Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:13]([O:17][C:18]([C@@:20]1([NH:30]C(OC(C)(C)C)=O)[C@@H:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:21]1[CH3:29])=[O:19])([CH3:16])([CH3:15])[CH3:14].[OH-].[Na+]>C(#N)C>[C:13]([O:17][C:18]([C@@:20]1([NH2:30])[C@@H:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@H:21]1[CH3:29])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: C[C@@H]1[C@H](c2ccccc2)[C@]1(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: C[C@@H]1[C@H](c2ccccc2)[C@]1(N)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
Under argon atmosphere, p-toluenesulfonic acid monohydrate (3.5 g, 18 mmol) was added to a solution of (1S,2R,3R)-1-t-butoxycarbonylamino-2-methyl-3-phenyl-cyclopropanecarboxylic acid t-butyl ester (3.2 g, 9.1 mmol) obtained in Preparation Example 5-2 in acetonitrile (30 mL) at 0° C., and the mixture was stirred at room temperature for 16 hours. The obtained solution was cooled to 0° C., and 1N aqueous sodium hydroxide solution (20 mL) was added. The aqueous layer was extracted twice with ethyl acetate (15 mL) and dried over magnesium sulfate. Then, the residue was filtrated and the solvent was evaporated to give a crude product of the title compound (1.8 g, yield 99%) as a crude product of a pale-yellow oil. The obtained product was used in the next step without purification.
Reaction SMILES: [CH:1]([NH2:5])([CH2:3][CH3:4])[CH3:2].Cl[C:7]1[C:8]([N+:18]([O-:20])=[O:19])=[C:9]([CH3:17])[C:10]([CH3:16])=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14]>C(O)C>[CH:1]([NH:5][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[C:9]([CH3:17])[C:8]=1[N+:18]([O-:20])=[O:19])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)N
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C
Solvent: CCO
Product: CCC(C)Nc1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]

Procedure:
(-)-sec-Butylamine [prepared according to L. Verbit and P. J. Heffron, Journal of Organic Chemistry 32, 3199 (1967)] was reacted with 4-chloro-3,5-dinitro-o-xylene as by the general procedure of Example 5 to give a yellow-orange solid with melting point 37° C. to 38.5° C., [α]D25° = -51.38° (c 2.071, ethanol). Concentrations, abbreviated c herein, are measured in grams per 100 ml. of solution.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1B(O)O.Cl[C:17]1[N:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH2:19][CH2:20][N:21]([S:27]([NH:30][C:31]1[S:35][N:34]=[CH:33][N:32]=1)(=[O:29])=[O:28])[CH2:22]2>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:17]1[N:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH2:19][CH2:20][N:21]([S:27]([NH:30][C:31]1[S:35][N:34]=[CH:33][N:32]=1)(=[O:29])=[O:28])[CH2:22]2
Reactant: O=S(=O)(Nc1ncns1)N1CCc2c(ccnc2Cl)C1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Product: COc1cc(C(F)(F)F)ccc1-c1nccc2c1CCN(S(=O)(=O)Nc1ncns1)C2

Procedure:
The title compound was prepared in a manner analogous to Example 1, except that (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid was used in place of (2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)boronic acid and 5-chloro-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2,6-naphthyridine-2(1H)-sulfonamide (Intermediate V) was used in place of 5-bromo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide. [M+H]+=472.0 1H NMR (400 MHz, Acetone-d6) δ ppm: 8.41 (d, J=5.1 Hz, 1H), 8.25 (s, 1H), 7.35-7.44 (m, 3H), 7.20 (d, J=5.1 Hz, 1H), 4.26-4.51 (m, 2H), 3.89 (s, 3H), 3.43-3.56 (m, 1H), 3.15-3.26 (m, 1H), 2.82-2.93 (m., 1H), 2.40-2.56 (m, 1H)
Reaction SMILES: [CH:1]([C:3]1[N:8]=[N:7][C:6]2[O:9][CH2:10][CH2:11][C:5]=2[CH:4]=1)=C.I([O-])(=O)(=O)=[O:13].[Na+].O1CCOCC1>O.[Os](=O)(=O)(=O)=O>[N:7]1[C:6]2[O:9][CH2:10][CH2:11][C:5]=2[CH:4]=[C:3]([CH:1]=[O:13])[N:8]=1
Reactant: C=Cc1cc2c(nn1)OCC2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1cc2c(nn1)OCC2
Reaction time: 3 h
Yield: 20.7 %

