Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].[C:6]([O:10][C:11](=O)[O:12]C(C)(C)C)([CH3:9])([CH3:8])[CH3:7]>>[CH3:7][C:6]([O:10][C:11](=[O:12])[NH:1][CH2:2][CH2:3][CH2:4][NH2:5])([CH3:9])[CH3:8]
Reactant: NCCCN
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)NCCCN

Procedure:
In Step 1, 1,3-diaminopropane (II) is reacted with a di-t-butylcarbonate (III) to give 3-aminopropyl carbamic acid 1,1-dimethylethyl ester (IV).
Reaction SMILES: Cl[C:2]1[C:3]2[S@:23](=[O:24])[CH2:22][CH2:21][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.[NH2:25][C@@H:26]([CH2:30][OH:31])[CH:27]([CH3:29])[CH3:28].CS(C)=O.C(N(C(C)C)CC)(C)C>O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[N:7]=[C:2]([NH:25][C@H:26]([CH:27]([CH3:29])[CH3:28])[CH2:30][OH:31])[C:3]4[S@:23](=[O:24])[CH2:22][CH2:21][C:4]=4[N:5]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: CC(C)[C@@H](N)CO
Reactant: O=[S@@]1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(Cl)c21
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CC(C)[C@H](CO)Nc1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1[S@](=O)CC2
Temperature: 25 °C
Yield: 178.9 %

Procedure:
Charge (R)-4-Chloro-2-[4-(4-chloro-phenyl)-piperazin-1-yl]-6,7-dihydro-thieno[3,2-d]pyrimidine-5-oxide (0.10 g), D-valinol (46.8 mg,), and DMSO (2 mL) to a 3 neck round bottom flask with temp. probe, nitrogen inlet and stir bar. Charge diisopropylethylamine (0.1 mL) and heat the mixture to 80° C. with stirring for 2 h. Cool the mixture to ambient temperature and charge water slowly (3-5 mL) which precipitates the product as an off-white solid. Filter the solid and rinse it with water. Dry the solid for 12 h at 50° C. under vacuum providing (R)-2-{(R)-2-[4-(4-Chloro-phenyl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-ylamino}-3-methyl-butan-1-ol (0.21 g, 92% yld.) as a off-white solid. Recrystallize from IPA/H2O (15 vols/0.5 vols) to give material of >99% purity. 1H NMR (400 MHz, CDCl3) δ 7.16-7.26 (m, 2H), 7.00 (bs, 1H), 6.80-6.90 (m, 2H), 4.02-4.12 (m, 1H), 3.90-4.00 (m, 4H), 3.68-3.85 (m, 3H), 3.55-3.65 (m, 1H), 3.35-3.45 (m, 1H), 3.12-3.20 (m, 4H), 2.94-3.08 (m, 2H), 1.92-2.06 (m, 1H), 0.95 (d, J=6.5 Hz, 3H), 0.90 (d, J=6.5 Hz, 3H); 13C NMR (400 MHz, CDCl3) δ 174.6, 163.1, 160.4, 150.1, 129.4, 125.3, 118.0, 107.6, 63.9, 58.6, 49.6, 44.1, 33.0, 29.7, 20.2, 19.8 (5 signals missing due to overlap); LCMS (ESI) for C21H29ClN5O2S (M+H)+: calcd. 450.2, obsvd. 450.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[F:12][CH2:13][C:14](=O)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[NH3:22]>C(O)C>[F:12][CH2:13][C:14]1[NH:22][C:14]([CH2:13][F:12])=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CC(=O)CF
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: N
Solvent: CCO
Product: CCOC(=O)C1=C(CF)NC(CF)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1

