Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:24])[C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([NH2:23])[N:17]=3)[CH2:11]2)=[N:3][CH:2]=1.S(=O)(=O)(O)O.[N:30]([O-])=O.[Na+].C([O-])(O)=O.[Na+]>O>[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:24])[C:16]3[N:17]=[C:18]4[NH:23][N:30]=[N:22][C:19]4=[CH:20][CH:21]=3)[CH2:11]2)=[N:3][CH:2]=1
Reactant: CN(c1ccc(N)c(N)n1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Reactant: O=N[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CN(c1ccc2nn[nH]c2n1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of (R)—N2-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N2-methylpyridine-2,5,6-triamine (50 mg, 0.15 mmol,) in water (0.6 mL) was added concentrated sulfuric acid (23 uL). The mixture was stirred at room temperature for 1 h. It was cooled to 0° C. and aqueous sodium nitrite (17 mg, 0.25 mmol, in 0.1 mL of water) was added. The reaction mixture was stirred at 0° C. for 1 h. It was then neutralized till pH equal to 5 with aqueous NaHCO3 (10%) and extracted with EtOAc (3×10 mL). The combined extracts were washed with brine (2×10 mL), concentrated, and the residue was purified by chromatography to give the title compound. MS (m/z): 336 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][C:5]2[C:12]3[CH2:17][CH2:16][N:15]([CH2:18][C:19](=O)[CH3:20])[CH2:14][C:13]=3[C:22](=[O:24])[O:23][C:4]=2[CH:3]=1.[CH3:25][NH2:26]>CO>[CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][C:5]2[C:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([NH:26][CH3:25])[CH3:20])[CH2:14][C:13]=3[C:22](=[O:24])[O:23][C:4]=2[CH:3]=1
Reactant: CN
Reactant: CC(=O)CN1CCc2c(c(=O)oc3cc(C)c(NC(C)=O)cc23)C1
Solvent: CO
Product: CNC(C)CN1CCc2c(c(=O)oc3cc(C)c(NC(C)=O)cc23)C1
Yield: 54.6 %

Procedure:
Prepared by the method described for Example 51 from N-[1,3,4,5-tetrahydro-8-methyl-5-oxo-3-(2-oxopropyl)-2H-[1]benzopyrano[3,4-c]pyridin-9-yl]acetamide (5.1 g, 0.016 moles) and methylamine (2.2 ml, 0.050 moles). Sufficient methanol is added to effect solution. Recrystallization from ethanol gave the product (3.0 g), mp 187°-188° C.
Reaction SMILES: Cl.[F:2][C:3]([F:32])([F:31])[C:4]1[CH:5]=[C:6]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:7]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)=[O:8].[C:33](=[O:36])([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:30][C:27]([F:29])([F:28])[C:25]1[CH:24]=[C:6]([CH:5]=[C:4]([C:3]([F:2])([F:31])[F:32])[CH:26]=1)[C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:4][C:5]#[C:6][CH2:7][N:9]2[CH2:14][CH2:33][O:36][CH2:11][CH2:10]2)[CH2:11][C@H:10]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)=[O:8]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CC#CCN2CCOCC2)C[C@H]1Cc1ccc(Cl)c(Cl)c1
Reaction time: 17 h

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)piperazine hydrochloride (150 mg) and 1-(4-chloro-2-butynyl)morpholine hydrochloride (63 mg) in N,N-dimethylformamide (0.5 ml) was stirred at room temperature in the presence of powdered potassium carbonate (160 mg). After 17 hours, the reaction mixture was diluted with ethyl acetate (30 ml) and then washed successively with water and brine, and dried over magnesium sulfate. After evaporation of the solvent in vacuo, the resulting residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and methanol (10:1) as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)-4-(4-morpholino-2-butynyl)piperazine. The product obtained was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)-4-(4-morpholino-2-butynyl)piperazine dihydrochloride (155 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[C:36]([CH3:40])=[CH:35][C:34]=1[S:41](Cl)(=[O:43])=[O:42]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:41]([C:34]4[CH:35]=[C:36]([CH3:40])[C:37]([Cl:39])=[CH:38][C:33]=4[Cl:32])(=[O:43])=[O:42])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: Cc1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cc(C)c(Cl)cc4Cl)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2,4-dichloro-5-methyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=644.6)=82%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.[CH3:29][N:30]([CH3:36])[CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1>C(OCC)(=O)C.CO>[CH3:29][N:30]([CH3:36])[CH:31]1[CH2:35][CH2:34][N:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]3[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:32]1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Reactant: CN(C)C1CCNC1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(N3CCC(N(C)C)C3)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 47 %

