Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([O:20]CC)=[O:19].[OH-].[Na+]>O>[NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([Cl:16])[CH:12]=[C:13]([Cl:15])[CH:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)Cc1cccc(Oc2cc(Cl)cc(Cl)c2)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(CC(=O)O)cccc1Oc1cc(Cl)cc(Cl)c1
Yield: 71.1 %

Procedure:
A mixture of ethyl 2-[2-amino-3-(3,5-dichlorophenoxy)phenyl]acetate (6.9 g.), sodium hydroxide (1.6 g.) and water (50 ml.) was treated in a similar manner to that of Example 5-(2). The resultant residue (6.2 g.) was crystallized with a mixture of ethyl acetate and n-hexane to give white crystals of 2-[2-amino-3-(3,5-dichlorophenoxy)phenyl]acetic acid (4.5 g.). mp 113° to 115° C.
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][O:9][C:10](=[O:25])[C@H:11]([CH2:23]Br)[NH:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10](=[O:25])[C:11](=[CH2:23])[NH:12][C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])=[CH:26][CH:27]=1)([O-:3])=[O:2]
Reactant: O=C(N[C@@H](CBr)C(=O)OCc1ccc([N+](=O)[O-])cc1)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(NC(=O)OCc1ccccc1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
To 20 ml solution of 2.18 g (5 mmols) N-carbobenzoxy-β-bromoalanine p-nitrobenzyl ester in tetrahydrofuran, 1.01 g (10 mmols) triethylamine was added and the mixture was stirred at room temperature for 30 minutes. Solvent was removed under reduced pressure, water was added and the crystals which formed were filtered to obtain 1.80 g (yield 100%) of the desired compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[C:5]2[C:12]([OH:14])=[O:13].[OH:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CC#N>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]([OH:14])=[O:13])=[N:6][NH:7]2)=[CH:3][C:2]=1[C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:15])[CH:21]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC#N
Product: O=C(O)c1n[nH]c2cc(Cl)c(-c3cccc(O)c3)cc12
Temperature: 110 °C
Yield: 3.8 %

Procedure:
A mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (100 mg, 0.36 mmol), 3-hydroxyphenylboronic acid (51.0 mg, 0.36 mmol), potassium carbonate (301 mg, 2.18 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30.0 mg, 0.036 mmol) in toluene (1.5 mL) and water (1.1 mL) was degassed with N2 for 3 minutes and heated to 110° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The brown residue was acidified to pH 4 with 1 N HCl and extracted with n-butanol (3×20 mL). The combined organic layers were washed with brine (2×20 mL), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Column: Phenomenex Synergi C18 150×30 mm, 4 μm; 25% MeCN in water (0.225% TFA) to 45% MeCN in water (0.225% TFA) to afford the title compound (4 mg, 4% yield) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([N:34]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:35]([NH:37][CH3:38])=[O:36])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([N:34]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:35]([NH:37][CH3:38])=[O:36])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCN(C(=O)NC)c1ccc2c(c1)nc(CCCC)n2Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCN(C(=O)NC)c1ccc2c(c1)nc(CCCC)n2Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5-(N-methylaminocarbonyl-n-pentylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([CH3:21])=[C:10]1[C:22](OCC)=[O:23].[C:27]1([N:33]=[C:34](Cl)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:20][C:13]1[NH:12][C:11]2[CH:21]=[C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:22](=[O:23])[C:10]=2[CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: ClC(=Nc1ccccc1)c1ccccc1
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1OC
Product: CCOC(=O)C1=C(C)Nc2cc(-c3ccccc3)n(-c3ccccc3)c(=O)c2C1c1ccccc1OC

Procedure:
This product is obtained using the procedure of Example 1 from diethyl 1,4-dihydro-4-(2-methoxyphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate and N-phenylbenzimidoyl chloride (3.1 g, 12.6%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[CH:4]=[CH:3]1>C(O)C.O1CCCC1.[Pd]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[CH:4]=[CH:3]1
Reactant: Cn1ccc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1ccc2ccc(N)cc21
Reaction time: 14 h

