Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:25]=[C:26]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:27]=[C:28]([CH3:30])[CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:7]1[N:8]=[C:3]([CH2:2][O:23][C:24]2[CH:25]=[C:26]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:27]=[C:28]([CH3:30])[CH:29]=2)[CH:4]=[CH:5][C:6]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22]
Reactant: COc1ccc(F)c(-c2ccc(CCl)nc2CC(C)(C)C)c1
Reactant: CCOC(=O)CCc1cc(C)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)CCc1cc(C)cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Yield: 81.5 %

Procedure:
To a solution of 6-(chloromethyl)-2-(2,2-dimethylpropyl)-3-(2-fluoro-5-methoxyphenyl)pyridine (320 mg) in acetonitrile (10 mL) were added ethyl 3-(3-hydroxy-5-methylphenyl)propanoate (260 mg) and cesium carbonate (546 mg), and the mixture was heated under reflux for 15 hr. The reaction mixture was concentrated, and water was added to the residue. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (400 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:19])[C:3]=1[NH2:4].[CH:20](O)=[O:21]>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:19])[C:3]=1[NH:4][CH:20]=[O:21]
Reactant: O=CO
Reactant: Nc1c(Cl)cccc1Sc1c(Cl)cccc1[N+](=O)[O-]
Product: O=CNc1c(Cl)cccc1Sc1c(Cl)cccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 2-chloro-6-(2-chloro-6-nitrophenylthio)aniline (689 mg, 2.18 mmol) in formic acid (5 mL) was heated at reflux for 16 hours. The mixture was allowed to cool to room temperature and the solvent was evaporated. The residue was used without purification.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]([CH3:12])[C:8]([NH:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:12])[C:8]([NH:10][CH3:11])=[O:9])=[CH:13][CH:14]=1
Reactant: CNC(=O)C(C)Oc1ccc(O)cc1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CNC(=O)C(C)Oc1ccc(OCc2cccc(F)c2)cc1

Procedure:
In analogy to the procedure described in Example 3b), the alkylation of (RS)-2-(4-hydroxy-phenoxy)-N-methyl-propionamide with 3-fluoro-benzylbromide in 2-butanone using potassium carbonate as the base yielded the (RS)-2-[4-(3-fluoro-benzyloxy)-phenoxy]-N-methyl-propionamide as a white solid; MS: m/e=304 (M+H)+
Reaction SMILES: N.[K].[CH2:3]([O:5][CH:6]([O:15][CH2:16][CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[CH3:4].[CH2:18]1[O:20][CH2:19]1.[Cl-].[NH4+]>C(OCC)C>[CH2:16]([O:15][CH:6]([O:5][CH2:3][CH3:4])[CH2:7][CH:8]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[CH2:18][CH2:19][OH:20])[CH3:17]
Reactant: C1CO1
Reactant: CCOC(CCc1ccncc1)OCC
Agent: N
Agent: [Cl-]
Agent: [K]
Solvent: CCOCC
Product: CCOC(CC(CCO)c1ccncc1)OCC
Reaction time: 2 h
Yield: 70 %

Procedure:
To stirred liquid ammonia (2 liters) was added ferric nitrate (0.1 gm) followed by potassium metal (14 gms) in 1 gram pieces over a period of 20 minutes. To the resulting solution 3-(4-pyridyl)-propionaldehyde diethyl acetal (21 gms) was added over a period of 3 minutes and a deep yellow colour was allowed to develop over a period of 2 hours. Liquid ethylene oxide (25 mls) was then added and the mixture was stirred for a further 3 hours. Solid ammonium chloride (20 gms) was added in small portions followed by diethyl ether (1 liter). The ammonia was allowed to evaporate overnight and the residual mixture was filtered. The solvent was evaporated from the filtrate and the residual oil was distilled to give 1,1-diethoxy-3-(4-pyridyl)-pentan-5-ol (18 gms, 70% conversion) b.p. 170°-175° C/1 mm Hg, as a thick colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([O:38][CH3:39])[C:35]=1[O:36][CH3:37])[C:30](Cl)=[O:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH2:13][N:12]([C:30](=[O:31])[C:29]3[CH:28]=[C:27]([O:26][CH3:25])[C:35]([O:36][CH3:37])=[C:34]([O:38][CH3:39])[CH:33]=3)[C:11](=[O:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CC(CCCOC2CCCCO2)(c2ccc(Cl)c(Cl)c2)CN1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Product: COc1cc(C(=O)N2CC(CCCOC3CCCCO3)(c3ccc(Cl)c(Cl)c3)CC2=O)cc(OC)c1OC

