Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.Cl[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][CH:18]=1)=[C:14]([C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26])[C:13](=[O:27])[CH:12]=[CH:11]2>CN(C=O)C.C(OCC)(=O)C.O>[CH:3]1([CH2:6][O:7][C:9]2[N:10]3[C:15]([CH:16]=[CH:17][CH:18]=2)=[C:14]([C:19]2[C:20]([Cl:26])=[CH:21][CH:22]=[CH:23][C:24]=2[Cl:25])[C:13](=[O:27])[CH:12]=[CH:11]3)[CH2:5][CH2:4]1
Reactant: O=c1ccn2c(Cl)cccc2c1-c1c(Cl)cccc1Cl
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1ccn2c(OCC3CC3)cccc2c1-c1c(Cl)cccc1Cl
Reaction time: 0.5 h

Procedure:
To oil free sodium hydride (24 mg) suspended in DMF was added cyclopropylmethanol (0.08 mL) at room temperature and stirred for ½ hr. To this mixture was added 6-chloro-1-(2,6-dichlorophenyl)-2H-quinolizin-2-one (Example 1, 15 mg) and stirred for approximately 1-3 hours. The mixture was diluted with ethyl acetate/water. The organic layers were washed with water (3×), brine, and dried over magnesium sulfate. Upon evaporation, the residue was purified by silica gel (methylene chloride/acetone=3/1) to give title compound (15 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=2[S:9][C:10]=1[NH:11]C(=O)C)=[O:5])[CH3:2].N1CCCC1>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=2[S:9][C:10]=1[NH2:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(NC(C)=O)sc2ccccc12
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: CCOC(=O)c1c(N)sc2ccccc12
Yield: 85.2 %

Procedure:
To a solution of 1b (1.06 g, 4.03 mmol) in toluene (100 mL) was added pyrrolidine (5 mL). The resultant mixture was heated at 100° C. for 8 h, diluted with brine solution (200 mL) and extracted with ethyl ether (300 mL, 3×). The combined organic phases were dried over MgSO4, filtered, and concentrated. Flash chromatography (hexanes/ethyl acetate, 4:1) then afforded the title compound (0.76 g, 85%) as a yellow solid: MS (ES) m/z 222 (M+H)+; 1H NMR (400 MHz, CDCl3) δ8.14 (d, J=8.0 Hz, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.28 (m, 1H), 7.04 (m, 1H), 6.51 (brs, 2H), 4.45 (q, J=7.2 Hz, 2H), 1.50 (t, J=7.2 Hz, 3H).
Reaction SMILES: ClC1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.[CH2:12]([N:14]1C(CCC(C)=C)=[N:17][N:16]=[N:15]1)[CH3:13].S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:12]([N:14]1[C:7]([CH2:6][CH2:5][C:4]2([CH3:3])[CH2:8][O:10]2)=[N:17][N:16]=[N:15]1)[CH3:13]
Reactant: C=C(C)CCc1nnnn1CC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCn1nnnc1CCC1(C)CO1
Temperature: 25 °C
Reaction time: 21 h
Yield: 115.3 %

Procedure:
m-Chloroperbenzoic acid (1.97 g, 7.99 mmol) was gradually added to a solution of 1-ethyl-5-(3-methyl-3-butenyl)-1H-tetrazole (0.95 g, 5.71 mmol) in methylene chloride (20 ml) while cooling in an ice-bath, and the mixture was stirred at room temperature for 21 hours. To the reaction mixture, sodium thiosulfate aqueous solution and sodium hydrogencarbonate aqueous solution were added, and the resulting mixture was filtered. The organic layer was separated, washed with sodium hydrogencarbonate aqueous solution, dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 1-ethyl-5-[2-(2-methyl-2-oxiranyl)ethyl]-1H-tetrazole (1.2 g, quantitative) as a pale yellow oil.
Reaction SMILES: [O:1]([C:8]1[C:9]([CH2:14][OH:15])=[N:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.O=[Mn]=O>[O:1]([C:8]1[C:9]([CH:14]=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ncccc1Oc1ccccc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1ncccc1Oc1ccccc1
Reaction time: 24 h
Yield: 66.1 %

