Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][NH:5][C@H:6]([C:8]([OH:10])=[O:9])[CH3:7].[CH2:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].Cl>C1(C)C=CC=CC=1>[CH2:26]([O:9][C:8](=[O:10])[C@H:6]([CH3:7])[NH:5][CH2:4][C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=1[OH:1])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15]
Reactant: CCCCCCCCCCCCO
Reactant: C[C@H](NCc1ccccc1O)C(=O)O
Agent: Cl
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOC(=O)[C@H](C)NCc1ccccc1O
Reaction time: 8 h
Yield: 93.4 %

Procedure:
L-alanine (2.9 g) was dissolved in 20 ml of a 2-N sodium hydroxide aqueous solution, and 3.5 ml of salicylaldehyde and 0.4 g of sodium borohydride were then added thereto in this order. After the mixture was stirred for 1 hour, 3.5 ml of salicylaldehyde and 0.4 g of sodium borohydride were added thereto again. The mixture was stirred at room temperature for 1 hour, and the insoluble matter was then separated through filtration. The filtrate was extracted with diethyl ether. The pH was adjusted to 6 with hydrochloric acid to obtain 5.8 g of N-(2-hydroxybenzyl)-L-alanine. The resulting N-(2-hydroxybenzyl)-L-alanine (4.6 g) and 8.8 g of 1-dodecanol were added to 150 ml of toluene, and a hydrogen chloride gas was blown thereto up to the saturation. Ten grams of a molecular sieve were added thereto, and the mixture was stirred overnight. After the insoluble matter was separated through filtration, the filtrate was concentrated, and the resulting oil was dissolved in methylene chloride. The mixture was washed with a saturated aqueous solution of sodium chloride. The resulting mixture was dried over magnesium sulfate, and concentrated under reduced pressure to give 8 g of N-(2-hydroxybenzyl)-L-alanine lauryl ester.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=1.I[CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH3:9][O:10][C:11](=[O:22])[CH:12]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=1)[CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: ICC1CCCC1
Reactant: COC(=O)Cc1ccc(OC)c(F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)c1ccc(OC)c(F)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 83.9 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (21.6 mL of 0.31M stock solution, 6.69 mmol) cooled to −78° C. was treated with a solution of (3-fluoro-4-methoxy-phenyl)-acetic acid methyl ester (1.26 g, 6.38 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (16 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.47 g, 7.02 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was warmed to 25° C. and stirred at 25° C. for 48 h. The reaction mixture was then quenched by the slow addition of a saturated aqueous ammonium chloride solution (10 mL). The reaction mixture was then poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with a saturated aqueous lithium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 90/10 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-propionic acid methyl ester (1.50 g, 83.8%) as a clear oil: EI-HRMS m/e calcd for C16H21FO3(M+) 280.1477 found 280.1474.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.N1(C(N2C=CN=C2)=O)C=CN=C1.Cl.[F:28][C:29]1[CH:38]=[C:37]2[C:32]([CH2:33][CH2:34][CH2:35][NH:36]2)=[CH:31][CH:30]=1>C1COCC1>[F:28][C:29]1[CH:38]=[C:37]2[C:32]([CH2:33][CH2:34][CH2:35][N:36]2[C:12]([C:3]2[C:2]([OH:1])=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[N:10]3)=[CH:5][CH:4]=2)=[O:14])=[CH:31][CH:30]=1
Reactant: Fc1ccc2c(c1)NCCC2
Reactant: O=C(O)c1ccc2cccnc2c1O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(c1ccc2cccnc2c1O)N1CCCc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.3 %

Procedure:
A mixture of 8-hydroxyquinoline-7-carboxylic acid (100 mg, 0.53 mmol) and di(1H-imidazol-1-yl)methanone (86 mg, 0.53 mmol) in THF (6 mL) was heated to reflux for 4 h, under nitrogen. The reaction mixture was allowed to cool to RT and 7-fluoro-1,2,3,4-tetrahydroquinoline hydrochloride (84.4 mg, 0.45 mmol) and TEA (0.062 mL, 0.45 mmol) were added. The resulting mixture was heated in a MW oven at 120° C. for 90 min and then at 140° C. for 2 h. The reaction mixture was then quenched with H2O and an aqueous saturated solution of sodium hydrogen carbonate, and twice extracted with DCM. The separated organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC. Product-containing fractions were combined, made basic with a saturated aqueous solution of sodium hydrogen carbonate and CH3CN was removed under reduced pressure. The aqueous phase was extracted with DCM and the separated organics dried over Na2SO4, filtered and concentrated to dryness, affording the title compound (19 mg, 0.06 mmol) as a off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH3:19])=[C:17]2[C:12]([C:13]([OH:21])=[CH:14][C:15](=[O:20])[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[C:18]([CH3:19])=[C:17]2[C:12]([C:13]([OH:21])=[C:14]([C:30](=[O:31])[NH:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([Br:22])[CH:24]=3)[C:15](=[O:20])[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=Nc1cccc(Br)c1
Reactant: Cc1c(OCc2ccccc2)ccc2c(O)cc(=O)oc12
Solvent: CCN(CC)CC
Product: Cc1c(OCc2ccccc2)ccc2c(O)c(C(=O)Nc3cccc(Br)c3)c(=O)oc12
Yield: 15.2 %

