Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([O:15][C:16]([N:18]1[CH2:21][CH2:20][C@H:19]1[CH2:22][O:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[CH2:33][NH2:34])[CH:27]=[N:28][CH:29]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:8]([O:15][C:16]([N:18]1[CH2:21][CH2:20][C@H:19]1[CH2:22][O:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[CH2:33][NH:34][C:1](=[O:3])[CH3:2])[CH:27]=[N:28][CH:29]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCc1cccc(-c2cncc(OC[C@@H]3CCN3C(=O)OCc3ccccc3)c2)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1cccc(-c2cncc(OC[C@@H]3CCN3C(=O)OCc3ccccc3)c2)c1
Reaction time: 1.42 h
Yield: 95.7 %

Procedure:
In a 15 mL round-bottom flask with magnetic stirrer, septum, and balloon (for pressure equalization and exclusion of moisture), neat acetic anhydride (23 μL, 0.24 mmol, 1.5 equiv.) was added with ice cooling in 5 min to a solution of 3-[5-[[1-(benzyloxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]benzylamine (65.3 mg, 162 μmol) and triethylamine (45 μL, 0.32 mmol, 2 equiv.) in anhydrous CH2Cl2 (1 mL). Stirring was continued at room temperature for 85 min, while the septum was replaced with a glass stopper to avoid evaporation losses. After 65 min, TLC (SiO2, CH2Cl2/MeOH 9:1, UV detection) demostrated complete conversion of the starting material (Rf approx. 0.05) to the acetamide (Rf approx. 0.45). Methanol (25 μL) was added, and the reaction mixture was stored at room temperature for 1 h before being directly applied on a SiO2 column (26×1.3 cm; eluent: CH2Cl2/MeOH 94:6 for a forerun, then 9:1). The product-containing fractions were evaporated and dried (50° C./oil pump) to yield 69.1 mg (96%) of the amide as a colorless glass. [α]D−40.7, [α]546−48.3 (c 14.8 g/L, EtOAc). 1H NMR (CDCl3, 500 MHz) δ 8.47 (s, 1H), 8.32 (br, 1H), 7.55-7.48 (m, 2H), 7.47 (t, 1H, J=7.5 Hz), approx. 7.4 (br and overlapping, 1H), 7.30 (d, 1H, J=7.4 Hz), 7.31 (br s, 5H), 5.89 (br, 1H), 5.12, 5.07 (ABq, 2H, J=12.3 Hz), 4.67 (br, 1H), 4.54 (d, 2H, J=5.7 Hz), approx. 4.4-4.5 (br, 1H), 4.22 (br, 1H), 4.09-4.00 (m, 2H), 2.51-2.32 (m, 2H), 2.08 (s, 3H). MS (EI) m/z 445 (M+, 8.46%), 354 (2.2%), 312 (2.8%), 310 (5.9%), 242 (6.5%), 199 (5.0%), 91 (100%), 43 (11%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])=[CH:7][CH:6]=1)=O.[Br:33][C:34]1[C:35]([NH2:40])=[N:36][CH:37]=[CH:38][CH:39]=1.C(=O)(O)[O-].[Na+]>C(O)(C)C>[Br:33][C:34]1[C:35]2[N:36]([CH:2]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]([CH2:11][C@H:12]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:13][N:14]4[C:15](=[O:24])[C:16]5[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=5)[C:22]4=[O:23])=[CH:9][CH:10]=3)[N:40]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: Nc1ncccc1Br
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(=O)CBr)cc1)CN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cn3cccc(Br)c3n2)cc1)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 72 %

Procedure:
A solution of 1,1-dimethylethyl {(1S)-2-[4-(bromoacetyl)phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (6.9 mmol), 3-bromo-2-pyridinamine (8.4 mmol), and sodium bicarbonate (10.4 mmol) in isopropanol (70 mL) were stirred at 80° C. for 18 h. The reaction was then cooled to RT and a precipitate formed which was filtered, washed with cold hexanes (3×100 mL), and dried to afford the title compound as light gray solid (72%). ESMS [M+H]+: 576.2.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[N:11]3[C:19]([C:22]#[N:23])=[N:20][N:21]=[C:10]3[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C[OH:26]>[OH-].[Na+]>[C:1]1([C:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[N:11]3[C:19]([C:22]([NH2:23])=[O:26])=[N:20][N:21]=[C:10]3[CH2:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 0.17 h

