Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12CC(C=[CH:6]1)[CH2:3][CH:2]2[O:8][C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[N:10]=1.C[N+]1([O-])CC[O:27]CC1.[C:31]([OH:35])([CH3:34])([CH3:33])C>C1COCC1.O=[Os](=O)(=O)=O>[CH3:20][O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:21][CH3:22])[N:10]=[C:9]([O:8][CH:2]1[CH2:3][CH:34]3[CH2:6][CH:1]1[CH:33]([OH:27])[CH:31]3[OH:35])[CH:18]=[N:17]2
Reactant: COc1cc2ncc(OC3CC4C=CC3C4)nc2cc1OC
Reactant: CC(C)(C)O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: C1CCOC1
Product: COc1cc2ncc(OC3CC4CC3C(O)C4O)nc2cc1OC
Reaction time: 2 h

Procedure:
To a solution of 2-(bicyclo[2.2.1]hept-5-en-2-yloxy)-6,7-dimethoxy-quinoxaline (149 mg, 0.5 mmole) and 4-methylmorpholine N-oxide (234 mg, 2 mmole) at room temperature in 5 mL of THF is added a solution of OsO4 in t-butanol (2.5% by wt., 0.2 mL). The brown solution is stirred vigorously for two hours before being quenched with saturated NaHS2O3 (2 mL). Ether (3×100 mL) is used to extract and then dried over magnesium sulfate. The residue after filtration and concentration is chromatographed on silica ;gel (50% ethyl acetate/hexane) to provide the desired product (m.p. 85-88° C.). Anal. Calcd. for C17H20N2O5.0.9H2O: C, 58.73; H, 6.29; N, 8.06; Found: C, 58.74; H, 5.91; N, 7.53.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[N:32][CH:33]=1)(=[O:27])=[O:26]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:30]5[CH:31]=[N:32][CH:33]=[C:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:29]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CS(=O)(=O)c1cncc(B(O)O)c1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(S(C)(=O)=O)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.105 mmol) and 5-(methylsulfonyl)pyridine-3-boronic acid (Combi-Blocks, San Diego, USA, 25 mg, 0.125 mmol) to give the title compound as a white solid. (HPLC: tR 2.30 min (Method A); M+H=449 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.09-9.01 (m, 3H), 8.32-8.27 (m, 1H), 8.21-8.14 (m, 2H), 8.11-8.06 (m, 1H), 7.67-7.62 (m, 1H), 3.92 (s, 3H), 3.59 (s, 3H), 3.40 (s, 3H), 1.94 (s, 3H))
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].C(#N)C>[CH2:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(OCc2ccccc2)cc1
Yield: 100.3 %

Procedure:
Add 4-cyanophenol (1.191 g, 10 mmol), benzyl bromide (1.881 g, 11 mmol), potassium carbonate (3.455 g, 25 mmol) and potassium iodide (166 mg, 1 mmol) to acetonitrile (80 mL) and heat at reflux for 12 h. Cool, partition between EtOAc and water, separate the organic layer, and extract the aqueous layer with EtOAc. Combine the organic extracts, wash with brine, dry over Na2SO4, filter and concentrate. Purify by chromatography on silica gel eluting with EtOAc/hexane (1:6) to give the desired intermediate as a white solid (2.098 g, 100%). MS (ES+) m/z: 227 (M+NH4)+.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].Cl.[CH2:7]([O:14][NH2:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>ClCCl>[CH2:7]([O:14][NH:15][C:1](=[O:4])[CH:2]=[CH2:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NOCc1ccccc1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)NOCc1ccccc1
Temperature: 0 °C

