Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC2N(O)N=[N:7]C=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:24]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:47]3[N:52]=[C:51]([CH2:53][CH2:54][C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=4[CH2:61][C:62]([OH:64])=O)[CH:50]=[CH:49][N:48]=3)=[CH:42][CH:41]=2)[CH2:36][CH2:35]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CN(C=O)C>[NH2:7][C:62](=[O:64])[CH2:61][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][C:55]=1[CH2:54][CH2:53][C:51]1[CH:50]=[CH:49][N:48]=[C:47]([NH:46][C:43]2[CH:44]=[CH:45][C:40]([N:37]3[CH2:36][CH2:35][N:34]([C:32]([O:31][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:33])[CH2:39][CH2:38]3)=[CH:41][CH:42]=2)[N:52]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)Cc1ccccc1CCc1ccnc(Nc2ccc(N3CCN(C(=O)OCc4ccccc4)CC3)cc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)Cc1ccccc1CCc1ccnc(Nc2ccc(N3CCN(C(=O)OCc4ccccc4)CC3)cc2)n1
Reaction time: 18 h
Yield: 97.8 %

Procedure:
HOBt (24 mg, 0.17 mmol), EDCl.HCl (33 mg, 0.17 mmol) and DI PEA (0.12 mL, 0.67 mmol) were added to a stirred solution of 2-(2-(2-(2-((4-(4-((benzyloxy)carbonyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)ethyl)phenyl)acetic acid (A5) (74 mg, 0.13 mmol) in dry THF (5 mL) and dry DMF (2 mL) under an atmosphere of nitrogen. After 10 minutes ammonium carbonate (65 mg, 0.67 mmol) was added and stirring was continued at room temperature for 18 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (65 mL) and saturated NaHCO3 (65 mL). The aqueous layer was extracted with EtOAc (2×50 mL) then the combined organic layers were washed with brine (50 mL) and dried over Na2SO4. After filtration the solvent was removed in vacuo to afford a pale yellow solid which was purified by silica gel column chromatography (Biotage Isolera, SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A6 as brown oil (70 mg, 95%); 1H-NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.64 (s, 1H), 7.48 (d, J=8.9 Hz, 2H), 7.37 (d, J=4.3 Hz, 4H), 7.32 (m, 1H), 7.25-7.17 (m, 4H), 6.91 (d, J=9.0 Hz, 2H), 6.51 (d, J=4.9 Hz, 1H), 5.77 (s, 1H), 5.51 (s, 1H), 5.16 (s, 2H), 3.69-3.64 (m, 4H), 3.64 (s, 2H), 3.11-3.06 (m, 4H), 3.05 (dd, J=9.6, 6.5 Hz, 2H), 2.91-2.84 (m, peak obscured), 2.07 (t, J=7.0 Hz 1H). LCMS-A: rt 5.646 min; m/z 551.2 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][C:7]1=[O:12])C.O.[NH2:15][NH2:16].O>C(O)C>[O:12]=[C:7]1[N:6]([CH2:5][C:4]([NH:15][NH2:16])=[O:3])[CH2:11][CH2:10][O:9][CH2:8]1
Reactant: NN
Reactant: CCOC(=O)CN1CCOCC1=O
Solvent: CCO
Solvent: O
Product: NNC(=O)CN1CCOCC1=O
Temperature: 80 °C

