Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13](/[CH:23]=[CH:24]/[C:25]2[N:39]=[C:28]3[CH:29]([CH:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)[CH2:30][CH2:31][CH2:32][N:27]3[N:26]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1.[Na].C(=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C.C(O)(=O)C>[CH2:1]([N:36]1[CH2:37][CH2:38][CH:33]([CH:29]2[CH2:30][CH2:31][CH2:32][N:27]3[N:26]=[C:25](/[CH:24]=[CH:23]/[C:13]4[CH:14]=[CH:15][C:16]([N:17]5[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]5)=[C:11]([O:10][CH3:9])[CH:12]=4)[N:39]=[C:28]23)[CH2:34][CH2:35]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(/C=C/c2nc3n(n2)CCCC3C2CCNCC2)ccc1-n1cnc(C)c1
Reactant: O=Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(/C=C/c2nc3n(n2)CCCC3C2CCN(Cc3ccccc3)CC2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzaldehyde (15 μl) and glacial acetic acid (16 μl) were added to a solution of racemic 2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(piperidin-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine obtained in Examples 118 and 119 (30 mg) in THF (2 ml), and the reaction solution was stirred at room temperature for 30 minutes. Sodium triacetoxyhydroborate (46 mg) was added to the reaction solution, and the reaction solution was stirred at room temperature for four hours. A saturated sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: ethyl acetate) to obtain 27 mg of racemic 8-(1-benzylpiperidin-4-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine. Then, the racemate was separated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: 50% ethanol-hexane) to obtain the title optically active compound with a retention time of 14 minutes and positive optical rotation (9.4 mg; >99% ee) and the title optically active compound with a retention time of 20 minutes and negative optical rotation (8.9 mg; 99% ee).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[CH:11][C:12]([O:18]C(C)(C)C)=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])=O)(C)(C)C.OC1C2N=NNC=2C=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.O[C:49]1[CH:57]=[CH:56][C:52]([C:53]([NH2:55])=[S:54])=[CH:51][CH:50]=1>CN(C)C=O.C(OCC)(=O)C>[C:53]([C:52]1[CH:56]=[CH:57][C:49]([O:16][C:14](=[O:15])[C:13]2[CH:17]=[C:9]([NH2:8])[CH:10]=[CH:11][C:12]=2[OH:18])=[CH:50][CH:51]=1)(=[S:54])[NH2:55]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(C)(C)C)c(C(=O)O)c1
Reactant: NC(=S)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=S)c1ccc(OC(=O)c2cc(N)ccc2O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To the solution of 4- or 5-tert-butoxycarbonylamino-2-hydroxy-benzoic acid (2) (3.0 mmol) in 50 mL of dimethylformamide, hydroxybenzotriazole (3.3 mmol) and DCC (3.3 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture, 4-hydroxy-thiobenzamide (3.0 mmol) was added and stirred mechanically for 3 h at 0°C. and 72 h at room temperature. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in ethyl acetate; the organic layer washed with brine, dried on anhydrous MgSO4, filtered and the solvent evaporated. The crude intermediate (7) was treated with a solution of 40% TFA in CH2Cl2. After 2 h the solvent was removed to obtain compound (8) as a crude residue. The residue was loaded on a silica gel open column and eluted with CH2Cl21MeOH (8/2), from which 4- or 5-Amino-2-hydroxy-benzoic acid 4-thiocarbamoyl-phenyl ester (8), compound of Formula XXVII, was obtained (48% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[C:21]([CH3:22])=[CH:20][C:19](/[CH:23]=[CH:24]/[C:25](O)=[O:26])=[CH:18][C:17]=3[CH3:28])=[N:13][CH:14]=2)=[CH:5][CH:4]=1.Cl.Cl.[CH3:33][C:34]1[CH:56]=[CH:55][C:37]([O:38][CH2:39]/[CH:40]=[CH:41]/[C:42]2[CH:54]=[CH:53][C:45]([CH2:46][N:47]3[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]3)=[CH:44][CH:43]=2)=[CH:36][CH:35]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCN(CC)CC>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[C:17]([CH3:28])=[CH:18][C:19](/[CH:23]=[CH:24]/[C:25]([N:50]4[CH2:49][CH2:48][N:47]([CH2:46][C:45]5[CH:53]=[CH:54][C:42](/[CH:41]=[CH:40]/[CH2:39][O:38][C:37]6[CH:36]=[CH:35][C:34]([CH3:33])=[CH:56][CH:55]=6)=[CH:43][CH:44]=5)[CH2:52][CH2:51]4)=[O:26])=[CH:20][C:21]=3[CH3:22])=[N:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(OC/C=C/c2ccc(CN3CCNCC3)cc2)cc1
Reactant: COc1ccc(COc2ccc(Oc3c(C)cc(/C=C/C(=O)O)cc3C)nc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(Oc3c(C)cc(/C=C/C(=O)N4CCN(Cc5ccc(/C=C/COc6ccc(C)cc6)cc5)CC4)cc3C)nc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 91.3 %

