Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21](C)[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.[CH3:29]O.[BH4-].[Li+].Cl>O1CCCC1.O>[CH:20]1([NH:19][N:16]2[C:17](=[O:18])[C:12]([C:4]3[NH:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[S:2](=[O:1])(=[O:28])[N:3]=3)=[C:13]([OH:27])[C:14]3[S:26][CH:25]=[CH:24][C:15]2=3)[CH2:29][CH2:22][CH2:21]1
Reactant: CO
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1NC1CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.077 g, 0.21 mmol) in tetrahydrofuran (4 mL) and methanol (0.030 mL, 0.8 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.200 mL, 0.4 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to pH of approximately 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 1% methanol in chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.81 (m, 6 H) 3.85 (m, 1 H) 6.84 (s, 1 H) 7.49 (d, J=5.15 Hz, 1 H) 7.55 (t, J=7.91 Hz, 1 H) 7.62 (d, J=8.09 Hz, 1 H) 7.78 (t, J=7.91 Hz, 1 H) 7.93 (d, J=8.09 Hz, 1 H) 8.33 (d, J=5.15 Hz, 1 H) 14.21 (s, 1 H) 14.82 (s, 1 H). MS (ESI−) m/z 415 (M−H)−.
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].[H-].[Na+].[CH2:9](Br)[CH:10]=[CH2:11]>CN(C=O)C.CCOCC>[CH2:11]([O:6][C:2]([CH3:3])([CH3:1])[C:4]#[CH:5])[CH:10]=[CH2:9]
Reactant: C=CCBr
Reactant: C#CC(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C#CC(C)(C)OCC=C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
To stirred solution of 2-methylbut-3-yn-2-ol (7.33 ml, 75 mmol) in DMF (100 mL) was added 60% NaH (3.00 g, 75 mmol) at 0° C. After 30 min, the cold bath was removed stirred for 1 h at rt. To this was added allyl bromide (9.74 ml, 113 mmol) over 5 min and continued stirring for 16 h. Then, diluted with Et2O (250 mL), washed with water (5×50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated to give yellow liquid (5.64 g). HNMR of this indicated it is 2:1 mixture of product and unreacted alcohol. This was used without purification. 1H NMR (500 MHz, CDCl3) δ 5.93-6.02 (m, 1H), 5.32 (qd, J=1.7, 17.2 Hz, 1H), 5.18 (qd, J=1.5, 10.4 Hz, 1H), 4.13 (td, J=1.4, 5.6 Hz, 2H), 2.45 (s, 1H), 1.52 (s, 6H).
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.[CH3:31][C:32]1[C:36](B2OC(C)(C)C(C)(C)O2)=[C:35]([CH3:46])[NH:34][N:33]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.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>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:36]4[C:32]([CH3:31])=[N:33][NH:34][C:35]=4[CH3:46])=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2c(-c3c(C)n[nH]c3C)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 100 °C
Yield: 25 %

Procedure:
To a solution of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (Example 33) (140 mg, 0.267 mmol) in 1,4-dioxane (2 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (89 mg, 0.401 mmol), bis(triphenylphosphine)palladium(II) chloride (18.76 mg, 0.027 mmol) and potassium carbonate (111 mg, 0.802 mmol). Water (1 mL) was added and the mixture heated at 100° C. in a microwave for 15 min (×2). Another portion of bis(triphenylphosphine)palladium(II) chloride (18.76 mg, 0.027 mmol) was then added and the reaction mixture degassed with nitrogen for 5 min and then heated at 100° C. in a microwave for 15 min (×2). The solvent was then removed in vacuo and the residue dissolved in ethyl acetate (20 mL) and washed with water (20 mL). The aqueous phase was re-extracted with ethyl acetate (20 mL×2). All organic phases were combined, dried over MgSO4, filtered and concentrated. The residue was purified on silica, eluting with a gradient of 0-80% ethyl acetate in cyclohexane and then further purified using MDAP (acidic conditions), to give the title compound (36 mg). LCMS (A) m/z: 539 [M+1]+, Rt 1.47 min (acidic).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][NH:27][CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:31][CH2:32][OH:33].C(N(CC)CC)C.[ClH:41]>CC#N>[ClH:41].[ClH:41].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][N:27]([CH2:31][CH2:32][OH:33])[CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCI
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CNCC2
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(CCO)CC2
Yield: 27 %

