Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([NH:27]C(=O)OC(C)(C)C)[CH2:8][CH2:7][CH:6]([O:9][C:10]2[C:21]3[C:20]4[C@@H:19]([CH2:22][C@H:23]([OH:26])[CH:24]=[CH2:25])[CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1)[CH3:2].Cl>ClCCl>[NH2:27][C:3]1([CH2:1][CH3:2])[CH2:8][CH2:7][CH:6]([O:9][C:10]2[C:21]3[C:20]4[C@@H:19]([CH2:22][C@H:23]([OH:26])[CH:24]=[CH2:25])[CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1
Reactant: C=C[C@@H](O)C[C@H]1CCc2sc3ncnc(OC4CCC(CC)(NC(=O)OC(C)(C)C)CC4)c3c21
Agent: Cl
Solvent: ClCCl
Product: C=C[C@@H](O)C[C@H]1CCc2sc3ncnc(OC4CCC(N)(CC)CC4)c3c21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 50-mL round-bottom flask was charged with a solution of tert-butyl N-(1-ethyl-4-[[(3R)-3-[(2S)-2-hydroxybut-3-en-1-yl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)carbamate (35 mg, 0.07 mmol, 1.00 equiv; prepared in a manner analogous to compounds 132.1 and 132.2 in Example 132) and hydrogen chloride (conc.) (0.2 mL) in dichloromethane (10 mL). After stirring for 1 h at 0° C. in an water/ice bath, the reaction was then quenched by the addition of 20 mL of saturated sodium bicarbonate. The resulting solution was extracted with 4×30 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The crude product (30 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-016(Waters)): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with 50 mL NH4CO3 and CH3CN (5.0% CH3CN up to 44.0% in 10 min, up to 95.0% in 2 min, down to 5.0% in 2 min); detector: 254/220 nm. The product was freeze-dried. This resulted in (2S)-1-[(3R)-12-[(4-amino-4-ethylcyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]but-3-en-2-ol (14.6 mg, 52%) as a white solid. 1H NMR (400 MHz, CD3OD): δ: 8.48 (s, 1H), 5.97-5.93 (m, 1H), 5.45-5.43 (m, 1H), 5.29 (d, J=8, 1H), 5.17 (d, J=8, 1H), 4.24-4.26 (m, 1H), 3.39-3.32 (m, 1H), 3.13-2.99 (m 2H), 2.66-2.47 (m, 2H), 2.20-2.16 (m, 3H), 1.93-1.55 (m, 9H), 0.99 (s, 3H). MS: m/z 388 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:18])[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][CH:9]=1
Reactant: CCOC(=O)CCC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC(=O)c1ccc(N)cc1
Yield: 30.7 %

Procedure:
A solution of ethyl 4-(4-nitrophenyl)-4-oxobutyrate (1.4 g, 5.6 mmol) and 10% palladium on carbon (0.18 g) in ethanol (50 ml) was shaken under hydrogen (50 psi) for 2 hours then filtered and concentrated in vacuo. The residue was absorbed onto silica gel (5 g) from an ethyl acetate solution and purified by chromatography on silica gel (100 g) eluting with ethyl acetate:hexane (1:2) to give ethyl 4-(4-aminophenyl)-4-oxobutyrate (0.38 g) as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ: 1.17 (t, J=7 Hz, 3H, CH3), 2.56 (t, J=6.5 Hz, 2H, CH2), 3.10 (t, J=6.5 Hz, 2H, CH2), 4.04 (q, J=7 Hz, 2H, ester CH2), 6.04 (br s, 2H, NH2), 6.57 (d, J=9 Hz, 2H, Ar), 7.69 (d, J=9 Hz, 2H, Ar). Anal. Calculated for C12H15NO3 : C, 65.14; H, 6.83; N, 6.33. Found: C, 65.23; H, 6.85; N, 6.32.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10](Br)[CH3:11]>>[C:1]1([CH:7]([CH2:10][CH3:11])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1ccccc1
Reactant: CCBr
Product: CCC(C#N)c1ccccc1
Yield: 98 %

