Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([NH2:18])=[N:14][CH:15]=[C:16](I)[C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:19]([N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32])[C:20]#[CH:21].O>COCCOC.C(N(CC)CC)C.[Cu]I>[NH2:18][C:13]1[C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=3)=[CH:9][S:10][C:11]=2[C:16]([C:21]#[C:20][CH2:19][N:22]2[C:26](=[O:27])[C:25]3[C:24](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:23]2=[O:32])=[CH:15][N:14]=1
Reactant: Nc1ccc(-c2csc3c(I)cnc(N)c23)cc1
Reactant: C#CCN1C(=O)c2ccccc2C1=O
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: COCCOC
Solvent: O
Product: Nc1ccc(-c2csc3c(C#CCN4C(=O)c5ccccc5C4=O)cnc(N)c23)cc1
Temperature: 80 °C
Yield: 43.4 %

Procedure:
A suspension of Example 77B (0.6 g, 1.63 mmol) in DME (3 mL) and triethylamine (2 mL) was degassed by bubbling nitrogen through the suspension for 5 minutes, treated with N-propargylphthalimide (0.45 g, 2.45 mmol), PdCl2(PPh3)4 (57 mg, 0.08 mmol), and CuI (15 mg, 0.08 mmol), then heated to 80° C. for 1 hour. The cooled solution was poured into water, extracted with ethyl acetate and the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel using 3% methanol/dichloromethane to provide 300 mg (43% yield) of the desired product. 1H NMR (300 MHz, DMSO-D6) δ ppm 4.72 (s, 2H), 5.37 (s, 2H), 5.86 (s, 2H), 6.66 (d, J=8.14 Hz, 2H), 7.07 (d, J=8.14 Hz, 2H), 7.35 (s, 1H), 7.87-7.89 (m, 1H), 7.90 (s, 1H), 7.93 (d, J=4.07 Hz, 2H), 7.96 (d, J=5.76 Hz, 1H); MS (ESI(+)) m/e 425 (M+H)+
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.C1COCC1.CCN(C(C)C)C(C)C.[C:41]([C:45]1[N:49]([CH2:50][CH:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)[C:48]2[CH:57]=[CH:58][C:59]([S:61]([N:64]3[CH:68]=[C:67]([C:69]([OH:71])=O)[CH:66]=[N:65]3)(=[O:63])=[O:62])=[CH:60][C:47]=2[N:46]=1)([CH3:44])([CH3:43])[CH3:42]>CN(C=O)C>[C:41]([C:45]1[N:49]([CH2:50][CH:51]2[CH2:52][CH2:53][O:54][CH2:55][CH2:56]2)[C:48]2[CH:57]=[CH:58][C:59]([S:61]([N:64]3[CH:68]=[C:67]([C:69]([NH:2][CH3:1])=[O:71])[CH:66]=[N:65]3)(=[O:62])=[O:63])=[CH:60][C:47]=2[N:46]=1)([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cnn(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)c1

Procedure:
Following the same procedure in Example 24, Step A, using HATU (37 mg, 0.09 mmol), methylamine in THF (0.07 mL, 2M, 0.14 mmol), DIPEA (0.02 mL, 0.10 mmol) and 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carboxylic acid (40 mg, 0.09 mmol) (see following step B for preparation) in DMF (5 mL). The crude product was purified by MPLC on silica gel using EtOAc/DCM (1:1) to provide the title compound as a white solid. The product was converted to its TFA salt. Yield: 15 mg (29%); 1H NMR (400 MHz, CD3OD) δ 1.38-1.46 (m, 2 H), 1.46-1.54 (m, 2 H), 1.54-1.59 (s, 9 H), 2.22-2.36 (m, 1 H), 2.83 (s, 3 H), 3.25-3.35 (m, 2 H), 3.89 (dd, J=11.43, 3.61 Hz, 2 H), 4.36 (d, J=7.42 Hz, 2 H), 7.79 (d, J=8.59 Hz, 1 H), 7.90 (dd, J=8.69, 1.86 Hz, 1 H), 8.01 (s, 1 H), 8.29 (d, J=1.95 Hz, 1 H), 8.72 (s, 1 H); MS (ESI) (M+H)+=459.8; Anal. Calcd for C22H29N5O4S+0.1H2O: C, 57.27; H, 6.38; N, 15.18. Found: C, 57.49; H, 6.55; N, 14.34.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:9]=32)[CH2:4][CH2:3]1.[OH-].[Na+].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([Cl:33])=[O:32])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[ClH:33].[CH3:17][O:16][C:14]1[C:13]([O:18][CH3:19])=[CH:12][C:9]2[CH:10]3[N:5]([CH2:6][CH2:7][C:8]=2[CH:15]=1)[CH2:4][CH2:3][CH:2]([NH:1][C:31](=[O:32])[CH2:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1)[CH2:11]3
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: COc1cc2c(cc1OC)C1CC(N)CCN1CC2
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc(CC(=O)NC2CCN3CCc4cc(OC)c(OC)cc4C3C2)cc1
Product: Cl
Reaction time: 1 h
Yield: 17 %