Procedure:
Ethyl-2-(3-oxomorpholino)acetate (600 mg, 3.21 mmol) was dissolved in ethanol (3 mL) and hydrazine hydrate (160.46 mg, 3.21 mmol) was added at room temperature. The reaction mixture was heated at 80° C. for 1 h. The reaction mixture was transferred into 50 mL water and extracted with EtOAc (3×50 mL). The combined organic layers was washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to give the crude product, which was used without further purification in the subsequent step (Crude yield: 54%). LCMS m/z 174.05 [M+H]+ tR 2.489 min.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)O)[CH:10]=2)[N:5]=[C:4]([O:28]C(C)(C)C)[CH:3]=1.[SiH](CC)(CC)CC.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[C:4]([OH:28])[CH:3]=[C:2]3[Br:1])=[CH:22][CH:23]=1
Reactant: CC(C)(C)Oc1cc(Br)c2cc(C(O)(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Oc1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of [4-bromo-2-(tert-butoxy)quinolin-6-yl]bis(4-chlorophenyl)methanol (1.5 g, 2.82 mmol, 1.00 equip) in dichloromethane (55 mL), Et3SiH (1.3 g, 4.00 equip), and trifluoroacetic acid (8 g, 70.77 mmol, 25.00 equip). The resulting solution was stirred overnight at room temperature. The pH value of the solution was adjusted to 7-8 with sodium bicarbonate. The resulting solution was extracted with DCM (3×50 ml) and the organic layers combined. The resulting mixture was washed with water (2×50 mL). The resulting mixture was washed with brine (1×50 mL). The resulting mixture was dried over anhydrous sodium sulfate and concentrated to yield 6-[bis(4-chlorophenyl)methyl]-4-bromoquinolin-2-ol as a white solid. (ES, m/z): [M+H]+ 433
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].C(N(CC)CC)C.[CH2:12]([O:14][C:15](=[O:37])[CH:16]([O:34][CH2:35][CH3:36])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[CH:20][CH:19]=1)[CH3:13].C(OCC)C>ClCCl>[CH2:12]([O:14][C:15](=[O:37])[CH:16]([O:34][CH2:35][CH3:36])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][C:3](=[O:4])[NH:2][CH3:1])=[CH:31][CH:32]=2)=[CH:20][CH:19]=1)[CH3:13]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(O)cc2)cc1)OCC
Reactant: CN=C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(OC(=O)NC)cc2)cc1)OCC
Yield: 47.1 %

Procedure:
Methyl isocyanate (70 mg; 1.22 mmole) was slowly added to a mixture of triethyl amine (180 mg; 1.17 mmole) and 2-ethoxy-3-{4-[2-(4-hydroxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester (described in Example 26b) (418 mg; 1.17 mmole) in dichloromethane (5 ml). After stirring at room temperature for 2.5 hours the excess of methyl isocyanate was evaporated in vacuo and water and dichloromethane were added. The phases were separated. Water and potassium hydrogensulfate (1 M) were added to the organic phase. The phases were separated, the organic phase was evaporated in vacuo and the residue was purified by chromatography on silica using toluene:diethylether (gradient 4:1 to 3:1) as eluant to give 229 mg (yield 47%) of 2-ethoxy-3-{4-[2-(4-methylcarbamoyloxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=3)[C:10]2=[O:26])[CH:6]=[CH:7][CH:8]=1.[N:27]#[C:28][NH2:29]>O1CCOCC1>[ClH:1].[NH:2]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=3)[C:10]2=[O:26])[CH:6]=[CH:7][CH:8]=1)[C:28]([NH2:29])=[NH:27]
Reactant: COC(=O)CCc1ccc(N2CCN(c3cccc(N)c3)C2=O)cc1
Reactant: N#CN
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)CCc1ccc(N2CCN(c3cccc(NC(=N)N)c3)C2=O)cc1

Procedure:
Prepared from 1-(3-amino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one hydrochloride by refluxing for three hours with cyanamide in dioxane.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9](Cl)(=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].CO>N1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N:6][CH:7]=1
Reactant: Nc1ncc(O)cn1
Reactant: CCCCCC(=O)Cl
Solvent: CO
Solvent: c1ccncc1
Product: CCCCCC(=O)Nc1ncc(O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
5-Hydroxypyrimidin-2-amine (40 g, 360 mmol) was dissolved in pyridine (200 mL), the solution was added with hexanoyl chloride (121 g, 899 mmol), and the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was added with methanol (100 mL), the mixture was concentrated under reduced pressure, and the resulting residue was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting residue was dissolved in methanol (200 mL). The solution was added with saturated ammonia solution in methanol (250 mL) under ice cooling and stirring, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:acetone=2:1) to obtain N-(5-hydroxypyrimidin-2-yl)hexanamide (39.5 g, 52%) as colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:17])[C:12](=[O:18])[CH2:11]3)[CH:5]=[N:6][CH:7]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:6]1[CH:5]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:17])[C:12](=[O:18])[CH2:11]3)[CH:3]=[C:2]([C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)[CH:7]=1
Reactant: OB(O)c1cccnc1
Reactant: CN1C(=O)Cc2cc(-c3cncc(Br)c3)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CN1C(=O)Cc2cc(-c3cncc(-c4cccnc4)c3)ccc21
Temperature: 120 °C

