Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]([C@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18](OCC1C=CC=CC=1)=O)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[CH3:18]
Reactant: O=C(c1c[nH]c2ccc(Br)cc12)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 117.5 %

Procedure:
A solution composed of 205 g of benzyl (2R)-2-[(5-bromo-1H-indole-3-yl)carbonyl]pyrrolidine-1-carboxylate in 820 mL of THF was dropped at 60° C. in 30 minutes into a flask containing 307.5 mL of THF and 479.2 mL of 10% LiAlH4. After 3 hours of reflux the control HPLC showed completion of the reaction and the reaction mixture was cooled to 20-25° C. At this temperature a mixture composed of 20.5 mL of H2O and 82 mL of THF was dropped in 15 minutes approximately. Then other 20.5 mL of H2O were added in about 15 minutes, then 41 ml, of 15% NaOH in about 15 minutes, and lastly other 123 mL of H2O in 15 minutes. After stirring for 30 minutes the salts were filtered, washing the cake with 410 mL of isopropanol. The reaction mixture (HPLC assay 65.3%) was concentrated to residue, obtaining 165.3 g of oil. This residue was diluted with 410 mL of isopropanol and used to obtain the oxalate salt.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]2[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:11]=2[CH:24]=1.CON(C)[C:28](=[O:30])[CH3:29].O>O1CCCC1>[C:28]([C:7]1[CH:8]=[CH:9][C:10]2[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:11]=2[CH:24]=1)(=[O:30])[CH3:29]
Reactant: CON(C)C(C)=O
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(Br)cc2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc2c(c1)CN(C(=O)OC(C)(C)C)CCO2
Temperature: -78 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
n-Butyllithium (2.5 Min hexane, 2.31 mL, 5.8 mmol) was added to a solution of 1,1-dimethylethyl 7-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.56 g, 4.76 mmol) in tetrahydrofuran (20 mL) and the resulting mixture was stirred at −78° C. for one hour. A solution of N-methoxy-N-methylacetamide (0.97 g, 9.4 mmol) in tetrahydrofuran (5 mL) was added to the reaction mixture dropwise then warmed to room temperature and stirred for an additional hour. Water (50 mL) was added and the resulting mixture was extracted with ethyl acetate (3×40 mL). The combined organic extract was washed with water, then brine solution (80 mL each), dried over sodium sulfate, filtered, concentrated to give 1,1-dimethylethyl 7-acetyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.34 g, 97% yield); MS (EI) for C16H21NO4: 292 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]([F:32])=[CH:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]3[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[CH:19]=[C:18]([CH:25]([CH3:27])[CH3:26])[C:17]=3[O:28][CH2:29][CH2:30][CH3:31])[C:9]=2[CH:8]=1)C.C1COCC1.[Li+].[OH-]>CO>[F:32]/[C:5](=[CH:6]/[C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]3[CH:21]=[C:20]([CH:22]([CH3:23])[CH3:24])[CH:19]=[C:18]([CH:25]([CH3:26])[CH3:27])[C:17]=3[O:28][CH2:29][CH2:30][CH3:31])[C:9]=2[CH:8]=1)/[C:4]([OH:33])=[O:3]
Reactant: CCCOc1c(-c2cccc3sc(C=C(F)C(=O)OCC)cc23)cc(C(C)C)cc1C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOc1c(-c2cccc3sc(/C=C(/F)C(=O)O)cc23)cc(C(C)C)cc1C(C)C
Temperature: 25 °C

Procedure:
A mixture of 0.450 mmol of 2-fluoro-3-[4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-prop-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at room temperature, the mixture was acidified to pH=2 and extracted with ethyl acetate. The organic layer was dried over MgSO4 and after evaporation of the solvents, the crude acid was recrystallized from acetonitrile. (E)-2-Fluoro-3-[4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-prop-2-enoic acid was isolated as a white solid. 1H-NMR (CDCl3), δ: 7.83 (d, J=7.7 Hz, 1H), 7.49 (broad s, 1H), 7.46 (s, 1H), 7.42 (t, J=7.0 Hz, 2H), 7.18 (d, J=2.1 Hz, 1H), 7.00 (d, J=2.1 Hz, 1H), 3.42 (dt, J=13.7, 6.8 Hz, 1H), 3.32 (m, 1H), 3.19 (m, 1H), 2.92 (dt, J=13.8, 6.9 Hz, 1H), 1.29 (m, 14H), 1.22 (m, 2H), 0.45 (t, J=7.3 Hz, 3H).
Reaction SMILES: CC([O-])(C)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23].[CH3:25][O:26][C:27]1[C:28]([NH2:33])=[CH:29][CH:30]=[CH:31][CH:32]=1>COCCOC.CCOCC.CCCCCCCCCCCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: COc1ccccc1N
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: COCCOC
Solvent: CCCCCCCCCCCC
Product: COc1ccccc1Nc1ccccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 81.9 %