Procedure:
Using the method of Procedure A.(a) 1, alkylation of phenylacetonitrile with ethyl bromide gave a 98% yield of the title compound, b.p. 110°-116° at 13 mm. (Lit.1 b.p. 124°-126° at 25 mm.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Br:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:33]2[CH2:32][CH2:31][N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([Br:23])[CH:25]=3)[CH2:35][CH2:34]2)=[O:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Brc1cccc(N2CCNCC2)c1
Reactant: COc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Product: COc1nc2ccccc2nc1NC(=O)N1CCN(c2cccc(Br)c2)CC1
Yield: 69.5 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate and 1-(3-bromophenyl)-piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH:6]=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)([O-:3])=[O:2].B(F)(F)F.CCOCC.[CH2:31]=[C:32]([CH3:34])[CH3:33]>C(#N)C>[CH3:31][C:32]1([CH3:34])[C:9]2[C:8](=[CH:13][CH:12]=[C:11]([C:14]([F:15])([F:16])[F:17])[CH:10]=2)[NH:7][CH:6]([C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:33]1
Reactant: O=[N+]([O-])c1ccccc1C=Nc1ccc(C(F)(F)F)cc1
Reactant: C=C(C)C
Agent: FB(F)F
Solvent: CC#N
Solvent: CCOCC
Product: CC1(C)CC(c2ccccc2[N+](=O)[O-])Nc2ccc(C(F)(F)F)cc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a suspension of N-(2-nitrobenzylidene)-4-(trifluoromethyl)aniline (2.7 g, 9.18 mmol) and Borontrifluoride etherate (289 μL) in anhydrous acetonitrile was added isobutene (16 mL, pre-cooled to −78° C.) at ice-bath. After addition, the resulting mixture was stirred at 90° C. in sealed tube overnight. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give 4,4-dimethyl-2-(2-nitrophenyl)-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline (2.56 g, yield 80%). LC/MS m/e obsd. (ESI+) [(M+H)+] 351.1.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O>C(O)C>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: Nc1ccc(NC(=O)c2ccc(N)cc2)cc1
Temperature: 25 °C
Reaction time: 20.7 h

Procedure:
A portion (22.0 grams, 0.1532 nitro equivalents) of 4,4'-dinitrobenzanilide from A above and ethanol (300 milliliters) are added to a 400 milliliter heavy walled glass bottle and then sparged with nitrogen. After removal of air by nitrogen sparging, Raney nickel catalyst (6.0 grams of a 75% wt. slurry in water at pH 10) is added to the slurry in the glass bottle which is then stoppered and multiply purged with hydrogen to replace the nitrogen atmosphere. The bottle is then placed on a shaking type agitator, and pressurized to 46.5 psig hydrogen. Shaking of the pressurized slurry at room temperature (25° C.) commences until 20.7 hours later, the hydrogen pressure reading indicated that 42 psig of hydrogen has been consumed. The product slurry is recovered, diluted into dimethylsulfoxide (250 milliliters) to provide a solution of product containing precipitated Raney nickel, then filtered through a medium porosity fritted glass funnel. The recovered dimethylsulfoxide product solution is rotary evaporated at 130° C. under vacuum to provide a solid product. The solid product is further dried in a vacuum oven at 120° C. and 3 mm Hg to a constant weight of 16.98 grams. The product thus recovered is light golden orange in color. Fourier transform infrared spectrophotometric analysis of a nujol mull of the product on a sodium chloride plate confirms the product structure (disappearance of the absorbances observed for the conjugated nitro group, secondary amide N--H stretching (solid state) and primary amine N--H group stretching absorbances observed at 3393, 3318 and 3207 cm-1 and secondary amide carbonyl stretching (solid state) absorbance observed at 1630 cm-1). Proton magnetic resonance spectroscopy further confirms the product structure.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:17]=[N:18][N:19]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[CH3:47][O:48][CH2:49][C:50](Cl)=[O:51].C(N(CC)CC)C>O1CCCC1>[CH3:47][O:48][CH2:49][C:50]([NH:46][C:42]1[CH:43]=[CH:44][CH:45]=[C:40]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:16]4[N:17]=[N:18][N:19]([C:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:20]=4)[CH:11]=3)[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=2)[CH:41]=1)=[O:51]
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4nnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4nnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[2-(triphenylmethyl)(1,2,3,4-tetrazol-5-yl)]-1H-indazol-3-yl}phenylamine (0.246 g, 0.407 mmol) in tetrahydrofuran (4 mL) was added 2-methoxyacetyl chloride (0.056 mL, 0.61 mmol) and triethyl amine (0.284 mL, 2.035 mmol). The reaction mixture was stirred overnight at room temperature before being partitioned between ethyl acetate and water. The product was purified by column chromatography (40% ethyl acetate in hexanes) (0.104 g, 38% yield): ES-MS (m/z) M+ was not detected.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(#N)C>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][CH:13]([CH2:12][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[O:18][C:17]=2[CH:19]=1)(=[O:24])=[O:25]
Reactant: C1COCCN1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc2c(c1)OC(CN1CCOCC1)CO2