Procedure:
To 5-(5-bromo-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one prepared as described in Example 21, (100 mg, 0.330 mmol) was added 3-pyridine boronic acid (52.7 mg, 0.429 mmol), 1,2-dimethoxyethane (3 mL), and 2 M aqueous sodium carbonate (0.429 mL, 0.858 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (150 mg, 0.016 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 120° C. for 2.5 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 1 to 8%) to furnish 5-[3,3′]bipyridinyl-5-yl-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 302.1301 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 3.29 (s, 3H), 3.64 (s, 2H), 6.97 (d, J=8.1 Hz, 1H), 7.46 (dd. J=7.5, 4.9 Hz, 1H), 7.53-7.62 (m, 2H), 7.92-7.99 (m, 1H), 8.02 (t, J=2.1 Hz, 1H), 8.71 (dd, J=4.8, 1.5 Hz, 1H), 8.81 (d, J=2.3 Hz, 1H), 8.87 (d, J=2.0 Hz, 1H), 8.93 (d, J=1.8 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:17])=O>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5]([Cl:17])=[O:6]
Reactant: COc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: O=S(Cl)Cl
Product: COc1ccc([N+](=O)[O-])cc1C(=O)Cl
Yield: 100 %

Procedure:
2-Methoxy-5-nitro benzoic acid (500 mg, 2.5 mmol) was heated to reflux with thionyl chloride (5 ml) for 4 hr. The excess thionyl chloride was evaporated under reduced pressure to yield 2-methoxy-5-nitro-benzoyl chloride (0.55 g, 100%), which was used as such for the next step.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[CH:11]=[C:10](C(OCC)=O)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:25].[Na+]>>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[C:11]([OH:25])=[CH:10][C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CCOC(=O)c1cc2cc(C)ccc2n(Cc2ccccc2)c1=O
Agent: [Na+]
Product: Cc1ccc2c(c1)c(O)cc(=O)n2Cc1ccccc1

Procedure:
The product from Step (3) was dissolved in 2N sodium hydroxide (150 ml) and the solution was refluxed for 4 hours. Then the solution was cooled and acidified with mineral acid to pH3. The solid was filtered, dried and crystallized from ethyl acetate/hexane to give 1-benzyl-4-hydroxy-6-methyl-2(1H)-quinolinone (4.0 gm). That the expected product was obtained was confirmed by the spectral data: MS: m/e 265 (M.+); NMR (DMSO): δ2.32 (s, 3H, CH3 --Ar), 5.43 (s, 2H, CH2 --Ar), 5.96 (s, 1H, =CH--), 11.48 (s, 1H, OH) ppm.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH2:19]([C:21]1[N:25]=[C:24]([C:26](O)=[O:27])[O:23][N:22]=1)[CH3:20]>CC#N>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:26]([C:24]3[O:23][N:22]=[C:21]([CH2:19][CH3:20])[N:25]=3)=[O:27])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: CCc1noc(C(=O)O)n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Solvent: CC#N
Product: CCc1noc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)n1
Yield: 11.5 %

Procedure:
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.77 mmol) was coupled with 3-ethyl-1,2,4-oxadiazole-5-carboxylic acid (131 mg, 0.92 mmol) using the method of Example 34(d). Crude product was suspended in MeCN and the precipitation was filtered to yield 34 mg (11%) of the title compound. Filtrate was purified by CombiFlash (column: C-18, eluent: 0-100% MeCN) to yield additional 118 mg (40%) of title product. Combined total yield was 152 mg (51%). 1H-NMR (400 MHz; d6-DMSO): δ 1.18 (d, 3H), 1.26 (t, 3H), 2.81 (q, 2H), 4.31-4.37 (m, 2H), 4.40-4.52 (m, 1H), 6.95 (d, 1H), 7.85 (d, 1H), 7.92 (dd, 1H), 7.97 (d, 1H), 8.06 (d, 1H), 9.39 (broad d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:9]([CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1)#[N:10]
Reactant: N#CCc1ccccc1N
Reactant: O=C(Cl)c1cccnc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#CCc1ccccc1NC(=O)c1cccnc1
Reaction time: 8 h