Procedure:
A solution of ligand 1 (see FIG. 1) [42 mg, 0.1 mmol (8.4 mg, 0.02 mmol, 4 mol % per reaction)] and NaOt-Bu [10 mg, 0.1 mmol (2 mg, 0.02 mmol, 4 mol % per reaction)] were stirred in 5 mL DME (anhy). After 10 minutes, 1 mL of the solution was added via syringe to a test tube containing (under an Argon atmosphere) Pd2(dba)3 (4.6 mg, 0.005 mmol, 2 mol % Pd), K3PO4 (148 mg, 0.7 mmol), 2-chloronitrobenzene (79 mg, 0.5 mmol), and o-anisidine (68 μL, 0.6 mmol). The test tube was capped (with a proper cap-no rubber septa) and heated at 100° C. for 18 hours. The reaction mixture was allowed to cool to r.t., diluted with ether and dodecane was added as an internal standard (the consumption of the aryl chloride was incomplete). The reaction mixture was purified by column chromatography (5% EtOAc/hexanes) to yield 100 mg (82% yield) of the product.
Reaction SMILES: [F:1][C:2]1[C:7](F)=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH2:12][C:13](=[O:15])[CH3:14].[C:16](=O)([O-])[O-:17].[K+].[K+]>CO>[F:1][C:2]1[C:7]([O:17][CH3:16])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH2:12][C:13](=[O:15])[CH3:14]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Cc1c([N+](=O)[O-])ccc(F)c1F
Agent: [K+]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(CC(C)=O)c1F
Yield: 73.6 %

Procedure:
A mixture of 1-(2,3-difluoro-6-nitrophenyl)-propan-2-one (183 g) and potassium carbonate (100 g) in methanol (1 L) was heated at reflux for 3 h. The reaction mixture was then cooled and concentrated in vacuo to remove most of the methanol. The residue was diluted with ethyl acetate (1 L), filtered and washed with water. The separated aqueous layer was neutralized with 2N HCl and extracted with ethyl acetate (2×500 mL). The combined organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo to give a brown solid. The solid was triturated with diethyl ether and filtered to provide 1-(2-fluoro-3-methoxy-6-nitrophenyl)-propan-2-one (121 g, 71%) as a yellow solid. LC/MS; (M+H)+=228.2.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH2:4]1.Cl[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([O:22][C:19]2[CH:18]=[CH:17][C:16]([C:15]([NH:14][C:11]3[CH:10]=[CH:9][C:8]([N:5]4[CH2:6][CH2:7][CH:3]([N:2]([CH3:24])[CH3:1])[CH2:4]4)=[CH:13][CH:12]=3)=[O:23])=[CH:21][CH:20]=2)=[N:27][CH:28]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(O)cc3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(Oc4ccc(Cl)cn4)cc3)cc2)C1

Procedure:
A solution of 0.05 g of N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-4-hydroxybenzamide, 0.017 g of 2,5-dichloropyridine and 0.064 g of potassium carbonate in 0.8 ml of DMF was heated at 230° C. in a microwave apparatus for 30 minutes. The solution was filtered and purified by preparative HPLC. This resulted in the product with the molecular weight of 436.17 (C24H25CIN4O2); MS (ESI): 437 (M+H+) as hydrotrifluoroacetate.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[O:11]/[C:12](=[CH:16]\[C:17]([OH:19])=O)/[C:13]([OH:15])=[O:14])([O-:8])=[O:7].[N+](C1C=CC=CC=1O/C(=C/C(O)=O)/C(O)=O)([O-])=O>>[N+:6]([C:9]1[C:10]2[O:11][C:12]([C:13]([OH:15])=[O:14])=[CH:16][C:17](=[O:19])[C:20]=2[CH:21]=[CH:22][CH:23]=1)([O-:8])=[O:7]
Reactant: O=C(O)/C=C(\Oc1ccccc1[N+](=O)[O-])C(=O)O
Agent: O=C(O)/C=C(/Oc1ccccc1[N+](=O)[O-])C(=O)O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(=O)c2cccc([N+](=O)[O-])c2o1
Reaction time: 2 h
Yield: 35 %