Procedure:
To a solution of (3-phenoxy-pyridin-2-yl)-methanol (0.130 g, 0.646 mmol) in CH2Cl2 (7 mL) was added MnO2 (10 microns, 90+%) (0.645 g, 7.42 mmol) and the resulting black mixture stirred for 24 h. The mixture was filtered through celite and washed with CH2Cl2. The solution was concentrated to give 3-phenoxy-pyridine-2-carbaldehyde as a yellow oil (0.085 g, 67%). 1H NMR (CDCl3) δ 6.97-7.43 (m, 7H), 8.50 (dd, 1H, J=2.8, 1.2 Hz), 10.42 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:14](=[O:15])[CH:13]([N:16]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:12][CH2:11][C:10](=[O:27])[N:9]1[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:14](=[O:15])[CH:13]([NH2:16])[CH2:12][CH2:11][C:10](=[O:27])[N:9]1[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N2C(=O)c3ccccc3C2=O)CCC(=O)N1Cc1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1C(=O)C(N)CCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
A solution of (2-benzyl-6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3,7-dioxo-[1,2]diazepan-1-yl]-acetic acid tert-butyl ester (5a) (150 mg, 0.31 mmol) and hydrazine monohydrate (17.3 mg, 35 mmol) in ethanol (1.5 mL) was stirred at room temperature for 6 hours. Solvent was removed in vacuo. The residue was taken up into acetic acid (1.5 mL) and stirred at room temperature for 30 min. The mixture was evaporated in vacuo and the resulting residue was dissolved in ethyl acetate (20 mL), washed with 5% Na2CO3 then water. The aqueous solution was extracted with ethyl acetate (20 mL×2). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was evaporated to dryness in vacuo to afford 107 mg (98% yield) of the title compound. 1H-NMR (500 MHz, CDCl3) δ 1.45 (s, 9H), 1.70-1.78 (m, 1H), 2.30-2.48 (m, 2H), 3.10-3.15 (m 1H), 3.30-3.38 (m, 1H), 3.95-4.00 (d, 1H), 4.36-4.40 (d, 1H), 4.45-4.49 (d, 1H), 5.07-5.12 (d, 1H), 7.28-7.38 (m, 5H). Analytical HPLC: 8.03 min. LC-MS (ES+): m/e=348 (M+H+).
Reaction SMILES: [NH2:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13]1([S:19]([NH:22][C@H:23]([C:28]([OH:30])=[O:29])[CH2:24][C:25]([OH:27])=[O:26])(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.S(=O)(=O)(O)O.[OH-].[Na+]>O>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13]1([S:19]([NH:22][C@H:23]([C:28]([OH:30])=[O:29])[CH2:24][C:25]([OH:27])=[O:26])(=[O:20])=[O:21])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NC(Cc1ccccc1)C(=O)O
Agent: O=C(O)C[C@H](NS(=O)(=O)c1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 50 °C

Procedure:
Six grams of DL-phenylalanine, 5.4 g of N-benzenesulfonyl-L-aspartic acid and 1.8 g of sulfuric acid were dissolved in 110 ml of water. While this solution was continuously stirred at 50° C., a 10% aqueous solution of caustic soda (7.3 ml) was added over five hours. The resulting crystal was separated, washed with 10 ml of water and dried to give 3.1 g of an L-phenylalanine/N-benzenesulfonyl-L-aspartic acid salt. Analysis of this salt revealed that the optical purity of the L-phenylalanine was 94%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:44][CH3:45])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13]1)[CH:8]=[C:7]2[O:21][C@@H:22]1[CH2:26][N:25](C(OC(C)(C)C)=O)[C@H:24]([C:34](=[O:43])[N:35]([CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])[CH3:36])[CH2:23]1.C(C1(S(N)(=O)=O)CC1)#C>>[Cl:1][C:2]1[C:3]([O:44][CH3:45])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[N:13]1)[CH:8]=[C:7]2[O:21][C@@H:22]1[CH2:26][NH:25][C@H:24]([C:34]([N:35]([CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])[CH3:36])=[O:43])[CH2:23]1
Reactant: C=CCCCCN(C)C(=O)[C@@H]1C[C@H](Oc2cc(-n3ccc(C(F)(F)F)n3)nc3c(Cl)c(OC)ccc23)CN1C(=O)OC(C)(C)C
Agent: C#CC1(S(N)(=O)=O)CC1
Product: C=CCCCCN(C)C(=O)[C@@H]1C[C@H](Oc2cc(-n3ccc(C(F)(F)F)n3)nc3c(Cl)c(OC)ccc23)CN1