Procedure:
2-aminophenylacetonitrile (5.0 g, 37.1 mmol) and nicotinoyl chloride (7.5 g, 40.8 mmol) are taken up in dry dichloromethane (200 mL) and diisopropylethylamine (12.1 g, 92.7 mmol) is added while cooling the mixture with a cold water bath. The mixture is stirred overnight, whereupon it is washed twice with saturated aqueous sodium bicarbonate. The combined aqueous layer is back-extracted with ethyl acetate. The combined organic phase is dried over MgSO4 and concentrated in vacuo to give a residue, which is purified by silica gel flash chromatography (dichloromethane-methanol, 1:0 to 19:1) to give N-(2-cyanomethyl-phenyl)-nicotinamide as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.02 (s, 2H), 7.32-7.37 (m, 1H), 7.39-7.44 (m, 2H), 7.50 (d, J=7.1 Hz, 1H), 7.59 (dd, J=8.1, 4.8 Hz, 1H), 8.30-8.33 (m, 1H), 8.78 (dd, J=4.8, 1.5 Hz, 1H), 9.14 (d, J=1.8 Hz, 1H), 10.36 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][O:7][CH2:8]2)([O-])=O.[H][H]>[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][O:7][CH2:8]2
Reactant: O=[N+]([O-])c1cccc2c1COC2
Reactant: [H][H]
Agent: [Pd]
Product: Nc1cccc2c1COC2

Procedure:
Nitration of the 1,3-dihydro-iso-benzofuran derivatives of Formula 17 provides the 1,3-dihydro-4-nitro-iso-benzofuran compounds of Formula 18. The nitro compounds of Formula 18 are reduced with hydrogen on a suitable catalyst, such as palladium, to give the 1,3-dihydro-4-amino-iso-benzofuran compounds of Formula 19.
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]([F:17])([F:16])[O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1>C1COCC1.CCOCC>[F:4][C:5]([F:17])([F:16])[O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH:2][NH2:3])=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: NN
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: NNC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
To an ice-cooled solution of hydrazine hydrate (16 mL, 25% (w/w), 125 mmol) in THF (100 mL) was added a solution of 4-trifluoromethoxybenzoyl chloride (4.3 g, 19.2 mmol) in THF (50 mL) over 30 min. The solution was stirred for a further 30 min and then diluted with ether (200 mL). The turbid organic solution was then washed with water (3×200 mL) and brine (200 mL). After drying (Na2SO4), solvent was removed by rotary evaporation. The solid residue was dissolved in ethanol/water (1:1, 200 mL), insoluble material was filtered off, and the filtrate taken to dryness to leave 3.63 g (86%) of pure 4-trifluoromethoxybenzoic acid hydrazide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([O:10]C)=[O:9].CO.O.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2ccc([N+](=O)[O-])cc2)ccc1C(=O)O
Temperature: 50 °C
Yield: 92.2 %

Procedure:
Methyl 3-methyl-4′-nitrobiphenyl-4-carboxylate (0.70 g, 2.1 mmol) was suspended in THF (5 mL), MeOH (5 mL) and water (2.5 mL), and NaOH (0.41 g, 10.3 mmol) was added. The reaction mixture was heated at 50° C. for 3 h. Upon cooling to rt, the reaction mixture was concentrated in vacuo and purified by reversed-phase HPLC to give 0.498 g (94%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 2.62 (s, 3H), 7.62-7.68 (m, 2H), 7.91-8.05 (m 3H), 7.18 (t, 1H), 8.31 (d, 1H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=2)O1>>[CH3:11][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([C:26]1[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=1)=[N:3][C:4]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cn1cnc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1cnc2c(N3CCOCC3)nc(-c3ccc(N)nc3)nc21

Procedure:
4-(2-Chloro-9-methyl-9H-purin-6-yl)morpholine (20 mg) was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine via General Procedure A and purified via reverse phase HPLC to give 9.3 mg of 128 as a white solid. MS (Q1) 312.3 (M)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=S)[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][O:37][CH2:38][CH2:39][C:40]([NH:42][NH2:43])=O>CC1C=CC(C)=CC=1>[CH3:36][O:37][CH2:38][CH2:39][C:40]1[N:26]2[C:21]3[CH:20]=[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:18]([C:15]4[CH:16]=[CH:17][C:12]([C:8]5([NH:7][C:6](=[O:35])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:11][CH2:10][CH2:9]5)=[CH:13][CH:14]=4)=[N:28][C:22]=3[O:23][CH2:24][C:25]2=[N:43][N:42]=1
Reactant: COCCC(=O)NN
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=S)CO4)cc2)CCC1
Solvent: Cc1ccc(C)cc1
Product: COCCc1nnc2n1-c1cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc1OC2
Temperature: 150 °C
Yield: 29.1 %