Procedure:
A mixture of 3-ethenyl-5,6-dihydrofuro[2,3-c]pyridazine (110 mg, 0.74 mmol), 4% osmium tetroxide in water (0.66 ml), sodium periodate (367 mg), 1,4-dioxane (6.6 ml) and water (1.3 ml) was stirred for 3 hours. The mixture was evaporated and the residue treated with chloroform and added to the top of a column. Elution with ethyl acetate afforded the product (23 mg).
Reaction SMILES: CC[O-].[Na+].[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:6].[N:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[N+:14]=[N-:15].O>CCO>[CH2:11]([O:10][C:8]([C:7]1[N:15]=[N:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]=1[NH2:6])=[O:9])[CH3:12]
Reactant: [N-]=[N+]=Nc1ccccc1
Reactant: CCOC(=O)CC#N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1nnn(-c2ccccc2)c1N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51 %

Procedure:
To a freshly prepared NaOEt (1.18 mmol) solution in EtOH (0.75 mL) is added ethyl cyanoacetate (100 mg, 0.88 mmol) at 0° C. After stirring at 0° C. for 10 min., azido-benzene (100 mg, 0.84 mmol, prepared according to the method reported by M. Kurumi et al. Heterocycles. 2000, 53, 2809) is added. After the addition, the mixture is allowed to slowly warm up to room temperature and stirred for 14 h. The mixture is then treated with water (3 mL) and extracted with EtOAc (3×3 mL). The combined extracts is concentrated and purified by flash column chromatography (silica gel, 0%-70% EtOAc/hexane) to provide 5-amino-1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester as a white solid (100 mg, 51%). HPLC-MS calculated C11H12N4O2 (M+1+): 233.1. Found: 233.1.
Reaction SMILES: [C:1]([N@@:4]1[CH2:6][CH:5]1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[CH2:11]([OH:14])[C:12]#[CH:13].B(F)(F)F.CCOCC>C(Cl)Cl>[C:1]([NH:4][C@H:5]([CH2:6][O:14][CH2:11][C:12]#[CH:13])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: C#CCO
Reactant: COC(=O)C1CN1C(C)=O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: C#CCOC[C@@H](NC(C)=O)C(=O)OC
Temperature: -20 °C
Reaction time: 2.5 h
Yield: 68.4 %