Procedure:
Compound 115 was synthesized from compound 114 as a white solid in quantitative yield, following the procedure as described for compound 82.
Reaction SMILES: O(C([N:10]1[CH2:15][CH2:14][CH:13]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:12][CH2:11]1)=O)C1C=CC=CC=1.[OH-].[K+].[ClH:27]>O.C(O)C>[ClH:27].[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([CH:13]1[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]1)=[O:24]
Reactant: O=C(c1ccccc1F)C1CCN(C(=O)Oc2ccccc2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(c1ccccc1F)C1CCNCC1
Temperature: 25 °C
Yield: 40 %

Procedure:
A solution of 40.5 g of 1-phenoxycarbonyl-4-(2-fluorobenzoyl)piperidine, 500 ml of ethanol and 500 ml of 30% of potassium hydroxide solution was stirred at a temperature slightly below reflux overnight. The reaction mixture was cooled to room temperature, diluted with 250 ml of water, and the ethanol partially removed under reduced pressure. The aqueous suspension was extracted with ether (2×150 ml) and the ether fraction subsequently extracted with 1N hydrochloric acid (2×200 ml). The aqueous solution was basified with 25% sodium hydroxide solution, extracted with ether (2×150 ml) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give an oil. The oil was dissolved in a minimum amount of ethanol and a solution of ethereal hydrogen chloride was added dropwise until a precipitate formed. The solid was collected and dried to give 9.7 g (40%) of product. Recrystallization twice from ethanol-ether gave the analytical sample, mp 185°-187° C.
Reaction SMILES: O1CCCC1.Br[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Br:13])[CH:12]=1.C([Mg]Cl)(C)C.[CH2:19]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1)[CH3:20]>O>[Br:13][C:11]1[CH:12]=[C:7]([CH:26]([C:25]2[CH:28]=[CH:29][C:22]([O:21][CH2:19][CH3:20])=[CH:23][CH:24]=2)[OH:27])[CH:8]=[N:9][CH:10]=1
Reactant: Brc1cncc(Br)c1
Reactant: CCOc1ccc(C=O)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(C(O)c2cncc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76.9 %

Procedure:
A tetrahydrofuran solution (25 mL) of 3,5-dibromo pyridine (5 g, 0.0211 mol) was added dropwise to a mixture of a tetrahydrofuran solution (21.1 mL) of 1M isopropyl magnesium chloride and tetrahydrofuran (10 mL) at 4° C. for 15 minutes. After stirred at room temperature for 2.5 hours, the reaction mixture was added with 4-ethoxybenzaldehyde (2.93 mL, 0.0211 mol) and stirred for further 1.5 hours. After the reaction mixture was added with water while cooled on ice and extracted with ethyl acetate, the organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain (5-bromopyridine-3-yl)(4-ethoxyphenyl)methanol (5.0 g, 77%) as a yellow oily substance.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[Mg].[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:16][C@H:17]([CH3:26])[C:18](N1CCOCC1)=[O:19].[Cl-].[NH4+]>O1CCCC1.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:18](=[O:19])[C@H:17]([O:16][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)[CH3:26])=[CH:3][CH:4]=1
Reactant: Clc1ccc(Br)cc1
Reactant: C[C@@H](OC1CCCCO1)C(=O)N1CCOCC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](OC1CCCCO1)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 235.1 %

