Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH2:12]O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[N:16][C:15]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)CC)C>S(Cl)(Cl)=O>[C:1]1([C:7]2[NH:11][C:10]([CH2:12][N:27]3[CH2:28][CH2:29][N:24]([C:15]4[N:16]=[CH:17][C:18]5[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=5)[N:14]=4)[CH2:25][CH2:26]3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2nc(N3CCNCC3)ncc2c1
Reactant: OCc1c[nH]c(-c2ccccc2)n1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: c1ccc(-c2ncc(CN3CCN(c4ncc5ccccc5n4)CC3)[nH]2)cc1
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
A sample of 2-phenyl-4-hydroxymethylimidazole (348 mg, 2 mmol) is heated for 5 min in thionyl chloride (5 mL) and subsequently concentrated. Chloroform (10 mL) is added and the solution reconcentrated. The resulting dark oil is then taken up in chloroform (10 mL) and treated with 1-quinazolin-2-ylpiperazine (428 mg, 2 mmol) and triethyl amine (2 mL). After 10 minutes, the reaction is washed with 2N NaOH solution, dried (Na2SO4) and concentrated to provide the title compound (Compound 4) as an oil (640 mg), the hydrochloride salt is prepared in a conventional manner, m.p. 101-105° C. (Compound 4a). 1H NMR (CDCl3) 9.0 (s, 1H), 7.9 (d, J=7 Hz, 2H), 7.65 (m, 2H), 7.55 (d, J=6 Hz, 1H), 7.2-7.4 (m, 4H), 7.0 (s, 1H, imidazole CH), 3.95 (m, 4H), 3.6 (s, 2H), 2.6 (t, J=5 Hz, 4H).
Reaction SMILES: [CH3:1][Li].[C:3]([C:6]1[CH:14]=[CH:13][C:9]2[O:10][CH2:11][O:12][C:8]=2[CH:7]=1)(=[O:5])[CH3:4].O>O1CCCC1>[O:10]1[C:9]2[CH:13]=[CH:14][C:6]([C:3]([OH:5])([CH3:1])[CH3:4])=[CH:7][C:8]=2[O:12][CH2:11]1
Reactant: CC(=O)c1ccc2c(c1)OCO2
Reactant: [Li]C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)c1ccc2c(c1)OCO2
Temperature: -20 °C
Reaction time: 1 h

Procedure:
About 600 ml of 1.5M methyllithium (solution in ether) was added to 500 ml of tetrahydrofuran. A suspension of 93.45 g of 5-acetyl-1,3-benzodioxole in 900 ml of tetrahydrofuran was added thereto under cooling at -20° C. The mixture was stirred under these conditions for 1 h. Water was added to the reaction mixture. The product was extracted with ethyl acetate, washed with a saturated aqueous common salt solution and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to obtain 97 g of the intended compound in the form of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[O:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25](O)=[O:26])[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH2:31][CH:32]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[O:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([NH:31][CH:32]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33]3)=[O:26])[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: COc1cc(-c2cc3nccc(-c4cccc(C(=O)O)c4)c3o2)cc(OC)c1OC
Product: COc1cc(-c2cc3nccc(-c4cccc(C(=O)NC5CCN(C(=O)OC(C)(C)C)C5)c4)c3o2)cc(OC)c1OC
Yield: 64 %