Procedure:
A mixture of 1-methyl-6-nitro-1H-indole (5.0 g, 28.4 mmol) and 10% Pd/C(1.0 g) in ethanol (200 ml) and tetrahydrofuran (100 ml) was hydrogenated at atmospheric pressure for 14 hours. The reaction mixture was filtered and concentrated to give 1-methyl-6-amino-1H-indole after crystallization from ether/hexane (3.8 g, 80%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]([NH:15][CH2:16][C:17]([OH:19])=O)=[O:14])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:52][C:53]1[CH:65]=[CH:64][C:63]([F:66])=[CH:62][C:54]=1[O:55][CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>CN(C=O)C.O>[Cl:52][C:53]1[CH:65]=[CH:64][C:63]([F:66])=[CH:62][C:54]=1[O:55][CH:56]1[CH2:57][CH2:58][N:59]([C:17](=[O:19])[CH2:16][NH:15][C: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][N:11]=2)=[O:14])[CH2:60][CH2:61]1
Reactant: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cn1
Reactant: Fc1ccc(Cl)c(OC2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1)c1ccc(-c2ccccc2)cn1
Reaction time: 8 h
Yield: 54.6 %

Procedure:
To a stirred solution of [(5-phenyl-pyridine-2-carbonyl)-amino]-acetic acid (0.07 g, 0.00027 mol) in DMF (1.5 mL) was added DIPEA (0.105 g, 0.000819 mol), HOBt (0.044 g, 0.00033 mol) and EDCI.HCl (0.062 g, 0.00033 mol) at ambient temperature. After 2 minutes 4-(2-chloro-5-fluoro-phenoxy)-piperidine hydrochloride (0.087 g, 0.00033 mol) was and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure afford 0.069 g (54%) of 5-phenyl-pyridine-2-carboxylic acid {2-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 468.14 (M+1)+, 82.99%, 1H NMR (DMSO-d6): δ 9.0 (d, 1H), 8.8 (t, 1H), 8.3 (dd, 1H), 8.1 (d, 1H), 7.8 (d, 2H), 7.6-7.4 (m, 4H), 7.2 (dd, 1H), 6.9-6.8 (m, 1H), 4.9-4.8 (m, 1H), 4.3 (d, 2H), 3.8-3.6 (m, 2H), 3.5 (m, 2H), 2.1-1.9 (m, 2H), 1.8-1.5 (m, 2H).
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)[C:2]([NH2:4])=[O:3].[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=O)[NH:19][CH:20]=1.N1CCCCC1>C(O)C>[NH:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2=[CH:21][C:18]1[NH:19][CH:20]=[C:16]([Br:15])[CH:17]=1)[C:2]([NH2:4])=[O:3]
Reactant: NC(=O)Nc1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1cc(Br)c[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: NC(=O)Nc1ccc2c(c1)C(=Cc1cc(Br)c[nH]1)C(=O)N2

Procedure:
To a solution 5-ureidoindolin-2-one (326 mg, 1.71 mmol) in ethanol was added 4-bromo-2-pyrrolecarboxaldehyde (297 mg, 1.71 mmol), and piperidine (0.2 mL). The reaction mixture was refluxed for 18 hours. The mixture was cooled and filtered to afford a golden-colored solid which was washed with ethanol and ether to afford 5-ureido-3-[(4-bromopyrrol-2-yl)methylene]indolin-2-one; (453 mg); 1H NMR (400 MHz, DMSO-d6) δ 5.77 (s, 2H); 6.74–6.76 (d, 1H); 6.96 (s, 1H); 7.02–7.04 (dd, 1H); 7.41–7.42 (m, 1H); 7.52–7.53 (m, 1H); 7.73–7.74 (d, 1H); 8.34 (s, 1H); 10.82 (bd, 1H); 13.5 (bs, 1H) ppm.
Reaction SMILES: [ClH:1].[OH:2][NH:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][C:10]2=[N:15]O)=[NH:5].Cl.N[N:19]1[CH2:23][CH2:22][N:21]=[C:20]1[NH2:24].CC1C=CC(S(O)(=O)=O)=CC=1.C=CC1C=CC=CC=1.C(C1C=CC=CC=1C=C)=C>C(O)(C)C>[ClH:1].[ClH:1].[OH:2][NH:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][C:10]2=[N:15][N:21]1[CH2:22][CH2:23][N:19]=[C:20]1[NH2:24])=[NH:5]
Reactant: NC1=NCCN1N
Reactant: N=C(NO)c1cccc2c1CCC2=NO
Agent: C=Cc1ccccc1C=C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: C=Cc1ccccc1
Solvent: CC(C)O
Product: N=C(NO)c1cccc2c1CCC2=NN1CCN=C1N