Procedure:
To a solution of 1-bromo-4-chlorobenzene (20 g) in tetrahydrofuran (260 ml) was added magnesium (turnings, 7.47 g). The mixture was vigorously stirred at room temperature. When the temperature of the mixture reached 40° C., the reaction vessel was cooled in a water bath. A solution of 1-bromo-4-chlorobenzene (38.9 g) in tetrahydrofuran (90 ml), was added dropwise to the mixture at 34°-40° C., followed by stirring for an hour at 30° C. To the mixture was added dropwise a solution of 4-[(2R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl] morpholine (60 g) in tetrahydrofuran (60 ml) over the period of 15 minutes at 0° C. The mixture was stirred for 3 hours at room temperature. To the reaction mixture were added a saturated aqueous ammonium chloride solution (120 ml) and water (100 ml). The mixture was extracted with ethyl acetate (500 ml). The organic layer was washed with water, dried over magnesium sulfate and distilled under reduced pressure. The residue was purified by silica gel column chromatography (silica gel 900 g, eluent: hexane/ethyl acetate=30:1→10:1) to give (2R)-4'-chloro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (66 g) as a pale yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:27])[C:10](=[O:26])[N:11]3[CH2:19][CH:18]([CH2:20][O:21]C(=O)C)[O:17][C:16](=[O:25])[C:12]3=2)[C:7]1=[O:28].C[O-].[Na+]>CO.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:27])[C:10](=[O:26])[N:11]3[CH2:19][CH:18]([CH2:20][OH:21])[O:17][C:16](=[O:25])[C:12]3=2)[C:7]1=[O:28]
Reactant: CC(=O)OCC1Cn2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C(=O)O1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: O=C1OC(CO)Cn2c1c1c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 9-(3-chloro-4-fluorobenzyl)-7-hydroxy-3-(acetyloxymethyl)-3,4,10,11-tetrahydro[1,4]oxazino[3,4-a]-2,6-naphthyridine-1,6,8(9H)-trione (46 mg, 0.10 mmol) and 30% sodium methoxide in methanol (39 mg) in dioxane (1.5 mL) was stirred at room temperature for 2 hours. The product mixture was concentrated under vacuum. The residue was dissolved in DMSO and subjected to reverse phase column chromatography on C-18 stationary phase eluted with a 95-5% water-acetonitrile gradient. Collection and Iyophilization of appropriate fractions afforded the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH2:12])=[CH:7][C:6]=1[O:13][C:14]([F:17])([F:16])[F:15])[CH3:2].[H][H]>[Pd].CO>[CH2:19]([N:3]([CH2:1][CH3:2])[C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:6]=1[O:13][C:14]([F:16])([F:15])[F:17])[CH3:20]
Reactant: [H][H]
Reactant: C=Cc1ccc(C(=O)N(CC)CC)c(OC(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(C(=O)N(CC)CC)c(OC(F)(F)F)c1
Reaction time: 1 h
Yield: 83 %

Procedure:
To a stirring degassed solution of N,N-diethyl-4-ethenyl-2-(trifluormethoxy)benzamide (1783 mg, 6.2 mmol) and 10% palladium on carbon (50 mg) in MeOH (30 mL) was added hydrogen (1 atm). The reaction was stirred for 1 h and then filtered. The filtrate was conc. in vacuo to a colorless oil. The oil was purified by flash chromatography (SiO2, 0–50% EtOAc in hexanes) to give 1489 mg of the desired product as a colorless oil. MS (ESI) 290 (M+H).
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:41]#[N:42])=[C:24]([C:26]2[C:31]([O:32][CH3:33])=[CH:30][N:29]([CH:34]([CH2:38][CH3:39])[C:35](O)=[O:36])[C:28](=[O:40])[CH:27]=2)[CH:25]=1.[NH2:43][C:44]1[CH:53]=[C:52]([F:54])[C:47]([C:48]([O:50][CH3:51])=[O:49])=[C:46]([F:55])[CH:45]=1.O>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:41]#[N:42])=[C:24]([C:26]2[C:31]([O:32][CH3:33])=[CH:30][N:29]([CH:34]([CH2:38][CH3:39])[C:35]([NH:43][C:44]3[CH:45]=[C:46]([F:55])[C:47]([C:48]([O:50][CH3:51])=[O:49])=[C:52]([F:54])[CH:53]=3)=[O:36])[C:28](=[O:40])[CH:27]=2)[CH:25]=1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: COC(=O)c1c(F)cc(N)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCC(C(=O)Nc1cc(F)c(C(=O)OC)c(F)c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
At 60-70° C., 110 μl (0.46 mmol, 4 eq.) of T3P (50% in ethyl acetate) were added dropwise to a solution of 46 mg (0.13 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 51 mg (0.27 mmol, 2 eq.) of methyl 4-amino-2,6-difluorobenzoate in 1 ml of pyridine. The reaction mixture was heated to 90° C., stirred at 90° C. for 30 min and cooled to RT, and water and ethyl acetate were added. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was purified by normal phase chromatography (mobile phase: cyclohexane/ethyl acetate 10-50% mixtures). Yield: 54 mg (79% of theory)
Reaction SMILES: S([O-])([O-])(=O)=O.[Cu+2:6].C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Na+].[Na+].[Na+].[NH:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[N:24]1>O>[Cu:6].[NH:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[N:24]1
Reactant: [Cu+2]
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: [Cu]