Procedure:
Preparation according to Example 25 using [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.018 g, 0.046 mmol), morpholine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 313 (M+, 1), 101 (6), 100 (bp), 70 (2), 56 (4).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:16])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:7]=1.C(NC(C)C)(C)C.[C:24]([Si:26]([CH3:29])([CH3:28])[CH3:27])#[CH:25]>O1CCCC1.[Cu](I)I>[O:16]=[C:9]([NH:8][C:5]1[CH:4]=[N:3][C:2]([C:25]#[C:24][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:7][N:6]=1)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)CCC(=O)Nc1cnc(Br)cn1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)CCC(=O)Nc1cnc(C#C[Si](C)(C)C)cn1
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of methyl 4-[(5-bromopyrazin-2-yl)amino]-4-oxo-butanoate (A2, 1.0 g, 3.5 mmol), copper iodide (0.17 mmol, 0.033 g), diisopropylamine (4.2 mmol, 0.42 g, 0.59 mL) and palladium(II)bis(triphenylphosphine)dichloride (0.17 mmol, 0.12 g) in tetrahydrofuran (30 mL) was degassed with Ar. Then ethynyl(trimethyl)silane (7.60 mmol, 0.75 g, 1.1 mL) was added slowly and the mixture was stirred overnight. The mixture was filtered through a pad of celite which was washed with ethyl acetate and filtrate was concentrated under reduced pressure. The product was purified by flash chromatography (ethyl acetate/cyclohexane: 1/99→99/1) to give methyl 4-oxo-4-[[5-(2-trimethylsilylethynyl)pyrazin-2-yl]amino]butanoate (E, 0.85 g, 2.8 mmol, 80% Yield). 1H NMR (400 MHz, CDCl3) 9.46 (1H, s), 9.00 (1H, s), 8.33 (1H, s), 3.71 (3H, s), 2.88-2.75 (2H, m), 0.20 (9H, s).
Reaction SMILES: C[Al](C)C.[Cl-].[NH4+:6].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][C:23]#[N:24])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.Cl>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][CH2:22][C:23](=[NH:6])[NH2:24])[CH2:18][CH2:19]2)=[CH:12][CH:13]=1
Reactant: N#CCCCN1CCN(c2ccc(Cl)cc2)CC1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: Cl
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: N=C(N)CCCN1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.5 %

