ccccc1)NO)N1CCN(c2ccc(F)cc2)CC1
Temperature: 60 °C
Yield: 29.9 %

Procedure:
To a solution of 1-(4-fluorophenyl)-4-{[(1E)-5-phenyl-1-penten-3-ynyl]sulfonyl}piperazine (155 mg; 0.40 mmol) in THF (8 mL) was added hydroxylamine (0.71 mL; 12.1 mmol). The reaction mixture was heated at 60° C. for 1 h. It was then diluted with EtOAc, washed with brine, dried over magnesium sulfate, filtrated and concentrated. Purification of the crude (135 mg) by flash chromatography on silica gave the title compound (50 mg, 30% yield). HPLC, Rt: 3.84 min (purity: 94.5%). LC/MS, M+(ESI): 418.3, M−(ESI): 416.2. 1H NMR (CDCl3) δ: 7.22-7.31 (m, 5H), 7.01 (m, 4H), 4.33 (m, 1H), 3.62 (d, J=1.9 Hz, 2H), 3.53-3.60 (m, 5H), 3.20-3.27 (m, 5H). 1H NMR (CDCl3) δ: 7.30 (m, 5H), 6.95 (m, 4H), 6.32 (d, J=15.6 Hz, 1H), 6.07 (dt, J=16.1, 7.4 Hz, 1H), 3.90 (s, 2H), 3.78 (d, J=6.6 Hz, 2H), 3.22 (m, 4H), 2.91 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[CH2:30]O)[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(Br)(Br)(Br)[Br:36].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[CH2:30][Br:36])[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1CBr
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 0° C. solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(hydroxymethyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (210 mg, 0.419 mmol) in CH2Cl2 (4 mL) was added CBr4 (292 mg, 0.880 mmol) and a solution of PPh3 (220 mg, 0.838 mmol) in CH2Cl2 (4 mL). The mixture was allowed to warm to room temperature, and, after 90 minutes had elapsed, it was concentrated on to silica gel. Purification of the residue by flash chromatography on silica gel (10 to 50% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(bromomethyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.10 (50% EtOAc/hexanes). LCMS=564.0 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.88 (s, 1H), 7.78 (s, 2H), 7.63-7.57 (m, 2H), 7.52 (s, 1H), 5.79 (d, J=8.0 Hz, 1H), 5.09 (d, J=15.8 Hz, 1H), 4.61 (dd, J=13.8, 10.5 Hz, 2H), 4.27 (d, J=15.8 Hz, 1H), 4.06-1.00 (m, 1H), 0.82 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH2:1]([N-:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].O.[OH-].[Na+].C(N(CC)CC)C>C1COCC1>[CH2:16]([NH:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCC[N-]CCCCCCCCCCCCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCCCNCCCCCCCCCCCCCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
47 mmol of ditetradecylamide (20 g) were dissolved in 700 ml of anhydrous THF, under nitrogen, in a round-bottomed flask equipped with a condenser and a drying tube. The mixture was cooled to 0° C. and then 89 mmol of lithium aluminum hydride LiAlH4 (3.4 g) were added. After addition, the mixture was then heated under reflux for 5 hours, with vigorous stirring. Once the reaction was complete, the mixture was cooled to 0° C. in order to carry out the hydrolysis by successive addition of 3.4 ml of water, 6.8 ml of 1N sodium hydroxide and 3.4 ml of water. After stirring for 1 hour at room temperature, the crude reaction material was filtered on a Büchner funnel and the filtrate was concentrated. The product obtained was then purified on 1.5 equivalents of A-15 resin (15 g) in 300 ml of THF, with stirring for 30 minutes. The resin was filtered and redissolved in 300 ml of THF, with addition of 2 equivalents of triethylamine (19.2 ml). After stirring for 30 minutes, the solution was filtered and the filtrate was concentrated to give 17.72 g of a white solid (yield: 92%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([NH:8][NH2:9])=[O:7])([O-:3])=[O:2].[C:14](=S)=[S:15].O.Cl>N1C=CC=CC=1>[SH:15][C:14]1[O:7][C:6]([C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])=[N:8][N:9]=1
Reactant: NNC(=O)c1ccccc1[N+](=O)[O-]
Reactant: S=C=S
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1-c1nnc(S)o1

Procedure:
The reactions of Equation 36 above can be run according to similar procedures described in E. Hoggarth, J. Chem. Soc., 4811 (1952). Thus, in reaction 36a, 2-nitrobenzhydrazide XLVIII is reacted with carbon disulfide in pyridine solvent at 25° to 80° C. for about 4 to 16 hours, followed by addition of water and acidification with hydrochloric acid to form a 2-mercapto-5-(2-nitrophenyl)-1,3,4-oxadiazole of Formula (L). In reaction 36b, L is reacted with sodium hydroxide and methyl iodide in water at 0° to 30° C. for 0.2 to 1 hour to form Xk".
Reaction SMILES: [CH2:1]([O:8]/[N:9]=[C:10]1\[CH2:11][CH2:12][C:13]2[C:18]\1=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:23]1[C:24]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)=[N:25][N:26]([CH3:28])[CH:27]=1>C(#N)C.O>[CH2:1]([O:8][N:9]=[C:10]1[C:18]2[C:13](=[CH:14][C:15]([C:23]3[C:24]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)=[N:25][N:26]([CH3:28])[CH:27]=3)=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cc(Br)c(-c2ccncc2)n1
Reactant: OB(O)c1ccc2c(c1)CC/C2=N\OCc1ccccc1
Solvent: O
Solvent: CC#N
Product: Cn1cc(-c2ccc3c(c2)CCC3=NOCc2ccccc2)c(-c2ccncc2)n1
Yield: 75.4 %