Procedure:
A 2:1 molar ratio of copper sulfate and trisodium citrate, respectively, and benzotriazole (BZT) were mixed in DI water to yield a 50 ppm copper and 25 ppm BZT CMP synthetic filtrate with a pH of 3.70. To aliquots of this solution mixing at 100 rpm, a polymeric chelant in the absence of a coagulant or a coagulant in the absence of a polymeric chelant was charged then allowed to mix for 15 minutes. Treated aliquots were filtered using a 0.45 micron filter. The isolated filtrate was then analyzed for pH and copper content via ICP, the results of which are summarized in Table 1. Test results demonstrated that non-dithiocarbamate polymeric chelant and coagulant as separate treatments are not as effective in precipitating copper from the test matrix.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10](O)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.CNOC.C(S(C=C)(=O)=O)=C.[NH:32]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C@H:33]([C:41]([N:43]([CH3:46])[O:44][CH3:45])=[O:42])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[NH:32]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C@H:33]([C:41]([N:43]([CH3:46])[O:44][CH3:45])=[O:42])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[C:16]([O:15][C:13]([NH:1][CH:2]([CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH:10]=[O:11])=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C=CS(=O)(=O)C=C
Agent: CNOC
Agent: CON(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)NC(C=O)Cc1ccccc1

Procedure:
Boc-Phe-N(OCH3)CH3 was prepared from Boc-Phe-OH and N,O-dimethylhydroxylamine hydrochloride using standard mixed anhydride coupling procedure, yield 93%. 1H-NMR (CDCl3) δ 1.4 (s, 9H, Boc), 2.8-2.9 (m, 1H, CH2-Phe), 3.0-3.1 (m, 1H, CH2-Phe), 3.2 (s, 3H, N—CH3), 3.6 (s, 3H, O—CH3), 4.9 (m, 1H, α-H), 5.2 (b, 1H, NH), 7.1-7.3 (m, 5H, Ph). MS (FAB+) m/z 309 (M+1, 30%), 253 (M−tBu+1, 100%). Reduction of Boc-Phe-N(OCH3)CH3 with lithium aluminum hydride according to a previous method described in J. A. Fehrentz et al., Synthesis (1983), 8, 676 gave Boc-Phe-H, yield 88%. 1H-NMR (CDCl3) δ 1.4 (s, 9H, Boc), 3.1 (d, 2H, CH2-Phe), 4.4 (m, 1H, α-H), 5.0 (b, 1H, NH), 7.1-7.3 (m, 5H, Ph), 9.6 (s, 1H, CHO). MS (FAB+) m/z 250 (M+1, 15%), 150 (M−Boc+1, 100%).
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][N:15]4[C:21]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.Br[CH2:29][C:30]([O:32][CH3:33])=[O:31].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:33][O:32][C:30](=[O:31])[CH2:29][O:20][C:18]1[CH:17]=[CH:16][N:15]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:12]([C:9]3[CH:8]=[CH:7][C:6]([C:2]4([NH2:1])[CH2:3][CH2:4][CH2:5]4)=[CH:11][CH:10]=3)[N:13]=[C:14]2[CH:19]=1
Reactant: NC1(c2ccc(-c3nc4cc(O)ccn4c3-c3ccccc3)cc2)CCC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2c1
Reaction time: 0.13 h
Yield: 34.5 %