Procedure:
According to the procedure of example 2, 7-benzyloxy-4-hydroxy-8-methylcoumarin (0.813 g, 2.88 mmol) and 3-bromophenylisocyanate (0.39 ml, 3.12 mmol) were reacted in the presence of triethylamine (0.1 ml) to generate the title compound as an off-white solid, mp 229°-231° C., (0.211 g, 0.44 mmol, yield 15.2%). Analysis: Calculated for C24H18NO5Br: C, 601.13; H, 3.76; N, 2.92. Found: C, 60.04; H, 3.51; N, 2.89. 1H NMR (CDCl3): 7.94 (br s, 1H), 7.87 (d, J=9.0 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.41 (m, 5H), 7.24 (m, 2H), 6.97 (d, J=9.0 Hz, 1H), 5.21 (s, 2H), 2.36 (s, 3H).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=O)[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2].C(=O)(O)[O-].[Na+].Cl.[CH2:20]([O:23][NH2:24])[CH:21]=[CH2:22].Cl>O.C(OCC)(=O)C>[CH2:20]([O:23][N:24]=[C:9]([C:7]1[N:8]=[C:4]([NH:3][CH:1]=[O:2])[S:5][CH:6]=1)[C:10]([OH:12])=[O:11])[CH:21]=[CH2:22]
Reactant: C=CCON
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 66.1 %

Procedure:
To a solution of 2-(2-formamidothiazol-4-yl)glyoxylic acid (30 g) and sodium bicarbonate (12.6 g) in water (1300 ml) was added allyloxyamine hydrochloride (19.8 g), and the mixture was stirred for 7 hours at ambient temperature at pH 6. To the reaction mixture was added ethyl acetate (500 ml). After the mixture was adjusted to pH 1.9 with 10% hydrochloric acid, the ethyl acetate layer was separated. The ethyl acetate layer was washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and then the solvent was distilled off. The residue was pulverized in diisopropyl ether, collected by filtration and then dried to give 2-allyloxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer)(25.3 g).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4](=[O:6])[CH3:5].[CH2:10]1OCOCO1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:4]([C:3]1([CH3:7])[CH2:8][O:9][CH2:10][O:1][CH2:2]1)(=[O:6])[CH3:5]
Reactant: C1OCOCO1
Reactant: CC(=O)C(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)C1(C)COCOC1

Procedure:
A solution of 3,3-bis(hydroxymethyl)-2-butanone (66.1parts) and s-trioxane (27 parts) in toluene (250 parts) containing p-toluenesulfonic acid (1.9 parts) is held under reflux while water of reaction is continuously removed (ca. 0.5 hr) by a Dean-Stark trap. The solution is cooled, neutralized by stirring with solid sodium bicarbonate and filtered Toluene is removed in vacuo and the residue distilled at 50-55° C. and 0.6 mm Hg. Proton NMR and combustion analysis are consistent with those values predicted for the desired product. Combustion Analysis for C7H12O3 --Calculated: C, 58.3%; H, 8.4%. Found: C, 57.9%; H, 8.2%.
Reaction SMILES: [OH:1][CH:2]([CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:31]([O:35]CC)(=O)[CH2:32][OH:33]>C1(C)C=CC=CC=1>[CH2:19]([N:18]([CH2:17][CH:2]([OH:1])[CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:32](=[O:33])[CH2:31][OH:35])[C:32](=[O:33])[CH2:31][OH:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCOC(=O)CO
Reactant: CCCCCCCCCCCCNCC(O)CNCCCCCCCCCCCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCN(CC(O)CN(CCCCCCCCCCCC)C(=O)CO)C(=O)CO
Temperature: 100 °C
Reaction time: 7.5 h
Yield: 79.8 %