Procedure:
To a solution of (E)-3-[4-({5-[(4-methoxybenzyl)oxy]pyridin-2-yl}oxy)-3,5-dimethylphenyl]prop-2-enoic acid (0.122 g) and 1-{4-[(E)-3-(4-methylphenoxy)prop-1-en-1-yl]benzyl}piperazine dihydrochloride (0.119 g) in DMF (2 mL) were added Et3N (0.08 mL), WSC (0.070 g), and HOBT (0.055 g) at room temperature under an Ar atmosphere. The mixture was stirred at room temperature for 14 hours, and evaporated under reduced pressure. To the residue was added saturated aqueous NaHCO3, and the mixture was extracted with AcOEt. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt). The resulting powder was crystallized from EtOH (10 mL) to give (2E)-3-[4-({5-[(4-methoxybenzyl)oxy]pyridin-2-yl}oxy)-3,5-dimethylphenyl]-1-(4-{4-[(1E)-3-(4-methylphenoxy)prop-1-en-1-yl]benzyl}piperazin-1-yl)prop-2-en-1-one (0.195 g) as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C@H:13]([C:15]2[CH:16]=[C:17]3[C:26](=[CH:27][C:28]=2Br)[O:25][CH2:24][C:23]2[N:18]3[C@H:19]([CH3:31])[C:20](=[O:30])[NH:21][N:22]=2)[CH3:14])([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C@@H:13]([C:15]2[CH:16]=[C:17]3[C:26](=[CH:27][C:28]=2[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[F:32])[O:25][CH2:24][C:23]2[N:18]3[C@H:19]([CH3:31])[C:20](=[O:30])[NH:21][N:22]=2)[CH3:14])([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(Br)c([C@H](C)C4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c([C@@H](C)C4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 90 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
To a solution of 3-[(S)-1-((R)-7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-ethyl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (Example #133, Step D, 0.08 g, 0.162 mmol), (2-fluorophenyl)boronic acid (0.027 g, 0.195 mmol) and sodium carbonate (0.034 g, 0.324 mmol) in 1,4-dioxane (2.0 mL) and water (0.5 mL) was added PdCl2(dppf)-DCM adduct (0.013 g, 0.016 mmol) and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was partitioned between EtOAc (30 mL) and water (30 mL). The organic layer was separated and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuo and the residue was purified by prep-TLC (eluting with 5% methanol in dichloromethane) to give 3-{(R)-1-[(R)-7-(2-fluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-ethyl}-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.083 g, 100%). 1H NMR (CDCl3, 400 MHz): δ 8.12 (br. s, 1H), 7.37 (m, 1H), 7.08-7.26 (m, 3H), 6.84-6.91 (m, 1H), 6.79 (m, 1H), 4.73-4.87 (m, 1H), 4.59-4.68 (m, 2H), 3.57 (m, 1H), 3.44-3.51 (m, 1H), 3.33-3.41 (m, 1H), 3.25 (m, 1H), 2.86 (m, 1H), 1.55 (d, J=6.8 Hz, 3H), 1.35-1.47 (m, 9H), 1.22-1.35 (m, 3H), 1.07-1.21 (m, 3H). LC/MS (Table 1, Method 25) Rt=0.883 min; MS (ESI): m/z 531 [M+Na]+ and 453 [M+H−56]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([CH2:15][C:16]([OH:18])=[O:17])[CH:13]=[CH:12][C@@H:11]1[OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH2:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([CH2:15][C:16]([O:18][CH3:20])=[O:17])[CH:13]=[CH:12][C@@H:11]1[OH:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C[C@H]1C=C[C@H](O)[C@@H]1COCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)C[C@H]1C=C[C@H](O)[C@@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 100.2 %