Procedure:
To a solution of 2-[4-(1-amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-7-ol (75 mg, 0.21 mmol), methyl bromoacetate (0.02 mL, 0.21 mmol, 1.0 equiv) and Cs2CO3 (138 mg, 0.422 mmol, 2 equiv) in DMF (2.5 mL) was stirred at room temperature for 12 h. The resulting mixture added to water (10 mL). The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried (Na2SO4 anh), and concentrated under reduced pressure. The remaining material was purified using MPLC (Biotage Isolera Flash NH2 Snap 10 reverse phase column; 100% CH2Cl2 for 8 min., gradient to 95% CH2Cl2: 5% MeOH over 5 min.; 95% CH2Cl2: 5% MeOH for 4 min., gradient to 80% CH2Cl2: 20% MeOH over 5 min., 80% CH2Cl2: 20% MeOH for 6.2 min., gradient to 75% CH2Cl2: 25% MeOH over 2.0 min., 75% CH2Cl2: 25% MeOH for 18.2 min.) to give {2-[4-(1-amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-7-yloxy}-acetic acid methyl ester (31 mg, 34%):
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:34])/[CH:20]=[C:21](/[C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=3)\[C:22]([F:25])([F:24])[F:23])=[CH:15][CH:14]=2)([F:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:35]([CH3:38])([O-:37])=[O:36].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:34])[CH2:20][C:21]([C:26]3[CH:27]=[C:28]([Cl:33])[CH:29]=[C:30]([Cl:32])[CH:31]=3)([CH2:38][N+:35]([O-:37])=[O:36])[C:22]([F:23])([F:25])[F:24])=[CH:15][CH:14]=2)([F:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C(=O)/C=C(/c3cc(Cl)cc(Cl)c3)C(F)(F)F)cc2)C1
Reactant: C[N+](=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C(=O)CC(C[N+](=O)[O-])(c3cc(Cl)cc(Cl)c3)C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.3 %

Procedure:
To the stirred solution of 3-{4-[(Z)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-phenyl}-3-fluoro-azetidine-1-carboxylic acid tert-butyl ester (1.2 g, 2.315 mmol, 1 eq.) in acetonitrile (10 mL) was added nitro methane (1.24 mL, 23.152 mmol, 10 eq) and DBU (0.33 mL, 2.246 mmol, 0.97 eq) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours. After complete consumption of starting material, the reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (2×25 mL). Combined organic layers were washed with brine (60 mL), dried over sodium sulphate and concentrated to get crude compound semi solid (1.37 g, crude). Crude compound was purified by column chromatography on silica gel using 230-400 mesh. Desired compound was eluted in 10% ethyl acetate in n-hexane to give product as light yellow sticky liquid (1.09 g, 81.34%). LC-MS (m/z): 576.8 (M−H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1)([O-])=O>CO.[Pd]>[N:10]1([C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH2:1])[CH:14]=[CH:13][CH:12]=[N:11]1
Reactant: O=[N+]([O-])c1cnccc1-n1cccn1
Agent: [Pd]
Solvent: CO
Product: Nc1cnccc1-n1cccn1
Reaction time: 8 h

Procedure:
To a solution of 3-nitro-4-(1H-pyrazol-1-yl)pyridine (410 mg, 2.15 mmol) in MeOH (15 mL) was added Pd on C (10%, wet, Degussa) (129 mg) and the reaction mixture was vigorously stirred overnight at RT under an atmosphere of hydrogen (balloon). The catalyst was filtered off and the filtrate was concentrated under reduced pressure yielding 4-(1H-pyrazol-1-yl)pyridin-3-amine. (285 mg, 82%). MS (ES+) 161.1.