Procedure:
A solution of 1.60 g (0.005 mole) of 6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carbonitrile in a mixture of 50 ml of methanol and 50 ml of 1N sodium hydroxide solution is allowed to stand for ca. 10 minutes at 25°. The reaction mixture is then neutralised with 2N hydrochloric acid, and concentrated to about half its volume. The concentrate is extracted in methylene chloride, the organic solution washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. The residue is crystallised from methanol/ethyl acetate/petroleum ether to obtain 6-phenyl-8-chloro-4H-s-triazolo [4,3-a][1,4]benzodiazepine-1-carboxamide, M.P. 285°-289°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N:10]([O-:12])=[O:11].[Na+].Cl>O.CCOCC>[N+:10]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)([O-:12])=[O:11]
Reactant: O=N[O-]
Reactant: c1ccc2c(c1)CCN2
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=[N+]([O-])N1CCc2ccccc21
Yield: 111.1 %

Procedure:
Following the procedure of Example 1, step 1, indoline (20 g, 170 mmol), sodium nitrite (14 g, 200 mmol), concentrated hydrochloric acid (30 mL) in water (70 mL) and ether (120 mL) provided 1-nitroindoline (31 g), which was reduced with zinc dust (˜50 g) in acetic acid (500 mL) to provide 1-aminoindoline (29 g). A mixture of 1-aminoindoline (17 g, 130 mmol), cycloheptanone (15 mL, 130 mmol), and concentrated sulfuric acid (20 mL) in water (180 mL) provided 8.2 g of 4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indole. MS (ESI) m/z 212.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH3:9].[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[Br:8][C:4]1[C:3]([CH3:9])=[C:2]([N:11]([CH3:10])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1c(Br)cccc1Br
Reactant: CNc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1c(Br)cccc1N(C)c1ccccc1
Temperature: 85 °C

Procedure:
1,3-Dibromo-2-methylbenzene (5.01 g) and N-methylaniline (1.00 g) were added to toluene (65 mL). The solution was degassed and flushed with nitrogen three times. Cesium carbonate (9.12 g), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.872 g), and palladium (II) acetate (0.314 g) were added. The solution was degassed and flushed with nitrogen and then heated to 85° C. for 72 hours. The solution was cooled, added to 1 M aqueous HCl, and extracted with diethyl ether. The extract was washed with brine, dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude material was purified on silica gel using 2% ethyl acetate in hexanes.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1(C)C=CC(S(O[CH2:26][C@@H:27]([O:36][Si](C(C)(C)C)(C)C)[CH2:28][CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)(=O)=O)=CC=1.F.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.O>[N:32]1[CH:33]=[CH:34][CH:35]=[C:30]([CH2:29][CH2:28][C@H:27]([OH:36])[CH2:26][O:13][C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][CH:11]=2)[CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](CCc2cccnc2)O[Si](C)(C)C(C)(C)C)cc1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: F
Agent: O=C([O-])O
Agent: [H-]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: O[C@@H](CCc1cccnc1)COc1ccc(-c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
Solid 4-phenylphenol (0.43 g) was added to a stirred suspension of sodium hydride (60%, 0.096 g) in dimethylformamide (5 ml) and the resulting solution stirred for 30 minutes. (2S)-2-(tert-Butyldimethylsilyloxy)-4-(3-pyridyl)-1-butyl para-toluenesulfonate (0.84 g) was added and the mixture stirred at 60° C. for 2 hours. After cooling the mixture was poured into water (50 ml) and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained was dissolved in acetonitrile (10 ml) and hydrofluoric acid (40%; 1 ml) was added. The mixture was stirred for 1 hour and then poured into a solution of saturated aqueous sodium hydrogencarbonate. The mixture was extracted with ethyl acetate and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.434 g) as a solid that was recrystallised from ethyl acetate:hexane.
Reaction SMILES: C([NH:4][C:5](=[CH:9][CH2:10][PH:11]([CH2:13]O)=[O:12])[C:6]([OH:8])=[O:7])(=O)C.[ClH:15].C[OH:17]>>[ClH:15].[ClH:15].[NH2:4][C@H:5]([C:6]([OH:8])=[O:7])[CH2:9][CH2:10][P:11]([CH3:13])(=[O:17])[OH:12]
Reactant: CO
Reactant: CC(=O)NC(=CC[PH](=O)CO)C(=O)O
Agent: Cl
Product: CP(=O)(O)CC[C@H](N)C(=O)O
Yield: 91.9 %