Procedure:
Starting from 3-[2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridin-7-yl]benzoic acid (0.099 mmol) and (+/−)-3-amino-1-N—BOC-pyrrolidine (0.102 mmol) the product is prepared analogously to “A43” and obtained as yellow solid in a yield of 64%. HPLC (method A): Rt 2.68 min (purity 99.3%); LCMS (ESI+) (method E): Rt 2.11 min, M+H+ 574.3 m/z; 1H NMR (500 MHz, DMSO-d6) δ[ppm] 8.82 (s, 1H), 8.71 (d, J=6.3, 1H), 8.62 (d, J=5.2, 1H), 8.28 (d, J=8.0, 1H), 8.06 (d, J=7.9, 1H), 7.79 (s, 1H), 7.74 (dd, J=13.0, 6.4, 2H), 7.37 (s, 2H), 4.46 (s, 1H), 3.93 (s, 6H), 3.75 (s, 3H), 3.48-3.39 (m, 1H), 3.34 (d, J=7.0, 2H), 3.22 (d, J=4.2, 1H), 2.19-2.09 (m, 1H), 1.99-1.86 (m, 1H), 1.41 (s, 9H).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[CH3:9].C(N(CC)CC)C.CS([Cl:28])(=O)=O>C(Cl)Cl>[Cl:28][CH2:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(-c2ccc(C)c(CO)c2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccc(C)c(CCl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-hydroxymethyl-4,4'-dimethylbiphenyl (1.3 g) and triethylamine (0.8 g) in methylene chloride (50 ml) was cooled to 0° C., and methanesulfonyl chloride (0.84 g) in methylene chloride was added dropwise. The mixture was allowed to warm to room temperature, and was stirred overnight. Ice/water was then added, the organic layer separated, the aqueous layer washed with methylene chloride, the organic layer washed with brine, dried over sodium sulfate, and the solvent evaporated under reduced pressure, to yield 3-chloromethyl-4,4'-dimethylbiphenyl as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH:8]=[CH:9][N:10](C)C)=[CH:3][CH:2]=1.[ClH:14].[F:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22]N)=[CH:18][CH:17]=1.O>C(O)C>[Cl:14][C:6]1[CH:5]=[C:4]([C:7]2[N:22]([C:19]3[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=3)[N:10]=[CH:9][CH:8]=2)[CH:3]=[CH:2][N:1]=1
Reactant: Cl
Reactant: CN(C)C=CC(=O)c1ccncc1
Reactant: NNc1ccc(F)cc1
Solvent: CCO
Solvent: O
Product: Fc1ccc(-n2nccc2-c2ccnc(Cl)c2)cc1
Yield: 91.3 %

Procedure:
To a mixture of 1-(4-pyridyl)-2-(dimethylaminomethylene)ethanone (2.1 g, 0.01 mol) and 4-fluorophenylhydrazine hydrochloride (1.63 g, 0.01 mol) in 50 mL of ethanol was added 1 mL of water. The reaction mixture was heated at reflux for 1.5 h. Solvent was removed and the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by chromatography on silica gel (ethyl acetate/hexane, 2:8) to give 2.5 g (93% yield) of product as a yellow oil: Anal. Calcd. for C14H9ClFN3: C, 61.44; H, 3.31; N, 15.35. Found: C, 61.52; H, 3.27; N, 14.73.
Reaction SMILES: CC[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13](=O)[CH3:14])[CH:10]=[CH:9][C:8]=1[Cl:16])=[O:4].[NH2:17][OH:18].[CH2:19]([OH:21])C>>[Cl:16][C:8]1[CH:9]=[CH:10][C:11]([C:13](=[N:17][OH:18])[CH3:14])=[CH:12][C:7]=1[CH2:6][NH:5][C:3](=[O:4])[O:21][CH3:19]
Reactant: NO
Reactant: CCC(=O)NCc1cc(C(C)=O)ccc1Cl
Reactant: CCO
Product: COC(=O)NCc1cc(C(C)=NO)ccc1Cl

Procedure:
To a solution of methyl N-[(5-acetyl-2-chlorophenyl)methyl]acetamide (0.5 g, 2.1 mmol) (prepared according the method given in European Patent Publication EP 1586552) in ethanol (10 mL) was added an aqueous solution hydroxylamine (50% by wt) (0.82 g, 12.4 mmol). The reaction mixture was heated at refluxed overnight, and then concentrated to provide methyl N-[[2-chloro-5-[1-(hydroxyimino)ethyl]phenyl]methyl]carbamate as a white solid, which was used without purification. To N,N-dimethylformamide (5.0 mL) was added methyl N-[[2-chloro-5-[1-(hydroxyimino)ethyl]phenyl]methyl]carbamate (0.28 g, 1.1 mmol), 3-(chloropropyl)trimethylsilane (0.33 g, 2.2 mmol) and potassium carbonate (0.45 g, 3.3 mmol). This reaction mixture was then heated at 100° C. overnight, and then concentrated under reduced pressure. The resulting oil was purified by medium pressure liquid chromatography (0 to 100% gradient of ethyl acetate in hexanes as eluant) to yield the title compound, a compound of the present invention, as a clear oil. (0.22 g).
Reaction SMILES: Br[C:2](=[C:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:31])[C:16]([C:18]2[C:26]3[C:21](=[C:22]([O:29][CH3:30])[N:23]=[CH:24][C:25]=3[O:27][CH3:28])[NH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Sn](CCCC)(CCCC)[C:37]1[S:38][CH:39]=[CH:40][N:41]=1)CCC>C1COCC1.CCOC(C)=O>[C:3]1([C:2](=[C:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:31])[C:16]([C:18]3[C:26]4[C:21](=[C:22]([O:29][CH3:30])[N:23]=[CH:24][C:25]=4[O:27][CH3:28])[NH:20][CH:19]=3)=[O:17])[CH2:11][CH2:10]2)[C:37]2[S:38][CH:39]=[CH:40][N:41]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ncc(OC)c2c(C(=O)C(=O)N3CCC(=C(Br)c4ccccc4)CC3)c[nH]c12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ncc(OC)c2c(C(=O)C(=O)N3CCC(=C(c4ccccc4)c4nccs4)CC3)c[nH]c12
Temperature: 90 °C
Yield: 34.1 %