Procedure:
After a reaction container equipped with a stirrer, a cooling tube and a thermometer was charged with 20 parts by weight of fuming sulfuric acid, 2 parts by weight of a mixture (content: 65.7% by weight) containing 2-(2-nitrophenoxy)fumaric acid and 2-(2-nitrophenoxy)maleic acid was added. After that, the mixture was stirred and kept at an inner temperature of 25° C. for 2 hours and then at an inner temperature of 50° C. for 2 hours to obtain a reaction solution containing 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran (reaction yield: 35%). After cooled to room temperature, the reaction solution was gradually added into 40 parts by weight of water and the mixture was gradually cooled to an inner temperature of 0° C. Precipitated crystals were filtered and dried to obtain 0.28 parts by weight of 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran as crystals (content: 95.2% by weight, yield: 20%).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:5]=1.O.[OH-].[Na+].Cl>O1CCOCC1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[CH:5][C:6]=1[O:11][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(Cl)c(OCCc2ccc(OC)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CCOc2cc(C(=O)O)ccc2Cl)cc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
1.27 g (3.96 mmol) of 4-Chloro-3-[2-(4-methoxy-phenyl)-ethoxy]-benzoic acid methyl ester was dissolved in 15 ml of dioxan. 5 ml of water and 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was heated at 60° C. for 2 h and stirred at room temperature for 16 h. The reaction solution was cooled to 0° C. and concentrated hydrochloric acid was added to give a pH of 1–2, whereupon the product precipitated from solution. The suspension was stirred for 30 min, then the product was filtered off and dried under reduced pressure.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]1)=[CH:11][C:10]([C:29]1[CH:34]=[C:33]([F:35])[C:32]([OH:36])=[C:31]([Cl:37])[CH:30]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].O.Cl>C1COCC1>[NH2:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([NH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:29]4[CH:34]=[C:33]([F:35])[C:32]([OH:36])=[C:31]([Cl:37])[CH:30]=4)[CH:11]=3)[N:6]=[CH:5][C:4]=2[C:1](=[O:3])[CH3:2])[CH2:16][CH2:17]1
Reactant: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](N)CC1

Procedure:
To a suspension of tert-butyl (trans-4-((3-acetyl-6-(3-chloro-5-fluoro-4-hydroxyphenyl)quinolin-4-yl)amino)cyclohexyl)carbamate (38 mg, 0.072 mmol) in THF (3 mL) was added water (2 mL) and 6N aqueous HCl (2 mL). The resultant solution was heated at 65° C. for 4 h. The reaction mixture was cooled and concentrated. The resultant residue was purified by preparative HPLC (C18 silica, 10-90% methanol/water with 0.05% TFA). The residue was eluted through an ion-exchange column (using methanol and 7 N methanol in ammonia) to obtain the desired product (18.1 mg, 59%) as a yellow solid. 1H NMR (500 MHz, MeOD+TFA-d) δ 9.12 (s, 1H), 8.47 (s, 1H), 8.32-8.26 (m, 1H), 7.99 (d, J=8.7 Hz, 1H), 7.59 (s, 1H), 7.52 (d, J=11.5 Hz, 1H), 4.57-4.53 (m, 1H), 2.74 (s, 3H), 2.51 (d, J=12.3 Hz, 2H), 2.26 (d, J=12.3 Hz, 2H), 1.87 (q, J=12.5 Hz, 2H), 1.71-1.62 (m, 2H). ESI MS m/z 428 [C23H23ClFN3O2+H]+; HPLC>99% (AUC), tR=9.43 min.
Reaction SMILES: [C:1]([C:9]1[CH:18]=[CH:17][C:12]2[N:13]=[CH:14][S:15](=[O:16])[C:11]=2[CH:10]=1)(=[O:8])[C:2]1C=C[CH:5]=[CH:4][CH:3]=1.C(C1C=CC2N=CS(=O)C=2C=1)(=O)CCCC>>[OH:8][CH:1]([C:9]1[CH:18]=[CH:17][C:12]2[N:13]=[CH:14][S:15](=[O:16])[C:11]=2[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(c1ccccc1)c1ccc2c(c1)S(=O)C=N2
Agent: CCCCC(=O)c1ccc2c(c1)S(=O)C=N2
Product: CCCCC(O)c1ccc2c(c1)S(=O)C=N2

