Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[CH:18][C:3]=1[C:4]([C:6](=[CH:12][NH:13][N:14]=[CH:15][CH2:16]C)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[F-].[Na+].[CH3:27]N(C)C=O>C(Cl)Cl.O>[F:24][C:19]1[CH:18]=[C:3]2[C:2](=[C:21]([F:22])[C:20]=1[F:23])[N:13]([N:14]=[C:15]([CH3:16])[CH3:27])[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4]2=[O:5]
Reactant: CN(C)C=O
Reactant: CCC=NNC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Agent: [F-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cn(N=C(C)C)c2c(F)c(F)c(F)cc2c1=O

Procedure:
10.38 g of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-(2-propylidenehydrazino)-acrylate, 2 g of sodium fluoride and 60 ml of dimethylformamide are heated at 150°-160° C. for 2.5 hours. The dimethylformamide is stripped off in vacuo, the residue is taken up in CH2Cl2 /H2O and the CH2Cl phase is concentrated in vacuo, after drying with Na2SO4. Recrystallization from ethanol gives 6 g of ethyl 6,7,8-trifluoro-1-(2-propylideneamino)-1,4-dihydro-4-oxo-3-quinolinecarboxylate of melting point 166° C. A suspension of 6 g of the propylideneamino-quinolinecarboxylic acid ester in 72 ml of isopropanol and 0.7 g of water is heated at 70° C. with 0.16 g of p-toluenesulphonic acid for 1 hour. About 50 ml are then distilled off under normal pressure, and 25 ml of water are added to the residue. The solid is filtered off with suction in the cold and rinsed with an isopropanol/water (1:1) mixture. 4.7 g of ethyl 1-amino-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate of melting point 217° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH2:12])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[C:17]([F:24])[CH:16]=1.[F-].[Cs+]>COCCOC.O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH2:12])[N:8]=[C:7]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][C:17]=2[F:24])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(Cl)nc(N)c1Cl
Reactant: OB(O)c1ccc(Cl)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1nc(-c2ccc(Cl)cc2F)nc(N)c1Cl
Temperature: 100 °C
Yield: 36.3 %

Procedure:
6-Amino-2,5-dichloropyrimidine-4-carboxylic acid methyl ester (1.11 g, 5 mmol, see WO 2007/082076 A1 for preparation), 4-chloro-2-fluorophenylboronic acid (1.13 g, 6.5 mmol), bis(triphenylphosphine)-palladium(II) dichloride (350 mg, 0.5 mmol), and cesium fluoride (1.52 g, 10 mmol) were combined in 10 mL of 1,2-dimethoxyethane (DME) and 10 mL of water. The reaction mixture was heated in a CEM microwave at 100° C. for 15 minutes. The cooled reaction mixture was diluted with ethyl acetate, washed with water, dried and concentrated. The product was purified by column chromatography (methylene chloride/ethyl acetate gradient) then purified again by column chromatography (ethyl acetate/hexane gradient) to yield the title compound (574 mg, 40.8% yield): mp 194-196° C.; 1H NMR (CDCl3): δ 7.96 (m, 1H), 7.2 (m, 2H), 5.64 (br s, 2H), 4.01 (s, 3H).
Reaction SMILES: [F:1][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22]I)=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C.CCOC(C)=O>CN(C=O)C>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][N:4]2[CH2:5][CH2:6][C:7](=[O:8])[CH:2]([F:1])[CH2:3]2)=[CH:14][CH:15]=1
Reactant: Clc1ccc(-c2ccccc2CI)cc1
Reactant: O=C1CCNCC1F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCN(Cc2ccccc2-c2ccc(Cl)cc2)CC1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.4 %