Procedure:
Prepare according to the procedure of example 59.1 using 4-(3,4-dichloro-phenyl)-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-pyrrolidin-2-one (5.0 mmol) and 3,4,5-trimethoxy-benzoyl chloride (5.0 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: C([NH:4][C:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1C(=O)C2=CC=CC=C2C1=O)(C(OCC)=O)[C:6]([O:8]CC)=[O:7])(=O)C.[ClH:32]>>[ClH:32].[NH2:4][CH:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(CCCCCN1C(=O)c2ccccc2C1=O)(NC(C)=O)C(=O)OCC
Agent: Cl
Product: NCCCCCC(N)C(=O)O

Procedure:
A mixture of 14.63 g (0.34 mole) the compound 5 and 6N HCl (200 ml) was heated at reflux for five hours then cooled to precipitate the phthalic acid which was removed by filtration. The filtrate was concentrated in vacuo to remove the excess HCl, and the residue was precipitated from absolute ethanol in acetone, as an oil. The oil was dissolved in 40 ml water and charged to the top of a strong acid cation exchange column, Bio Rad AG50W-X8 (3.75 cm W×48 cm L). Following a water wash of two column volumes an ammonium hydroxide gradient (0.3-0.5N) was used to elute the product. Concentration of the column effluent, pH adjustment to pH 5.8 and crystallization from water/ethanol afforded the monohydrochloride of DL-homolysine 7. Yield: 10.2 g (94%). Mp 263° C. (lit. mp 264° C. for monohydrochloride, lit mp 176° C. for monohydrochloride monohydrate). TLC: Rf =0.11 (C), 0.30 (D). MW calc 160.12, found 160. Anal. calc. for C7H16N2O2.HCl: C, 42.74; H, 8.20; N, 14.24; Cl, 18.02. Found: C, 42.90; H, 8.65; N, 14.17; Cl, 18.35. HPLC 96%. 1H NMR (D2O) 1.45 (4H, m), 1.70 (2H, m), 1.88 (2H, m), 3.00 (2H, m), 3.75 (1H, t, 7 Hz). Spinco analysis: single peak with elution time equivalent to ammonia.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[NH2:24][C:25]1[CH:34]=[CH:33][C:28]([NH:29][C:30](=[O:32])[CH3:31])=[CH:27][CH:26]=1>>[C:30]([NH:29][C:28]1[CH:33]=[CH:34][C:25]([NH:24][C:1]([C:4]23[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]2)[CH2:6][CH2:5]3)=[O:2])=[CH:26][CH:27]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: CC(=O)Nc1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 16.9 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4′-aminoacetanilide (51.0 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(4-acetamidophenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (11.9 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:20])=[C:4]([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16](Br)[CH:17]=3)[NH:12][CH:11]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:21][N:22](C)C(=O)C>[Zn].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[NH2:1][C:2]1[C:3]([F:20])=[C:4]([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:21]#[N:22])[CH:17]=3)[NH:12][CH:11]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: N#Cc1cnc2[nH]cc(C(=O)c3cccc(N)c3F)c2c1
Temperature: 120 °C
Yield: 67.7 %