Procedure:
4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (75 mg, 0.16 mmol), 2-iodoethanol (17 μL, 36 mg, 0.21 mmol) and triethylamine (105 μL, 0.82 mmol) were dissolved in MeCN (2 mL) and heated to reflux for 3 h. The mixture was then concentrated and purified by flash column chromatography (4 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 85% methylene chloride over 30 min) providing the free base. This was converted to the HCl salt (2 N HCl/Et2O) providing the title compound (22 mg, 27%) as a yellow solid: mp 162-168° C.; 1H NMR (500 MHz, CD3OD) δ 7.63 (dd, J=7.6, 2.0 Hz, 2H), 7.51-7.50 (m, 3H) 7.46-7.43 (m, 2H), 7.41-7.38 (m, 1H), 7.09 (dd, J=8.3, 1.7 Hz, 1H), 6.36 (dd, J=7.6, 2.7 Hz, 1H), 6.18 (d, J=2.7 Hz, 1H), 5.23 (s, 2H), 4.82 (d, 1H, partially masked by solvent), 4.520 (d, J=14.3 Hz, 1H), 4.06-4.02 (m, 3H), 3.77 (s, 3H), 3.70-3.68 (m, 1H), 3.55-3.51 (m, 2H), 3.33-3.31 (m, 2H, partially masked by solvent); ESI MS m/z 430 [M+H]+; HPLC (Method B) 95.1% (AUC), tR=12.4 min.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][OH:7].Br[C:9]1[C:10]([NH2:16])=[N:11][CH:12]=[C:13]([Br:15])[N:14]=1>C1COCC1>[Br:15][C:13]1[N:14]=[C:9]([O:7][CH2:6][CH2:5][O:4][CH3:3])[C:10]([NH2:16])=[N:11][CH:12]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1nc(Br)cnc1N
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A flame-dried round bottom flask was charged with a suspension of 95% NaH (1.3 eq) in anhydrous THF (0.2 M). The stirring mixture was cooled to 0° C. in an ice-water bath and 2-methoxyethanol (1.2 eq) was added drop wise via syringe. After 30 min 3,5-dibromopyrazin-2-amine (1 eq) was added, the reaction was warmed to rt and stirred for 3 h. The crude mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic phases were washed once each with H2O and brine, then dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 5-bromo-3-(2-methoxyethoxy)pyrazin-2-amine. LC/MS (m/z): 250.0 (MH+).
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11]([C:13]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:14]=2[O:15][C@@H:16]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)=[O:12])/[N:7]([CH2:36][C@H:37]2[CH2:41][CH2:40][CH2:39][O:38]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:12])[C:13]2[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:29]=[CH:28][C:14]=2[O:15][C@@H:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)/[N:7]([CH2:36][C@H:37]2[CH2:41][CH2:40][CH2:39][O:38]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(C(F)(F)F)cc2C(=O)/N=c2\sc(C(C)(C)C)cn2C[C@H]2CCCO2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2O[C@@H]2CCNC2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
To a solution of Example 384A (1.223 g, 2.046 mmol) in dichloromethane (5 mL) was added 2,2,2-trifluoroacetic acid (2.333 g, 20.46 mmol). The mixture was stirred at room temperature for 2 hr and then concentrated. The mixture was taken up in dichloromethane and washed with sodium bicarbonate. The organic layers were combined, dried and concentrated to give the title compound (0.92 g, 90%). 1H NMR (300 MHz, CDCl3) δ ppm 1.37 (s, 9H) 1.58-1.72 (m, 1H) 1.79-1.94 (m, 2H) 2.01-2.15 (m, 3H) 2.96-3.06 (m, 2H) 3.23-3.34 (m, 2H) 3.74-3.89 (m, 2H) 4.14-4.21 (m, 1H) 4.24-4.32 (m, 1H) 4.39-4.46 (m, 1H) 4.97-5.03 (m, 1H) 6.88 (s, 1H) 7.05 (d, J=8.73 Hz, 1H) 7.60 (dd, J=8.72, 2.38 Hz, 1H) 8.17 (d, J=2.38 Hz, 1H); MS (DCI/NH3) m/z 498 (M+H)+. Anal. calcd C24H30F3N3O3S.1.2 H2O: C, 55.52; H, 6.29; N, 8.09. Found: C, 55.39; H, 6.63; N, 8.01.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Br)=[CH:8][N:9]=1)(=[O:3])[CH3:2].Cl.[SH:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(Br)s1
Reactant: Sc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2cccnc2)s1
Temperature: 90 °C
Yield: 79.2 %