Procedure:
0.0087 g (0.019 mmol) of chloronorbornadienerhodium(I) dimer and 0.022 g (0.053 mmol) of the compound Va are dissolved in 5 ml of methanol under an atmosphere of argon. The catalyst solution obtained is added under argon to a solution of 2.21 g (0.01 mol) of 2-acetamido-4-(hydroxymethylphosphinyl)-2-butenoic acid in 45 ml of methanol. The reaction vessel is evacuated, then hydrogenation is performed at a pressure of 3.0 bar. After a reaction time of 44 hours, the reaction vessel is depressurized, the reaction mixture evaporated down, the residue taken up in water and the precipitated catalyst separated off. As a result of adding an equivalent quantity of concentrated hydrochloric acid to the filtrate, a 6N hydrochloric acid solution is prepared which is boiled under reflux for 12 hours. After evaporating this solution down, 2.0 g (91.9% of theory) of L-homoalanin-4-yl(methyl)phosphinic acid hydrochloride is obtained as a white solid which is purified by recrystallization from an ethanol/water mixture.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([N:15]=[C:16]=[O:17])[CH2:13][CH3:14]>C1(C)C=CC=CC=1>[C:1]1([N:7]2[CH2:8][C:9](=[O:11])[N:15]([CH2:12][CH2:13][CH3:14])[C:16]2=[O:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CNc1ccccc1
Reactant: CCCN=C=O
Solvent: Cc1ccccc1
Product: CCCN1C(=O)CN(c2ccccc2)C1=O
Yield: 59.6 %

Procedure:
In a similar manner, N-phenyl glycine (0.1 mole), n-propyl isocyanate (0.12 mole) and toluene (30 ml) was refluxed for about 51/2 hours producing 13 grams (59% yield) of 1-phenyl-3-n-propyl hydantoin having a melting point of about 97° C. and the structure: ##STR7##
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][NH2:40])[CH:34]=1>>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:32]=[CH:31][C:27]([C:28]([NH:40][CH2:39][C:35]4[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=4)=[O:29])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])(=[O:16])=[O:15])=[CH:12][CH:13]=1
Reactant: NCc1cccnc1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(Br)cc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(Br)cc1
Yield: 49.7 %