Procedure:
The procedure is as in Example 28, but replacing the 6-benzoyl benzothiazolinone by the 6-valerylbenzothiazolinone obtained in Example 9. The agitation is maintained for 48 hours.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:25])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=1.Cl[C:27](OC)=O>ClCCl.C(N(CC)CC)C.O>[CH3:27][O:23][C:22](=[O:24])[C:21](=[O:25])[C:18]1[CH:19]=[CH:20][C:15]([S:14][CH2:13][CH2:12][O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:16][CH:17]=1
Reactant: O=C(O)C(=O)c1ccc(SCCOc2ccc3ccccc3c2)cc1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(=O)c1ccc(SCCOc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of crude 4-[[2-(2-naphthalenyloxy)ethyl]thio]-alpha-oxobenzeneacetic acid (1.6 g) in dichloromethane (500 mL) and triethylamine (1 mL) was treated with methyl chloroformate (0.58 mL) and stirred at room temperature for 1 hour. The mixture was diluted with water, extracted with dichloromethane, dried (Na2SO4), filtered and evaporated. The material from dichloromethane extraction was purified by HPLC (dichloromethane-hexane; 2:1) and crystallized from dichloromethane-diethyl ether to provide 0.85 g of 4-[[2-(2-naphthalenyloxy)ethyl]thio]-alpha-oxobenzeneacetic acid methyl ester, mp 124°-125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(OC([N:23]1[CH2:27][C@H:26]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][C@H:24]1[C:35](O)=[O:36])=O)(C)(C)C>>[CH2:28]([C@H:26]1[CH2:27][NH:23][C@H:24]([C:35]([NH:11][C:10]2[CH:12]=[CH:13][C:7]([O:6][C:5]3[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:8][CH:9]=2)=[O:36])[CH2:25]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)O
Product: O=C(Nc1ccc(Oc2ccc(Cl)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Yield: 47 %

Procedure:
Proceeding as in Reference 6, but substituting 4-(4-chlorophenoxy)aniline and (2S,4R)-1-(tert-butoxycarbonyl)-4-(benzyl)pyrrolidine-2-carboxylic acid, gave (2S,4R)-4-benzyl-N-(4-(4-chlorophenoxy)phenyl)pyrrolidine-2-carboxamide (190 mg, 47%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH3:20][C:21]([CH3:23])=O>>[CH2:23]([O:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1)[CH:21]=[CH2:20]
Reactant: CC(C)=O
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1ccc(-c2ccccc2)cc1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a solution of 4-phenylphenol (1 eq) in acetone, K2CO3 (2 eq) and alkyl bromide (1.2 eq) were added and the mixture reaction was stirred at 55° C. overnight. Quenched with water and extracted with ethyl acetate. The organic layer was dried (MgSO4) and concentrated to give 4-allyloxybiphenyl. This crude product was dissolved in Me2NPh and heated to reflux for 6 hours and then stirred at room temperature over 3 days. Refluxed again for 8 hours and then poured into and ice-cold HCl 1M solution, extracted with ethyl acetate and washed with water. Dried and concentrated to give a crude product which was purified by chromatography to give the title product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([Cl:17])=[CH:11][C:10]=2[O:18][CH3:19])=[O:5])[CH3:2].[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:13][C:12]([Cl:17])=[CH:11][C:10]=2[O:18][CH3:19])=[O:5])[CH3:2]
Reactant: NC1CCCC1
Reactant: CCOC(=O)c1cnc2c(OC)cc(Cl)cc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)cc(Cl)cc2c1NC1CCCC1

Procedure:
4,6-Dichloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.83 mmol) was treated with cyclopentylamine following general procedure B to afford 6-chloro-4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (240 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into the corresponding ethylamide (170 mg) following general procedure E.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)([OH:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[F:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[F:37][C:38]1[CH:43]=[CH:42][C:41]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([C:13]3[N:14]=[CH:15][N:16]([C:18]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:17]=3)([OH:12])[CH:9]([CH3:10])[CH3:11])=[CH:4][CH:3]=2)=[CH:40][CH:39]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)C(O)(c1ccc(Br)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
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
Product: CC(C)C(O)(c1ccc(-c2ccc(F)cc2)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 85.4 %