Procedure:
A mixture of 1-[4-(1-bromo-1-phenyl-methylene)-piperidin-1-yl]-2-(4,7-dimethoxy-6-azaindol-3-yl)-ethane-1,2-dione (0.032 g, 0.066 mmol), 2-(tri-n-butylstannyl)thiazole (0.025 g, 0.066 mmol) and bistriphenylphosphinepalladium dichloride (0.001 g, 1 mol %) in THF (4 mL) was heated at 90° C. in a sealed tube under Ar for 15 h. The cooled mixture was then diluted with EtOAc, washed (1M KF, brine), dried (Na2SO4) and evaporated to give a clear yellow oil. Purification by preparative HPLC afforded the product (0.011 g, 34%) as a white solid:
Reaction SMILES: [CH:1]([NH:5][C:6]1[S:7][C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[C:10]([CH:15]=O)[N:9]=2)([CH2:3][CH3:4])[CH3:2].[NH4+].[OH-].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]([N+:37]#[C-:38])S(C1C=CC(C)=CC=1)(=O)=O.[NH:39]1CCNCC1>C1COCC1.CCOC(C)=O>[CH:1]([NH:5][C:6]1[S:7][C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[C:10]([C:15]1[NH:39][CH:38]=[N:37][C:26]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[F:19])[N:9]=2)([CH2:3][CH3:4])[CH3:2]
Reactant: C1CNCCN1
Reactant: CCC(C)Nc1nc2ccc(C=O)nc2s1
Reactant: [C-]#[N+]C(c1ccccc1F)S(=O)(=O)c1ccc(C)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(C)Nc1nc2ccc(-c3[nH]cnc3-c3ccccc3F)nc2s1
Reaction time: 8 h
Yield: 25.9 %

Procedure:
A solution of 2-(sec-butylamino)thiazolo[5,4-b]pyridine-5-carbaldehyde (presumed 0.24 mmol, 1.0 eq.) and concentrated aqueous NH4OH (0.050 mL) in THF (0.8 mL) was stirred overnight. 1-Fluoro-2-(isocyano(tosyl)methyl)benzene (0.0841 g, 0.291 mmol, 1.2 eq.) and piperazine (0.0394 g, 0.457 mmol, 1.9 eq.) were added, and the reaction mixture was stirred overnight. It was then diluted with EtOAc and washed with water, saturated aqueous NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated in vacuo. MeOH was added to the residue, and the mixture was subjected to autoprep. The appropriate fractions were collected, and NaHCO3 (s) was added. The solution was then concentrated in vacuo not to dryness and extracted with CH2Cl2 (3×). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo to give N-sec-butyl-5-(4-(2-fluorophenyl)-1H-imidazol-5-yl)thiazolo[5,4-b]pyridin-2-amine as a yellow solid (0.0228 g, 26% yield). LC/MS (MH)=368.23.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]3([C:18]#N)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[CH2:8][CH2:7]2)[N:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:4][NH:3]1.[CH2:26]([Mg]Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([C:12]1([N:9]2[CH2:8][CH2:7][C:6]3([N:5]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:4][NH:3][C:2]3=[O:1])[CH2:11][CH2:10]2)[CH2:18][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: N#CC1(N2CCC3(CC2)C(=O)NCN3c2ccccc2)CCCCC1
Product: O=C1NCN(c2ccccc2)C12CCN(C1(Cc3ccccc3)CCCCCC1)CC2
Yield: 54 %