Procedure:
A solution of acryloyl chloride dissolved in dry dichloromethane was cooled at 0° C. with an ice bath. A mixture of O-benzyl hydroxylamine hydrochloride (29) and N,N-diisopropylethylaamine in dry dichloromethane was added. Water was added and the layers were separated. The organic solution was washed with diluted hydrochloric acid, a saturated sodium bicarbonate solution, water, and brine. The organic layer was dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure. The residue was purified by flash chromatography using a mixture of hexane and ethyl acetate. The purification gave N-benzyloxyacrylamide (30).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[N:11][CH:12]=1)=O.C(O)(=O)C.O.[NH2:23]N>CO>[NH:2]1[CH:3]=[CH:4][C:5]([C:7]2[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[N:11][CH:12]=2)=[N:23]1
Reactant: COC(=O)c1cncc(C(=O)C=CN(C)C)c1
Reactant: NN
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cncc(-c2cc[nH]n2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The mixture of methyl 5-(3-dimethylamino-1-oxo-2-propenyl)-3-pyridinecarboxylate (1.7 g), acetic acid (0.62 ml) and hydrazine monohydrate (0.53 ml) in methanol (34 ml) was stirred for 24 hours at ambient temperature, and the mixture was evaporated in vacuo. To the residue was added a mixture of tetrahydrofuran, ethyl acetate and water, and the mixture was adjusted to pH 9 with potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. The solvent was removed by concentration and the residue was triturated with diisopropyl ether to give methyl 5-(pyrazol-3-yl)-3-pyridinecarboxylate (1.24 g).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:10][C:9]=1[O:27][CH3:28])(=[O:3])[CH3:2].[CH2:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[CH:39][N:38]=2)[CH2:33][CH2:32]1)[CH3:30]>C1(C)C(C)=CC=CC=1>[CH2:29]([N:31]1[CH2:32][CH2:33][N:34]([C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[C:39]([C:11]3[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])=[C:9]([O:27][CH3:28])[CH:10]=3)[N:38]=2)[CH2:35][CH2:36]1)[CH3:30]
Reactant: CCN1CCN(c2nccc3ccccc23)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CCCOC(C)=O)c(OC)c1
Solvent: Cc1ccccc1C
Product: CCN1CCN(c2nc(-c3ccc(CCCOC(C)=O)c(OC)c3)cc3ccccc23)CC1
Yield: 40.8 %

Procedure:
2-(3-Acetoxypropyl)-5-tributylstannylanisole (0.92 g) and 3-bromo-1-((4-ethylpiperazin-1-yl)isoquinoline (0.37 g) were reacted in the presence of tetrakistriphenylphosphine (0.3 g) in xylene in nitrogen atmosphere for 4 hr. After cooling, the reaction solution was filtered and extracted with ethyl acetate. The resulting organic layer was washed with water and brine, dried and concentrated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give 0.28 g of the title compound.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][CH:31]=1)[C:8]([NH:10][CH2:11][C:12]1([C:18]2[S:19][CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:22]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:9])[NH2:4].Cl[C:33](=O)[C:34]([O:36][CH2:37][CH3:38])=[O:35]>N1C=CC=CC=1>[C:23]1([C:21]2[N:22]=[C:18]([C:12]3([CH2:11][NH:10][C:8]([C:7]4[CH:6]=[C:5]([C:3]5[N:4]=[C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[O:1][N:2]=5)[CH:31]=[CH:30][CH:29]=4)=[O:9])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:19][CH:20]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NC(=NO)c1cccc(C(=O)NCC2(c3nc(-c4ccccc4)cs3)CCOCC2)c1
Reactant: CCOC(=O)C(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(-c2cccc(C(=O)NCC3(c4nc(-c5ccccc5)cs4)CCOCC3)c2)no1
Temperature: 0 °C
Yield: 84.2 %