Procedure:
To (3-amino-2-fluoro-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (22, 1.080 g, 3.232 mmol) in a vial, N,N-dimethylacetamide (2.90 mL, 31.2 mmol) was added. The suspension was degassed by bubbling with argon and zinc powder (0.032 g, 0.48 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.0568 g, 0.102 mmol), zinc cyanide (0.223 g, 1.90 mmol), and tris(dibenzylideneacetone)dipalladium (0) (0.053 g, 0.052 mmol) were added at room temperature under argon. The mixture was heated to 120° C., resulting in most of the solid dissolving, and the mixture was heated at 120° C. for 2 hours, then cooled to 100° C. and 8 mL of water was added and the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate and saturated sodium chloride in water. The organic layer was washed with water and brine, then dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The residue was suspended in acetonitrile and sonicated for 30 minutes, after which the precipitated material was collected by filtration to provide the desired compound as a tan solid (23, 613 mg). Additional material was recovered from the filtrate by silica gel chromatography eluting with ethyl acetate and hexanes, the appropriate fractions were combined and the solvent removed to provide an additional 42 mg. MS (ESI) [M+H+]+=280.9.
Reaction SMILES: Br.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)[S:14][CH:15]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3].[C:28](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CN(C)C=O>[CH3:28][N:16]([C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1)[C:13]1[S:14][CH:15]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=2)[N:12]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccc(Nc2nc(-c3ccc([N+](=O)[O-])cc3)cs2)cc1
Agent: Br
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)c1ccc(N(C)c2nc(-c3ccc([N+](=O)[O-])cc3)cs2)cc1
Yield: 99.5 %

Procedure:
Under a nitrogen stream, N,N-dimethylformamide (1.05 L, 7.0 v/w) was added to ethyl 4-((4-(4-nitrophenyl)-2-thiazolyl)amino)benzoate hydrobromide (150 g, 0.333 mol) obtained in Example 3(1). With stirring under ice-cooling, potassium carbonate (138 g, 0.999 mol) was added carefully. After stirring at room temperature for 20 min., dimethyl sulfate (63.2 ml, 0.666 mol) was added. After stirring at 60° C. for 2 hr., distilled water (1.05 L, 7.0 v/w) was added with stirring under ice-cooling. After stirring under ice-cooling for 1 hr., the resulting crystal were collected by filtration, washed with distilled water (450 mL) and dried in vacuo to give the title compound (127 g, yield 99.3%) as an orange crystal.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([CH:34]([CH3:38])[CH2:35][CH2:36][OH:37])[CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1.Cl>[CH2:27]([O:26][C:24]1[CH:23]=[C:22]([CH:34]([CH3:38])[CH2:35][CH2:36][O:37][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])[CH:21]=[C:20]([O:19][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:25]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(CCO)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC(C)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)cc1
Reaction time: 18 h

Procedure:
Tosyl chloride (11.1 g., 58.1 mM) is added to a solution of 3-(3,5-dibenzyloxyphenyl)-1-butanol (20.7 g., 57 mM) in pyridine (90 ml.) at -45° C. The reaction mixture is held at -35° C. for 18 hours and is then diluted with cold 2 N hydrochloric acid (1500 ml.) and extracted with ether (5×250 ml.). The combined extracts are washed with saturated sodium chloride solution (4×250 ml.) and then dried (Na2SO4). Concentration of the dried extract affords the product as an oil. It is crystallized by treatment with ether-hexane. Yield: 24.63 g. (84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C@@H:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)[N:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:7]=2[CH:22]=1.[C:23]([O:27][C:28]([NH:30][C@H:31]([CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=1)[CH2:32][C:33](O)=[O:34])=[O:29])([CH3:26])([CH3:25])[CH3:24].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C@@H:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:33](=[O:34])[CH2:32][C@H:31]([NH:30][C:28](=[O:29])[O:27][C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:36][C:37]4[CH:46]=[CH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[CH:38]=4)[CH2:12]3)[N:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:7]=2[CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc2ccccc2c1
Reactant: COCCCn1c([C@@H]2CCCNC2)nc2ccc(OC)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 22.3 %

Procedure:
(R)-6-Methoxy-1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole (41E) (2.82 mmol, 0.86 g) in DMF (16 mL) was added (R)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoic acid (3.10 mmol, 1.02 g) and N-methylmorpholine (11.28 mmol, 1.24 mL). The reaction mixture was stirred at rt for 5 min and then added HATU (3.10 mmol, 1.18 g) and kept stirring at rt overnight. The reaction mixture was poured into H2O, extracted with EtOAc. The extract was washed with H2O, NaHCO3, brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and purified by preparative LC/MS (40-90% CH3CN in H2O) to afford tert-butyl (R)-4-((R)-3-(6-methoxy-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (42F) (0.63 mmol, 0.387 g, three-step yield: 22.3%). ESI-MS: m/z 616.5 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1Br)=[O:9])([CH3:6])[CH3:5]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:6])([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:16]#[C:15][CH2:14][CH2:13][C:12]1[CH:17]=[CH:18][CH:19]=[CH:10][CH:11]=1)=[O:9])[CH3:5]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1Br
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1C#CCCc1ccccc1
Temperature: 130 °C
Yield: 109.6 %