Procedure:
The title compound was prepared from 1-[6-Bromo-4-(4-methanesulfonyl-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 23] and 3-(dimethylamino)pyrrolidine according to the procedure of example 25, except that the reaction time was of 16 h and that ethyl acetate/methanol (9:1) was used. Yield: 47%; MS: m/z=506 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:42])[C:25]1[CH:30]=[C:29]([N:31]([CH2:33][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH3:32])[CH:28]=[CH:27][C:26]=1[N+:39]([O-])=O>[Pd].CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:42])[C:25]1[CH:30]=[C:29]([N:31]([CH2:33][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH3:32])[CH:28]=[CH:27][C:26]=1[NH2:39]
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cc(N(C)CCCN(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cc(N(C)CCCN(C)C)ccc1N
Yield: 71.9 %

Procedure:
A mixture of N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-5-[N-(3-dimethylaminopropyl)-N-methylamino]-2-nitrobenzamide (0.22 g), 10% palladium-on-carbon (0.02 g) and methanol (15 ml) was stirred under an atmosphere of hydrogen gas. After cessation of hydrogen uptake, the catalyst was removed by filtration through diatomaceous earth and the filtrate was evaporated. There was thus obtained the title compound (0.15 g); Mass Spectrum M+H+ 546.
Reaction SMILES: C(OC([CH2:8][NH:9][CH:10]([CH2:14][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)[C:11]([OH:13])=O)=O)(C)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[Cl:42][C:43]([Cl:59])([Cl:58])[CH2:44][O:45][C:46](=[O:57])[NH:47][CH2:48][CH2:49][CH2:50][CH2:51][C@H:52]([NH2:56])[C:53](=[O:55])[NH2:54]>C(Cl)Cl>[Cl:42][C:43]([Cl:58])([Cl:59])[CH2:44][O:45][C:46](=[O:57])[NH:47][CH2:48][CH2:49][CH2:50][CH2:51][C@@H:52]([C:53](=[O:55])[NH2:54])[NH:56][C:11](=[O:13])[C@H:10]([NH:9][CH3:8])[CH2:14][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)CNC(Cc1cccs1)C(=O)O
Reactant: NC(=O)[C@@H](N)CCCCNC(=O)OCC(Cl)(Cl)Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN[C@H](Cc1cccs1)C(=O)N[C@@H](CCCCNC(=O)OCC(Cl)(Cl)Cl)C(N)=O
Reaction time: 8 h
Yield: 64.4 %

Procedure:
2-(tert-Butoxycarbonylmethylamino)-3-(2-thienyl)propionic acid (10.07 g; 35 mmole), HOBt (5.72 g; 42 mmole) and EDAC (7.09 g; 37 mmole) were added to methylene chloride (200 ml) and stirred for 15 min. ((5S)-5-amino-5-carbamoylpentyl)carbamic acid 2,2,2-trichloroethyl ester hydrochloride (12.61 g; 35 mmole) was added and the mixture was stirred overnight. Methylene chloride (200 ml) was added and the organic phase was washed with water (200 ml), an aqueous solution of sodium hydrogensulphate (200 ml), an aqueous solution of sodium hydrogencarbonate (200 ml) and water (200 ml). The organic phase was dried (magnesium sulphate) and the solvent was removed in vacuo. The residue was dissolved in a solution of hydrogen chloride in ethyl acetate (3 M; 100 ml) and stirred for 30 min. Diethyl ether and water (500 ml) was added, the phases were separated and the acidic aqueous phase was treated with a solution of sodium carbonate to pH 10. The aqueous phase was extracted with methylene chloride (4×700 ml) and the phases were separated. The organic phase was dried (magnesium sulphate) and the solvent was removed in vacuo to afford 11.0 g of [(5S)-5-carbamoyl-5-((2R)-2-methylamino-3-(2-thienyl)-propionylamino)-pentyl]-carbamic acid 2,2,2-trichloroethyl ester.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:12][O:13][CH3:14])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:15][S:16](O)(=[O:18])=[O:17]>C(Cl)(Cl)Cl>[CH3:1][O:2][CH2:3][CH:4]([CH2:12][O:13][CH3:14])[O:5][C:6]1[CH:11]=[CH:10][C:9]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:8][CH:7]=1
Reactant: COCC(COC)Oc1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: COCC(COC)Oc1ccc(S(=O)(=O)Cl)cc1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
(2-Methoxy-1-methoxymethyl-ethoxy)-benzene (1.0 g) was dissolved in 10 mL of chloroform and the solution was cooled to −30° C. Chlorosulfonic acid (1 ml) was added dropwise while maintaining the temperature of the mixture below −20° C. Stirring was continued in succession for one hour at −20° C., for one hour at 5oC and for 30 minutes at room temperature. The mixture was poured on ice, the organic layer washed with cold water, dried (sodium sulfate) and concentrated yielding 0.8 g of 4-(2-methoxy-1-methoxymethyl-ethoxy)-benzenesulfonyl chloride as an oil. EI-MS: 294 (M+).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=[O:22])=[CH:17][CH:16]=2)=[N:13][NH:12][C:11]=1[NH2:24]>CN(C=O)C.C(O)C.[Cl-].[NH4+].[Zn]>[NH2:24][C:11]1[NH:12][N:13]=[C:14]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][OH:22])=[CH:17][CH:16]=2)[C:10]=1[C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: Nc1[nH]nc(-c2ccc([N+](=O)[O-])cc2)c1-c1nc2ccccc2s1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1[nH]nc(-c2ccc(NO)cc2)c1-c1nc2ccccc2s1
Yield: 3.3 %