Procedure:
Reaction of oxalyl chloride (61 λL, 0.70 mmol) and benzoic acid 29 (204 mg, 0.47 mmol) with subsequent couping to 3-pyridinylmethylamine (53 λL, 0.52 mmol) gave benzamide 30 (123 mg, 50%) as a white powder: mp (EtOAc) 224-227° C.; 1H NMR δ 9.20 (t, J=5.9 Hz, 1H, CONH), 8.57 (d, J=1.7 Hz, 1H, H-2′), 8.47 (dd, J=4.7, 1.6 Hz, 1H, H-6′), 8.00 (d, J=8.6 Hz, 2H, H-2, H-6), 7.88 (d, J=8.6 Hz, 2H, H-3, H-5), 7.85 (ddd, J=8.6, 2.3, 1.9 Hz, 2H, H-2″, H-6″), 7.70-7.76 (m, 3H, H-4′, H-3″, H-5″), 7.36 (ddd, J=7.8, 4.7, 0.6 Hz, 1H, H-5′), 4.73 (s, 2H, CH2SO2), 4.51 (d, J=5.9 Hz, 2H, CH2N), 2.22 (s, 3H, CH3); 13C NMR δ 165.5, 158.1, 150.0, 148.9, 148.1, 137.8, 135.5, 135.2, 134.9, 132.3 (2), 130.4 (2), 128.8, 128.2, 128.1 (2), 125.7, 125.4 (2), 123.5, 52.8, 40.5, 9.7; MS m/z 526.1 (MH+, 100%), 528.1 (MH+, 100%). Anal. calcd for C24H20BrN3O4S.½H2O: C, 52.95; H, 4.07; N, 7.72. Found: C, 52.74; H, 3.67; N, 7.60%.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]([F:25])([F:24])[C:15]([O:18][CH:19]([O:21][CH2:22][CH3:23])[CH3:20])([CH3:17])[CH3:16])(=O)=O)=CC=1.C(N(C(C)C)CC)(C)C.[I-:35].[Na+]>CC(C)=O>[CH2:22]([O:21][CH:19]([O:18][C:15]([CH3:17])([CH3:16])[C:14]([F:25])([F:24])[CH2:13][CH2:12][I:35])[CH3:20])[CH3:23]
Reactant: [I-]
Reactant: CCOC(C)OC(C)(C)C(F)(F)CCOS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: CCOC(C)OC(C)(C)C(F)(F)CCI
Temperature: 25 °C
Reaction time: 64 h

Procedure:
A mixture of 3.50 g (0.0087 mol) of 4-(1-ethoxyethoxy)-3,3-difluoro-4-methyl-1-pentanol 1-(4-methylbenzenesulfonate), 40 mL of acetone, 0.5 mL of diisopropylethylamine and 13.10 g (0.087 mol) of sodium iodide was stirred at 25° C. for 64 hr. The mixture was evaporated to dryness. The residue was partitioned between 5% aqueous sodium sulfite solution and methylene chloride. The organic phase was washed with saturated aqueous sodium bicarbonate solution. The organic phase was then dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was chromatographed on 0.06-0.20 mm silica gel to yield 4-(1-ethoxyethoxy)-3,3-difluoro-1-iodo-4-methylpentane.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:7]=1.[OH-].[K+]>O1CCCC1>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:17]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)(=[O:19])=[O:18])[CH:7]=[C:6]2[CH2:5][CH2:4][C:3]([OH:28])=[O:2]
Reactant: COC(=O)CCc1cn(S(=O)(=O)c2ccc(OC)cc2)c2ccc(OC)cc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2cc(CCC(=O)O)c3cc(OC)ccc32)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of the methyl ester 5 (830 mg, 2.06 mmol) in tetrahydrofuran (15 mL) was added an aqueous solution of potassium hydroxide (5 mL of 1M) and stirred at room temperature for 5 h. The acid 1 was isolated by neutralizing the reaction mixture by aqueous hydrochloric acid, extracting the product with ethyl acetate, drying over anhydrous magnesium sulfate, evaporating under reduced pressure, and purifying using flash chromatography with 5% methanol in dichloromethane to afford a white solid (697.5 mg, 91%; M−1=373.1).
Reaction SMILES: O[C:2]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C(O)c1cc(O)nc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Product: O=C(O)c1cc(Cl)nc2ccccc12
Temperature: 0 °C

Procedure:
2-Hydroxyquinoline-4-carboxylic acid (34, 2.57 g, 13.6 mmol) and POCl3 (25 mL) were refluxed for 24 h. The reaction mixture was poured onto crushed-ice (300 g). The solid that separated was filtered, washed with water, and dried well under high vacuum afforded 2.47 g (87%) white flasks of desired product. 1H NMR (CDCl3, 300 MHz): δ 8.67 (d, 1H, J=8.4 Hz), 7.91 (d, 1H, J=8.1 Hz), 7.83 (s, 1H), 7.76 (t, 1H, J=7.2 Hz), 7.54 (t, 1H, J=7.2 Hz); LCMS (m/z): 208 (MH+).
Reaction SMILES: [F:1][CH2:2][C:3](=O)[C:4](=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl.[NH2:22][C:23]([NH2:30])=[CH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].[Na]>C(O)C>[NH2:22][C:23]1[NH:30][C:3]([CH2:2][F:1])=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:24]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)CF
Reactant: CCOC(=O)C=C(N)N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(CF)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1