Procedure:
0.5 ml of 32% hydrochloric acid (Merck, Darmstadt, Germany; p.a.) is added, with stirring, to a mixture of 0.51 g (0.0025 mol) of 4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 0.342 g (0.0025 mol) of 1,2-diamino-4,5-dihydro-imidazole hydrochloride [m.p. 245°-246° C.; prepared from the corresponding p-toluenesulfonate salt, see EP 0 327 919, Example 12, by ion exchange on ®Amberlite IRA-400 (anion exchanger based on a styrene/divinylbenzene polymer with quaternary ammonium groups in the Cl- form; Fluka, Buchs, Switzerland)] and 12 ml of isopropanol, and the reaction mixture is stirred at 80°-90° C. for 16 hours. The reaction mixture is filtered while hot and the filtration product is washed with isopropanol and recrystallized from hot water. In that manner there is obtained the title compound, m.p. >245° C., 1H-NMR (D2O): δ=8.08 (d, 1H); 7.72 (d, 1H); 7.56 (t, 1H); 4.14 (t, 2H); 3.81 (t, 2H); 3.3 (m, 2H); 3.15 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:20][C:21]4[CH:26]=[C:25]([CH2:27][NH:28][C:29](=[O:34])[CH2:30][CH2:31][CH2:32]Br)[N:24]=[CH:23][N:22]=4)=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)=[O:10])=[CH:4][C:3]=1[C:35]([F:38])([F:37])[F:36].[H-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:20][C:21]4[CH:26]=[C:25]([CH2:27][N:28]5[CH2:32][CH2:31][CH2:30][C:29]5=[O:34])[N:24]=[CH:23][N:22]=4)=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)=[O:10])=[CH:4][C:3]=1[C:35]([F:38])([F:37])[F:36]
Reactant: O=C(CCCBr)NCc1cc(Oc2ccc3c(ccn3C(=O)Nc3ccc(F)c(C(F)(F)F)c3)c2)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCCN1Cc1cc(Oc2ccc3c(ccn3C(=O)Nc3ccc(F)c(C(F)(F)F)c3)c2)ncn1
Temperature: 0 °C

Procedure:
5-{6-[(4-Bromo-butyrylamino)-methyl]-pyrimidin-4-yloxy}-indole-1-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide (0.353 g, 0.595 mmol) is dissolved in 10 mL THF and cooled to 0° C. Sodium hydride (63 mg, 1.5 mmol, 60% in mineral oil) is added and the reaction is allowed to warm to room temperature overnight. The reaction is quenched with water and diluted with ethyl acetate. The organic layer is removed, dried, and concentrated and the residue is separated via semi-prep HPLC (C18; 20-100% I/H2O with 0.1% TFA) to provide the title compound. MS (ESI) m/z 514.9 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.40 (s, 1H), 8.68 (d, J=1.01 Hz, 1H), 8.28 (d, J=9.09 Hz, 1H), 8.09-8.12 (m, 2H), 7.99-8.03 (m, 1H), 7.57 (t, J=9.85 Hz, 1H), 7.49 (d, J=2.27 Hz, 1H), 7.15 (dd, J=8.97, 2.40 Hz, 1H), 6.94 (d, J=1.01 Hz, 1H), 6.81 (d, J=3.79 Hz, 1H), 4.45 (s, 2H), 3.42 (t, J=6.95 Hz, 2H), 2.29-2.34 (m, 3H), 2.00 (t, J=7.58 Hz, 2H).
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(CCCN=C=N)C.O.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:37][CH:38]1[CH2:42][CH2:41][N:40]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=2)[CH2:39]1>C(Cl)(Cl)Cl.CCN(CC)CC>[C:1]([NH:9][CH2:10][C:11]([NH:37][CH:38]1[CH2:42][CH2:41][N:40]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=2)[CH2:39]1)=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)c1ccccc1
Reactant: NC1CCN(Cc2ccc(Cl)cc2)C1
Agent: CN(C)CCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(CNC(=O)c1ccccc1)NC1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-Benzoylglycine (9.9 mg, 0.055 mmol), 3-ethyl-1-(3-(dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (10.5 mg) and 1-hydroxybenzotriazole hydrate (HOBt) (7.4 mg) were added to a solution of 3-amino-1-(4-chlorobenzyl)pyrrolidine dihydrochloride (14.2 mg, 0.050 mmol) and Et3N (15.2 mg) in CHCl3 (2.5 mL). The reaction mixture was stirred at 25° C. for 16 h, washed with 2 N aqueous NaOH (2 mL×2) and brine (1 mL). After filtration through a PTFE membrane filter, the solvent was removed under reduced pressure to afford 3-(N-benzoylglycyl)amino-1-(4-chlorobenzyl)pyrrolidine (compound No. 1) as a pale yellow oil (17.7 mg, 95%): The purity was determined by RPLC/MS (95%); ESI/MS m/e 372.0 (M++H, C20H22ClN3O2).
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.O.[CH3:17][O:18][C:19]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:17][O:18][C:19]1[C:24]([C:2]2[C:3]([O:8][C:9]3[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: Nc1ccc(Oc2nccnc2Cl)cc1
Reactant: COc1ncccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ncccc1-c1nccnc1Oc1ccc(N)cc1
Temperature: 100 °C