Procedure:
3-Fluoro-piperidin-4-one (0.32 g, 2.7 mmol) was dissolved in DMF (13 mL) and 4′-chloro-2-(iodomethyl)biphenyl (1.03 g, 3.13 mmol) was added followed by DIPEA (1.06 g, 8.2 mmol). The reaction was stirred at ambient temperature for 16 hours, and then poured into EtOAc (100 mL). The organics were washed with water followed by brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography on silica gel afforded the title compound (0.75 g, 86% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.47-7.59 (m, 1H), 7.21-7.47 (m, 7H), 4.72-5.00 (m, 1H), 3.62-3.65 (d, J=12 Hz, 1H), 3.56-3.59 (d, J=12 Hz, 1H), 3.25-3.42 (m, 1H), 2.88-3.06 (m, 1H), 2.28-2.63 (m, 4H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[I-].[Na+].Cl[CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:38]=[CH:37][C:28]2[CH:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:30][O:31][C:27]=2[CH:26]=1.[Cl-].[NH4+]>CN(C)C=O.O>[C:1]1([C:7]2[N:8]([CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:38]=[CH:37][C:28]4[CH:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:30][O:31][C:27]=4[CH:26]=3)[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CC1COc2cc(OCCCCl)ccc21
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC1COc2cc(OCCCn3c(-c4ccccc4)cc4ccccc43)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
To a solution of 2-phenyl-1H-indole (0.425 g, 2.20 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (60% in oil, 88 mg, 2.20 mmol), and the mixture was stirred at room temperature for 30 min. A solution of sodium iodide (0.330 g, 2.20 mmol) and methyl [6-(3-chloropropoxy)-2,3-dihydro-1-benzofuran-3-yl]acetate (0.589 g, 2.07 mmol) in N,N-dimethylformamide (3 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 18 hr. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10%-40% ethyl acetate/hexane) to give the title compound (0.160 g, yield 18%) as a colorless oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][S:12][C:13]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][NH:22][C:21](=[O:25])[CH:20]=2)[CH:16]=[CH:15][N:14]=1.CS(O[C@H:31]([C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([F:48])[CH:42]=1)[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])(=O)=O>C1COCC1>[Si:34]([O:33][CH2:32][C@@H:31]([N:22]1[CH:23]=[CH:24][C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([S:12][CH3:11])[N:18]=2)=[CH:20][C:21]1=[O:25])[C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([F:48])[CH:42]=1)([C:37]([CH3:39])([CH3:40])[CH3:38])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](OS(C)(=O)=O)c1ccc(Cl)c(F)c1
Reactant: CSc1nccc(-c2cc[nH]c(=O)c2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CSc1nccc(-c2ccn([C@H](CO[Si](C)(C)C(C)(C)C)c3ccc(Cl)c(F)c3)c(=O)c2)n1
Temperature: 25 °C
Yield: 62.9 %

Procedure:
1.0M KHMDS (5.09 mL, 5.09 mmol) as a solution in THF was added to a cold (0° C.) suspension of 4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (0.93 g, 4.24 mmol) in THF (20 mL). The reaction mixture was stirred at 0° C. for 10 minutes before (R)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl methanesulfonate (2.44 g, 6.36 mmol) was added as a solution in THF (5 mL). The reaction was heated to reflux for 30 hours and then cooled to room temperature and concentrated. The residue was taken up in ethyl acetate (200 mL) and washed with water. The organics were dried, filtered and concentrated. The crude product was purified via column chromatography, eluting with hexanes/ethyl acetate (4:1) to give (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (1.35 g, 63%) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J=5.0 Hz, 1H), 7.43 (m, 2H), 7.34 (d, J=5.0 Hz, 1H), 7.32-7.28 (m, 2H), 7.16 (m, 1H), 6.85 (m, 1H), 6.24 (m, 1H), 4.35 (m, 1H), 4.23 (m, 1H), 2.65 (s, 3H), 0.88 (s, 9H), 0.03 (s, 3H), −0.03 (s, 3H); m/z (APCI-pos) M+1=506.1, 508.1.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][P:6]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])=[O:7]>CCCCCC>[CH:5]([P:6](=[O:7])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH2:4]
Reactant: CCOP(=O)(CCBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: C=CP(=O)(OCC)OCC
Temperature: 0 °C
Yield: 94 %