Procedure:
3-Nitrobenzaldehyde (1.51 g, 10 mmoles), ethyl 4-fluoro-3-oxo-butanoate (3 g, 20 mmoles) and aqueous ammonia (1.1 ml, d=0.88) in ethanol (15 ml) were heated at reflux for 14 hours more aqueous ammonia (0.55 ml) was added after 6 hours. The solvent was removed in vacuo and the residue was chromatographed on silica eluting with ether/petroleum ether (60°-80°) mixtures and the product obtained was recrystallised from 2-propanol to give the title compound as yellow crystals (0.4 g) mp 113°-4°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:11][N:12]2[CH2:17][C@@H:16]3[CH2:18][C@H:13]2[CH2:14][N:15]3C(OC(C)(C)C)=O)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[F:26][C:27]([F:39])([F:38])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34]([Cl:37])(=[O:36])=[O:35]>>[ClH:37].[ClH:37].[C@H:13]12[CH2:18][C@H:16]([NH:15][CH2:14]1)[CH2:17][N:12]2[CH2:11][C:4]1[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=[C:2]([NH:1][S:34]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([F:26])([F:38])[F:39])(=[O:36])=[O:35])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2Cc1cc(N)cc2ccoc12
Product: Cl
Product: O=S(=O)(Nc1cc(CN2C[C@@H]3C[C@H]2CN3)c2occc2c1)c1ccccc1C(F)(F)F
Yield: 45.8 %

Procedure:
starting from tert-butyl (1S,4S)-5-[(5-amino-1-benzofuran-7-yl)methyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (44 mg crude starting material, 0.10 mmol; obtained in Example 118, Step 2) and 2-(trifluoromethyl)benzenesulfonyl chloride (24 μL, 0.15 mmol). The title compound (18 mg, 34%) was obtained as an off-white solid. HPLC 99%, RT=1.46 min (System A; 10-97% MeCN over 3 min), 100%, RT=1.29 min (System B; 10-97% MeCN over 3 min). 1H NMR (400 MHz, methanol-d4) δ ppm 2.31-2.37 (m, J=13.05 Hz, 1H) 2.65-2.78 (m, J=6.27 Hz, 1H) 3.53-3.60 (m, J=13.43, 2.89 Hz, 1H) 3.67-3.76 (m, 1H) 3.88-3.96 (m, J=12.80 Hz, 1H) 4.51 (s, 1H) 4.66 (s, 1H) 4.72-4.79 (m, 1H) 4.84 (d, 2H) 6.88 (d, J=2.01 Hz, 1H) 7.46 (d, J=2.01 Hz, 1H) 7.51 (d, J=2.01 Hz, 1H) 7.68-7.75 (m, 2H) 7.88 (d, J=2.26 Hz, 1H) 7.89-7.94 (m, 1H) 8.09-8.13 (m, 1H). MS (ESI+) for C21H20F3N3O3S m/z 452 (M+H)+.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=O)[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[N:20]=1)[NH2:18]>C(O)(=O)C>[F:35][C:32]([F:33])([F:34])[C:29]1[CH:30]=[CH:31][C:26]([O:25][C:21]2[N:20]=[C:19]([N:17]=[N:18][C:13]3[C:14]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:12]=3[OH:16])[CH:24]=[CH:23][CH:22]=2)=[CH:27][CH:28]=1
Reactant: O=C1C(=O)c2ccccc2-c2ccccc21
Reactant: NNc1cccc(Oc2ccc(C(F)(F)F)cc2)n1
Solvent: CC(=O)O
Product: Oc1c(N=Nc2cccc(Oc3ccc(C(F)(F)F)cc3)n2)c2ccccc2c2ccccc12
Temperature: 100 °C

Procedure:
Then, a reaction flask was loaded with acetic acid (30 ml) and 9,10-phenanthrenequinone (2.0 g), and the temperature was raised to 100° C. with stirring to dissolve 9,10-phenanthrenequinone. To this mixture, 2-hydrazino-6-(4-trifluoromethylphenoxy)pyridine (3.0 g) was added in 15 minutes. After stirring at 95 to 105° C. for two hours, the reaction mixture was filtrated. The filtrated crystals were successively washed with hot water and hot methanol, followed by recrystallization with dioxane-water to give crystals, which were then filtrated and dried to give intended crystals (3.5 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.OO.[OH2:16].C(O)(=[O:19])C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)(=[O:19])=[O:16])=[CH:6][CH:7]=1
Reactant: O
Reactant: Fc1ccc(Sc2cccs2)cc1
Reactant: CC(=O)O
Agent: OO
Product: O=S(=O)(c1ccc(F)cc1)c1cccs1
Temperature: 100 °C
Yield: 63 %