Procedure:
3-(N′-Hydroxycarbamimidoyl)-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamide (6.8 g, 15.57 mmol) was dissolved in anhydrous pyridine (68 mL) and the reaction mixture was cooled to 0° C. Ethyl chlorooxoacetate (5.2 mL, 46.73 mmol) was added dropwise, and the reaction mixture was heated at 60° C. for 1 h, quenched with 1.5N HCl solution, and diluted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 25-30% EtOAc in petroleum ether) to afford ethyl 3-(3-(((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)phenyl)-1,2,4-oxadiazole-5-carboxylate (6.8 g, yield 87%). 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J=7.9 Hz, 1H), 8.11-8.09 (m, 1H), 7.78-7.76 (m, 1H), 7.61-7.59 (m, 2H), 7.44 (s, 1H), 7.32-7.27 (m, 1H), 7.23-7.21 (m, 3H), 4.62-4.57 (q, J=7.0 Hz, 2H), 3.97-3.94 (m, 2H), 3.81-3.76 (m, 2H), 3.56-3.50 (m, 2H), 2.41-2.37 (m, 2H), 2.19-2.12 (m, 2H), 1.53-1.50 (t, J=7.2 Hz, 3H). MS (ESI) m/z: Calculated for C27H26N4O5S: 518.16. found: 517.1 (M−H)−.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH:28]1[CH2:31][CH:30]([CH2:32][C:33]([OH:35])=[O:34])[CH2:29]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:28]3[CH2:31][CH:30]([CH2:32][C:33]([OH:35])=[O:34])[CH2:29]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)CC1CNC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(CC(=O)O)C3)ccc2n1CC1CCC(F)(F)CC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (1.06 g, 2.6 mmol), azetidin-3-ylacetic acid hydrochloride (1.17 g, 7.8 mmol) and DIPEA (4 mL) in CH2Cl2 (20 mL), provided the title compound as crude product (930 mg, 74% yield), which was used directly in Step A.
Reaction SMILES: [F:1][C:2]1[C:22]([C:23]([OH:26])([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11](O)=[O:12])[C:7](=[O:18])[CH:6]=1.[CH3:27][N:28]1[CH:32]=[CH:31][C:30]([NH2:33])=[N:29]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:27][N:28]1[CH:32]=[CH:31][C:30]([NH:33][C:11](=[O:12])[C@@H:10]([N:8]2[CH2:9][C:5]([O:4][C:3]3[CH:19]=[CH:20][CH:21]=[C:22]([C:23]([OH:26])([CH3:24])[CH3:25])[C:2]=3[F:1])=[CH:6][C:7]2=[O:18])[CH2:14][CH:15]([CH3:16])[CH3:17])=[N:29]1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(C(C)(C)O)c2F)=CC1=O
Reactant: Cn1ccc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C)n1)N1CC(Oc2cccc(C(C)(C)O)c2F)=CC1=O
Temperature: 0 °C
Yield: 92.7 %

Procedure:
To a solution of (S)-2-{4-[2-fluoro-3-(1-hydroxy-1-methyl-ethyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid (0.392 g, 1.07 mmol) in dichloromethane (10 mL) was added 1-methyl-1H-pyrazol-3-ylamine (0.208 g, 2.14 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.522 g, 1.18 mmol). The mixture was stirred at 0° C. and N,N-diisopropylethylamine (0.304 g, 2.35 mmol) was added. The mixture was stirred at room temperature overnight and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 112 g, 60% to 100% ethyl acetate/hexanes) which afforded (S)-2-{4-[2-fluoro-3-(1-hydroxy-1-methyl-ethyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid (1-methyl-1H-pyrazol-3-yl)-amide (0.441 g, 92%) as an off-white solid: HR-ES-MS m/z calculated for C23H29FN4O4 [M+H]+ 445.2246, observed 445.2246, 1H NMR (300 MHz, DMSO-d6) δ 1.00 0.90 (d, J=6.4 Hz, 3H), 0.93 (d, J=6.4 Hz, 3H), 1.36-1.47 (m, 1H), 1.49 (s, 6H), 1.52-1.65 (m, 1H), 1.67-1.82 (m, 1H), 3.73 (s, 3H), 4.20 (d, J=18.4 Hz, 1H), 4.58 (d, J=18.4 Hz, 1H), 4.81 (s, 1H), 4.88 (dd, J=10.7, 5.0 Hz, 1H), 5.42 (s, 1H), 6.40 (d, J=2.1 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.29-7.40 (m, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.51-7.60 (m, 1H), 10.73 (s, 1H).
Reaction SMILES: O=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]2[C:14](=O)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:4]2=[C:3]1[C:22]#[N:23].[OH-].[K+].CC(C)([OH:29])C.C(O)(=O)C>O>[C:8]1([C:6]2[NH:7][CH2:2][C:3]([C:22]([NH2:23])=[O:29])=[C:4]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[CH2:14][C:5]=23)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#Cc1c2c(c(-c3ccccc3)[nH]c1=O)C(=O)c1ccccc1-2
Reactant: CC(C)(C)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)C1=C2C(=C(c3ccccc3)NC1)Cc1ccccc12

Procedure:
A mixture of 1 part of 3,9-dihydro-3,9-dioxo-1-phenyl-2H-indeno[2,1-c]pyridine-4-carbonitrile, 5 parts of potassium hydroxide, and 39 parts of 1,1-dimethylethanol is heated at the boiling point under reflux for 16 hours. The resultant mixture is diluted with 1000 parts of water, followed by sufficient acetic acid to neutralize the base present. The precipitate which forms is filtered off; consecutively washed with water, methanol, and 1,1'-oxybisethane; and dried in vacuo. The resultant yellow solid is crystallized from aqueous N,N-dimethylformamide to afford 3,9-dihydro-1-phenyl-2H-indeno[2,1-c]pyridine-4-carboxamide melting above 300°. The product has the formula ##STR19##
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]=[O:9])(=[O:5])[CH2:2][CH2:3][CH3:4].[SH:10][CH2:11][C:12](O)=[O:13]>C(#N)C.CC1C=CC(S(O)(=O)=O)=CC=1.O>[C:1]([O:6][CH2:7][CH:8]1[S:10][CH2:11][C:12](=[O:13])[O:9]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)OCC=O
Reactant: O=C(O)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: CCCC(=O)OCC1OC(=O)CS1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.3 %