Procedure:
A reactor was charged with 10.7 g (0.03 mole) of 15-hydroxy-13,17-diazanonacosan, 50 ml of toluene and 7.1 ml (0.07 mole) of ethyl glycolate, and the contents were heated to 100° C. and continuously stirred for 7.5 hours while purging ethanol formed with a nitrogen stream. After completion of a reaction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (on 200 g of silica gel, developing solvent: chloroform/methanol=100/1), thereby obtaining 13 g (yield: 96%) of the title compound as a viscous liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([F:24])[F:23])=[C:14]([CH2:25][OH:26])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:29]I>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([F:24])[F:23])=[C:14]([CH2:25][O:26][CH3:29])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(CO)c(C(F)F)nc3N21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COCc1cc2c(nc1C(F)F)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
This compound was prepared in analogy to example 1, intermediate d) from (4R,9aR)-6-difluoromethyl-7-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, sodium hydride and methyl iodide.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:32])[CH2:14][CH:15]([NH:20][C:21](=[O:31])[C@@H:22]([N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]1=[O:30])[CH3:23])[C:16](=[O:19])[CH2:17][F:18])(C)(C)C>ClCCl>[F:18][CH2:17][C:16](=[O:19])[CH:15]([NH:20][C:21](=[O:31])[C@@H:22]([N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]1=[O:30])[CH3:23])[CH2:14][C:13]([OH:32])=[O:12]
Reactant: C[C@@H](C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF)n1ccccc1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](C(=O)NC(CC(=O)O)C(=O)CF)n1ccccc1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (2 ml) was added to a stirred ice cold solution of 5-Fluoro-4-oxo-3-[(S)-2-(2-oxo-2H-pyridin-1-yl)-propionylamino]-pentanoic acid tert-butyl ester (115 mg, 0.32 mmol)in anhydrous dichloromethane (2 ml). The mixture was stirred at 0° C. for 0.5 h then at room temperature for 0.5 h. The mixture was concentrated under reduced pressure and then the residue was redissolved in dry dichloromethane. This process was repeated several times in order to remove excess trifluoroacetic acid. The gum was lyophilized twice from HPLC grade water to afford the title compound as an off white solid: IR (solid) 1789, 1730, 1654 cm−1; 1H NMR (400 MHz, DMSO) δ 1.4-1.6 (3H, m), 2.5-2.9 (2H, m), 4.2-4.7 (2H, m), 5.0-5.5 (2H, m), 6.2-6.3 (1H, m), 6.3-6.5 (1H, m), 7.3-7.4 (1H, m), 7.6-7.7 (1H, m), 8.4-8.9 (1H, m); 13C NMR (100 MHz, DMSO) δ 17.15, 17.27, 17.61, 17.87, 17.94, 33.50, 33.57, 35.02, 35.23, 35.31, 52.69, 53.08, 53.31, 53.42, 53.47, 53.79, 53.91, 54.49, 54.85, 81.55, 81.92, 83.31, 83.68, 83.95, 84.07, 85.72, 85.84, 105.87, 106.07, 106.19, 119.67, 119.86, 120.26, 137.05, 137.31, 137.36, 137.40, 137.43, 140.60, 140.65, 140.74, 140.85, 162.14, 162.18, 162.28, 162.32, 171.25, 171.48, 171.62, 171.69, 172.55, 172.63, 173.63, 173.67, 174.52, 203.04, 203.18, 203.28, 203.42; MS (FAB+ve, HR) Calculated for C13H16FN2O5 (MH+) 299.1043, found 299.1045.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([O:7][C:8]2[C:16]([F:17])=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:9]=2)=[CH:5][CH:4]=1)#[N:2].[C:32]([O:36][C:37](=[O:47])[NH:38][CH2:39][CH2:40][CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37](=[O:47])[NH:38][CH2:39][CH2:40][CH:41]1[CH2:42][CH2:43][N:44]([C:12]([C:11]2[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:27])[F:28])[CH:20]=3)=[N:9][C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:31][CH:30]=3)=[C:16]([F:17])[CH:15]=2)=[O:14])[CH2:45][CH2:46]1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Reactant: N#Cc1ccc(Oc2nc(Oc3cccc(OC(F)(F)F)c3)c(C(=O)O)cc2F)cc1
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2cc(F)c(Oc3ccc(C#N)cc3)nc2Oc2cccc(OC(F)(F)F)c2)CC1
Yield: 57.1 %