Procedure:
To a cold mixture of 2-amino-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-2H-benzo[a]quinolizine (7.3 g, 0.029 mole), 200 ml of toluene and 50 ml of 20% NaOH was added dropwise 5.5 g of 4-methoxyphenylacetyl chloride. The resulting mixture was stirred in the cold for 1 hour whereupon the solid product was collected by filtration and chromatographed over silica gel using ethyl acetate-methanol (3:1) as eluant. The major fraction (3.4 g) was converted to the HCl salt with hydrogen chloride in 2-propanol and concentrated by removal of the solvent in vacuo. The concentrate was crystallized from methanol-ether and recrystallized from methanol-ether to yield 2.2 g of the desired product, m.p. (decomposed at 188°-90°). This compound conforms to Formula II where R1 and R2 are --OCH3, R3 is H and R4 is ##STR24##
Reaction SMILES: [CH2:1]1[CH2:29][O:28][C:3]2([CH:8]=[CH:7][C@H:6]3[C@H:9]4[C@H:18]([CH2:19][CH2:20][C@:4]23[CH3:5])[C:17]2[CH:16]=[CH:15][C:14]([OH:21])=[CH:13][C:12]=2[CH2:11][C@H:10]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[O:2]1.[OH-].[Li+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:32]([O:21][C:14]1[CH:15]=[CH:16][C:17]2[C@@H:18]3[C@H:9]([C@H:6]4[C@@:4]([CH2:20][CH2:19]3)([CH3:5])[C:3]3([O:2][CH2:1][CH2:29][O:28]3)[CH:8]=[CH:7]4)[C@H:10]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[CH2:11][C:12]=2[CH:13]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1C=CC21OCCO1
Reactant: BrCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1C=CC21OCCO1

Procedure:
A solution of 32.7 g of 17,17-ethylenedioxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-3-ol (see Example 1h) in 327 ml of dimethylformamide is mixed at room temperature with 5.73 g of lithium hydroxide and stirred with 15.1 ml of benzyl bromide for 2 hours at 60° C. Then, it is diluted with ethyl acetate, washed with water, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/methanol. 32.8 g of 3-benzyloxy-17,17-ethylenedioxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraene is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH:10][C:11](=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][CH2:20][CH3:21])[C:4]([CH2:23][CH2:24][CH3:25])=[N:3]1.OO.C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[CH3:1][N:2]1[C:6]2[C:7](=[O:8])[NH:9][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH2:19][CH2:20][CH3:21])=[N:10][C:5]=2[C:4]([CH2:23][CH2:24][CH3:25])=[N:3]1
Reactant: CCCOc1ccccc1C(=O)Nc1c(CCC)nn(C)c1C(N)=O
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCOc1ccccc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 58.8 %

Procedure:
1-Methyl-4-(2-n-propoxybenzamido)-3-n-propylpyrazole-5-carboxamide (0.34 g, 0.99 mmol) was added to a stirred mixture of 30% hydrogen peroxide solution (1.0 ml), potassium carbonate (0.54 g, 3.92 mmol), water (10 ml) and ethanol (5ml). The mixture was heated under reflux for 38 hours and then evaporated under vacuum. The residue was suspended in water (20 ml), then the suspension acidified with 2N hydrochloric acid and extracted with dichloromethane (3×20 ml). The extracts were combined, dried (Na2SO4) and evaporated under vacuum. The resulting residue was chromatographed on silica gel (6 g), using a methanol in dichloromethane elution gradient (0-1% methanol), to give an oil, successive trituration of which with ether gave the required product as a white solid (0.19 g, 59%), m.p. 111°-114° C. Found: C,66.26; H,6.92; N,17.15. C18H22N4O2 requires C,66.23; H,6.80; N, 17.17%
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:53][C:54]([F:70])([F:69])[O:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[C:62]1[CH:67]=[CH:66][CH:65]=[C:64]([NH2:68])[CH:63]=1>CN(C=O)C>[F:53][C:54]([F:69])([F:70])[O:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[C:62]1[CH:67]=[CH:66][CH:65]=[C:64]([NH:68][C:24]([C:19]2[C:20](=[O:23])[O:21][C:22]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:63]=1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Reactant: Nc1cccc(-c2ccccc2OC(F)(F)F)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: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccccc2OC(F)(F)F)c1)c1cc2cccc(OC(F)(F)F)c2oc1=O
Temperature: 25 °C
Yield: 89.8 %