Procedure:
A sample of 60% NaH in mineral oil (32 mmol) was placed in a 2-neck round bottom flask and charged with dry hexane (20 mL). This solution was allowed to stir for ten minutes, after which the hexane-mineral oil layer was completely removed. The flask was then charged with dry tetrahydrofuran (100 mL), followed by dropwise addition of 1,2-HS(C6H4)SH (14 mmol) with constant stirring. The resulting solution was cooled at 0° C. and BrCH2CH2P(O)(OC2H5)2 (30 mmol) was added dropwise with constant stirring over a period of 30 minutes. Excess NaH was quenched by addition of 50 mL of deionized water. The solution was extracted from the ethyl acetate (3×50 mL) and washed with a saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. Upon filtering, the solvent was removed in vacuo to afford 6 in 94% yield along with a trace amount of diethyl vinylphosphonate. The compounds were separated on a silica gel column (20 cm; 60 mesh) using 90:10 ethyl acetate to hexane solvent mixture. Removal of the solvent in vacuo, afforded compound 6 as a viscous, yellow-green oil with an overall yield of 91%. High resolution FAB/MS Anal. Calcd. for C18H32O6P2S2 : 470.1115; Found: [M+H+ ], m/z=471.1119. 1H NMR (CDCl3): δ 1.27 (t, 3JHH =9.0 Hz, 12H, OCH2CH3), 2.02 (m, 4H, PCH2CH2), 3.06 (m, 4H, PCH2CH2), 4.05 (m, 8H, OCH2CH3), 7.2 (m, 4H, C6H4). 13C NMR (CDCl3): δ 16.3 (d, 3JPC =6.0 Hz, OCH2CH3), 25.8 (d, 1JPC =136 Hz, PCH2CH2), 26.2 (s, PCH2CH2), 61.7 (d, 2JPC =6.0 Hz, OCH2CH3). 31P NMR (CDCl3): δ29.4 (s).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]2[C:14](SC)=[N:15][C:16]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:12]2=[N:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](OCC)(=[O:27])C=C.C[O-].[Na+].C(O)(=O)C>CO>[CH2:1]([S:8][C:9]1[N:13]=[C:12]2[N:11]([C:14]([O:27][CH3:24])=[N:15][C:16]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=32)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1nc2ncccc2c2nnc(SCc3ccccc3)n12
Reactant: C=CC(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1nc2ncccc2c2nc(SCc3ccccc3)nn12
Yield: 86.8 %

Procedure:
A mixture of 17.7 g (52 mmol) of 3-benzylthio-5-methylthiopyrido[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine in 200 mL of methanol was prepared and to this was added at ambient temperature with stirring 8.5 mL (7.8 g, 78 mmol) of ethyl acrylate and 2.4 mL of 25 percent sodium methoxide in methanol (10 mmol). Everything dissolved fairly quickly and after 15 min new precipitate formed. After about 1 hour the mixture was acidified with acetic acid and the volatile components were removed by evaporation under reduced pressure. The residue was dissolved in dichloromethane and the resulting solution was washed with water, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue was diluted with ether, recovered by filtration, and dried to obtain 14.6 g of the title compound as a brown powder melting at 282°-284° C. with decomposition.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]3[CH2:17][CH2:16][CH2:15][C:14]([C:18]([O-:20])=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]3[CH2:17][CH2:16][CH2:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:22][CH:23]=1
Reactant: O=C([O-])C1=Cc2cc(OCc3ccc(F)cc3)ccc2CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(OCc3ccc(F)cc3)ccc2CCC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 103.3 %