Procedure:
To (E)-1-(benzyloxyimino)-2,3-dihydro-1H-inden-5-ylboronic acid (3.00 g; Example 2, Step 4) in 32 mL acetonitrile and 8.0 mL water was added 4-(4-bromo-1-methyl-1H-pyrazol-3-yl)pyridine (2.00 g; Example 3, Step 3). The solution was deoxygenated by bubbling nitrogen through the solution for 10 min. To the resulting mixture was added 5.62 g potassium carbonate, 10 mL N,N-dimethylformamide, and 290 mg tetrakis(triphenyphosphine)palladium(0). The mixture was then refluxed for 8 hours (over the course of this time a small portion of catalyst was added twice). The cooled reaction mixture was filtered through celite and the filter cake was washed with ethyl acetate. The filtrate was washed with water, brine, dried over sodium sulfate, filtered, and evaporated under vacuum to yield 5.1 g crude product as an oil. The crude material was purified by chromatography, eluting with ethyl acetate to afford 2.50 g (80% yield) product as a light yellow foam. 1H NMR (CDCl3) was consistent with the desired structure. LC/MS showed one peak with a M+1 molecular ion of m/z 395.2 by positive ESI.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][NH:3]1.[CH3:18][N:19]1[CH2:24][CH2:23][CH:22](O)[CH2:21][CH2:20]1.C(C=P(C)(C)C)#N>C1(C)C=CC=CC=1>[CH3:18][N:19]1[CH2:24][CH2:23][CH:22]([N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]3[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=3)[C:2]2=[O:1])[CH2:21][CH2:20]1
Reactant: CN1CCC(O)CC1
Reactant: COC(=O)c1ccc(-c2ccc[nH]c2=O)cc1
Agent: CP(C)(C)=CC#N
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2cccn(C3CCN(C)CC3)c2=O)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 18.9 %

Procedure:
Methyl 4-(2-oxo-1,2-dihydropyridin-3-yl)benzoate (316 mg) was suspended in toluene (7 mL), and 1-methyl-4-piperidinol (318 mg) and cyanomethylenetrimethylphosphorane (317 mg) were added thereto, followed by stirring at 100° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/chloroform=0% to 10%) to obtain methyl 4-[1-(1-methylpiperidin-4-yl)-2-oxo-1,2-dihydropyridin-3-yl]benzoate (85 mg) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][C:9](=[O:12])[CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[BH4-].[Na+]>C(O)C>[CH2:16]([O:15][C:13]([C:3]1[CH:4]=[N:5][C:6]2[CH2:7][CH2:8][CH:9]([OH:12])[CH2:10][C:11]=2[C:2]=1[OH:1])=[O:14])[CH3:17]
Reactant: CCOC(=O)c1cnc2c(c1O)CC(=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc2c(c1O)CC(O)CC2

Procedure:
To a suspension of 6 g of ethyl 4-hydroxy-6-oxo-5,6,7,8-tetrahydroquinoline-3-carboxylate in 200 mL of ethanol, 1.92 g of NaBH4 is added in small portions under ice-cooling and stirring. The reaction mixture is then stirred at room temperature for 6 hours and evaporated to dryness. The residue is taken up in CHCl3, washed successively with 6N NH4OH, and sat. aq. NaCl, dried (MgSO4) and evaporated dryness obtaining ethyl-4,6-dihydroxy-5,6,7,8-tetrahydroquinoline-3-carboxylate.
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:12]2(OCC[O:14]2)[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)C>[CH:1]1([O:4][N:5]=[C:6]([C:12](=[O:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=NOC1CC1)C1(C)OCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C(=NOC1CC1)C(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To a solution of ethyl 2-cyclopropyloxyimino-3,3-ethylenedioxybutyrate (syn isomer)(487 mg) in methylene chloride (0.8 ml) was added 90% trifluoroacetic acid (0.8 ml) under ice-cooling. The mixture was stirred at ambient temperature for 2 hours. The mixture was concentrated in vacuo to give a residue. The residue was dissolved in diethyl ether and washed successively with saturated aqueous solution of sodium bicarbonate and water, dried over magnesium sulfate and concentrated in vacuo to give ethyl 2-cyclopropyloxyimino-3-oxobutyrate (syn isomer)(382 mg) as an oil.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][C:4]2[O:8][C:9]([F:12])([F:11])[O:10][C:3]=2[CH:2]=1.Cl.[C:14](Cl)(Cl)=[S:15].ClCCl>O>[N:7]([C:6]1[CH:1]=[CH:2][C:3]2[O:10][C:9]([F:11])([F:12])[O:8][C:4]=2[CH:5]=1)=[C:14]=[S:15]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc2c(c1)OC(F)(F)O2
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: FC1(F)Oc2ccc(N=C=S)cc2O1
Reaction time: 0.5 h

Procedure:
34.6 g of 5-amino-2,2-difluorobenzodioxole were added dropwise to a solution of 90 ml of conc. hydrochloric acid in 350 ml of water. The mixture was stirred for a further 30 minutes and then 27 g of thiophosgene were metered in rapidly. The mixture was stirred at the given temperature for a further 3 hours, the almost colourless suspension was admixed with 150 ml of dichloromethane and the dichloromethane was removed. The crude product was distilled at 45 mbar. 28 g (=89% of theory) were obtained as a colourless to yellowish liquid.