Procedure:
To a solution of 2-(4-fluorophenylthio)thiophene (1.09 g, 5.18 mmol) in acetic acid (14.3 mL) was added a 30% aqueous solution of H2O2 (1.30 mL). The reaction mixture was heated at 100° C. for 45 min, then was treated with water. The resulting suspension was extracted with CH2Cl2. The combined organic layers were washed with a saturated NaHCO3 solution, dried (MgSO4) and concentrated under reduced pressure to yield 2-[(4-fluorophenyl)sulfonyl]thiophene (0.79 g, 63%) as a white solid: TLC (hex) Rf 0.08; 1H NMR (CDCl3) δ 7.09-7.27 (m, 3H), 7.67-7.71 (m, 2H), 7.99-8.04 (m, 2H).
Reaction SMILES: C[Al](C)C.[I:5][C:6]1[C:7]([S:12]([NH2:15])(=[O:14])=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:16][O:17][C:18]1[N:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([NH:26][C:27](=O)[O:28]C)[N:19]=1>C1(C)C=CC=CC=1.ClCCl>[CH3:25][O:24][C:22]1[N:23]=[C:18]([O:17][CH3:16])[N:19]=[C:20]([NH:26][C:27](=[O:28])[NH:15][S:12]([C:7]2[C:6]([I:5])=[CH:11][CH:10]=[CH:9][N:8]=2)(=[O:13])=[O:14])[N:21]=1
Reactant: COC(=O)Nc1nc(OC)nc(OC)n1
Reactant: NS(=O)(=O)c1ncccc1I
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1nc(NC(=O)NS(=O)(=O)c2ncccc2I)nc(OC)n1
Temperature: 0 °C

Procedure:
9.0 ml (18 mmol) of a 2M solution of trimethylaluminum in toluene are added dropwise at room temperature to 4.3 g (15 mmol) of 3-iodo-2-pyridinesulfonamide in 150 ml of dichloromethane. After evolution of gas has ceased, 3.85 [lacuna] (18 mmol) of methyl 4,6-dimethoxy-1,3,5-triazin-2-yl-carbamate in 20 ml of dichloromethane is added dropwise and the resulting solution is refluxed for 24 hours. The mixture is cooled and poured into 150 ml of ice-cold 1N hydrochloric acid. The organic phase is separated off and the aqueous phase is extracted 2× using dichloromethane. The organic phase is dried and evaporated. After triturating the crude product with diethyl ether, 3.1 g (44% of theory) of 3-(4,6-dimethoxy-1,3,5-triazin-2-yl)-1-(3-iodo-2-pyridylsulfonyl)urea of melting point 155° C. (dec.) are obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][CH3:13])=[CH:8][CH:7]=[CH:6][CH:5]=2.I([O-])(=O)(=O)=[O:15].[Na+].[OH2:20]>CO>[O:20]=[C:10]([C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:3][C:2](=[O:15])[CH3:1])[CH2:11][CH2:12][CH3:13]
Reactant: O
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCCc1c(C)[nH]c2ccccc12
Agent: [Na+]
Solvent: CO
Product: CCCC(=O)c1ccccc1NC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A solution of 2-methyl-3-propylindole (159 g) in methanol (1370 ml) was stirred under nitrogen while a solution of sodium periodate (430.4 g) in water (2450 ml) was added over a period of one hour. External cooling was applied as necessary to maintain the reaction temperature at or below 25°. After stirring at room temperature overnight, the mixture was diluted with water (7 liters) and was extracted with dichloromethane (2 liters). The phases were separated, and the aqueous layer was extracted twice more with dichloromethane (1 liter each). The combined organic phases were washed twice with water (1.5 liter each), dried (MgSO4), and evaporated to provide 246.5 grams of crude product. This material was purified by two successive chromatographies over flash silica gel, eluting the desired product with dichloromethane. Upon evaporation of the appropriate fractions, there was obtained 160.6 grams (85% yield) of the title compound as a white crystalline solid, m.p. 46.5°-47°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:22]=[C:23]1[O:27][C:25](=[O:26])[CH2:24]1>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:25](=[O:26])[CH2:24][C:23]([CH3:22])=[O:27])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OC1CCN(Cc2ccccc2)CC1
Reaction time: 1.5 h
Yield: 50 %