Procedure:
To a glass microwave vial was added 4-(3-chloropyrazin-2-yloxy)aniline (1.0591 g, 4.78 mmol), 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine hydrate, trans-dichlorobis(triphenylphosphine) palladium (II) (0.268 g, 0.382 mmol), and sodium carbonate (2.53 g, 23.89 mmol) in DME (7.65 mL) and water (1.911 mL). The reaction mixture was stirred and heated in a Biotage Initiator microwave reactor at 100° C. for 15 min. The crude product was adsorbed onto a plug of silica gel and chromatographed to provide 4(3-(2-methoxypyridin-3-yl)pyrazin-2-yloxy)aniline. MS (ESI, pos. ion) m/z:295.2.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]#[C:3][CH3:4].[CH:7]1[C:19]2[CH:18]([CH2:20]O)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:1]([O:6][CH2:20][CH:18]1[C:19]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:5])[C:2]#[C:3][CH3:4]
Reactant: OCC1c2ccccc2-c2ccccc21
Reactant: CC#CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC#CC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 55.3 %

Procedure:
First, 9-fluorenylmethyl 2-butynoate was prepared. A mixture of 2-butynoic acid (11.6 g, 138 mmol), 9-fluorenemethanol (35.2 g, 179 mmol), dimethylamino-pyridine-p-toluenesulfonic acid salt (16.3 g, 55 mmol), and anhydrous dichloromethane (210 mL) was cooled to 0° C. under nitrogen, and 1,3-dicyclohexylcarbodiimide (34.2 g, 166 mmol) was added. After 15 min, the reaction mixture was warmed to ambient and stirred for 12 h. The urea by product was filtered, and the filtrate was washed successively with 10% aqueous HCl, 10% aqueous NaHCO3, water, and brine. The solution was dried (Na2SO4) and concentrated to deposit a yellow oil. The product was purified by column chromatography to provide 20.0 g (54% of theory) of 9-fluorenylmethyl 2-butynoate as a yellow-green solid. 1H NMR (CDCl3): δ 1.98 (s, 3H), 4.20 (m, 1H), 4.45 (d, 2H), 7.32 (m, 4H), 7.60 (d, 2H), 7.70 (d, 2H).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]([Cl:28])=[CH:25][CH2:26]Cl.CN(C)C=O>O>[C:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:26][CH:25]=[C:24]([Cl:28])[Cl:23])=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCC=C(Cl)Cl
Reactant: O=C(Oc1ccc(O)cc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Oc1ccc(OCC=C(Cl)Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.8 %

Procedure:
A reaction vessel was charged with 30.5 g of 4-hydroxyphenyl benzoate, 21.6 g of potassium carbonate, 20.8 g of 1,1,3-trichloropropene and 100 ml of N,N-dimethylformamide. After stirring at room temperature for 15 hours, the reaction mixture was poured into water, and extracted twice with 50 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 44.1 g of 4-(3,3-dichloro-2-propenyloxy)phenyl benzoate (96% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1cccc(Cl)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)c1cccc(Cl)c1

Procedure:
A 53.6 g portion of ethyl m-chlorophenylacetate (prepared by esterification of the corresponding acid), 51.5 g of N-bromosuccinimide and one gram of benzoyl peroxide in 1.25 liters of carbon tetrachloride is stirred with a Nichrome metal stirrer and refluxed for 20 hours. The mixture is cooled, filtered and concentrated to an orange oil. Vacuum distillation yields the product ethyl α-bromo-m-chlorophenylacetate.
Reaction SMILES: [CH3:1][C:2]([CH3:14])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:13])=[CH:7]/[CH:8]=[CH:9]/[C:10]([CH3:12])=[O:11].S(=O)(=O)(O)O.O>C(Cl)Cl>[CH3:13][C:6]1[CH2:5][CH2:4][CH2:3][C:2]([CH3:14])([CH3:1])[C:7]=1/[CH:8]=[CH:9]/[C:10]([CH3:12])=[O:11]
Reactant: CC(=O)/C=C/C=C(\C)CCC=C(C)C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: CC(=O)/C=C/C1=C(C)CCCC1(C)C
Yield: 97 %