Procedure:
This was prepared according to the procedure described in Example 1 using 1-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)cyclohexanecarbonitrile instead of 1-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)cycloheptanecarbonitrile and benzylmagnesium bromide instead of phenylmagnesium bromide. Yield was 54%.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:26][CH3:27])[C:16]2[C:21]([NH:22][CH:23]([CH3:25])[CH3:24])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[Pt+2].[OH-]>[CH2:26]([N:15]([CH2:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:16]1[C:21]([NH:22][CH:23]([CH3:25])[CH3:24])=[CH:20][CH:19]=[CH:18][N:17]=1)[CH3:27]
Reactant: [H][H]
Reactant: CCN(CC1CCN(Cc2ccccc2)CC1)c1ncccc1NC(C)C
Agent: [Pt+2]
Agent: [OH-]
Solvent: CCO
Product: CCN(CC1CCNCC1)c1ncccc1NC(C)C

Procedure:
1-Benzyl-4-[N-ethyl-N-(3-isopropyl-2-pyridinyl)amino]methylpiperidine (EXAMPLE 178, 1.82 g, 4.97 mmol) and platinum hydroxide on carbon (675 mg) in 30 ml ethanol is hydrogenated at 40 p.s.i. hydrogen for 48 hrs. Filtration and evaporation of the solvent gives the title compound, NMR (300 MHz, CD3OD) 7.56, 6.97, 3.60, 2.94, 2.44, 1.69, 1.48, 1.20, 1.10 and 0.99δ.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22](O)=[O:23])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[NH:49]1[CH2:59][CH2:58][CH2:57][CH2:56][CH:50]1[C:51]([O:53]CC)=[O:52]>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([N:49]3[CH2:59][CH2:58][CH2:57][CH2:56][CH:50]3[C:51]([OH:53])=[O:52])=[O:23])[C:17]1=[O:26])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: CCOC(=O)C1CCCCN1
Reactant: C[C@@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](C(=O)N1CCCCC1C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.9 %

Procedure:
To a solution of (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid (0.025 g) in DCM (10 ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.036 g), HOBT (0.026 g) and triethylamine (0.026 ml) and the mixture was stirred at room temperature for 30 min. Ethyl pipecolinate (0.030 g) was added and the resultant mixture stirred at room temperature for 16 h. The mixture was partitioned between DCM and water. The aqueous layer was re-extracted with DCM and the combined, dried (over magnesium sulphate) organic extracts were concentrated under reduced pressure. The residue was then dissolved in a mixture of THF (1 ml) and water (1 ml), treated with lithium hydroxide (0.005 g) and stirred at room temperature for 18 h. The reaction mixture was acidified to pH5 using hydrochloric acid (2N) and concentrated under reduced pressure. The residue was purified using SPE (aminopropyl stationary phase, washed with methanol and eluted with 10% hydrochloric acid in methanol) to give the title compound (0.007 g) as white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.N(C([C:19]1[C:20]([CH3:25])=[N:21][CH:22]=[CH:23][CH:24]=1)=O)=[N+]=[N-].C[N:27](C)[CH:28]=[O:29]>>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:28]([NH:27][C:19]2[C:20]([CH3:25])=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:29])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: CN(C)C=O
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Reactant: Cc1ncccc1C(=O)N=[N+]=[N-]
Product: Cc1ncccc1NC(=O)Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Yield: 31 %