Procedure:
(R)-Methyl 1-acetylaziridine-2-carboxylate (1.50 g, 10.49 mmol) was dissolved in CH2Cl2 (40 mL) and cooled to −20° C. under Ar, and then propargyl alcohol (0.92 mL, 15.74 mmol) was added. After the solution was stirred (2 min), BF3.Et2O (1.39 mL, 11.01 mmol) was added dropwise. The reaction mixture was allowed to stir at room temperature (2-3 h) and then washed with saturated aqueous NaHCO3 (30 mL) and saturated aqueous brine (30 mL). The organic layer was dried (Na2SO4) and evaporated in vacuo, and then the crude product was purified by column chromatography (SiO2; 3/1 EtOAc/hexanes) and crystallized (cold hexanes) to yield 1.43 g (68%) of desired product as a white solid: mp 58.5-59.5° C.; [α]25D −64.6° (c 1, CHCl3); Rf=0.35 (3/1 EtOAc/hexanes); IR (nujol mull) 3301, 2919, 2114, 1750, 1639, 1542, 1457 cm−1; 1H NMR (CDCl3) δ 2.06 (s, CH3C(O)), 2.46 (t, J=2.3 Hz, CH2CCH), 3.78 (s, OCH3), 3.79 (dd, J=3.3, 9.6 Hz, CHH′OCH2), 3.98 (dd, J=2.9, 9.6 Hz, CHH′OCH2), 4.09-4.21 (m, OCH2C), 4.77-4.82 (m, CH), 6.33-6.35 (br d, J=7.2 Hz, NHCH); 13C NMR (CDCl3) δ 23.3 (CH3C(O)), 52.6 (CH), 52.8 (OCH3), 58.7 (CH2CCH), 69.6 (CH2OCH2), 75.3 (CH2CCH), 79.0 (CH2CCH), 170.1, 170.8 (2 C(O)); HRMS (ESI) 200.0916 [M+H+] (calcd. for C9H14NO4 200.0923); Anal. (C9H13NO4) Calcd.: C, 54.26%; H, 6.58%; N, 7.03%. Found: C, 54.30%; H, 6.66%; N, 6.89%.
Reaction SMILES: [CH:1]([O:4][C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16]C(=O)OCC3C=CC=CC=3)[C:12]2=[O:27])[C@H:7]([CH2:28][S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH2:6]1)([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:16][C@H:13]1[CH2:14][CH2:15][N:11]([C@H:8]2[CH2:9][CH2:10][C@@H:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH2:6][C@H:7]2[CH2:28][S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])[C:12]1=[O:27]
Reactant: [H][H]
Reactant: CC(C)O[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)O[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Reaction time: 8 h

Procedure:
A sample of benzyl (S)-1-((1S,2R,4R)-4-isopropoxy-2-(isopropylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate A (faster ismer, 0.41 g) and Pd/C (0.08 g) were taken in MeOH (20 mL) and stirred at rt under 50 psi hydrogen pressure. After stirring overnight, the reaction mixture was filtered through Celite using EtOAc. Upon concentration and drying in vacuo, (S)-3-amino-1-((1S,2R,4R)-4-isopropoxy-2-(isopropylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one was obtained as a clear viscous oil.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O-:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.O1C=CC[CH2:14][CH2:13]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:13]([O:11][C:9](=[O:10])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1)[CH3:14]
Reactant: O=C([O-])Cc1cccc(O)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Cc1ccccc1
Reaction time: 3 h

Procedure:
To a 0° C. solution of 116 g (0.644 mol) of the above 3hydroxyphenylacetate in 645 ml dichloromethane and 64.6 ml (0.71 mol) dihydropyran was added a few crystals of 4-toluenesulfonic acid monohydrate. The reaction was stirred for 3 hours at 0° and then added to 200 ml saturated sodium bicarbonate. The organic extract was dried over magnesium sulfate and evaporated to give 161 g (95%) of 3-(tetrahydro-2H-pyran-2-yl)oxy]-phenylacetic acid ethyl ester as an oil.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:25][N:26]([CH3:36])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[CH3:25][N:26]([CH3:36])[C:27]1[CH:32]=[C:31]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: CN(C)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3cccc(N(C)C)c3)n2n1
Temperature: 110 °C
Yield: 25.5 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 80 mg, 0.232 mmol), 3-(dimethylamino)phenylboronic acid (49.8 mg, 0.302 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17 mg, 23 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.774 mL of 1,4-dioxane and 0.387 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (35-40% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (25.4 mg, 26%). 1H NMR (DMSO-d6) δ: 11.09 (s, 1H), 7.90-7.98 (m, 2H), 7.86 (s, 1H), 7.48-7.60 (m, 2H), 7.31-7.38 (m, 1H), 7.28-7.32 (m, 1H), 7.19 (d, J=8.1 Hz, 1H), 6.92 (dd, J=8.1, 2.3 Hz, 1H), 6.30 (s, 1H), 2.91 (s, 6H), 2.33 (s, 3H), 1.39 (s, 6H); ESI-MS: m/z 430.3 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:13]=[CH:14][C:15]([F:28])=[C:16]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:17]=3)=[N:7][N:6]2[CH:29]=1.[C:30](Cl)(=[O:33])[CH2:31][CH3:32].O>CN(C)C(=O)C>[F:28][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]3[N:6]([CH:29]=[C:3]([NH:2][C:30](=[O:33])[CH2:31][CH3:32])[N:4]=3)[N:7]=2)=[CH:17][C:16]=1[NH:18][C:19]([C:21]1[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=1)=[O:20]
Reactant: CCC(=O)Cl
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2F)n(C)n1
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCC(=O)Nc1cn2nc(Oc3ccc(F)c(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
To a solution of N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide.hydrochloride (200 mg, 0.48 mmol) in N,N-dimethylacetamide (2.0 mL) was added propionyl chloride (49.9 μL, 0.57 mmol), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=3/1→ethyl acetate alone) and washed with ethyl acetate to give the title compound (78 mg, 37%) as a white powder.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([O-:4])=[O:3].C(=O)([O-])O.[Na+].[C:18](Cl)(=[O:22])[C:19]([CH3:21])=[CH2:20]>O.C(OCC)(=O)C>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])=[CH:11][CH:12]=1)([O-:4])=[O:3]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(C)C(=O)NCc1ccc([N+](=O)[O-])cc1