Procedure:
To a solution of 4-benzothiazol-2-yl-5-(4-nitrophenyl)-2H-pyrazol-3-ylamine (218 mg, 0.65 mmol) in DMF (4 mL) and 95% ethanol (4 mL) at room temperature was added under rapid stirring a suspension of zinc powder (200 mg) in aqueous ammonium chloride (0.15 g in 2 mL of water). The resulting mixture was then stirred for 2 hrs. The residual zinc was removed by filtration and the mother liquor was poured into water (100 mL). A yellow solid was removed by filtration. The aqueous phase was extract with ethyl acetate (2×75 mL). The combined extracts were washed with water, brine, dried over anhydrous sodium sulfate, filtered and evaporated. The resulting crude material was purified by preparative TLC eluting with 10:1 CH2Cl2:MeOH=10:1 to yield 7 mg (4%) of the title compound as cream coloured solid. MS (m/z, ES+): 324.1 (M+1, 100%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[CH2:11][CH2:12][CH3:13].Br.[C:15](O)(=[O:17])[CH3:16]>O>[CH2:11]([C:4]1[C:5]([OH:9])=[C:6]([C:15](=[O:17])[CH3:16])[CH:7]=[CH:8][C:3]=1[OH:2])[CH2:12][CH3:13]
Reactant: CC(=O)O
Reactant: CCCc1c(OC)cccc1OC
Agent: Br
Solvent: O
Product: CCCc1c(O)ccc(C(C)=O)c1O
Temperature: 25 °C
Yield: 41 %

Procedure:
1,3-Dimethoxy-2-(n-propyl)benzene (0.90 g, 5.0 mmol), 48% aqueous hydrobromic acid (30 ml, 265 mmol), and glacial acetic acid (150 ml) were combined and stirred at reflux temperature for 72 hours. The reaction mixture was cooled to room temperature then added to water (250 ml). The aqueous mixture was extracted with ether (500 ml, 2×). The organic phases were combined, washed with brine (100 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was flash chromatographed over Kieselgel 60 (230-400 mesh, 4 cm diameter×16 cm length) eluted with 1% ethyl acetate in hexane, followed by a step gradient (2%, 3%, 4%) of ethyl acetate in hexane to give 0.4 g, 41% of the title product.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5](=[O:9])[N:6](C)[CH:7]=1.BrC1C(=O)[NH:15]C(=O)NC=1>>[Br:1][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:7])[N:15]=1
Reactant: O=c1[nH]cc(Br)c(=O)[nH]1
Reactant: Cn1cc(Br)c(=O)n(C)c1=O
Product: Cn1nc(Br)c(=O)n(C)c1=O
Yield: 82 %

Procedure:
Synthesis of the intermediate 1c is achieved from 5-bromo-1H-pyrimidine-2,4-dione according to the operating procedure described for the synthesis of 1b (solid, yield 82%).
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:12][CH2:21][C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: O=Cc1cccnc1
Product: c1ccc(Oc2ccc(NCc3cccnc3)cc2)cc1