Procedure:
A solution of 24 (3.90 g, 0.030 mol), mercaptoacetic acid (3.32 g, 0.036 mol) and p-TsOH.H2O (0.28 g, 1.5 mmol) in acetonitrile (600 ml) was heated at reflux for 3.5 hours. During the period of reflux, four portions of 25 ml each were drained from a Dean-Stark trap (to remove the water-acetonitrile azeotrope). Analysis of the reaction solution by TLC (6:1 hexane:AcOEt) revealed one major new component and no unreacted aldehyde (visualized by PMA and 2,4-DNP stains). The reaction solution was allowed to stir at room temperature for 16 hours, and then evaporated to dryness. The residue was partitioned between concentrated NaHCO3 (50 ml) and AcOEt (75 ml); the aqueous portion was extracted with additional AcOEt (2×75 ml). The organic fractions were combined, dried (MgSO4), filtered, and concentrated in vacuo. The crude material (6 g) was purified by flash chromatography (125 grams silica gel with 20% ethyl acetate in hexane). Compound 25 (3.27 g, 16 mmol, 53%) was obtained as an oil: TLC (3:1 hexane:AcOEt)—one spot with Rf=0.41; 1H-nmr (CDCl3)—compatible with structure; mass spectrum (FAB)—m/z=205.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.BrC1C=CC(OC)=CC=1.[Mg].Br[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: Brc1ccccn1
Agent: COc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccn2)cc1

Procedure:
That is, as shown in the Reaction Scheme below, (4-methoxyphenyl)magnesium bromide was synthesized from 22.4 g (120 mmol) of 4-bromoanisole by a conventional method by using 3.4 g of magnesium (Mg) in dry tetrahydrofuran (THF) under argon stream and added slowly into a solution of 15.8 g (100 mmol) of 2-bromopyridine and 1.8 g of (1,2-bis(diphenylphosphino)ethane)dichloronickel (II) (Ni(dppe)Cl2) in dry THF and the mixture was refluxed for 1 hour. After adding 250 ml of an aqueous solution of 5% hydrochloric acid to the reaction mixture, the reaction mixture was washed with chloroform. The water layer was neutralized with an aqueous solution of sodium hydrogen carbonate and the objective compound was extracted with chloroform and the organic layer was distilled off under reduced pressure. The distillate immediately solidified at room temperature to obtain 15.1 g (81.5 mmol) of 2-(4-methoxy-phenyl)pyridine (4-MeO-PPy) as white solid. Identification was performed by elementary analysis of C, H and N and 1H-NMR.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C:6]1[CH:7]=[C:8]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[C:9]([C:12]#N)=[N:10][CH:11]=1.[OH-:26].[K+].CCO.Cl.[OH2:32]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C:6]1[CH:7]=[C:8]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[C:9]([C:12]([OH:32])=[O:26])=[N:10][CH:11]=1
Reactant: COc1cccc(Sc2cc(Oc3cccc(Br)c3)cnc2C#N)c1
Reactant: [OH-]
Reactant: O
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: COc1cccc(Sc2cc(Oc3cccc(Br)c3)cnc2C(=O)O)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
A 25 mL round-bottomed flask was charged with 5-(3-bromophenoxy)-3-(3-methoxyphenylthio)picolinonitrile (225 mg, 0.544 mmol), potassium hydroxide (2.5 M, 1.09 mL, 2.72 mmol), and EtOH (5 mL). The reaction was heated to reflux overnight. After cooling to room temperature the reaction was poured into water and pH adjusted with 1N HCl to˜pH=3. The cloudy solution was extracted with CH2Cl2. The organic layer was dried over sodium sulfate, filtered and concentrated to afford the title compound (235 mg, 100%) which was taken forward without further purification.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C[OH:17]>C(OC(C)COC)(=O)C>[C:1]([OH:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:17])=[O:5].[CH2:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CO
Reactant: O=C1C=CC(=O)O1
Solvent: C=CCCCCCC
Solvent: COCC(C)OC(C)=O
Product: O=C(O)/C=C\C(=O)O
Temperature: 95 °C
Reaction time: 2 h