Procedure:
4-Nitrobenzylamine hydrochloride (1.51 g) and sodium hydrogencarbonate (4.13 g) were dissolved in water (25 mL), to which ethyl acetate (25 mL) was added, followed by being stirred in an ice bath. Methacryloyl chloride (1.26 g) was added dropwise thereto. After stirring for 10 minutes, the mixture was extracted with ethyl acetate. After washing with water and brine, the organic layer was dried over anhydrous sodium sulfate and evaporated. After that, the recrystallization was performed by using a mixture solvent of hexane and ethyl acetate. N-(4-Nitrobenzyl)methacrylamide was obtained as pale yellowish crystals. The yield was 1.05 g (60%). Spectrum data of 1H-NMR (400 MHz, CDCl3) is shown for the obtained compound.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[C:10]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:9](Cl)[N:8]=[CH:7][N:6]=1>CO.COCCOC>[Cl:4][C:5]1[C:10]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:9]([O:2][CH3:1])[N:8]=[CH:7][N:6]=1
Reactant: C[O-]
Reactant: COC(=O)Cc1c(Cl)ncnc1Cl
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Product: COC(=O)Cc1c(Cl)ncnc1OC
Reaction time: 0.5 h

Procedure:
Sodium methylate in methanol (112 ml of a 5.4 molar solution) is added at room temperature to a solution of methyl 4,6-dichloro-pyrimidin-5-yl-acetate (120 g, 0.54 mol) in 1,2-dimethoxyethane (200 ml) with cooling. The reaction mixture is stirred for 30 minutes and poured on crushed ice. The precipitated crystals are filtered and dried to give the methyl 4-chloro-6-methoxy-pyrimidin-5-yl-acetate (106 g), m.p. 64° C.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][C@H:27]1[C:32]([OH:34])=[O:33]>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:26]2[CH2:31][CH2:30][O:29][CH2:28][C@H:27]2[C:32]([OH:34])=[O:33])=[C:4]1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Reactant: O=C(O)[C@@H]1COCCN1
Product: COC(=O)C1=C(CN2CCOC[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 81.8 %

Procedure:
Methyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.55 g, 3.37 mmol) was reacted with (S)-morpholine-3-carboxylic acid (0.44 g, 3.37 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (1.41 g, 82%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][C:18]=1[O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].CC(C)=[O:28].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[C:2]([CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][C:18]=1[O:19][C:20](=[O:25])[C:21]([CH3:22])([CH3:24])[CH3:23])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])([OH:28])=[O:1]
Reactant: CC(C)=O
Reactant: CC(C)(C)C(=O)Oc1ccc(C(=O)c2ccccc2)cc1CCCO
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(C)(C)C(=O)Oc1ccc(C(=O)c2ccccc2)cc1CCC(=O)O
Yield: 74 %