Procedure:
To a solution of 10.0 g of 1-benzyl-4-hydroxypiperidine and a catalytic amount of triethylamine in 10 ml of THF was added dropwise 4.62 g of diketene over 15 minutes. After the addition, the reaction was effected at room temperature for 1.5 hours and then at 50°-60° C. for 4.5 hours. The reaction mixture was concentrated, and then distilled under reduced pressure to obtain 7.20 g of acetoacetic acid-N-benzyl-4-piperidinyl ester (yield: 50.0%), b.p. 146° C./0.13 mmHg.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:20](O)=[O:21])[C:7]3[C:12](C)=[N:11][N:10]([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[NH2:23][CH2:24][C:25]1[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=1[CH3:31].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CS(C)=O>[CH:1]1([C:4]2[CH:5]=[C:6]([C:20]([NH:23][CH2:24][C:25]3[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=3[CH3:31])=[O:21])[C:7]3[CH:12]=[N:11][N:10]([C:14]4[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=4)[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: Cc1nn(-c2ccncc2)c2nc(C3CC3)cc(C(=O)O)c12
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CC3)nc3c2cnn3-c2ccncc2)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described for intermediate 56 using 6-cyclopropyl-3-methyl-1-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (89 mg, 0.302 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (69.0 mg, 0.454 mmol), 1-hydroxy-7-azabenzotriazole (82 mg, 0.605 mmol), DMSO (20 mL), EDC (116 mg, 0.605 mmol), and N-methylmorpholine (0.133 mL, 1.210 mmol). The final product was collected as 0.110 g (80%). LCMS E-S (M+H)=429.1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (br. s., 4H), 2.13 (br. s., 3H), 2.25 (br. s., 4H), 3.34 (br. s., 3H), 4.37 (br. s., 2H), 5.89 (br. s., 1H), 7.30 (br. s., 1H), 8.33 (br. s., 2H), 8.67 (br. s., 3H), 11.54 (br. s., 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][C@@H:19]1[CH2:24][N:25]1C(=O)C2C(=CC=CC=2)C1=O.Cl[C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1>>[F:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([C:7]([N:20]2[CH2:21][CH2:22][CH2:23][C@@H:18]([CH3:17])[C@H:19]2[CH2:24][NH:25][C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=2)=[O:9])[CH:10]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: Cc1cc(-n2nccn2)c(C(=O)O)cc1F
Product: Cc1cc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)cc1F

Procedure:
The title compound was prepared following the same general protocol as described in Example A318, using 5-fluoro-4-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid, 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione and 2-chloro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 477 (M+H).
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:10])[CH2:4][C:5]([O:7]CC)=[O:6].[CH3:11][N:12]([CH3:14])[CH3:13]>O>[OH:10][C@H:3]([CH2:4][C:5](=[O:6])[O-:7])[CH2:2][N+:12]([CH3:14])([CH3:13])[CH3:11]
Reactant: CN(C)C
Reactant: CCOC(=O)C[C@@H](O)CCl
Solvent: O
Product: C[N+](C)(C)C[C@H](O)CC(=O)[O-]
Temperature: 80 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
110 g of ethyl (+) (R)-4-chloro-3-hydroxybutyrate, prepared according to Example 2, and 280 ml of 45% trimethylamine in H2O are placed in a 0.6-liter reactor. The reaction mixture is heated to 80° C. and kept at this temperature for 2 h. After cooling and removing the excess of trimethylamine, the aqueous solution is extracted with 0.5 l of methylene chloride and analyzed with HPLC. L-carnitine is obtained with 71% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[Cl:11].[CH2:12]([O:14][C:15](=[O:24])[CH:16]=[CH:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH3:13].C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=CN2)C1C=CC=CC=1)C>>[CH2:12]([O:14][C:15](=[O:24])[CH:16]=[C:17]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[Cl:11])[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH3:13]
Reactant: Clc1n[nH]c2ccc(Br)cc12
Reactant: CCOC(=O)C=Cc1cccnc1
Agent: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CCOC(=O)C=C(c1cccnc1)c1ccc2[nH]nc(Cl)c2c1