Procedure:
Trimethylaluminium (2M solution in toluene, 12.32 ml, 24.64 mmol) was added dropwise to a suspension of ammonium chloride (1.32 g, 24.64 mmol) in dry toluene (20 ml) over a period of 20 min at 0° C. under nitrogen atmosphere. The resulting mixture was allowed to stir for 15 min at room temperature. To this was added dropwise a solution of 4-(4-(4-chlorophenyl) piperazin-1-yl)butanenitrile (1.3 g, 4.93 mmol) in dry toluene (10 ml) over a period of 10 min and the reaction mixture was heated at about 90° C. - about 100° C. for 15 h under stirring. The reaction mixture was cooled to 25° C., slowly poured into a slurry of silica gel (100-200 mesh, 30 g) in chloroform (100 ml) and was stirred for 10 min. The silica was filtered through celite and washed with methanol (3 ×50 ml). Combined filtrate was evaporated to obtain a crude solid which was dissolved in 10% hydrochloric acid (100 ml) and washed with diethyl ether (2 x 25 ml). To the resulting aqueous layer was added saturated aqueous solution of sodium hydroxide (30 ml) to bring the pH between 13 and 14. The aqueous layer was extracted with chloroform (3 ×100 ml). The combined organic layer was dried over anhydrous sodium sulphate. The solvent in the organic was evaporated under reduced pressure to obtain the title compound (1.1 g, 79% yield).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:14]([NH:16][C@H:17]([C:21]([N:23]1[CH2:30][CH:29]([O:31][CH2:32][CH:33]=[CH2:34])[CH2:28][C@H:24]1[C:25](O)=[O:26])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[C:35]([O:39][C:40](=[N:46][NH:47][C:48]([NH2:50])=[O:49])[CH2:41][CH:42]([NH2:45])[CH:43]=[O:44])([CH3:38])([CH3:37])[CH3:36]>>[C:35]([O:39][C:40](=[N:46][NH:47][C:48]([NH2:50])=[O:49])[CH2:41][C@H:42]([NH:45][C:25](=[O:26])[C@@H:24]1[CH2:28][C@@H:29]([O:31][CH2:32][CH:33]=[CH2:34])[CH2:30][N:23]1[C:21](=[O:22])[C@H:17]([CH:18]([CH3:19])[CH3:20])[NH:16][C:14](=[O:15])[C@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[NH:4][C:1](=[O:3])[CH3:2])[CH:43]=[O:44])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(CC(N)C=O)=NNC(N)=O
Reactant: C=CCOC1C[C@@H](C(=O)O)N(C(=O)[C@@H](NC(=O)[C@H](Cc2ccc(O)cc2)NC(C)=O)C(C)C)C1
Product: C=CCO[C@@H]1C[C@@H](C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C)N(C(=O)[C@@H](NC(=O)[C@H](Cc2ccc(O)cc2)NC(C)=O)C(C)C)C1
Yield: 20 %

Procedure:
N-Acetyl-tyrosinyl-valinyl-4-allyloxyproline (420 mg, 0.88 mmol) and 3-amino-4-oxobutyric acid tert-butyl ester semicarbazone (184 mg, 0.8 mol, Graybill et al., Int. J. Protein Res., 44, pp. 173-82 (1994)) to give 100 mg (20%) of the title compound as a white amorphous solid: 1H NMR (CD3OD) δ 7.24-7.2 (1H, m), 7.04-6.97 (2H, d), 6.73-6.65 (2H, d), 5.98-5.86 (1H, m), 5.35-5.24 (1H, d), 5.17-5.12 (1H, m), 4.12-3.98 (2H, m), 3.72-3.67 (1H, m), 2.98-2.92 (3H, m), 2.38-2.32 (1H, m), 2.1-2.02 (2H, m), 1.92 (3H, s), 0.98-0.89 (6H, 2×d).
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][C:5]1=[N:6][C:7](=[O:17])[S:8]/[C:9]/1=[CH:10]\[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[Cs+].[Cs+].F[C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[C:33]([F:36])([F:35])[F:34].O>CS(C)=O>[CH3:3][NH:4][C:5]1=[N:6][C:7](=[O:17])[S:8]/[C:9]/1=[CH:10]\[CH:11]1[CH2:16][CH2:15][N:14]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=2[C:33]([F:34])([F:36])[F:35])[CH2:13][CH2:12]1
Reactant: CNC1=NC(=O)S/C1=C\C1CCNCC1
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CNC1=NC(=O)S/C1=C\C1CCN(c2ccc(C#N)cc2C(F)(F)F)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 11 %