Procedure:
To a suspension of 1-(4-bromophenyl)-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (3.60 g), 4-fluorophenylboronic acid (1.50 g) and 2M aqueous sodium carbonate solution (26.8 ml) in dimethoxyethane (50 ml) was added tetrakis(triphenylphosphine)palladium(0) (387 mg). Under an argon atmosphere, the mixture was heated under reflux for 12 h. The reaction mixture was extracted with ethyl acetate-THF (8:3), washed with water and saturated brine, and dried. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chomatography (eluent, hexane:ethyl acetate=6:1→4:1) to give the title compound (3.16 g) as colorless needle crystals.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:16])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][Br:16])[CH:5]=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccnc(Br)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccnc(Br)n1
Temperature: 80 °C
Reaction time: 48 h
Yield: 20 %

Procedure:
To a stirred solution of 2-bromo-4-methylpyrimidine (1.5 g, 8.67 mmol) in CCl4 (15 mL) was added NBS (3.39 g, 19.07 mmol) and benzoyl peroxide (0.476 g, 1.907 mmol) then it was heated to 80° C. After 48 hours, the reaction mixture was cooled to ambient temperature and filtered. The black solid was discarded and liquid was concentrated to brown solid which was purified by column chromatography (10% EtOAc/Hex) to obtained a yellow solid of 2-bromo-4-(bromomethyl)pyrimidine (437.6 mg, 1.737 mmol, 20.04% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.74 (d, J=4.9 Hz, 1H), 7.75 (d, J=4.9 Hz, 1H), 4.66 (s, 2H)), Mass spec.: 252.9 (MH)+.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C([O-])([O-])=O.[K+].[K+].O.[Cl:13][CH:14]([Cl:18])[C:15](Cl)=[O:16]>C1(C)C=CC=CC=1>[Cl:13][CH:14]([Cl:18])[C:15]([N:3]([O:4][CH3:5])[CH3:2])=[O:16]
Reactant: CNOC
Reactant: O=C(Cl)C(Cl)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CON(C)C(=O)C(Cl)Cl
Temperature: 0 °C
Yield: 92.5 %

Procedure:
N,O-Dimethylhydroxylamine hydrochloride (7.94 g, 81.4 mmol) and K2CO3 (17.2 g, 124.1 mmol) were added to a water (70 ml) and toluene (70 ml) mixture. The mixture was then cooled to 0° C. Dichloroacetyl chloride (10 g, 67.85 mmol) was added drop wise and the reaction was allowed to warm to room temperature overnight. The toluene was collected and then the aqueous layer was extracted with EtOAc (2×100 ml). The organic layers were dried over sodium sulfate and concentrated in vacuo to give the title product (10.8 g).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][NH:16][C:10]3=[N:9][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[CH:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]>>[C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][N:16]([CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:10]3=[N:9][C:8]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCC=O
Reactant: c1ccc(-c2nc3c(nc2-c2ccccc2)NCCC3)cc1
Product: COC(=O)CCCN1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21

Procedure:
The title compound was prepared from 2,3-diphenyl-5,6,7,8-tetrahydropyrido[3,2-b]pyrazine (Ex. 4.1 step 1) and methyl 4-oxobutanoate analogously to Example 10, step 1;
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19].[Cl:21][CH2:22][C:23](Cl)=[O:24].C(Cl)(Cl)Cl>O>[Cl:21][CH2:22][C:23]([NH:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])=[O:24]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)c1cc(C(=O)c2ccccc2Cl)c(N)s1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cc(C(=O)c2ccccc2Cl)c(NC(=O)CCl)s1

Procedure:
Ethyl 5-amino-4-(2-chlorobenzoyl)thiophene-2-carboxylate (280 g) and chloroacetyl chloride (218 ml) were added to chloroform (4 l), and the mixture was refluxed under heating for 2.5 hours. Water was added thereto. The organic layer was taken out, and dried over magnesium sulfate. The solvent was evaporated. Then, diisopropyl ether was added, and the resulting crystals were collected by filtration and washed with diisopropyl ether to give 325 g of ethyl 5-(2-chloroacetylamino)-4-(2-chlorobenzoyl)thiophene-2-carboxylate.