Procedure:
DIEA (0.011 mL, 0.065 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.016 g, 0.059 mmol) and HATU (0.025 g, 0.065 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′-trifluoromethoxy-biphenyl-3-ylamine (0.015 g, 0.059 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected were collected and the solvent removed under vacuum to give 0.027 g of product in 90% yield: LCMS (ESI) m/z 510 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9](Cl)[C:8]([Cl:13])=[C:7]([Cl:14])[N:6]=1)=[O:4].[F-:15].[Cs+]>CC#N.CCOC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([F:15])[C:8]([Cl:13])=[C:7]([Cl:14])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(Cl)c(Cl)c(Cl)c1Cl
Reactant: [F-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(Cl)c(Cl)c(F)c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3,4,5,6-tetrachloropyridine-2-carboxylic acid methyl ester (1.00 equivalent) in MeCN is added CsF (1.00 equivalent) at room temperature. The resulting mixture is refluxed with stirring for 16 hours. The reaction mixture is cooled to room temperature and diluted with EtOAc and water. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product that is purified by flash column chromatography as necessary.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[CH:7][CH:8]=2)[N:3]=1.[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)[CH3:15]>CC(N(C)C)=O>[Cl:13][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([NH2:12])=[N:11][C:2]([NH:27][CH:24]3[CH2:25][CH2:26][N:21]([CH2:20][C:19]4[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:17]([O:16][CH2:14][CH3:15])[CH:18]=4)[CH2:22][CH2:23]3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: Nc1nc(Cl)nc2cc(Cl)ccc12
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Solvent: CC(=O)N(C)C
Product: CCOc1cc(CN2CCC(Nc3nc(N)c4ccc(Cl)cc4n3)CC2)ccc1OC
Yield: 28 %

Procedure:
A solution of 2,7-dichloro-quinazolin-4-ylamine (32.1 mg, 0.15 mmol, 1.0 equiv; commercially available) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol, 1.2 equiv; intermediate A1) in DMAc (2 mL) was heated by microwave irradiation to 200° C. for 15 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 22.0 mg (28%) of the title compound. MS (ISP): 442.4 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:12]([C:13]([OH:15])=O)=[CH:11][O:10][N:9]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]23[NH:39][CH2:38][CH2:37][N:25]2[C:26](=[O:36])[C:27]2[N:28]([CH:30]=[C:31]([N+:33]([O-:35])=[O:34])[CH:32]=2)[CH2:29]3)=[CH:20][CH:19]=1>CN(C=O)C.C(Cl)Cl.N1C=CC=CC=1>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]23[N:39]([C:13]([C:12]4[C:8]([CH3:7])=[N:9][O:10][CH:11]=4)=[O:15])[CH2:38][CH2:37][N:25]2[C:26](=[O:36])[C:27]2[N:28]([CH:30]=[C:31]([N+:33]([O-:35])=[O:34])[CH:32]=2)[CH2:29]3)=[CH:20][CH:19]=1
Reactant: Cc1nocc1C(=O)O
Reactant: COc1ccc(C23Cn4cc([N+](=O)[O-])cc4C(=O)N2CCN3)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C23Cn4cc([N+](=O)[O-])cc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
To generate the acid chloride, oxalyl chloride (600 μL, 7.0 mmol) and DMF (1 drop) were added to 3-methyl-1,2-oxazole-4-carboxylic acid (441 mg, 3.47 mmol) in CH2Cl2 (6 mL) at 0° C. The suspension was allowed to stir 15 minutes at 0° C. followed by 1 hour at room temperature. The resulting solution was concentrated in vacuo (without heating) to give a oil that was further dried under nitrogen. To a chilled suspension of the acid chloride (generated as above, 3.47 mmol) in pyridine (3 mL) was added 10a-(4-methoxyphenyl)-7-nitro-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (190 mg, 0.58 mmol) in pyridine (4 mL). The reaction mixture was stirred at 0° C. to room temperature for 45 minutes and was then quenched with water (15 mL) and extracted with CH2Cl2 (4×15 mL). The organic fractions were washed with brine, dried (MgSO4), filtrated and concentrated to yield a residue that was purified by triturating with acetone to give 10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-7-nitro-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (124) (170 mg, yield 68%).
Reaction SMILES: Cl.[C:2]([O:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[Cl:8][CH2:9][C:10](=O)[CH3:11].C(OCC)C>O>[C:2]([O:6][N:7]=[C:10]([CH2:9][Cl:8])[CH3:11])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(=O)CCl
Reactant: CC(C)(C)ON
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CC(CCl)=NOC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1.51 g of O-tert-butylhydroxylamine hydrochloride, 0.93 g of chloroacetone, and 10 ml of diethyl ether is stirred at room temperature for 3 hours, poured into water, and extracted twice with diethyl ether. The diethyl ether layers are combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated, which affords chloroacetone O-tert-butyloxime.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][C:12]=2[Cl:18])=[C:6]([CH3:20])[CH:5]=1.[F:22][C:23]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=1[NH2:25]>>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([NH:25][C:24]3[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:23]=3[F:22])=[CH:13][C:12]=2[Cl:18])=[C:6]([CH3:20])[CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)c2ccc(Br)cc2Cl)c(C)c1
Reactant: Nc1ccc(F)cc1F
Product: COC(=O)c1ccc(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c(C)c1