Procedure:
3-(3-Chloro-1H-indazol-5-yl)-3-pyridin-3-yl-acrylic acid ethyl ester CCXXIII was prepared from 5-bromo-3-chloro-1H-indazole and 3-pyridin-3-yl-acrylic acid ethyl ester using the procedure described for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (Example 14).
Reaction SMILES: Cl.[C:2]([CH2:7][NH2:8])(=[O:6])[CH:3]([CH3:5])[CH3:4].C(=O)(O)[O-].[Na+].[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:8][CH2:7][C:2](=[O:6])[CH:3]([CH3:5])[CH3:4])=[O:20])=[CH:17][CH:16]=1
Reactant: CC(C)C(=O)CN
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)C(=O)CNC(=O)c1ccc(F)cc1
Yield: 89.4 %

Procedure:
4.0 g of isobutyrylmethylamine hydrochloride, 6.1 g of sodium bicarbonate and 5.1 g of 4-fluorobenzoyl chloride are treated in the same manner as described in Preparation 1-(4). 5.8 g of N-(4-fluorobenzoyl)isobutyrylmethylamine are thereby obtained. Yield: 89.2%.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH3:13])=[CH:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][CH:7]=2.[F:19][C:20]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=1[CH2:22]Br>CN(C=O)C>[F:19][C:20]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=1[CH2:22][N:5]1[C:6]2[C:11](=[CH:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][CH:7]=2)[C:12]([CH3:13])=[C:4]1[CH3:3]
Reactant: CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(F)cc1F
Reaction time: 0.5 h

Procedure:
NaH (1.1 equiv) was added to a solution of ethyl 2,3-dimethyl-1H-indole-5-carboxylate in DMF at room temperature. After 30 min, 2,4-difluorobenzyl bromide (1.1 equiv) was added to the reaction mixture and stirred for 1 h. After the reaction was completed, the solvent was removed in vacuo to obtain the crude which was purified by flash chromatography to obtain the compound. LC-MS 344 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20](OS(C1C=CC(C)=CC=1)(=O)=O)[C@H:21]1[O:23][CH2:22]1>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[CH:11][C:10]=1[O:19][CH2:20][C@H:21]1[CH2:22][O:23]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(C(F)(F)F)cc1OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Product: FC(F)(F)c1ccc(OC[C@H]2CO2)c(OCc2ccccc2)c1

Procedure:
The title compound was prepared from compound C and (S)-glycidyl-p-toluene sulfonate (B) employing the procedure used for the preparation of compound 5′.
Reaction SMILES: CN(C)C1C=CC=CC=1.ON=C(C1C=CC=CC=1)C#N.C(Cl)(Cl)=O.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][OH:32])=[CH:29][CH:28]=1.Cl[C:36]([O:38][N:39]=[C:40]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:41]#[N:42])=[O:37]>C1C=CC=CC=1.N1C=CC=CC=1>[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][O:32][C:36]([O:38][N:39]=[C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:41]#[N:42])=[O:37])=[CH:29][CH:28]=1
Reactant: COc1ccc(CO)cc1
Reactant: N#CC(=NOC(=O)Cl)c1ccccc1
Agent: N#CC(=NO)c1ccccc1
Agent: O=C(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)c1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(COC(=O)ON=C(C#N)c2ccccc2)cc1
Reaction time: 2 h