Procedure:
A solution of 600 g of a 96% pure pseudoionone in 1,200 ml of methylene chloride was introduced continuously in the course of 10 minutes, while stirring vigorously (800 rpm), through one of the two connections of the reactor, and 1,000 ml of a 96% strength sulfuric acid were fed in simultaneously through the other connection. The product, which was discharged at 42° C., was hydrolyzed in a downstream thin film reactor with 2,000 ml of water, the organic phase was separated off, washed neutral with 2% strength sodium carbonate solution and then with water and freed from solvent under reduced pressure, and the residue was then distilled under 0.2 mbar. 495 g of 97.0% pure β-ionone were obtained, corresponding to a yield of β-ionone of 83.3% of theory. In this case too, the residue produced was a resin which exhibited good flow.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[CH:11]=[C:10]3[N:19]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:20](=O)[CH2:21][O:22][C:9]3=[CH:8][C:7]=2[N:6]=1)([CH3:3])[CH3:2].[CH2:29]1COCC1>[CH3-].C[Al]C.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Cl-].[Ti+4]>[CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[C:12]2[CH:11]=[C:10]3[N:19]([CH2:24][C:25]([F:26])([F:27])[F:28])[C:20](=[CH2:29])[CH2:21][O:22][C:9]3=[CH:8][C:7]=2[N:6]=1)([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)Oc1cc(C(F)(F)F)c2cc3c(cc2n1)OCC(=O)N3CC(F)(F)F
Agent: [Ti+4]
Agent: C[Al]C
Agent: [CH3-]
Product: C=C1COc2cc3nc(OC(C)C)cc(C(F)(F)F)c3cc2N1CC(F)(F)F

Procedure:
This compound was made from General Method 14 from 7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-one (0.689 g, 1.69 mmol), Tebbe's reagent (3.7 mL, 1.9 mmol) in 11 mL THF to afford 0.728 g of (±)-2,3-dihydro-7-isopropoxy-2-methylene-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline, an orange solid after filtration through silica gel. 1H NMR (400 MHz, CDCl3) δ 7.64 (broad s, 1H), 7.49 (s, 1H), 7.29 (s, 1H), 5.59 (hept, 1H, J=6.2), 4.95 (s, 2H), 4.91 (q, 2H, J=9.1), 1.58 (d, 6H, J=6.2). Subsequent treatment of the above solid (0.728 g) as described in General Method 14 with NaBH3CN (0.531 g, 8.45 mmol) and 4.2 mL acetic acid in 8.4 mL dichloroethane afforded 0.366 g (53%) of (±)-2,3-dihydro-7-isopropoxy-2-methyl-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline, a yellow solid, after flash chromatography (hexanes:EtOAc, 9:1). Rf 0.28 (9:1 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.29 (s, 1H), 7.12 (s, 1H), 7.00 (s, 1H), 5.48 (hept, 1H, J=6.2), 4.26 (dd, ABX, 1H, J=10.7, 2.4), 4.16 (dd, ABX, 1H, J=10.7, 2.8), 3.97-4.07 (m, 1H), 3.77-3.87 (m, 1H), 3.61-3.68 (m, 1H), 1.38 (d, 6H, J=6.2), General Method 15: Hydrolysis of an isopropyl imino ether to a pyridone. A solution of the imino ether in a 3:1 acetic acid:concentrated HCl (0.1-0.2 M) solution was heated at 60-110° C. for 4-16 h. The solution was poured into sat'd NaHCO3 (80 mL/mmol), extracted with EtOAc (2×80 mL/mmol), washed with brine (60 mL/mmol), dried over MgSO4, filtered, concentrated, and purified as indicated.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:30]2[CH2:29][CH2:28][N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=3)[CH2:32][CH2:31]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Reactant: Clc1cccc(N2CCNCC2)c1
Product: COc1nc2ccc(C)cc2nc1NC(=O)N1CCN(c2cccc(Cl)c2)CC1
Yield: 72 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 72%). 1H NMR (300 MHz, CDCl3): δ 2.45 (s, 3H), 3.26 (s, 4H), 3.77 (s, 3H), 4.08-4.18 (m, 4H), 6.78-6.90 (m, 3H), 7.15-7.38 (m, 3H), 7.56-7.64 (m, 2H).