Procedure:
To a solution of 23.6 g of (1S,2S,3S)-2-benzyloxymethyl-3-carboxymethyl-4-cyclopenten-1-ol [the compound described in J. Am. Chem. Soc., 93, 1492 (1971)] in 200 ml of acetone, 27.6 g of potassium carbonate and 11.36 g of methyl iodide were added. The mixture was stirred for 50 min at room temperature, and then refluxed for 2 hrs. After reacting, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (2:1) as eluent to give 24.9 g of the title compound having the following physical characteristics, in a 99% yield.
Reaction SMILES: [CH2:1](I)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[C:17]([C:20]1[S:24][C:23]2[C:25]3[C:30]([CH2:31][CH2:32][C:22]=2[CH:21]=1)=[CH:29][C:28]([OH:33])=[CH:27][CH:26]=3)(=[O:19])[CH3:18]>C(OCC)(=O)C.CCCCCC.O>[C:17]([C:20]1[S:24][C:23]2[C:25]3[C:30]([CH2:31][CH2:32][C:22]=2[CH:21]=1)=[CH:29][C:28]([O:33][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:27][CH:26]=3)(=[O:19])[CH3:18]
Reactant: CCCCI
Reactant: CC(=O)c1cc2c(s1)-c1ccc(O)cc1CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCOc1ccc2c(c1)CCc1cc(C(C)=O)sc1-2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
0.46 mL of butyl iodide and 0.83 g of potassium carbonate were added to a 10 mL dimethylformamide solution of 0.5 g of the compound obtained in Example 39, and the system was stirred for 2 hours at 80° C. After the reaction, water was added and extraction was performed with ethyl acetate. The extracted organic layer was washed with saturated brine, dried with magnesium sulfate, and then subjected to reduced-pressure solvent distillation. The residue thus obtained was refined by silica gel column chromatography (10% ethyl acetate/hexane) and then recrystallized with ethanol to obtain 0.48 g of 2-acetyl-4,5-dihydro-7-(n-butyloxy)naphtho[1,2-b]thiophene (Table 7-1) in the form of yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][Si](C)(C)C)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].O>CO>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[Si](C)(C)C#Cc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1ccc([N+](=O)[O-])cc1

Procedure:
4-Nitrophenyltrimethylsilylacetylene is reacted at ambient temperature for 3 hours with 3 g of potassium carbonate in 300 ml of methanol. The resulting reaction product mixture is poured into 1500 ml of distilled water to precipitate crude 4-nitrophenylacetylene product. The crude product is separated by filtration, washed with water, and dried in a vacuum oven at 50° C. and 1 Torr.
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[F:24][C:25]1[CH:26]=[C:27]([CH:44]=[CH:45][C:46]=1[O:47][CH3:48])[CH2:28][N:29]1[CH2:33][CH2:32][N:31]([C:34]2[S:35][C:36]([C:40]([OH:42])=O)=[C:37]([CH3:39])[N:38]=2)[C:30]1=[O:43]>>[F:24][C:25]1[CH:26]=[C:27]([CH:44]=[CH:45][C:46]=1[O:47][CH3:48])[CH2:28][N:29]1[CH2:33][CH2:32][N:31]([C:34]2[S:35][C:36]([C:40]([NH2:7])=[O:42])=[C:37]([CH3:39])[N:38]=2)[C:30]1=[O:43]
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: COc1ccc(CN2CCN(c3nc(C)c(C(=O)O)s3)C2=O)cc1F
Product: COc1ccc(CN2CCN(c3nc(C)c(C(N)=O)s3)C2=O)cc1F