Procedure:
6-(4-cyano phenoxy)-5-fluoro-2-(3-trifluoromethoxy phenoxy)nicotinic acid (1.3 g, 2.99 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.684 g, 3.0 mmol) were coupled using the procedure of Example 5(c) to afford 1.1 g of the required product. 1HNMR (DMSO-d6): δ 1.2 (2H, m), 1.4 (9H, d), 1.5 (2H, m), 1.6 (2H, m), 2.2 (1H, m), 2.35 (1H, m), 3.0 (3H, m), 3.7 (1H, m), 4.45 (1H, m), 6.78 (1H, m), 7.18 (1H, m), 7.26 (2H, m), 7.32 (1H, s), 7.46 (1H, m), 7.76 (1H, m), 7.86 (1H, s), 8.1 (1H, m).
Reaction SMILES: [Cl:1]C1C=CC=CC=1O.[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[OH:17]>>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:1])[C:11]=1[OH:17]
Reactant: Oc1ccccc1Cl
Reactant: Oc1ccc(Cl)cc1Cl
Product: Oc1c(Cl)cc(Cl)cc1Cl

Procedure:
The addition of ortho-chlorophenol was then stopped and the chlorination was continued until the orthochlorophenol present and the 2,4-dichlorophenol had completely disappeared.
Reaction SMILES: [CH2:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[C:5]1=[O:16])[CH:2]=[CH2:3].[CH:17](=[O:21])/C=C/C>>[CH3:15][O:14][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:16])[N:4]([CH2:1]/[CH:2]=[CH:3]/[CH:17]=[O:21])[CH2:13][CH2:12]2
Reactant: C=CCN1CCc2cc(OC)ccc2C1=O
Reactant: C/C=C/C=O
Product: COc1ccc2c(c1)CCN(C/C=C/C=O)C2=O

Procedure:
The title compound 44 is prepared according to the procedure reported in step C of Example 8 with amide 43 (222.4 mg, 1.03 mmol) and crotonaldehyde (4.12 mmol, 4 equiv) as reactants. Brown solid. (Yield 242.5 mg, 96%).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:33])[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[CH3:34][N:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH:40]=O.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:1]([N:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:33])[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH2:40][C:36]3[N:35]([CH3:34])[CH:39]=[CH:38][N:37]=3)[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=3)=[CH:19][CH:18]=2)=[CH:13][CH:14]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CNCc3ccc(C)cn3)cc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ccc(C)cn3)Cc3nccn3C)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The compound (40.0 mg) obtained in Example 76-1 was dissolved in methanol (1.2 ml) and then added with 1-methylimidazol-2-aldehyde (11.9 mg) and sodium cyanoborohydride (11.3 mg). Then, the solution was adjusted to pH 5 with acetic acid and then stirred at room temperature for 14 hours. After completion of the reaction, a 1 mol/l sodium hydroxide aqueous solution was added to the reaction solution, followed by separation/extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and then treated with hydrochloric acid, thereby obtaining hydrochloride (42.5 mg) of the subject compound as a white solid.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[NH:7][CH:8]=1)([CH3:3])[CH3:2].[C:18](O)(=[O:21])[C:19]#[CH:20].N1(C(N2C=CN=C2)=O)C=CN=C1>>[C:10]([C:9]1[CH:20]=[CH:19][C:18](=[O:21])[N:7]2[CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[NH:5][C:6]=12)(=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)c1c[nH]c(CC(=O)c2ccccc2)n1
Reactant: C#CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)c1cn2c(=O)ccc(C(=O)c3ccccc3)c2[nH]1

Procedure:
The compound is prepared as described in example 15 with 105 mg (0.46 mmol) of 2-(4-isopropyl-1H-imidazol-2-yl)-1-phenylethanone (example X, 48.3 mg (0.69 mmol) of propiolic acid and 134 mg (0.83 mmol) of 1-(1H-imidazol-1-yl-carbonyl)-1H-imidazole.
Reaction SMILES: [Cl:1][C:2]1[S:17][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:4]=2[C:3]=1[CH3:18].Br[CH2:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>>[Cl:1][C:2]1[S:17][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:12][CH2:13][N:14]([CH2:20][C:21]4[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=4[C:23]#[N:24])[CH2:15][CH2:16]3)[C:4]=2[C:3]=1[CH3:18]
Reactant: Cc1c(Cl)sc2ncnc(NC3CCNCC3)c12
Reactant: N#Cc1ccccc1CBr
Product: Cc1c(Cl)sc2ncnc(NC3CCN(Cc4ccccc4C#N)CC3)c12