Procedure:
Using the method of Example 343 using 4-phenoxyaniline (Aldrich) and 3-pyridinecarboxaldehyde (Aldrich) and purifying via preparative HPLC eluting with 95:5 to 60:40 DCM/ethyl acetate gave N-(4-phenoxypheny)pyridin-3-ylmethylamine. Anal Calcd for C18H16N2O: C, 78.24; H, 5.84; N, 10.14. Found: C, 78.19; H, 5.67; N, 10.03. 1H NMR (400 MHz, DMSO) 4.00 (1H, bt), 4.35 (2H, d, J=5.1 Hz), 6.62 (2H, m), 6.89-6.93 (4H, m), 6.99-7.03 (1H, m), 7.25-7.30 (3H, m), 7.71 (1H, m), 8.54 (1H, dd, J=1.8, 4.8 Hz), 8.64 (1H, d, J=1.8 Hz) MS found 277.0 [M+H]+
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8][CH2:7][C:6]=2[O:5][C:4](=[O:16])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30]Cl)[CH2:25][CH2:24]1>>[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][O:1][C:2]2[C:11]3[CH2:10][CH:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8][CH2:7][C:6]=3[O:5][C:4](=[O:16])[C:3]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:25][CH2:24]1
Reactant: CC(C)(C)C1CCc2oc(=O)c(-c3ccccc3)c(O)c2C1
Reactant: ClCCN1CCOCC1
Product: CC(C)(C)C1CCc2oc(=O)c(-c3ccccc3)c(OCCN3CCOCC3)c2C1
Yield: 84.6 %

Procedure:
Obtained according to Example 14, Stage B, by treating 14.2 g. (0.05 mol) of 4-hydroxy-3-phenyl-6-tert.butyl-5,6,7,8-tetrahydro-coumarin with 9.7 g. (0.065 mol) of 2-morpholino-1-chlorethane. After evaporation of the chloroform, 17 g. of an oil are obtained, which cannot be crystallised. Yield 84.6% (theoretical yield 20.35 g.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15][C:14]([CH3:17])([CH3:16])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32](OC(=O)C(F)(F)F)=[CH:31][CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[Cl-].C([Sn](CCCC)(CCCC)[C:56]1[CH:61]=[CH:60][N:59]=[CH:58][CH:57]=1)CCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15][C:14]([CH3:16])([CH3:17])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:56]2[CH:57]=[CH:58][N:59]=[CH:60][CH:61]=2)=[CH:33][CH:34]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1Cc1ccc(OC(=O)C(F)(F)F)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1Cc1ccc(-c2ccncc2)cc1
Temperature: 100 °C
Yield: 48.6 %

Procedure:
A solution containing the product from Example 23I (0.64 g, 0.906 mmol) in DMF (10 mL) was treated with LiCl (0.384 g, 9.06 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.19 g, 0.271 mmol), and 4(tri-n-butylstannyl)pyridine (1.0 g, 2.72 mmol), heated at 100° C. for 16 hours, cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-25% ethyl acetate in dichloromethane to give the title compound (0.28 g, 49% yield).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13](=O)[CH3:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O1CCOCC1.[C:22]([NH2:26])(=[O:25])[CH:23]=[CH2:24].CC(C)([O-])C.[K+]>O>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH2:24][CH2:23][C:22](=[O:25])[NH:26][C:13]=3[CH3:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C=CC(N)=O
Reactant: CC(=O)Cc1ccc(-n2ccnc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC1=C(c2ccc(-n3ccnc3)cc2)CCC(=O)N1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 3 g 1-[4-(1-imidazolyl)-phenyl]-2-propanone (EPA 102 227, example 4), 30 ml 1,4-dioxane, 1,2 g acrylic acid amide and 1.73 g potassium tert-butoxide is stirred for 40 minutes at room temperature and subsequently for 2 hours at 100° C. After cooling it, water is added, the precipitated solid is sucked off, washed with water, dried and purified by column chromatography (silica gel/dichloromethan/methanol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:19]=[CH:18][C:10]=1[O:11][CH2:12][C:13](OCC)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[OH2:8].[CH2:1]([O:8][C:9]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:19]=[CH:18][C:10]=1[O:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([O:8][C:9]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:19]=[CH:18][C:10]=1[O:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)COc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCOc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
Ethyl (2,4-dibenzyloxyphenoxy)acetate (3.9 g) is added in small portions to a stirred suspension of lithium aluminium hydride (0.21 g) in dry tetrahydofuran (100 mL) with ice-cooling. The mixture is allowed to warm to room temperature and stirred for a further 30 minutes. The reaction mixture is cooled in an ice-bath and water is added dropwise. After stirring for 1 hour the mixture is filtered through hyflo and the insolubles washed with tetrahydrofuran. Evaporation of the combined filtrate plus washings and crystallisation of the resulting solid from petroleum ether (bp 40-60° C.) containing a little ethyl acetate gives 2-(2,4-dibenzyloxy-phenoxy)ethanol hemihydrate (1.8 g) as a white solid, m.p. 47-52° C. [Elemental analysis:- C,73.3; H,6.25%. Calculated for C22H22O4.0.5H2O:- C,73.5; H,6.45%].
Reaction SMILES: [H][H].[O:3]=[C:4]([C:10]1[C:14]2[CH:15]=[CH:16][C:17]([N+:19]([O-])=O)=[CH:18][C:13]=2[S:12][CH:11]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]>[Pd].C(O)C.O1CCCC1>[O:3]=[C:4]([C:10]1[C:14]2[CH:15]=[CH:16][C:17]([NH2:19])=[CH:18][C:13]=2[S:12][CH:11]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: [H][H]
Reactant: CCOC(=O)C(=O)c1csc2cc([N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(=O)c1csc2cc(N)ccc12