Procedure:
A solution of dimethylaniline (6.0 ml.) in benzene (15 ml.) was added dropwise to a suspension of 2-hydroxyimino-2-phenylacetonitrile (7.3 g.) and phosgene (5.0 g.) in benzene (50 ml.) for 40 minutes under ice-cooling. The mixture was stirred for 2 hours at the same temperature and allowed to stand overnight. A solution of 4-methoxybenzyl alcohol (6.9 g.) and pyridine (4.0 ml.) in benzene (20 ml.) was added dropwise, for 30 minutes under ice-cooling to the mixture containing 2-chlorocarbonyloxyimino-2-phenylacetonitrile. The mixture was stirred for 7 hours at room temperature. The reaction mixture was then washed with water, 1N hydrochloric acid, water, a sodium bicarbonate aqueous solution and water, and dried over magnesium sulfate. The solution was concentrated and the residual crystals were triturated in n-hexane and collected by filtration. The crystals were recrystallized from a mixture of ethyl acetate and n-hexane to give 2-(4-methoxybenzyl)oxycarbonyloxyimino-2-phenylacetonitrile (3.1 g.). Mp 112° to 113° C. The mother liquor was concentrated to give the desired compound (2.4 g.). Total yield (5.5 g.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[C:30]1[C:34]([CH2:35][CH2:36][CH2:37]O)=[C:33]([CH:39]([CH3:41])[CH3:40])[O:32][N:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Cl:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[C:24]=1[C:30]1[C:34]([CH2:35][CH2:36][CH2:37][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[C:15](=[CH:16][CH:17]=3)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]4)=[CH:4][CH:3]=2)=[C:33]([CH:39]([CH3:40])[CH3:41])[O:32][N:31]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCCO
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(-c3ccc(OCCCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Temperature: 90 °C
Yield: 22.1 %

Procedure:
To a solution of methyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate (31 mg, 0.11 mmol), 3-[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]-1-propanol (35 mg, 0.11 mmol) and triphenylphosphine (29 mg, 0.11 mmol) in dichloromethane (1 mL) was added diisopropyl azodicarboxylate (0.020 mL, 0.11 mmol). The solution was heated in a microwave reactor at 90° C. for 10 minutes and was then adsorbed onto silica gel and purified by chromatography (silica gel, 0-35% ethyl acetate in hexanes gradient elution) to afford methyl 6-[4-({3-[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]propyl}oxy)phenyl]-2-quinolinecarboxylate (14 mg, 22%). 1H-NMR (400 MHz, CDCl3) δ 8.33 (m, 2H), 8.21 (d, J=8 Hz, 1H), 8.03-7.99 (m, 2H), 7.63 (d, J=9 Hz, 2H), 7.40-7.28 (m, 3H), 6.91 (d, J=9 Hz, 2H), 4.09 (s, 3H), 3.89 (t, J=6 Hz, 2H), 3.19 (septet, J=7 Hz, 1H), 2.51 (t, J=6 Hz, 2H), 1.82-1.76 (m, 2H), 1.33 (d, J=7 Hz, 6H).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[F:22][C:23]([F:34])([F:33])[O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>>[F:22][C:23]([F:33])([F:34])[O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:8]2[C:9]([C:10](=[O:19])[C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]2=[O:20])=[CH:27][CH:26]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccc(OC(F)(F)F)cc2)c1
Yield: 66 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 4-trifluoromethoxybenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (304 mg, yield: 66.0%).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O)([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Product: O=[N+]([O-])c1ccccc1-n1cnc2ccc(O)nc21

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 2-nitrophenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=257.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[CH:18]=[CH:17][C:14]([CH2:15]O)=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Br:48])C(=O)C1.CCOCC>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[CH:18]=[CH:17][C:14]([CH2:15][Br:48])=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(OC)c1-c1ccc(CO)c([N+](=O)[O-])c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cccc(OC)c1-c1ccc(CBr)c([N+](=O)[O-])c1

Procedure:
To a solution of 1.8 g (6.23 mmol) of 4-(2′,6′-dimethoxyphenyl)-2-nitrobenzyl alcohol and 2.3 g (8.72 mmol) of Ph3P in CH2Cl2 (20 mL) at 0° C. was added 1.32 g (7.5 mmol) of NBS. The reaction mixture was stirred at 0° C. for 30 min at which time TLC analysis (eluted with 25% Et2O in hexanes) indicated that the starting material had been consumed. The reaction mixture was concentrated and the crude residue was purified by flash column chromatography on silica gel eluted with 50% Et2O in hexanes to give 4-(2′,6′-dimethoxyphenyl)-2-nitrobenzyl bromide as a pale yellow solid. Trituration with hexanes gave the product as a white solid.