Procedure:
To 2-(4-fluorobenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (462 mg, 1.42 mmol) dissolved in a mixed solvent of methanol (5 ml) and THF (5 ml) was added a 1N aqueous solution of sodium hydroxide (4.3 ml), and the resulting mixture was stirred at 50° C. for 2 hours. The reaction mixture was mixed with 1 N hydrochloric acid (4.3 ml) at 0° C., was concentrated under reduced pressure and was mixed with water, and an insoluble material was collected by filtration. The insoluble material was washed with water and was dried under reduced pressure to obtain 2-(4-fluorobenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (458 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH:11]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:17][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:9]
Reactant: NC1CCCCC1
Reactant: O=C(O)c1cncc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)c1cncc(Br)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 5-bromonicotinic acid (XLII) (500 mg, 2.49 mmol) in DMF (8 mL) was added cyclohexanamine (XLIII) (247 mg, 2.49 mmol) and DIPEA (643 mg, 4.98 mmol). The reaction was cooled at 0° C. before adding HATU (947 mg, 2.49 mmol). The reaction was warmed to room temperature and stirred for 4 hrs. The reaction was diluted with EtOAc, washed with 2× water, brine, dried over MgSO4 and concentrated under vacuum to yield crude 5-bromo-N-cyclohexylnicotinamide (XLIV). The product was used without further purification. ESIMS found for C12H15BrN2O m/z 283 (M+H).
Reaction SMILES: [F:1][C:2]1[C:12]([C:13]2[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[H-].[Na+].[CH2:27](Br)[C:28]#[CH:29].O>CN(C=O)C>[F:1][C:2]1[C:12]([C:13]2[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=2)=[CH:11][C:5]2[N:6]([CH2:29][C:28]#[CH:27])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc3c(cc2F)OCC(=O)N3)c1=O
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCN1C(=O)COc2cc(F)c(-c3ccc(C(F)(F)F)n(C)c3=O)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
0.3 g (0.87 mmol) of 3-(7-fluoro-2,3-dihydro-1,4-benzoxazin-3-on-6-yl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone was dissolved in 1 ml of DMF, and 0.04 g (1 mmol) of 60% sodium hydride was added under cooling with ice, followed by stirring at room temperature for 15 minutes. Then, 0.12 g (1 mmol) of propargyl bromide was added thereto. The mixture was stirred at room temperature for 3 hours, then poured into water and extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and then, the obtained residue was purified by silica gel column chromatography to obtain 0.24 g (yield: 72%) of the desired product. Melting point: 166-168° C. 1H-NMR (400 MHz, CDCl3) δ value: 2.24(1H,t), 3.68(3H,s), 4.63(2H,s), 4.68(2H,d), 6.76(1H,d), 6.83(1H,d), 7.40(1H,d), 7.51(1H,d)ppm.
Reaction SMILES: O1CCCCC1[N:7]1[C@@H:10]([CH2:11][CH2:12][O:13]C2CCCCO2)[C@H:9]([CH2:20][CH2:21][O:22][O:23][C:24]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:25])[C:8]1=[O:36].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.P([O-])([O-])([O-])=O>CO>[N+:33]([C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C:24]([O:23][O:22][CH2:21][CH2:20][C@H:9]2[C@H:10]([CH2:11][CH2:12][OH:13])[NH:7][C:8]2=[O:36])=[O:25])=[CH:32][CH:31]=1)([O-:35])=[O:34]
Reactant: O=C(Cc1ccc([N+](=O)[O-])cc1)OOCC[C@@H]1C(=O)N(C2CCCCO2)[C@H]1CCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Solvent: O
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)OOCC[C@@H]1C(=O)N[C@H]1CCO
Reaction time: 2 h