Procedure:
A mixture of 2-acetylamino-5-bromothiazole (1 g), 3-mercaptopyridine hydrochloride (1 g) and potassium carbonate (1.5 g) in N,N-dimethylformamide (10 ml) was heated at 90° C. for 4.5 hours with stirring. The reaction mixture was poured into ice water. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-acetylamino-5-(3-pyridylthio)thiazole (0.9 g, yield: 81.8%). mp: 203°-205° C. (dec.) IR (Nujol): 3170, 1700, 1570, 1300 cm-1
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[NH:21][C:22]([C:24]1[S:25][C:26]3[CH2:27][NH:28][CH2:29][CH2:30][C:31]=3[N:32]=1)=[O:23])=[O:13])=[CH:6]2.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>N1C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[NH:21][C:22]([C:24]1[S:25][C:26]3[CH2:27][N:28]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:29][CH2:30][C:31]=3[N:32]=1)=[O:23])=[O:13])=[CH:6]2
Reactant: CS(=O)(=O)Cl
Reactant: O=C(N[C@H]1CCCC[C@H]1NC(=O)c1nc2c(s1)CNCC2)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CS(=O)(=O)N1CCc2nc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (100 mg) obtained in Example 34 was dissolved in pyridine (3 mL), triethylamine (168 μl) and methanesulfonyl chloride (48 μl) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and methylene chloride and 1N hydrochloric acid were added to the residue to separate an organic layer. The resultant organic layer was dried over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride:methanol=100:1) to give the title compound (79 mg).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26](B(O)O)[CH:25]=1>>[N:18]1([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:8]3[N:7]=[CH:6][C:5]4=[CH:4][CH:3]=[C:2]([C:26]5[CH:25]=[N:24][C:33]6[C:28]([CH:27]=5)=[CH:29][CH:30]=[CH:31][CH:32]=6)[N:10]4[N:9]=3)=[CH:13][CH:14]=2)[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: Brc1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Product: c1ccc2ncc(-c3ccc4cnc(Nc5ccc(N6CCOCC6)cc5)nn34)cc2c1

Procedure:
(4-Morpholin-4-yl-phenyl)-(7-quinolin-3-yl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine was prepared from (7-bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-(4-morpholin-4-yl-phenyl)-amine and 3-quinolineboronic acid in an analogous manner to Example 1031b. Product isolated as a yellow solid (21 mg, 17%). m.p.=decomposed at 268° C.; LCMS (m/e) 423 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 9.40 (s, 1H), 9.30 (s, 1H), 8.77 (s, 1H), 8.14 (d, 1H, J=8.7 Hz), 7.85 (d, 1H, J=7.7 Hz), 7.77-7.68 (m, 2H), 7.63-7.55 (m, 2H), 7.24-7.19 (m, 1H), 6.96 (d, 2H, J=7.6 Hz), 6.93-6.86 (m, 1H), 6.70 (s, 1H), 3.95-3.87 (m, 4H), 3.22-3.14 (m, 4H).
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9])(=O)[CH3:2].Cl.[C:11]([NH2:14])(=[NH:13])[CH3:12].C[O-].[Na+].C(O)(=O)C>CO>[OH:6][CH2:7][CH2:8][C:4]1[C:5](=[O:9])[NH:14][C:11]([CH3:12])=[N:13][C:1]=1[CH3:2]
Reactant: CC(=N)N
Reactant: CC(=O)C1CCOC1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nc(C)c(CCO)c(=O)[nH]1
Yield: 22.6 %

Procedure:
3-acetyldihydro-2(3H)-furanone (25.6 g) was added to a stirred mixture of acetamidine hydrochloride (20 g) and sodium methylate (110 g) in methanol (150 ml). The reaction mixture was stirred and refluxed overnight. The reaction mixture was cooled and acetic acid (36 g) was added dropwise. The precipitate was filtered off and the filtrate evaporated. The residue was purified by column chromatography over silica gel (eluent: CHCl3 /(CH3OH/NH3) 90/10). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanol. The crystals were filtered off and dried, yielding 7.6 g (22%) of 5-(2-hydroxyethyl)-2,6-dimethyl-4(3H)-pyrimidinone (intermediate 4).
Reaction SMILES: C(N(CC)C(C)C)(C)C.C(O[C:15]([O:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O)(C)(C)C.C(=O)[C:26]1[C:27](=[CH:29][CH:30]=[CH:31][CH:32]=1)[OH:28].Cl>O1CCCC1>[C:21]([O:20][C:18]([O:17][C:15]1[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=1[CH:27]=[O:28])=[O:19])([CH3:22])([CH3:23])[CH3:24]
Reactant: O=Cc1ccccc1O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Oc1ccccc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.1 %