Procedure:
To a solution of (5Z)-4-(methylamino)-5-(piperidin-4-ylmethylidene)-1,3-thiazol-2(5H)-one dihydrochloride (100 mg) in dimethyl sulfoxide (2 mL) were added cesium carbonate (327 mg) and 4-fluoro-3-(trifluoromethyl)benzonitrile (76 mg), and the mixture was stirred at 100° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/methanol) to give the title compound (14.5 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=O.[CH:11]([NH2:13])=O>O>[N:1]1[C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8](=[O:10])[NH:13][CH:11]=1
Reactant: Nc1cnccc1C(=O)O
Reactant: NC=O
Solvent: O
Product: O=c1[nH]cnc2cnccc12
Reaction time: 1 h

Procedure:
A mixture of 4 g of 3-amino-pyridine-4-carboxylic acid in 15 mL of formamide was heated in an oil bath to 160°-180° C. After one hour the mixture was allowed to cool. Then, the mixture was slurried in 25 mL of water and filtered. The product was recrystallized from water. Yield 3.3 g. M.P. 317° C. (with sublimation).
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]\[CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Cl:36])[C:20]=1[NH:21][C:22]1[C:31]2[C:26](=[C:27]([OH:34])[C:28]([O:32][CH3:33])=[CH:29][CH:30]=2)[O:25][C:24](=[O:35])[CH:23]=1>>[Si:7]([O:6][CH2:5]/[CH:4]=[CH:3]\[CH2:2][O:34][C:27]1[C:28]([O:32][CH3:33])=[CH:29][CH:30]=[C:31]2[C:26]=1[O:25][C:24](=[O:35])[CH:23]=[C:22]2[NH:21][C:20]1[C:19]([Cl:36])=[CH:18][N:17]=[CH:16][C:15]=1[Cl:14])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OC/C=C\CBr
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OC/C=C\CO[Si](C)(C)C(C)(C)C

Procedure:
(Z)-8-(4-(tert-Butyldimethylsilyloxy)but-2-enyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one was prepared from (Z)-(4-bromobut-2-enyloxy)(tert-butyl)dimethylsilane and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. MS (ESI): 537.0.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:7][C:8]1[CH:9]=[C:10]([CH:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][NH2:16])[CH:11]=[CH:12][CH:13]=1)[CH2:4][CH2:5][CH3:6].Cl[CH2:25][C:26]([N:28]([CH3:30])[CH3:29])=[O:27].O>CN(C=O)C>[CH2:3]([O:7][C:8]1[CH:9]=[C:10]([CH:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:15][NH:16][CH2:25][C:26]([N:28]([CH3:30])[CH3:29])=[O:27])[CH:11]=[CH:12][CH:13]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CN(C)C(=O)CCl
Reactant: CCCCOc1cccc(C(CN)C(=O)OC(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1cccc(C(CNCC(=O)N(C)C)C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a suspension of NaH (60%, 2.0 g, 51 mmol) in dry DMF (125 ml) cooled at 0° C., a solution of 2-(3-butoxyphenyl)-(tert-butoxycarbonyl)ethylamine (7.5 g, 25.5 mmol) in dry DMF (125 ml) was added dropwise. After 1 h at room temperature, 2-chloro-N,N-dimethylacetamide (5.2 ml, 51 mmol) was added and the mixture was stirred for 16 h at room temperature. H2O (10 ml) was added and the solvent was evaporated under reduced pressure. The residue was dissolved in H2O (150 ml) and extracted with CH2Cl2 (2×150 ml). The collected organic phases were dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography (petroleum ether/EtOAc 4:6) affording the title compound (7.2 g, 75%) as light yellow oil.
Reaction SMILES: [CH3:1][CH:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1)[CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[C:19]([O:22][CH2:23][CH2:24]Br)(=[O:21])[CH3:20].O>CN(C=O)C>[C:19]([O:22][CH2:23][CH2:24][S:12][C:9]1[CH:8]=[CH:7][C:6]([S:5][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:11][CH:10]=1)(=[O:21])[CH3:20]
Reactant: CCC(C)Sc1ccc(S)cc1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)Sc1ccc(SCCOC(C)=O)cc1