Procedure:
A solution of trans-1-(2-tetrahydropyranyl)-3-(1-p-nitrobenzylcarbonyldioxyethyl)-4-[2-(2-tetrahydropyranyl)oxyethyl]-2-azetidinone in methanol at 25° C. is treated with 0.1 molar equivalent of p-toluenesulfonic acid monohydrate. The solution is stirred for a period of 2 hours and then neutralized with 1 M pH7 phosphate buffer. The product is extracted into ethyl acetate. The ethyl acetate solution is washed with brine, dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure to give trans-3-(1-p-nitrobenzylcarbonyldioxyethyl)-4-(2-hydroxyethyl)-2-azetidinone. The cis diastereoisomers are obtained in an analogous manner.
Reaction SMILES: [CH:1]1([C:6]2[CH:10]=[C:9]([NH:11][C:12]([NH:14][C:15]3[CH:20]=[C:19]([C:21]4[C:32](=[O:33])[N:31]([CH3:34])[C:24]5[N:25]=[C:26]([NH:29][CH3:30])[N:27]=[CH:28][C:23]=5[CH:22]=4)[C:18]([CH3:35])=[CH:17][C:16]=3[F:36])=[O:13])[N:8]([CH3:37])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:38][N:39]([CH3:43])[CH2:40]CN>C1COCC1.CCOC(C)=O>[CH:1]1([C:6]2[CH:10]=[C:9]([NH:11][C:12]([NH:14][C:15]3[CH:20]=[C:19]([C:21]4[C:32](=[O:33])[N:31]([CH3:34])[C:24]5[N:25]=[C:26]([NH:29][CH2:30][CH2:38][N:39]([CH3:43])[CH3:40])[N:27]=[CH:28][C:23]=5[CH:22]=4)[C:18]([CH3:35])=[CH:17][C:16]=3[F:36])=[O:13])[N:8]([CH3:37])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)CCN
Reactant: CNc1ncc2cc(-c3cc(NC(=O)Nc4cc(C5CCCC5)nn4C)c(F)cc3C)c(=O)n(C)c2n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(F)c(NC(=O)Nc2cc(C3CCCC3)nn2C)cc1-c1cc2cnc(NCCN(C)C)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.2 %

Procedure:
A solution 1-(3-cyclopentyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 122 (80 mg, 0.15 mmol) in THF (1 mL) was treated with N,N-dimethylethylenediamine (0.080 mL, 0.74 mmol). The reaction was stirred 1 h at RT, diluted with EtOAc (15 mL) and washed with 2 M aq Na2CO3 (2×10 mL), water (10 mL) and brine (10 mL). The organics were dried (Na2SO4), concentrated in vacuo and chromatographed on reverse phase silica gel to provide 1-(3-cyclopentyl-1-methyl-1H-pyrazol-5-yl)-3-(5-(2-(2-(dimethylamino)ethylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyl)urea (33 mg, 39% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.87 (s, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.65 and 8.60 (br s, 1H), 7.91 (d, J=8.6 Hz, 1H), 7.75 and 7.59 (m, 1H), 7.66 (s, 1H), 7.14 (d, J=8.4 Hz, 1H), 5.98 (s, 1H), 3.59-3.43 (m, 8H), 2.86 (m, 1H), 2.21 (br s, 6H), 2.49 (m, 2H obscured by solvent), 2.06 (s, 3H), 1.87 (m, 2H), 1.66-1.48 (m, 6H); MS (ESI) m/z: 562.3 (M+H+).
Reaction SMILES: C(#N)C=C.C=CC1C=CC=CC=1.C(C1C=C[C:19]([OH:22])=[CH:18][CH:17]=1)(C)=C.C[CH:24]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:25]#N.N(C(C)(CC(C)C)C#N)=NC(C)(CC(C)C)C#N>C(OCC)(=O)C>[C:28]([C:27]1[CH:24]=[CH:25][CH:17]=[CH:18][C:19]=1[OH:22])([CH3:29])=[CH2:30]
Reactant: CC(C)CC(C)C#N
Reactant: C=C(C)c1ccc(O)cc1
Agent: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Solvent: C=Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C=CC#N
Product: C=C(C)c1ccccc1O