Procedure:
Ethyl 4-fluoro-2-(3-nitrophenylmethylene)-3-oxobutanoate (0.6 g, 2.1 mmoles) and ethyl 3,3-diamino-2-propenoate hydrochloride (0.34 g, 12.0 mmoles) were heated at reflux in ethanol (10 ml) and a solution of sodium (0.05 g) in ethanol (5 ml) was added over one hour. The resulting solution was heated at reflux for a further 10 minutes and then filtered hot. The ethanolic solution was evaporated to dryness in vacuo and the resulting solid triturated with 2-propanol. The resulting solid was chromatographed on silica eluting with ether/petroleum ether (60°-80°) mixtures to give pure title compound, mp 177°-8°.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[N:20][CH:21]=1>>[CH:1]([C:4]1[CH:5]=[C:6]([C:12]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[N:20][CH:21]=2)=[O:14])[O:7][C:8]=1[CH:9]([CH3:10])[CH3:11])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(N)cn1
Reactant: CC(C)c1cc(C(=O)O)oc1C(C)C
Product: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)o2)cn1
Yield: 77 %

Procedure:
In the same manner as that of Example 2, 4,5-diisopropylfuran-2-carboxylic acid (86 mg, 0.439 mmol) was condensed with methyl 5-aminopyridine-2-carboxylate, and the resultant was purified by silica gel chromatography (3% methanol-chloroform) to obtain methyl 5-[(4,5-diisopropylfuran-2-carbonyl)amino]pyridine-2-carboxylate (111 mg, 77%) as colorless prisms.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([S:20][CH3:21])[CH:19]=2)[C:3]=1[CH3:22].[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[C:34]([NH2:35])=[CH:33][C:32]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[C:34]([NH:35][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([C:14]4[CH:15]=[N:16][CH:17]=[C:18]([S:20][CH3:21])[CH:19]=4)[C:3]=3[CH3:22])=[CH:33][C:32]([N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1
Reactant: CSc1cncc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CSc1cncc(-c2nc3cc(F)cc(F)c3c(Nc3cc(N4CCOCC4)cnc3N3CCOCC3)c2C)c1
Temperature: 105 °C
Reaction time: 2 h

Procedure:
A screw-cap vial was charged with 4-chloro-5,7-difluoro-3-methyl-2-(5-(methylthio)pyridin-3-yl)quinoline (50 mg, 0.15 mmol), 2,5-dimorpholinopyridin-3-amine (39.2 mg, 0.15 mmol), tris(dibenzylideneacetone)dipalladium (0) (13.6 mg, 0.015 mmol), XPhos (14.2 mg, 0.030 mmol), sodium tert-butoxide (42.8 mg, 0.445 mmol), and toluene (1.5 mL). The mixture was stirred at 105° C. for 2 h, then cond. The resulting residue was partitioned between DCM and water, and the organic layer was dried over magnesium sulfate and cond. The crude material was purified by recrystallization in MeOH, affording N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(5-(methylthio)pyridin-3-yl)quinolin-4-amine. Mass Spectrum (ESI) m/e=565.0 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.61 (1H, d, J=2.3 Hz), 8.59 (1H, s), 7.86 (2H, m), 7.68 (2H, m), 7.09 (1H, m), 6.39 (1H, br. s.), 3.92 (4H, br. s.), 3.83 (4H, br. s.), 3.05-3.50 (4H, br. s.), 3.05 (4H, br. s.), 2.60 (3H, s), 2.18 (3H, br. s.).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])([O-])=O.[Cs+].[Cs+].[N:19]1[NH:20][N:21]=[CH:22][CH:23]=1.CN[C@@H]1CCCC[C@H]1NC>[Cu]I.CCOC(C)=O.O.O1CCOCC1>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([N:20]2[N:21]=[CH:22][CH:23]=[N:19]2)[CH:10]=1
Reactant: COc1ccc(C(=O)O)c(Br)c1
Reactant: c1cn[nH]n1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C(=O)O)c(-n2nccn2)c1
Temperature: 100 °C
Yield: 68.6 %