Procedure:
Under Ar, a solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (64 mg, 0.29 mmol) and 3-(azidocarbonyl)-2-methylpyridine (390 mg, 2.41 mmol) in 1 mL of N,N-dimethyl-formamide was stirred at room temperature for 20 hours. Purification upon Gilson HPLC, eluting with acetonitrile/water (10/90, v/v to 90/10, v/v, over 10 min), gave the desired product (32 mg, 31%). LC-MS (m/z) 357.0 (M+).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH3:16])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34](OCC)=[O:35]>O1CCCC1>[C:1]1([C:7]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH2:16][C:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=3)=[O:35])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNC(=O)c1c(-c2ccccc2)noc1C
Reactant: CCOC(=O)c1ccccn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccccc2)noc1CC(=O)c1ccccn1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
A suspension of 28 g. (0.13 mole) of 3-phenyl-N,5-dimethyl-isoxazole-4-carboxamide and 330 milliliters of tetrahydrofuran is cooled to -65° C. and 180 milliliters of 1.6M n-butyllithium in hexane (0.288 mole) is added dropwise, maintaining the temperature between -60° and -70° C. After the addition is complete, the organic suspension is stirred for 11/2 hours at -60° to -70° C., and then 19.6 g. (0.13 mole) of ethyl picolinate in 196 ml. tetrahydrofuran is added dropwise maintaining the temperature between -60° and -70° C. After addition is complete, the mixture is stirred 11/2 hours at -60° to -70° C. and then warmed to -30° C. and quenched by the addition of saturated ammonium chloride solution. The mixture is further diluted with tetrahydrofuran and the layers are separated. The tetrahydrofuran layer is washed twice with 50% brine, and once with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The solid residue is triturated with ether and filtered to give 3-phenyl-5-(2-pyridylcarbonylmethyl)-N-methyl-isoxazole-4-carboxamide; m.p. 146° to 149° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[O:14][C:13](=[O:15])[NH:12][CH2:11]2)=[CH:6][CH:5]=1.Br[CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[C:28]1[CH:33]=[C:32]([CH:34]([CH3:36])[CH3:35])[CH:31]=[CH:30][C:29]=1[O:37][CH3:38]>C1COCC1>[CH:34]([C:32]1[CH:31]=[CH:30][C:29]([O:37][CH3:38])=[C:28]([C:19]2[CH:20]=[CH:21][C:22]([C:24]([F:27])([F:25])[F:26])=[CH:23][C:18]=2[CH2:17][N:12]2[CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=3)[O:14][C:13]2=[O:15])[CH:33]=1)([CH3:36])[CH3:35]
Reactant: Cc1ccc(C2CNC(=O)O2)cc1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1CC(c2ccc(C)cc2)OC1=O
Reaction time: 0.5 h

Procedure:
Sodium hydride (6.4 mg of a 60% dispersion in mineral oil, 0.161 mmol) was added to a stirred solution of 5-(4-methylphenyl)-1,3-oxazolidin-2-one (37.7 mg, 0.0973 mmol) in dry THF (1 mL) at room temperature under N2. The reaction was stirred for 30 min and a solution of 2-(bromomethyl)-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl (19.0 mg, 0.107 mmol) in dry THF (2 mL) was added by cannula. The reaction was stirred at room temperature for 3 days. The reaction was quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-80% EtOAc in hexanes gradient) to afford 3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-(4-methylphenyl)-1,3-oxazolidin-2-one as a colorless oil. Rf=0.37 (20% EtOAc/hexanes). LCMS calc.=484.21; found=484.2 (M+1)+. 1H NMR (benzene-d6, 500 MHz, 1:1 mixture of atropisomers) δ 7.76 (s, 0.5H), 7.65 (s, 0.5H), 7.31 (d, J=7.7 Hz, 1H), 7.08 (dd, J=8.4, 2.4 Hz, 1H), 7.05 (br d, J=7.8 Hz, 1H), 6.95-6.86 (m, 5H), 6.58 (t, J=7.7 Hz, 1H), 4.74 (t, J=8.0 Hz, 0.5H), 4.70 (t, J=8.0 Hz, 0.5H), 4.50 (d, J=15.7 Hz, 0.5H), 4.42 (d, J=15.7 Hz, 0.5H), 4.25 (d, J=15.7 Hz, 0.5H), 4.11 (d, J=15.7 Hz, 0.5H), 3.26 (s, 1.5H), 3.21 (s, 1.5H), 2.81 (t, J=8.6 Hz, 0.5H), 2.76 (septet, J=7.0 Hz, 1H), 2.68 (t, J=8.6 Hz, 0.5H), 2.55 (t, J=8.6 Hz, 0.5H), 2.53 (t, J=8.6 Hz, 0.5H), 2.04 (s, 3H), 1.20 (t, J=7.0 Hz, 3H), 1.19 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1](=[O:4])(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].[C:9]1([CH3:16])[C:10]([CH3:15])=[CH:11][CH:12]=[CH:13][CH:14]=1>>[NH2:7][C:6]1[N:8]=[C:1]([OH:4])[C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:15][CH2:13][CH2:14][CH2:9][CH2:10][C:16]=2[N:5]=1
Reactant: N=C(N)N
Reactant: O=C(O)O
Reactant: Cc1ccccc1C
Product: Nc1nc(O)c2c(n1)CCCCCCCCCC2