Procedure:
40 mg 2-[(1-bromo-naphthalene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester and 0.8 mg bis(triphenylphosphine)palladium(II)chloride were placed in a reaction vial, which was evaporated and backfilled with argon three times. Via septum 18 mg of 4-phenyl-1-butyne, 180 μl diethylamine and 0.2 ml abs. DMF were added. In a microwave reactor the reaction was heated to 130° C. for 5 min. Then, water and ethyl acetate were added, the layers were separated, and the aqueous phase was extracted with ethyl acetate twice. The combined organic layers were dried over magnesium sulphate and concentrated. The resulting residue was purified by chromatography on silica (ethyl acetate/heptane) to yield 25 mg of 2-methyl-2-{[1-(4-phenyl-but-1-ynyl)-naphthalene-2-carbonyl]-amino}-propionic acid methyl ester.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH2:18])[CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.[CH3:19][S:20]C1C=C(B(O)O)C=CC=1>>[CH3:19][S:20][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH2:18])[CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc2cccnc2c(-c2cccc(F)c2)n1
Reactant: CSc1cccc(B(O)O)c1
Product: CSc1cccc(-c2nc(N)cc3cccnc23)c1

Procedure:
8-(3-Methylsulfanyl-phenyl)-[1,7]naphthyridin-6-ylamine is prepared in an analogous manner to compound D (see Example 22) using 3-methylthiophenyl boronic acid to yield the product, MS (ES+) 268.04
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[N:22][CH:23]=1>CN(C)C=O>[N+:24]([C:21]1[N:22]=[CH:23][C:18]([O:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: NC(=O)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc([N+](=O)[O-])nc2)cc1
Yield: 38.6 %

Procedure:
4-hydroxybenzamide (150 mg, 1.1 mmol) and caesium carbonate (394 mg, 1.21 mmol) was dissolved in dimethylformamide (7 ml). 5-bromo-2-nitropyridine (244 mg, 1.21 mmol) was then added. The mixture was left at 50 degrees until the starting material was consumed according to TLC (1% methanol in ether). Purification by flash chromatography yielded 4-[(6-nitro-3-pyridinyl)oxy]benzamide (110 mg, 38%)
Reaction SMILES: FC(F)(F)C(O)=O.[BH3-]C#N.[Na+].[CH2:12]([O:14][C:15]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH3:13]>O>[CH2:12]([O:14][C:15]([CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1Cc2ccccc2N1
Yield: 89.8 %