Procedure:
Compound 534 (184 mg, 0.50 mmol) and 2,4-difluoroaniline (0.066 mL, 0.65 mmol) were treated as described for compound 529. Flash chromatography (ethyl acetate/petroleum ether: graduated from 0/100 to 20/80) gave the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[OH:23].[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[Cl:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:14]=2[OH:23])=[N:3][N:4]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: Clc1nnc(Cl)c2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Oc1ccc2ccccc2c1-c1nnc(Cl)c2ccccc12
Temperature: 80 °C
Reaction time: 17 h
Yield: 76.9 %

Procedure:
To a solution of 1,4-dichlorophthalazine (9.96 g, 50 mmol) in dichloroethane (180 ml) was added 2-naphthol (7.24 g, 50 mmol) and aluminum chloride (7.38 g, 55 mmol) and the mixture was stirred at 80° C. for 17 hrs. The dark red solution was poured in ice water (600 ml) and the resulting brown suspension was stirred vigorously for 1 hr. The solid was collected by filtration, washed with diethyl ether and dried to give 11.8 g of the title compound as a beige solid. (Yield: 77%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.CN(CCN(C)C)C.[Li]C(CC)C.[F:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28](OC)=[O:29]>C1COCC1.C1(C)C=CC=CC=1>[F:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]([C:10]1[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=[O:8])=[O:29]
Reactant: COC(=O)c1ccccc1F
Reactant: COc1ccc(C(=O)O)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)c(C(=O)c2ccccc2F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.3 %

Procedure:
4-(Methoxy)benzoic acid (5.00 g, 32.9 mmol) was azeotroped with toluene thrice, then dissolved in 80 mL of dry THF. TMEDA (10.9 mL, 72.3 mmol) was added, and the mixture was cooled to −78° C. sec-BuLi (51.6 mL of 1.40 M in cyclohexane, 72.3 mmol) was added dropwise over a period of 30 minutes, and the solution was stirred for 15 minutes. Methyl 2-fluorobenzoate (5.02 mL, 39.4 mmol) was added in 1 portion and, after stirring for 15 minutes, the reaction was quenched with 20 mL of water. The mixture was warmed to ambient temperature and poured into 1.5 L of water. 30 mL 1N NaOH was added and the aqueous layer was extracted 1× with EtOAc; after which the organic layer was discarded. The aqueous layer was acidified with conc. HCl until pH=1 and then extracted 2× with EtOAc. The combined organic extracts were dried with Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by flash chomatography through SiO2 (40-100% EtOAc/hexane) to provide the desired product (4.72 g, 52% yield) as a white solid. ESI+MS: 275.2 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[OH:12][C:3]1[C:2]([NH:1][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=3)=[CH:26][CH:27]=2)=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(N)c1O
Reactant: O=C(Cl)c1ccc(-c2ccccn2)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(NC(=O)c2ccc(-c3ccccn3)cc2)c1O
Temperature: 70 °C
Reaction time: 4 h
Yield: 76.6 %