Procedure:
To a mixture of 4-(1-methylpropylthio)benzenethiol (53.7 g, 271.0 mmol) and potassium carbonate (49.4 g, 358.0 mmol) in DMF under N2 and with stirring is added dropwise 2-bromoethyl acetate (34.0 ml, 298.0 mmol). The mixture is stirred at RT overnight, after which water is added and the mixture is extracted with ether. The combined organic layers are washed with water and brine, dried, the solvent removed and the residue purified by distillation to give 2[4-(1-methylpropylthio)phenylthio]ethyl acetate. To the acetate (60.9 g, 214.0 mmol) in 200 ml of ethanol is added 50% sodium hydroxide (20 ml). The reaction mixture is stirred at RT for 7 hours and is then neutralized by addition of 10% sulfuric acid and extracted with ether. The organic layer is washed with water and brine, dried and the solvent removed to give 2-[4-(1-methylpropylthio)phenylthio]ethanol.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[C:10]([F:19])=[C:11]([C:15]([F:18])=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.C([Sn](CCCC)(CCCC)[C:33]1[N:34]=[CH:35][S:36][CH:37]=1)CCC.O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:19][C:10]1[C:9]([O:8][CH2:7][C:5]2[S:6][C:2]([C:33]3[N:34]=[CH:35][S:36][CH:37]=3)=[C:3]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:4]=2)=[CH:17][CH:16]=[C:15]([F:18])[C:11]=1[C:12]([NH2:14])=[O:13]
Reactant: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2Br)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2-c2cscn2)cc1
Temperature: 120 °C
Yield: 364.4 %

Procedure:
To a solution of 3-[5-bromo-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (0.20 g, 0.043 mmol) in 5 ml of anhydrous DMF was added 4-tributylstannyl thiazole (0.16 g, 0.43 mmol) and degassed the reaction mixture for 10 minutes. Tetrakis(triphenylphosphine) palladium (0) (0.05 g, 0.043 mmol) was then added and the reaction mixture was heated at 120° C. for 12 h under the nitrogen atmosphere. Then reaction mixture was cooled to room temperature added water (25 mL) and extracted the compound with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (230-400 M) using ethyl acetate/Hexane (40:60) as the eluent to provide the title compound as white solid (0.072 g, 36%). 1H NMR (DMSO-d6, 400 MHz): δ 3.80 (s, 3H), 5.56 (s, 2H), 7.01 (d, J=8.80 Hz, 2H), 7.13 (m, 1H), 7.41-7.50 (m, 4H), 7.90 (br s, 1H), 8.18 (br s, 1H) and 9.18 (s, 1H). MS ES+ (460.32), HPLC (method II) Rt=16.37 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH:14]2[CH2:16][CH2:15]2)=[N:4][N:3]=1.[NH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH2:20][CH2:19]1>>[CH:14]1([C:5]2[C:6]3[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=3)[C:2]([NH:17][CH:18]3[CH2:19][CH2:20][N:21]([CH2:24][C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH:26]=4)[CH2:22][CH2:23]3)=[N:3][N:4]=2)[CH2:16][CH2:15]1
Reactant: COc1ccc2c(C3CC3)nnc(Cl)c2c1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Product: COc1ccc2c(C3CC3)nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-4-cyclopropyl-7-methoxyphthalazine with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=O.[CH2:13]([NH2:15])[CH3:14]>>[Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([NH:15][CH2:13][CH3:14])=[O:7]
Reactant: CCN
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1O
Product: CCNC(=O)c1cc(Cl)cc(Cl)c1O

Procedure:
Prepared from 3,5-dichloro-2-hydroxybenzoic acid and ethylamine using the method of preparation 57 to give the title compound as a pale yellow solid.