Procedure:
To cooled trifluoroacetic acid (40 mL) at 0° C., NaCNBH3 (1.57 g, 25 mmol) was added portionwise with stirring. The reaction mixture was stirred for 15 min, and to which indole-2-carboxylic acid ethyl ester (1.2 g, 6.35 mmol) was added slowly, then the mixture was stirred at rt for an hour. After the completion of the reaction, water (150 mL) was added to the mixture, and which was stirred for 5 hr. The reaction was extracted by CH2Cl2 (40 mL×3), then organic layer was washed with saturated aqueous solution of NaHCO3 (40 mL×2) and water (40 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1) to give the desired compound (1.09 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([OH:13])([CH3:12])[CH3:11])[C:5]([C:14]([OH:16])=O)=[CH:4][N:3]=1.C(N(CC)CC)C.N1C(F)=NC(F)=NC=1[F:26]>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([OH:13])([CH3:12])[CH3:11])[C:5]([C:14]([F:26])=[O:16])=[CH:4][N:3]=1
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)(O)CNc1nc(Cl)ncc1C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(O)CNc1nc(Cl)ncc1C(=O)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a solution containing 12.64 g (51.45 mmol) of the acid prepared in step 17.1 and 7.89 mL (56.60 mmol) of triethylamine in 250 mL of dichloromethane are added 6.51 mL (77.18 mmol) of cyanuric fluoride. The mixture is stirred at room temperature overnight and the solution is diluted with 590 mL of CH2Cl2 and 190 mL of ice-cold aqueous NaHCO3. The organic phase is washed twice with 250 mL of ice-cold aqueous NaHCO3 and dried over MgSO4. The solvent is then evaporated off under reduced pressure. 12.3 g of the expected product are obtained in the form of a yellow oil that solidifies slowly, and which is used as obtained in the following step. Yield=96%.
Reaction SMILES: [C:1]([C:13]1[CH:14]=[C:15]([CH2:18][CH:19]([NH:22]C(=O)C)[CH2:20][OH:21])[S:16][CH:17]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(O)C>[NH2:22][CH:19]([CH2:18][C:15]1[S:16][CH:17]=[C:13]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:14]=1)[CH2:20][OH:21]
Reactant: CCCCCCCCCCC#Cc1csc(CC(CO)NC(C)=O)c1
Solvent: CCO
Product: CCCCCCCCCCC#Cc1csc(CC(N)CO)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
To a solution of N-[1-[4-(1-dodecynyl)-2-thienyl]-3-hydroxy-2-propyl]acetamide (4.6 g) in 95% ethanol (30 ml) was added degassed 2N sodium hydroxide solution. The reaction mixture was stirred at 65° C. overnight. The solution was diluted with saturated ammonium chloride solution and extracted with ethyl acetate. The organic extracts were evaporated, and the residue was flashed chromatographed on silica gel (9:1 dichloromethane:methanol). The appropriate fractions were collected and evaporated. The residue was taken up in ether, an ethereal hydrogen chloride was added, and the mixture was stirred at room temperature for 30 mins. The precipitate was collected and air-dried to give 2.05 g (45.4%) of product, mp 85°-135° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[N:17]=[C:16](Cl)[CH:15]=[C:14]([CH3:19])[N:13]=1.[Cl-].[NH4+]>CN(C=O)C>[CH2:3]([O:10][C:12]1[N:17]=[C:16]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:15]=[C:14]([CH3:19])[N:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: OCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)nc(OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
To a solution of sodium hydride (3.2 g, 80 mmol) in DMF (20 ml) was added under ice-cooling benzylalcohol (8.6 g, 80 mmol). To the solution was added 2,4-dichloro-6-methylpyrimidine (3.2 g, 20 mmol). The mixture was stirred at room temperature for 1 hour. To the reaction mixture was added an aqueous solution of ammonium chloride. The mixture was extracted with diethyl ether, washed with water, dried and concentrated. The obtained residue was chromatographed on silica gel (n-hexane-ethyl acetate). The obtained fraction was concentrated under reduced pressure to give 2,4-bisbenzyloxy-6-methylpyrimidine (3.5 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:8]=[CH:7]2)([O-])=O>CO.[Ni]>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([N:9]2[C:10]3[C:6](=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=3)[CH:7]=[CH:8]2)[CH:14]=1
Reactant: O=[N+]([O-])c1ccc2c(ccn2-c2cccnc2)c1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc2c(ccn2-c2cccnc2)c1
Yield: 98.2 %

Procedure:
A solution of compound 72 (350 mg, 1.46 mmol) in methanol (10 mL) was added to Raney Nickel (slurry in H2O, 50 mg) in a round bottom flask. The suspension was heated at reflux for 10 minutes then filtered through a pad of celite. The celite pad washed with methanol (20 mL). The filtrate was concentrated and the residue was subjected to silica gel chromatography (CH2Cl2 to MeOH:CH2Cl2, 5:95) to give compound 73 (300 mg, 98.4%) as a viscous oil. 1H NMR (DMSO-d6) δ 8.81 (d, J=2.6 Hz, 1H), 8.53-8.51 (m, 1H), 8.02-7.99 (m, 1H), 7.56-7.54 (m, 2H), 7.32 (d, J=8.7 Hz, 1H), 6.77 (d, J=1.9 Hz, 1H), 6.59 (dd, J=2.1, 6.7 Hz, 1H), 6.47 (d, J=3.4 Hz, 1H), 4.72 (brs, 2H); ESI-MS (m/z, %): 210 (M+1, 100%).