Procedure:
A suspension of tert-butyl(1-(4-(7-phenyl-2-thioxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (100 mg, 0.205 mmol) and 3-methoxypropanehydrazide (48 mg, 0.410 mmol) in p-xylene (2 ml) was heated to 150° C. for 15 minutes under microwave irradiation. The resulting reaction mixture was concentrated to dryness under reduced pressure and purified by Biotage silica gel chromatography (gradient 0% to 20% ethyl acetate in cyclohexane) to give the title compound (33 mg, 30%). LCMS (Method D): RT=1.414 min, M+1=554. 1H NMR (500 MHz, CDCl3) δ 8.16 (1H, s), 7.27-7.36 (7H, m), 7.23-7.18 (2H, m), 5.60 (2H, s), 3.99 (2H, t), 3.43 (3H, s), 3.38 (2H, t), 2.57-2.40 (4H, m), 2.12-2.01 (1H, m), 1.87-1.77 (1H, m), 1.49-1.27 (9H, bs).
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]([OH:7])=[O:6].[CH3:8][CH:9]([CH:11]1[CH2:13][CH2:12]1)[OH:10].O>C1COCC1>[CH:11]1([CH:9]([O:10][CH2:4][C:5]([OH:7])=[O:6])[CH3:8])[CH2:13][CH2:12]1
Reactant: O=C(O)CBr
Reactant: CC(O)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(OCC(=O)O)C1CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 29.9 %

Procedure:
To a suspension of NaH (80% in oil) (15.7 g, 523 mmol) in THF (180 mL) at 0° C. were added bromoacetic acid (28.0 g, 203 mmol) and a-methylcyclopropane methanol (10.0 g, 116 mmol). The resulting mixture was then stirred at 70° C. After a period of 18 h, the reaction mixture was poured over cold H2O and the H2O phase was extracted once with Et2O. The water phase was acidified with HCl and extracted twice with Et2O. The ether was dried over MgSO4, filtered and evaporated under reduced pressure. The crude oil was then purified by flash chromatography (40% EtOAc in hexane to 40% EtOAc in Hexane+AcOH) to provide 5.0 g of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:15])[NH:8][C:9]=1[CH:10]=[CH:11][N:12](C)C)(=O)[CH3:2].C(O)(=O)C.C(N)=N>CN(C)C=O>[CH3:2][C:1]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](=[O:15])[NH:8]2
Reactant: CC(=O)c1ccc(=O)[nH]c1C=CN(C)C
Agent: N=CN
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1nccc2[nH]c(=O)ccc12
Yield: 83.8 %

Procedure:
A mixture containing 10.3 g of 5-acetyl-6-(2-dimethylaminoethenyl)-2(1H)-pyridinone, 10.4 g of formamidine acetate and 75 ml of dimethylformamide was heated on a steam bath for 5 hours and then concentrated to dryness on a rotary evaporator. The residue was treated with 50 ml of water and again stripped to dryness. The white residue was recrystallized from isopropyl alcohol to yield 6.7 g of 5-methyl-1,6-naphthyridin-2(1H)-one, m.p. 238°-240° C. This compound was the same as the compound of Example E-7a, e.g., a mixed melting point showed no depression and the infrared and nuclear magnetic resonance spectral data for the compounds were respectively the same.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[N:7][C:8](Cl)=[C:9]([CH:26]=1)[C:10]([NH:12][C:13](=[NH:25])[CH2:14][O:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)=[O:11])[CH2:2][CH2:3][CH3:4].CC([O-])(C)C.[K+]>CS(C)=O>[CH2:1]([C:5]1[CH:6]=[N:7][C:8]2[N:25]=[C:13]([CH2:14][O:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[NH:12][C:10](=[O:11])[C:9]=2[CH:26]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cnc(Cl)c(C(=O)NC(=N)COCCc2cccc(Cl)c2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCc1cnc2nc(COCCc3cccc(Cl)c3)[nH]c(=O)c2c1

Procedure:
In analogy to the procedure described in example 78.4, 5-butyl-2-chloro-N-{2-[2-(3-chloro-phenyl)-ethoxy]-1-imino-ethyl}-nicotinamide was treated with KOtBu in DMSO to obtain 6-butyl-2-[2-(3-chloro-phenyl)-ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one as off-white crystals. MS: m/e=370.4 [M−H−].