Procedure:
350 mg (2.8 mmol) of N,N-dimethylaminopyridine and 8.1 ml (46.9 mmol) of N,N-diisopropylethylamine are added to a solution containing 20.9 g (95.7 mmol) of di(tert-butyl)dicarbonate in 150 ml of tetrahydrofuran under a stream of nitrogen. 10 ml (93.8 mmol) of salicylaldehyde are added dropwise. After stirring at ambient temperature for 2 hours, the medium is treated with a 1N aqueous hydrochloric acid solution and then extracted with a heptane/ethyl acetate 1/1 mixture. The organic phase is dried over magnesium sulphate, filtered and concentrated. 21.5 g of 2-(tert-butoxycarbonyloxy)benzaldehyde are obtained in the form of a yellow oil with a quantitative yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[CH:18][C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: O=Cc1ccncc1
Reactant: O=C(O)Cc1ccc(F)cc1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: O=C(O)C(=Cc1ccncc1)c1ccc(F)cc1
Temperature: 150 °C

Procedure:
A mixture of 4-fluorophenylacetic acid (9 g, 58.4 mmol), 4-pyridinecarboxaldehyde (5.6 ml, 58.6 mmol), pyridine (6 ml) and acetic anhydride (6 ml) was heated at 150° C. for 1 h followed by evaporation and co-distillation with water. The resulting material crystallized on addition of ethanol. The solids were filtered and washed with ethanol and ethyl acetate to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4](Br)[CH:3]=1.[C:12]1([C:18]#[CH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCN(CC)CC.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.[Cu]I>[N+:8]([C:6]1[CH:7]=[C:2]([C:19]#[C:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=[C:4]([C:19]#[C:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cc(Br)cc(Br)c1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(C#Cc2ccccc2)cc(C#Cc2ccccc2)c1
Reaction time: 8 h
Yield: 51 %

Procedure:
A mixture of 1,3-dibromo-5-nitrobenzene (0.56 g, 2.00 mmol), bis(triphenylphosphine)palladium(II) chloride (0.10 g, 0.14 mmol) and copper(I) iodide (0.027 g, 0.14 mmol) in Et3N was degassed (three times). Phenylacetylene (0.50 g, 4.88 mmol) was added and mixture was stirred overnight. The reaction mixture was filtered through a celite pad and the pad was rinsed with CH2Cl2. The filtrate was washed with brine and the organic layer was dried with (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (Dichloromethane;Hexane=1:10) to afford ((5-nitro-1,3-phenylene)bis(ethyne-2,1-diyl))dibenzene (0.33 g, 51% yield): 1H-NMR (400 MHz, CDCl3) δ 8.30 (d, J=1.3 Hz, 2H), 7.96 (t, J=1.3 Hz, 1H), 7.56 (m, 4H), 7.40 (m, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:12]2[C:7](=[C:8]([Cl:14])[CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:5](=[O:6])[C:3]1=[O:4].[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[Mg]Br>>[CH3:1][N:2]1[C:12]2[C:7](=[C:8]([Cl:14])[CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:5]([C:17]2[CH:16]=[CH:15][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)([OH:6])[C:3]1=[O:4]
Reactant: CN1C(=O)C(=O)c2c(Cl)cc(Cl)cc21
Reactant: Br[Mg]c1ccc2ccccc2c1
Product: CN1C(=O)C(O)(c2ccc3ccccc3c2)c2c(Cl)cc(Cl)cc21
Yield: 1.5 %

Procedure:
The title compound (59.1 mg, 1.5%) was prepared from 1-methyl-4,6-dichloroisatin (250 mg) and 2-naphthyl magnesium bromide by the procedure similar to that described in Example 1.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]([CH3:29])([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[CH:19]=[CH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:8])[CH3:5].[OH-].[Na+]>CO.C1COCC1>[CH3:29][C:4]([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[CH:19]=[CH:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:8])([CH3:5])[C:3]([OH:30])=[O:2]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1C=CCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(NC(=O)c1ccc2ccccc2c1C=CCCc1ccccc1)C(=O)O