Procedure:
A solution of 1.01 g of 3-(hydroxypropyl)-4-pivaloyloxybenzophenone in 40 ml of acetone was treated with 1.5 ml of 8N Jones' Reagent at 0° C. for 1 h. The reaction mixture was treated with 5 ml of isopropyl alcohol and filtered to remove inorganic material. The filtrate was evaporated and the residue was taken up with toluene. The toluene phase was extracted with 3% KHCO3 solution and the aqeuous extract was acidified to pH 2. The acidic product was extracted with ethyl acetate. The ethyl acetate extact was washed with brine, dried (MgSO4), and concentrated to give 0.784 mg (74%) of product.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][N:24]1[C:28](=O)[CH2:27][CH2:26][C@H:25]1[CH2:30][C:31]#[N:32]>C1C=CC=CC=1>[CH3:23][N:24]1[C:28](=[S:10])[CH2:27][CH2:26][C@H:25]1[CH2:30][C:31]#[N:32]
Reactant: CN1C(=O)CC[C@H]1CC#N
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: CN1C(=S)CC[C@H]1CC#N
Yield: 160.6 %

Procedure:
Lawesson's reagent (Tokyo Kasei Kogyo) (1.54 g, 3.8 mmols) was added to a benzene (25 ml) solution of the 2-((2S)-1-methyl-5-oxopyrrolidin-2-yl)ethanenitrile (1.05 g, 7.6 mmols), and the mixture was heated for 2 hours under reflux. The solvent was distilled off under reduced pressure, and then the residue was subjected to silica gel column chromatography (SiO2 60 g, MeOH—CHCl3 1:9 v/v) to obtain 2-((2S)-1-methyl-5-thioxopyrrolidin-2-yl)ethanenitrile (941 mg, 80.6%): IR νmax (film) cm−1: 2246. 1H-NMR (CDCl3)δ: 4.20-4.10 (1H, m), 3.30 (3H, s), 3.25-2.98 (2H, m), 277 (1H, dd, J=17.0, 4.9 Hz), 2.68 (1H, dd, J=17.0, 6.6 Hz), 2.50-2.36 (1H, m), 2.06-1.94 (1H, m). MS m/z: 154 (M+), 114 (100%). HRMS: Calcd. for C7H10N2S: 154.0565 (M+). Found: 154.0561 (M+).
Reaction SMILES: [O:1]=[C:2]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[C@@H:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][CH:15]=[C:16]([C:17](O)=[O:18])[C:9]=12)[CH2:4][CH3:5].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C)C=O>[O:1]=[C:2]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[C@H:3]([N:6]1[C:17](=[O:18])[C:16]2=[CH:15][NH:14][C:10]3[C:9]2=[C:8]([CH:13]=[CH:12][N:11]=3)[CH2:7]1)[CH2:4][CH3:5]
Reactant: CC[C@H](NCc1ccnc2[nH]cc(C(=O)O)c12)C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC[C@H](C(=O)N1CCCC1)N1Cc2ccnc3[nH]cc(c23)C1=O
Yield: 19.7 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (S)-4-((1-oxo-1-(pyrrolidin-1-yl)butan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (8.7 mg, 0.026 mmol). N,N-dimethylformamide (2 mL), HATU (12.02 mg, 0.032 mmol) and 4-methylmorpholine (3.20 mg, 0.022 mmol) were added and the solution was allowed to stir at room temperature for 1 h. The solvent was removed and the resulting residue was further purified via preparative mass trigger LC-MS (AcCN/H2O, 5-90%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow solid (1.6 mg, 19.5%). 1H NMR (500 MHz, CD3OD) δ 0.88-1.04 (m, 3 H) 1.75-1.98 (m, 4 H) 1.98-2.05 (m, 2 H) 3.43-3.50 (m, 3 H) 3.50-3.57 (m, 1 H) 5.07 (s, 2 H) 5.62 (dd, J=8.79, 6.83 Hz, 1H) 7.13 (d, J=4.88 Hz, 1 H) 7.81 (s, 1 H) 8.28 (d, J=5.37 Hz, 1 H). [M+H] calc'd for C17H20N4O2, 313; found, 313.6.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[CH3:2].C(N(CC)CC)C.[C:18](Cl)(=[O:21])[CH:19]=[CH2:20]>>[CH2:1]([N:3]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[C:18](=[O:21])[CH:19]=[CH2:20])[CH3:2]
Reactant: C=CC(=O)Cl
Reactant: CCNCc1ccncc1
Solvent: CCN(CC)CC
Product: C=CC(=O)N(CC)Cc1ccncc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.4 %