Procedure:
To 2-bromo-4-methoxybenzoic acid (4 g, 17.3 mmol), CuI (266 mg, 1.4 mmol) and Cs2CO3 (11.2 g, 34.6 mmol) was added dioxane (36 mL), water (94 μL, 5.1 mmol), 2H-1,2,3-triazole (2.0 mL, 34.6 mmol) and (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (683 μL, 4.3 mmol). The reaction mixture was heated to 100° C. for 3 hr. The reaction mixture was cooled rt, then EtOAc and water were added. The mixture was transferred to a separatory funnel and the aqueous layer separated. The aqueous layer was acidified with conc. HCl to pH˜2 and extracted with EtOAc (2×). The organic layers were washed with brine and dried (Na2SO4) to give a yellow solid. This material was slurried with EtOAc (˜20 mL) and the solids filtered (>95% 4-methoxy-2-(1H-1,2,3-triazol-1-yl)benzoic acid by HPLC). Purification (FCC) (50% DCM to 100% DCM containing 10% (5% formic acid/MeOH)) gave the title compound (2.6 g) as a yellow solid. 1H NMR (CDCl3): 7.99-7.90 (m, 1H), 7.83 (s, 2H), 7.20 (d, J=2.5 Hz, 1H), 7.03 (dd, J=8.8, 2.6 Hz, 1H), 3.89 (s, J=17.6 Hz, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[CH:7][N:6]=1)=O.[OH-].[NH4+:13]>>[NH2:11][C:10]1[C:5]([C:3]([NH2:13])=[O:2])=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: COC(=O)c1nccnc1N
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1nccnc1N
Temperature: 25 °C

Procedure:
A solution of 3-amino-pyrazine-2-carboxylic acid methyl ester (5.0 g, 33 mmol) in concentrated ammonium hydroxide solution (30 mL) was heated at 60° C. for 3 h. The mixture was cooled to RT and the resulting solid filtered. After thoroughly washed with water followed by ether, the title compound was obtained as a brown solid (3.7 g, 82%).
Reaction SMILES: [C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[NH4+:9].C(O)(=O)CCC(O)=O.[OH-].[Na+]>>[NH2:9][C@H:2]([C:1]([OH:8])=[O:7])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: [NH4+]
Reactant: O=C([O-])/C=C\C(=O)O
Agent: O=C(O)CCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: N[C@@H](CC(=O)O)C(=O)O
Reaction time: 0.67 h

Procedure:
Monoammonium maleate (3.00 g of 94% wet salt, 0.0212 mole) and succinic acid (.[.0,278.]. 0.278 g, 0.0024 mole) were thoroughly mixed together and then were reacted as in Example 2 and 3 by heating in a convection oven at .[.230°240°.]. 230°-240° C. for 40 minutes. A brittle, red-brown solid was obtained which weighed .[.2,204.]. 2.204 g. Hydrolysis of this product with sodium hydroxide produced an aspartic acid copolymer having molecular weights by GPC of Mw 1717, Mn 1016, Mw/Mn 1.69.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.Cl>C1COCC1>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[B:20]([OH:25])[OH:21])(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 11.2 mmol of N-t-butylbenzenesulfonamide (from Step C) in anhydrous THF (20 mL) cooled to -40° C. under N2 was addeel 2.5M n-BuLi solution (11.2 mL, 2.5 equiv). The mixture was warmed to room temperature and stirred for 2 hours. To the mixture, containng the dianion at 0° C., was added triisopropyl borate (3.9 mL, 1.5 equiv). The next day, 2 N HCl (3 mL) was added and the mixture was stirred for 1 hour. The solvent was removed under reduced pressure and the residue was extracted with EtOAc. The organic solution was washed with 2N HCl, H2O and brine. The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo to afford the titled compound. The material was used in the next step without further purification.