Procedure:
80 mg of a mixture of the (E)- and (Z)-isomers of 2-methyl-2-{[1-(4-phenyl-but-1-enyl)-naphthalene-2-carbonyl]-amino}-propionic acid methyl ester were reacted with 0.5 ml of 2 M sodium hydroxide in 1 ml methanol and 2 ml THF for 15 min at 60° C. The organic solvents were removed in vacuo, the mixture was acidified with 2 M hydrochloric acid and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over magnesium sulphate and concentrated to yield 75 mg of a mixture of the (E)- and (Z)-isomers of 2-methyl-2-{[1-(4-phenyl-but-1-enyl)-naphthalene-2-carbonyl]-amino}-propionic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](=[O:20])[CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24](=[O:27])[CH:25]=[O:26])[CH3:22]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH2:21]([O:23][C:24](=[O:27])[CH:25]([OH:26])[CH:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)[C:16](=[O:20])[CH2:17][CH2:18][CH3:19])[CH3:22]
Reactant: CCCC(=O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCC(=O)C(c1ccc(OCc2ccccc2)cc1)C(O)C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1-(4-benzyloxy-phenyl)-pentan-2-one (2.98 mmol, 11.4 g), oxo-acetic acid ethyl ester solution in toluene (8 mL, 50% solution in toluene) and triethylamine (2 mL) was stirred at ambient temperature for 24 h. The volatiles were removed under reduced pressure, and the resultant residue was purified by flash silica gel chromatography using by eluting with 30% ethyl acetate in hexanes to provide 3-(4-benzyloxy-phenyl)-2-hydroxy-4-oxo-heptanoic acid ethyl ester.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:6]([CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1)=[O:7]>O1CCCC1.CCCCCC>[OH:7][CH:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Reactant: c1cscn1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCCC(C(O)c2nccs2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
Under a nitrogen atmosphere, 1.25 ml (17.62 mmol) of thiazole were dissolved in 20 ml of tetrahydrofuran at −70° C. 11.1 ml (17.62 mmol) [15% in n-hexane] were subsequently added dropwise at such a rate that the temperature did not exceed −67° C. The mixture was warmed to room temperature, then cooled to −70° C., and 3.76 g (17.62 mmol) of tert-butyl 3-formylpiperidine-1-carboxylate, dissolved in 5 ml of tetrahydrofuran, were added dropwise. The mixture was stirred at −70° C. for 1 h, warmed to room temperature and stirred for a further 2 h. Conventional work-up gave 5.18 g of tert-butyl 3-(hydroxythiazol-2-ylmethyl)-piperidine-1-carboxylate; HPLC/MS (M+H)+=299 as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:23][CH2:24][CH:25]=[C:26]1[C:32]2[CH:33]=[CH:34][CH:35]=[N:36][C:31]=2[CH2:30][O:29][C:28]2[CH:37]=[CH:38][C:39]([C:41]([OH:44])([CH3:43])[CH3:42])=[CH:40][C:27]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH2:10][NH:11][CH2:23][CH2:24][CH:25]=[C:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[N:36][C:31]=3[CH2:30][O:29][C:28]3[CH:37]=[CH:38][C:39]([C:41]([OH:44])([CH3:43])[CH3:42])=[CH:40][C:27]2=3)=[CH:6][CH:7]=1
Reactant: NCCNc1ccc(Cl)cc1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCNCCNc1ccc(Cl)cc1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of N-(4-chloro-phenyl)-ethane-1,2-diamine (0.68 g, 3.96 mmol) in isopropanol (8.0 mL) was added 2,6-lutidine (0.31 mL, 2.64 mmol) and catalytic potassium iodide. This mixture was heated to 80° C. and then treated with 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.15 g, 0.4 mmol) in portions over 2 h. The solution was then stirred at 80° C. for an additional 18 h. The reaction mixture was concentrated in vacuo, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl acetate/5% methanol to 90% ethyl acetate/20% methanol) to yield the title compound. 1H-NMR (DMSO) δ: 1.40 (6H, s), 2.20–2.40 (2H, m), 2.70–2.90(3H, m), 3.10–3.30 (3H,m), 5.20 (2H, br, s), 5.80 (1H, m), 6.15 (1H, t), 6.60–6.70 (1H, m), 7.10–7.30 (4H, m) 7.50 (2H, m), 7.80 (1H, dd), 8.50 (1H, dd). ESI-MS m/z: 464 (M+1), UV retention time: 1.40 min.