Procedure:
The title compound was prepared (100 mg, 75%) from 6-chloro-5-methyl-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine (95 mg, 0.336 mmol) and 2-(bromomethyl) benzonitrile (73 mg, 0.37 mmol) by following the general procedure described for Preparation 12. 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.65 (d, 1H), 7.55 (m, 2H), 7.35 (m, 1H), 5.30 (d, 1H), 4.25 (m, 1H), 3.7 (s, 2H), 2.85 (m, 2H), 2.50 (s, 3H), 2.40 (m, 2H), 2.10 (m, 2H), 1.40 (m, 2H). MS (ESI) m/z: Calculated: 397.92; Observed: 398.2 (M++1).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].Br[CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([S:28][CH3:29])[N:23]=1.[H-].[Na+]>C1COCC1>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH2:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([S:28][CH3:29])[N:23]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)[nH]1
Reactant: CSc1nccc(CBr)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nccc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)n1
Temperature: 55 °C
Reaction time: 16 h
Yield: 59.8 %

Procedure:
To a mixture of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one 5.0 g, 0.015 mol) and 4-(Bromomethyl)-2-(methylthio)pyrimidine (4.0 g, 0.018 mol) in THF (50.0 mL) was added NaH (0.4 g, 0.0017) and stirred at 55° C. under argon for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between 5% citric acid (25 mL) and EtOAc (50 mL). A precipitate was formed, it was filtered, washed with water, EtOAc, and dried in vacuo to afford the title compound (4.2 g, 59%) as a light brown powder, 1H NMR (CD3OD/400 MHz) δ 8.45 (d, 1H, J=5.2 Hz), 7.6 (m, 1H), 7.06 (d over m, 2H, J=5.2 Hz), 6.54 (s, 1H), 5.39 (s, 2H), 5.32 (s, 2H), 2.43 (s, 3H), 2.33 (s, 3H); ES-HRMS m/z 468.0173 (M+H C19H17N3O2BrSF2 requires 468.0187).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH2:9][CH2:8]2)=[N:3][CH:2]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:18]2[CH2:19][CH2:20][CH:15]([C:13]([N:10]3[CH2:9][CH2:8][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][N:3]=4)[CH2:12][CH2:11]3)=[O:14])[CH2:16][CH2:17]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: O=C(C1CCNCC1)N1CCN(c2ccncn2)CC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CCN(S(=O)(=O)c2ccc(Cl)cc2)CC1)N1CCN(c2ccncn2)CC1
Yield: 26 %

Procedure:
4-(1-(4-Pyrimidinyl)piperazin-4ylcarbonyl)piperidine (412 mg; 1.5 mmol) was dissolved in CH2Cl2 (16 ml), cooled in an ice bath, stirred and treated dropwise with a mixture of 4-Chlorobenzenesulfonyl chloride (338 mg; 1.6 mmol) and Et3N (0.3 ml; 2 mmol) in CH2Cl2 (16 ml). The reaction mixture was allowed to reach room temperature and stirred thus for 18 h before treating with saturated NaHCO3 (aq) This mixture was then extacted twice with CH2Cl2. The combined organic extracts were washed twice each with water and brine, dried over MgSO4, filtered and evaporated under reduced pressure to a yellow solid. The solid thus obtained was chromatographed through a 10 g silica "bond elut" prepacked column, eluting with 1% methanol, 1% ammonimum hydroxide and 98% CH2Cl2 to obtain 1-(4-chlorophenylsulphonyl)-4-(1-(4-pyrimidinyl)piperazin-4-ylcarbonyl)piperidine (178 mg; 26% yield based on the amine ), a white solid, m.p. 125-128° C.;
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[S:5][CH:6]=1.CI.[C:18]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:18][O:1][C:2]1[N:3]=[C:4]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Cc1nc(O)cs1)c1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1csc(CC(=O)c2ccccc2)n1
Temperature: 25 °C
Yield: 8014 %

Procedure:
To a suspension of 2-(4-hydroxy-1,3-thiazol-2-yl)-1-phenylethan-1-one (0.5 g, 2.3 mmol) in acetone (10 mL) at r.t. was added MeI (0.17 mL, 2.7 mmol), followed by K2CO3 (315 mg, 2.3 mmol). After stirring ON at r.t., the solvent was removed and the residue was taken up in Et2O/H2O. The organic layer was dried (MgSO4), filtered, and evaporated to yield o.43 g of the title compound.