Procedure:
Following the procedure as described in Example 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-thiazole-5-carboxylic acid with 2-(3-(3-fluoro-4-methoxybenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid: mp 182-184° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.31 (br, 2H), 7.20-7.07 (m, 3H), 4.37 (s, 2H), 4.03-3.97 (m, 2H), 3.82 (s, 3H), 3.48-3.42 (m, 2H), 2.46 (s, 3H); MS (ES+) m/z 365.2 (M+1).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:39]([CH2:40][CH2:41][CH2:42][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([CH2:51][OH:52])[CH:36]=3)[C:31]2=[O:53])=[CH:26][CH:25]=1>ClCCl.[O-]S([O-])(=S)=O.[Na+].[Na+]>[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:39]([CH2:40][CH2:41][CH2:42][CH2:43][C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45])=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([CH:51]=[O:52])[CH:36]=3)[C:31]2=[O:53])=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)CCCCc1cc2cc(CO)ccc2c(=O)n1-c1ccc(F)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCCCc1cc2cc(C=O)ccc2c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
Dess-Martin Periodinane (1296 mg, 3.06 mmol) was added to a stirred, room temperature mixture of tert-butyl 5-(2-(4-fluorophenyl)-6-(hydroxymethyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (650 mg, 1.528 mmol) in dichloromethane (15 mL), and the mixture was stirred at room temperature for 2 h. The mixture was diluted with dichloromethane (20 mL), Na2S2O3 saturated (20 mL) was added, stirred at room temperature for 20 min, the aqueous layer was extracted once more with dichloromethane (15 mL), the combined organic was washed with aqueous sodium hydrogen carbonate saturated (3×15 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give tert-butyl 5-(2-(4-fluorophenyl)-6-formyl-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (638 mg, 1.507 mmol) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:5][C:4]([C:12]([O:14]C(C)C)=[O:13])([C:6]([O:8]C(C)C)=[O:7])[CH2:3]1.[OH-].[K+]>C(O)C.O>[CH3:1][C:2]1([CH3:18])[CH2:5][C:4]([C:6]([OH:8])=[O:7])([C:12]([OH:14])=[O:13])[CH2:3]1
Reactant: CC(C)OC(=O)C1(C(=O)OC(C)C)CC(C)(C)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)CC(C(=O)O)(C(=O)O)C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 89.4 %

Procedure:
To a stirred solution of Intermediate 285B (1.5 g, 5.85 mmol) in ethanol (20 ml) was added a solution of KOH (1.313 g, 23.41 mmol) in water (10 mL). The resulting solution was stirred at 80° C. for 16 h. The reaction mixture was cooled to RT, quenched with crushed ice and extracted with diethyl ether (2×50 mL). The combined organic layers were dried over Na2SO4 and evaporated to afford Intermediate 285C as a viscous liquid (0.9 g, 89% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.64 (br. s., 2H), 2.17-2.29 (m, 4H), 1.01-1.12 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH3:30])=[C:21]([C:23]([O:25]CCCC)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH3:30])=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)oc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C(=O)O)c(C)o3)C[C@H]2OC)nc1Cl
Yield: 98.5 %

Procedure:
The same operation as in Example (91d) was performed using butyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-methyl-1,3-oxazole-4-carboxylate obtained in Example (106d) (0.32 g, 0.69 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (2 mL) and THF (5 mL), to obtain 0.28 g of the title compound as a colorless solid (99%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Br[CH2:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH:8]1([CH2:7][N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: c1cn[nH]c1
Reactant: BrCC1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1cnn(CC2CCCC2)c1
Temperature: 110 °C

Procedure:
A flask was charged with pyrazole (380 mg), (bromomethyl)cyclopentane (968 mg), tetrabutylammonium bromide (18 mg), 50% aqueous NaOH (0.6 mL) and toluene (1.5 mL) and the mixture was heated to 110° C. for 4.5 hours. The reaction mixture was cooled to room temperature and partitioned between toluene (3×10 mL) and H2O (10 mL). The extracts were dried (MgSO4), filtered, and concentrated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:12])[N:3]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O>CN(C)C=O>[C:17]1([C:15]2[N:1]=[C:2]3[C:7]4[N:8]=[CH:9][CH:10]=[CH:11][C:6]=4[NH:5][C:4](=[O:12])[N:3]3[CH:14]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1nc(=O)[nH]c2cccnc12
Solvent: CN(C)C=O
Product: O=c1[nH]c2cccnc2c2nc(-c3ccccc3)cn12
Temperature: 150 °C