Procedure:
To a stirred suspension of 1.1 g of 5% palladium on carbon in 100 ml of ethanol under 60 psi of hydrogen was added in one portion a solution of 1.1 g of ethyl α-oxo-α-(6-nitro-3-benzothienyl)acetate in 25 ml of tetrahydrofuran. The reaction mixture was stirred at 25° C. under 60 psi of hydrogen for forty-five minutes, and then the mixture was filtered and the solvent was evaporated from the filtrate to give ethyl α-oxo-α-(6-amino-3-benzothienyl)acetate. Reaction with methoxylamine and subsequent hydrolysis and hydrogenation provides (6-amino-3-benzothienyl)glycine.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:10]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH2:26](O)[CH3:27].C1(C)C=CC=CC=1.S(=O)(=O)(O)O>O>[CH2:26]([O:2][C:1]([C:4]1[O:8][C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:10]=2)=[CH:6][CH:5]=1)=[O:3])[CH3:27]
Reactant: CCO
Reactant: O=C(O)c1ccc(-c2nn(CCc3ccccc3)c3ccccc23)o1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2nn(CCc3ccccc3)c3ccccc23)o1
Reaction time: 3 h
Yield: 46 %

Procedure:
0.8 g (2.4 mmol) of 3-(5-carboxy-2-furyl)-1-(2-phenylethyl)indazole were admixed with 25 ml of ethanol, 150 ml of toluene and 2 ml of conc. sulfuric acid and heated on a water separator for 3 h. Silica gel chromatography using dichloromethanelhexane (2:1) of the residue that was obtained after concentration using a rotary evaporator gave 400 mg (46%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])=[CH:4][C:5]2[O:9]C(C3C=CC=CC=3)(C3C=CC=CC=3)[O:7][C:6]=2[CH:22]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:22]=[C:6]([OH:7])[C:5]([OH:9])=[CH:4][C:3]=1[C:23]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:24]
Reactant: O=C(c1cc2c(cc1F)OC(c1ccccc1)(c1ccccc1)O2)N1CCOCC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc(O)c(O)cc1F)N1CCOCC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 94.1 %

Procedure:
To a cooled (ice-bath) solution of (6-fluoro-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone (5.70 g, 14.06 mMol) in trifluoroacetic acid (60 ml) was added triethylsilane (2.1 eq, 4.7 ml) over 10 min. The mixture was stirred 20 min at 0° C. and 4 h at room temperature. The volatiles were removed under reduced pressure and the residue purified by column chromatography on silica gel (2:1 ethyl acetate/heptane-ethyl acetate—10:1 ethyl acetate/methanol) to afford (2-fluoro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone as liht brown solid (3.19 g, 94%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][C:11](=[O:20])[CH:12](Br)[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH3:9]>[Na].CN(C=O)C>[CH2:8]([O:10][C:11](=[O:20])[CH:12]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[O:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[CH3:9]
Reactant: Oc1ccncc1
Reactant: CCOC(=O)C(Br)c1cccnc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1ccncc1)c1cccnc1
Yield: 8 %

Procedure:
The product was formed in a manner similar to preparation 396 using the in situ-generated sodium salt of the 4-hydroxypyridine (2.13 g; 18.2 mmol; 1.2 equiv) and an aliquot of bromo-pyridin-3-yl-acetic acid ethyl ester (approx. 3.6 g; 15 mmol) in DMF (20 mL). Column chromatographic purification over SiO2 (1% methanol/chloroform) produced a yellow/orange oil (320 mg; approx. 8% yield). MS(ES) calc'd: [M+H]+=259.2 m/z. Pound: 259.1 m/z.