Procedure:
A solution of 9.8 g of maleic anhydride (0.1 mole) and 11.2 g of 1-octene (0.1 mole) in 30 g of propylene glycol methyl ether acetate was heated under agitation and nitrogen to 95° C. A solution of 2 g of t-butyl peroxy-2-ethylhexanoate in 6 g of propylene glycol methyl ether acetate was then injected into the reaction vessel within half hour via a syringe pump. The reactants were agitated for another 2 hours at 95° C. before being cooled to room temperature. The product was then poured into methanol which caused precipitation of a white solid which was filtered and air-dried to give 12.7 g of a maleic acid/1-octene copolymer having a number 2 0 average molecular weight by vapor phase osmometry (VPO) of 2800. The approximate composition of the copolymer by 13CNMR:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=[O:8])[CH2:2]1.[C:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]1)(=[NH:12])[NH2:11]>>[NH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[C:19]([OH:21])=[O:20].[C:10]([N:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH:18]1[C:7]([OH:9])=[O:8])(=[NH:12])[NH2:11]
Reactant: N=C(N)N1CCC(C(=O)O)CC1
Reactant: O=C(O)C1CCCNC1
Product: N=C(N)N1CCCCC1C(=O)O
Product: O=C(O)C1CCCCN1

Procedure:
The above-named acylating agent is prepared from 3-piperidine carboxylic acid according to the procedure of Example XX for making 1-guanyl-4-piperidine carboxylic acid. Utilization of 2-piperidine carboxylic acid in place of the 4-isomer provides 1-guanyl-2-piperidine carboxylic acid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:9][O:10][C:11]([C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[CH:15][CH:14]=1)=[O:12].O>C(Cl)Cl>[CH3:9][O:10][C:11]([C:13]1[CH:21]=[C:20]2[C:16]([C:17]([C:1](=[O:3])[CH3:2])=[CH:18][NH:19]2)=[CH:15][CH:14]=1)=[O:12]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C(C)=O)c[nH]c2c1
Yield: 99.7 %

Procedure:
To a solution of acetyl chloride (0.23 mL, 3.3 mmole) and aluminum chloride (0.88 g, 6.6 mmol) in methylene chloride (30 mL) was added 1H-indole-6-carboxylic acid methyl ester (0.53 g, 3.0 mmol). After stirring 1 hr at room temperature water (300 mL) was added and then this was extracted with ethyl acetate (300 mL). The organic layer was dried (MgSO4), filtered and concentrated to collect 0.65 g (99% yield) of 3-acetyl-1H-indole-6-carboxylic acid methyl ester a light yellow solid. 1H NMR (300 MHz, DMSO) δ 12.27 (s, 1H), 8.52 (s, 1H), 8.24 (d, 1H, J=8.2 Hz), 8.08 (d, 1H, J=1.0 Hz), 7.78 (dd, 1H, J=8.2, 1.0 Hz), 3.86 (s, 3H), 2.47 (s, 3H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[N:41]1[CH:46]=[CH:45][CH:44]=[C:43]([S:47](Cl)(=[O:49])=[O:48])[CH:42]=1>O1CCCC1.O>[Cl:3][C:4]1[C:9]([C:10]2[N:14]([S:47]([C:43]3[CH:42]=[N:41][CH:46]=[CH:45][CH:44]=3)(=[O:49])=[O:48])[CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CN(Cc1c[nH]c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2cccnc2)c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) were added tert-butyl {[5-(2-chloropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate, 15-crown-5 (330 mg) and pyridine-3-sulfonyl chloride (266 mg) under ice-cooling and the mixture was stirred for 15 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→1:1) to give the title compound as a pale-yellow oil (yield 465 mg, 97%).
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Cl:20][C:21]1[C:29]([Cl:30])=[CH:28][C:27]([Cl:31])=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[Cl:20][C:21]1[C:29]([Cl:30])=[CH:28][C:27]([Cl:31])=[CH:26][C:22]=1[C:23]([N:7]1[C:8](=[O:9])[CH:3]2[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]1=[O:6])=[O:24]
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(c1cc(Cl)cc(Cl)c1Cl)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,3,5-Trichlorobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,3,5-trichlorobenzoyl)-3,4-dibromohexahydrophthalimide.