Procedure:
Acrylonitrile (270 g), styrene (630 g), p-isopropenylphenol (100 g), ethyl acetate (250 g) and 2,2'-azobis(2,4-dimethylvaleronitrile (5 g) were fed and polymerized at 60° C. for 4 hours, followed by further adding ethyl acetate (250 g) and 2,2'-azobis(2,4-dimethylvaleronitrile) (5 g) and further polymerization at 60° C. for 4 hours. Solvent was then removed under reduced pressure to obtain a copolymer of isopropenylphenol (hereinafter abbreviated to phenolic polymer B). The viscosity of 5% solution of phenolic polymer B in ethyl acetate, at 25° C., was 1.75 cps.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]([CH:9]([NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=O)[O:33]C4C=CC=CC=4)[CH:26]=3)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1)=[O:14])[CH2:10][CH3:11])[CH3:8].C(C(NC(N1C2C(=CC(OC3C=CN=C(NC(N4CCC(N5CCCC5)CC4)=O)C=3)=CC=2)C=C1)=O)CC)C>CN(C)C=O>[CH2:7]([CH:9]([NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:33])[CH:26]=3)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1)=[O:14])[CH2:10][CH3:11])[CH3:8]
Reactant: CCC(CC)NC(=O)n1ccc2cc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)ccc21
Reactant: C1COCCN1
Agent: CCC(CC)NC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(N5CCCC5)CC4)c3)ccc21
Solvent: CN(C)C=O
Product: CCC(CC)NC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCOCC4)c3)ccc21
Reaction time: 2 h
Yield: 29.7 %

Procedure:
N,N-dimethylformamide (3 ml) and morpholine (0.22 ml, 2.5 mmol) were added to a mixture (0.324 g) of phenyl N-(4-(1-((1-ethylpropyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate and phenyl N-(4-(1-((1-ethylpropyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate synthesized in Example 96; and the reaction mixture was stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and water; the organic layer was concentrated; and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate:methanol=10:1) to yield the title compound as white crystals (95 mg, 0.21 mmol).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[CH:3]=1.O.[NH2:17][NH2:18]>C(O)C>[NH:17]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[CH:3]=1)[NH2:18]
Reactant: NN
Reactant: CCCn1c(=O)cc(Cl)c2ccccc21
Solvent: CCO
Solvent: O
Product: CCCn1c(=O)cc(NN)c2ccccc21
Yield: 94 %

Procedure:
In 140 ml of ethanol was dissolved 6.02 g (27 mmol) of 4-chloro-1-propylquinolin-2(1H)-one, and 140 ml of hydrazine monohydrate was added thereto, followed by refluxing for 3 hours. The reaction mixture was concentrated to an about half of its original volume and then allowed to cool to obtain 5.53 g (94%) of the titled compound as a pale yellow crystal.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH3:19])[N:7]2[CH:16]1[CH2:18][CH2:17]1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][CH2:31][CH2:32][NH2:33].C(N(CC)CC)C.[NH4+].[Cl-]>CS(C)=O.O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:33][CH2:32][CH2:31][NH:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH3:19])[N:7]2[CH:16]1[CH2:17][CH2:18]1
Reactant: NCCNc1ccccn1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)c(C)n(C3CC3)c12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1c(NCCNc2ccccn2)c(F)c(N)c2c(=O)c(C(=O)O)c(C)n(C3CC3)c12
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
A solution of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-2-methyl-4-oxoquinoline-3-carboxylic acid (140 mg, 0.432 mmol), N-2-pyridyl-1,2-ethanediamine (88.9 mg, 0.648 mmol) and triethylamine (0.0903 mL, 0.648 mmol) in DMSO (4 mL) was stirred at 100° C. for 2 h. To the reaction mixture, water and NH4Cl was added to neutralize and the suspension was stirred for 30 min. The crude product was extracted with EtOAc, washed with brine, dried over MgSO4 and the sovent was removed in vacuo. The crude product was purified by preparative thin layer chromatography (Hexane:EtOAc 1:4) to yield 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-2-methyl-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylic acid (79.9 mg, 42%) as a yellow amorphous solid.