Procedure:
To a 0° C. solution of 0.835 ml (6.0 mmol) of 4-(ethylaminomethyl) pyridine and 1.05 ml (7.5 mmol) of triethylamine in 10 ml dichloomethane, was dropwise added 0.406 ml (5.0 mmol) of acryloyl chloride. The reaction mixture was warmed to room temperature and stilred for 18 hr. The resulting nmxture was washed with water and brne, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel with 3% MeOH/CH2Cl2 as the eluant to provide 651 mg (68%) of the desired product as a yellow gum. Electrospray Mass Spec 191(M+H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14].[Br:15]Br.O>CC(O)=O.II>[Br:15][C:9]1[C:2]([OH:1])=[C:3]([O:13][CH3:14])[C:4]([N+:10]([O-:12])=[O:11])=[C:5]([CH:8]=1)[CH:6]=[O:7]
Reactant: COc1c(O)ccc(C=O)c1[N+](=O)[O-]
Reactant: BrBr
Agent: II
Solvent: O
Solvent: CC(=O)O
Product: COc1c(O)c(Br)cc(C=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.9 %

Procedure:
To the mixture of aldehyde 153 (28.0 g, 142 mmol) and I2 (1.5 g) in AcOH (160 mL) was added Br2 (8.0 mL, 157 mmol) at 0° C. The mixture was warmed up to r.t. and stirred at r.t. for 15 hours. The mixture was poured into water (2.0 L) with stirring. The mixture was stirred at r.t. for 30 min. The mixture was extracted with EtOAc (1 LX2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo to provide the compound 154 (38 g, 98%).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](=[O:22])[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])=[CH:8][CH:7]=1)([OH:3])=[O:2].CO[CH:25](OC)[N:26]([CH3:28])[CH3:27].Cl>CN(C)C=O>[C:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:13](=[O:22])[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:15])=[CH:25][N:26]([CH3:28])[CH3:27])=[CH:8][CH:7]=1)([OH:3])=[O:2]
Reactant: COC(OC)N(C)C
Reactant: O=C(O)CCc1ccc(CC(=O)C(=O)c2ccccc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)C=C(C(=O)C(=O)c1ccccc1)c1ccc(CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To a solution of 4.44 g of 3-[4-(2-carboxyethyl)phenyl]-1-phenyl-1,2-propanedione in 25 ml of dry dimethylformamide, cooled in an ice-bath, was added 11 ml of dimethylformamide dimethyl acetal. After stirring at room temperature for 15 min., the reaction mixture was poured onto 300 ml of crushed ice and the reaction mixture was acidified with 25 ml of 1N hydrochloride acid. The mixture was extracted with methylene chloride. The layers were separated and the organic phase was washed with water, dried, filtered and evaporated under vacuum. Recrystallization of the residue from methylene chloride-ether gave 3.95 g (75%) of 2-[4-(2-carboxyethyl)phenyl]-1-dimethylamino-4-phenyl-1-butene-3,4-dione as yellow crystals after drying at 50° C. for 3 hrs.