Procedure:
A mixture of 4-Amino-pyrido[2,3-e]pyrimidin-2-one (95 mg) and α-bromo-acetophenone (117 mg) in 4 mL of dimethylformamide (DMF) was heated at about 150° C. for 20 min. The reaction mixture was concentrated in vacuo and the residue was subjected to flash chromatography on silica gel with 10% methanol/methylene chloride as the eluent to afford 2-Phenylimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one. (Compound 15), m.p. 329°-330° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[CH:52]=[C:53]2[C:58](=[CH:59][CH:60]=1)[CH:57]=[C:56]([C:61]1[CH:62]=[C:63]([NH2:67])[CH:64]=[CH:65][CH:66]=1)[CH:55]=[CH:54]2>CN(C)C=O>[CH3:49][O:50][C:51]1[CH:52]=[C:53]2[C:58](=[CH:59][CH:60]=1)[CH:57]=[C:56]([C:61]1[CH:62]=[C:63]([NH:67][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:64]=[CH:65][CH:66]=1)[CH:55]=[CH:54]2
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: COc1ccc2cc(-c3cccc(N)c3)ccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2cc(-c3cccc(NC(=O)c4cc5cccc(O)c5oc4=O)c3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
Diisopropylethylamine (DIEA, 0.0115 mL, 0.067 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.012 g, 0.06 mmol) and O-(7-Azabenzotriazole-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (HATU, 0.025 g, 0.067 mmol) in 0.5 mL of dimethylformamide (DMF) with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(6-methoxy-naphthalen-2-yl)-phenylamine (0.015 g, 0.06 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in dimethylsulfoxide (DMSO). The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% acetonitrile (ACN)/H2O with 0.05% trifluoroacetic acid (TFA) at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected. Solvent was removed under vacuum and the resulting solid was left overnight in vacuo to give 0.010 g of product in 38% yield: LCMS (ESI) m/z 438 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1C(=O)C(=O)O[C:7]12[CH3:17].IC1C=CC=CC=1CCNC(=O)C.C(Cl)(C(Cl)=O)=O.Cl>C(Cl)Cl>[I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]=[C:7]2[CH3:17]
Reactant: CC12OC(=O)C(=O)N1CCc1c(I)cccc12
Agent: CC(=O)NCCc1ccccc1I
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC1=NCCc2c(I)cccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
7-iodo-10b-methyl-5,6-dihydro-2H-oxazolo[2,3-a]isoquinoline-2,3(10bH)-dione. A solution of N-(2-iodophenethyl)acetamide (16.0 g, 55.3 mmol) in DCM (600 mL) under N2, was treated dropwise with (COCl)2 (5.33 mL, 60.9 mmol). The reaction was stirred at RT for 45 min and then cooled to 0° C. FeCl3 (10.8 g, 66.4 mmol) was then added and the mixture was allowed to slowly warm to RT and stirred at RT for 18 h. An aq. solution of 2N HCl (50 mL) was added and the mixture was stirred for 2 h. The organic phase was separated, dried over Na2SO4, filtered and concentrated in vacuo to provide the title compound as a brown solid (20.8 g) that was used as it is in the next step. UPLC-MS: MS 344.3 (M+H+); UPLC rt 1.10 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:22][C:23]#[N:24])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[CH:3]=1.C([Sn](=O)CCCC)CCC.[N:44]([Si](C)(C)C)=[N+:45]=[N-:46]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:22][C:23]2[NH:46][N:45]=[N:44][N:24]=2)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[CH:3]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1ccc(S(=O)(=O)N(CC#N)c2ccc(Cl)cc2C(=O)c2ccccc2Cl)cc1OC
Agent: CCCC[Sn](=O)CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)N(Cc2nnn[nH]2)c2ccc(Cl)cc2C(=O)c2ccccc2Cl)cc1OC

Procedure:
To 1 g of N-[4-chloro-2-(2-chlorobenzoyl)phenyl]-N-(cyanomethyl)-3,4-dimethoxybenzenesulfonamide dissolved in 20 ml of THF are successively added 0.3 g of dibutyltin oxide and 2.6 ml of azidotrimethylsilane, and the mixture is refluxed for 18 hours. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is purified by filtration on silica H, eluting with dichloromethane, to give 0.95 g of the expected product.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](Cl)=[O:6].[CH3:12][NH:13][CH3:14]>>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([N:13]([CH3:14])[CH3:12])=[O:6]
Reactant: Cc1ccc(C(=O)Cl)cc1I
Reactant: CNC
Product: Cc1ccc(C(=O)N(C)C)cc1I

Procedure:
By the reaction in the same manner as in Example 27-i) using 3-iodo-4-methylbenzoyl chloride (2.00 g) and 50% aqueous dimethylamine solution (20 ml), the title compound (1.72 g) was obtained as a pale-yellow oil.