Procedure:
Thionyl chloride (10 mL) was added to 4-(pyridin-2-yl)benzoic acid (1.8 g, 9 mmol) and the mixture was stirred under reflux overnight. The solvent was evaporated under reduced pressure and the residue was dried in vacuum to give crude 4-(pyridin-2-yl)benzoyl chloride. To a solution of methyl 3-amino-2-hydroxybenzoate (1 g, 6 mmol) and pyridine (480 mg, 6 mmol) in toluene (50 mL) were added the crude 4-(pyridin-2-yl)benzoyl chloride (1.3 g, 6 mmol) portion wise at 0° C. and then stirred at 70° C. for 4 h. The resulting mixture was extracted with ethyl acetate (100 mL×4), the organic phase was washed with water and saturated sodium bicarbonate, dried with anhydrous sodium sulfate and evaporated under reduced pressure to obtain yellow solid of methyl 2-hydroxy-3-(4-(pyridin-2-yl)benzamido)benzoate (1.6 g, yield 76%). LC-MS (ESI) m/z: 349 (M+1)+. (M+1)+.
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH3:8].C1C=CC=CC=1.[OH-].[Na+].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[N:25]=[C:26]=[O:27]>O>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[NH:25][C:26]([N:2]=[C:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH3:8])=[O:27]
Reactant: CN1CCCC1=N
Reactant: O=C=Nc1c(Cl)cccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CN1CCCC1=NC(=O)Nc1c(Cl)cccc1Cl

Procedure:
To a slurry of 6.73 g (0.05 mole) of 2-imino-1-methylpyrrolidine hydrochloride in 75 ml. of dry benzene is added, with stirring, 2 ml. of water, followed by 6 ml. of 50% NaOH. The benzene is decanted onto anhydrous K2CO3 and the aqueous layer washed twice with 50 ml. portions of benzene, the benzene being collected by decanting onto the K2CO3. The benzene extracts are put under nitrogen and dried for 15 minutes, then filtered rapidly through diatomaceous earth (nitrogen blanket) and washed with 100 ml. of benzene. To the filtrate is added 9.4 g. (0.05 mole) of 2,6-dichlorophenylisocyanate, put under nitrogen, stoppered and stirred at room temperature for 2 hours. The mixture is filtered and the solvent removed under reduced pressure. Trituration of the oily residue results in crystallization, 1-(2,6-dichlorophenyl)-3-(1-methyl-2-pyrrolidylidene)urea, and the white crystals are filtered and collected. After recrystallization from benzene-ether-petroleum ether, the m.p. is 134°-136° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=O)[CH3:11])=[CH:4][CH:3]=1.Cl.[NH2:14][OH:15].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[N:14][OH:15])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(=O)C=Cc1ccc(F)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C=Cc1ccc(F)cc1)=NO
Yield: 63.3 %

Procedure:
In a 250 ml single neck flask was charged 4.92 g (30 mmoles, 1.0 eq.) of 4-(4-fluorophenyl)-3-buten-2-one and 5.2 g (75.4 mmoles, 2.5 eq) of hydroxylamine hydrochloride and 6 g of 50% sodium hydroxide (75 mmoles, 2.5 eq) and 100 ml of methanol. The reaction mixture was stirred at reflux for 2 hours. The reaction mixture was concentrated, diluted with water (50 ml), and then extracted with ethyl acetate (2×50 ml). The organic phase was dried and concentrated, to obtain 3.4 of 4-(4-fluorophenyl)-3-buten-2one 2-oxime (E/Z mixture of isomers) as an oil in 63.3% yield.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=O)[C:3]1=[O:23].[F:24][C:25]1[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=1.N1C=CC=CC=1>O=S(Cl)Cl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([F:24])=[CH:30][N:29]=2)=[O:18])[C:3]1=[O:23]
Reactant: Cc1cc2c(cn1)cc(-c1cc(C(=O)O)ccc1C)c(=O)n2C
Reactant: Nc1ccc(F)cn1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: Cc1cc2c(cn1)cc(-c1cc(C(=O)Nc3ccc(F)cn3)ccc1C)c(=O)n2C
Reaction time: 0.5 h

Procedure:
A solution of 3-(1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylbenzoic acid 29 (154 mg, 0.5 mmol) in SOCl2 (1 mL) is heated at reflux for 2 h. Excess SOCl2 is removed in vacuo and the resultant solid is added to a solution of 5-fluoropyridin-2-amine (112 mg, 1 mmol) and pyridine (0.4 mL, 5 mmol) at rt. The resulting mixture is stirred for 30 min and evaporated. The residue is purified by preparative LC/MS to give the desired product M32 as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.28 (m, 1H), 8.04 (s, 1H), 7.95 (dd, J=8, 2 Hz, 1H), 7.86 (d, J=1.9 Hz, 1H), 7.65 (dt, J=9.1, 2.9 Hz, 1H), 7.57 (s, 1H), 7.48 (d, J=8 Hz, 1H), 3.8 (s, 3H), 2.73 (s, 3H), 2.32 (s, 3H); LC/MS (M+1, m/z): 403.1.