Procedure:
A mixture of ethyl-2-cyclododecanone carboxylate (4.0 g) and guanidine carbonate (3.12 g) in xylene (50 ml) was refluxed overnight; after cooling the white solid was collected by filtration, washed with water, and recrystallized from ethanol. 2.15 g of white powder were recovered.
Reaction SMILES: N(C1C(C2C=C(Cl)C=CC=2)=CC=CC=1C([O-])=O)=NC1C(C2C=C([Cl:18])C=CC=2)=CC=CC=1C([O-])=O.[C:35]([O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[N+:50]([O-])=O)(=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[Cl:18][C:48]1[CH:47]=[CH:46][C:45]2[N:50]=[C:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:43][C:44]=2[CH:49]=1
Reactant: O=C([O-])c1cccc(-c2cccc(Cl)c2)c1N=Nc1c(C(=O)[O-])cccc1-c1cccc(Cl)c1
Reactant: O=C(Oc1ccccc1[N+](=O)[O-])c1ccccc1
Product: Clc1ccc2nc(-c3ccccc3)oc2c1

Procedure:
When the above procedure is followed substituting an equivalent amount of 2,2'-azobis(5-chlorophenyl benzoate) for the o-nitrophenyl benzoate, 6-chloro-2-phenylbenzoxazole is obtained.
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@:9]3([O:38][CH3:39])[CH2:10][CH2:11][C@@H:12]2[N:20](C(OC(C)(C)C)=O)[C:21]([NH:23]C(OC(C)(C)C)=O)=[NH:22])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([OH:40])[CH:4]=[CH:5]2.[ClH:41]>CCOCC.O>[ClH:41].[ClH:41].[O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@:9]3([O:38][CH3:39])[CH2:10][CH2:11][C@@H:12]2[NH:20][C:21]([NH2:23])=[NH:22])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([OH:40])[CH:4]=[CH:5]2
Reactant: CO[C@@]12CC[C@H](N(C(=N)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)[C@@H]3Oc4c(O)ccc5c4[C@@]31CCN(C)[C@@H]2C5
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CO[C@@]12CC[C@H](NC(=N)N)[C@@H]3Oc4c(O)ccc5c4[C@@]31CCN(C)[C@@H]2C5

Procedure:
A solution of Compound 18 (50 mg, 0.089 mmol) in Et2O (3 ml) was mixed through to a clear acidic reaction with ethereal HCl and with 4 drops of H2O. The mixture was subjected to ultrasound for 1.5 h at room temperature and then evaporated. The residue (40 mg of white foam resin) was dissolved in H2O and freeze dried. Yield: 35 mg (92%) 19.2 HCl as white lyophilisate: 1H-NMR (CDCl3): δ 9.29 (s, br, NH+); 9.20 (s, OH—C(3)); 7.57 (d, J=8.8, C(6)-NH—); 7.46 (s, br, C(6)-NH—C(NH2)2+), 6.76 (d, J=8.1, 1 arom. H); 6.62 (d, J=8.1, 1 arom. H); 4.70 (d, J=4.0, H—C(5)); 3.36 (s, CH3O—C(14)); 2.88 (s, CH3N).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Na].Cl.[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=3)=[N:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1.Cl>C(Cl)(Cl)Cl.O.C(O)C>[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([S:28]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)(=[O:29])=[O:30])=[CH:26][CH:27]=3)=[N:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1
Reactant: CN1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Nc2ncnc3cc(Cl)ccc23)cc1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CN1CCN(S(=O)(=O)c2ccc(Nc3ncnc4cc(Cl)ccc34)cc2)CC1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
N-Methylpiperazine (1.0 g, 0.01 mole) was dissolved in chloroform (50 ml). Sodium carbonte (10 g) was dissolved in water (50 ml). The solutions were combined and cooled to 10° C. 4-(7-Chloro-4-quinazolinylamino)benzenesulphonyl chloride hydrochloride (3.85 g, 0.01 mole) was added in portions to the vigorously stirred solution. Stirring was continued for one hour. The chloroform layer was separated, dried and evaporated. The resulting gummy solid was redissolved in chloroform and chromatographed on an alumina column. Elution with chloroform gave a first band which was discarded. The second band was obtained as a low melting solid, which was converted to the hydrochloride by dissolving in ethanol and adding ethereal hydrogen chloride to give the title compound as the sesquihydrochloride (650 mg) m.p. 237°-239° C.