Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15][C:5]=3[C:4]=2[C:3]=1[Cl:23].[H-].[Na+].Br[CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:6]3[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:15][C:5]=3[C:4]=2[C:3]=1[Cl:23]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccc(Cl)c(Cl)c3c2CC1
Reactant: BrCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCCc3ccccc3)c3ccc(Cl)c(Cl)c23)CC1
Reaction time: 0.42 h
Yield: 63.4 %

Procedure:
To a solution of tert-butyl 9,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.40 g, 1.1 mmol) in DMF (6 mL), sodium hydride (60% dispersion in mineral oil, 68 mg, 1.7 mmol) was added. After 25 min, 1-bromo-3-phenyl propane (0.34 mL, 2.3 mmol) was added. The reaction was quenched with saturated aqueous NH4Cl after 3 h and extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40M) with heptane/EtOAc (17:3) to give 0.33 g (62%) of a yellow solid: mp 113.5-115.5° C.; 1H NMR (300 MHz, CDCl3) δ 7.14 (m, 3H), 6.93 (d, J=8.7 Hz, 1H), 4.02 (m, 2H), 3.70 (m, 4H), 3.50 (m, 2H), 2.93 (m, 2H), 2.65 (t, J=7.5 Hz, 2H), 1.99 (m, 2H), 1.48 (s, 9H); IR (diffuse reflectance) 2976, 1686, 1447, 1416, 1366, 1360, 1247, 1180, 1168, 1152, 1108, 930, 788, 747, 701 cm−1; MS (FAB) m/z 473 (M+H+), 475, 474, 473, 472, 419, 418, 417, 416, 91, 57; HRMS (FAB) calcd for C26H30Cl2N2O2+H 473.1762, found 473.1759; Anal. Calcd for C26H30Cl2N2O2: C, 65.96; H, 6.39; N, 5.92, found: C, 66.00; H, 6.41; N, 5.85.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:22]([C:27](Cl)=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=1>C1COCC1.C(N(CC)CC)C>[C:1]1([CH2:7][N:8]2[CH2:9][CH2:10][N:11]([C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:27]([C:22]4[C:21]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:28])=[CH:18][CH:19]=3)[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Reactant: Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1)c1ccccc1-c1ccccc1
Yield: 1.6 %

Procedure:
A mixture of 4-[4-(phenylmethyl)-1-piperazinyl]-benzenamine (0.12 mole) in THF (300 ml) and triethylamine (50 ml) was stirred. [1,1′-Biphenyl]-2-carbonyl chloride (0.12 mole) was added dropwise. The mixture was stirred overnight. The solvent was evaporated. The residue was dissolved in DCM. The organic layer was separated, washed, dried, filtered and the solvent was evaporated. The residue was triturated in DIPE/2-propanol. The precipitate was filtered off and dried. A part (1 g) of this fraction was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 99/1). The pure fractions were collected and the solvent was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried, yielding 0.84 g of N-[4-[4-(phenylmethyl)-1-piperazinyl]phenyl]-[1,1′-biphenyl]-2-carboxamide (intermediate 9, melting point 162° C.).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[N:8]=[CH:9][C:10]3[NH:11][C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:3]=1.[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][Cl:26]>CN(C=O)C>[Cl:26][CH2:25][CH2:24][CH2:23][N:11]1[C:10]2[CH:9]=[N:8][C:7]([C:4]3[N:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2
Reactant: Cc1nc(-c2cc3c(cn2)[nH]c2ccccc23)no1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2cc3c4ccccc4n(CCCCl)c3cn2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To a solution of 3-(5-methyl-1,2,4-oxadiazol-3-yl)-β-carboline (0.25 g, 0.001 mol) in anhydrous DMF (30 mL) was added 50% sodium hydride in mineral oil (0.03 g, 0.0011 mol). The mixture was stirred for 1 h at room temperature, and then carefully added to a solution of 1-bromo-3-chloropropane (0.17 g, 0.0011 mol) in anhydrous DMF (20 mL). The resulting mixture was stirred at ambient temperature for 96 h. The reaction mixture was concentrated in vacuo, and the crude product was purified twice on a silica gel column 1) (Eluent: CH2Cl2 /methanol (9:1)); 2) (Eluent: ethyl acetate/toluene (1:1)) to give the title compound 0.21 g (64%). M.p. 130°-135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][CH:6](/[CH:10]=[CH:11]/[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[CH:7]([NH2:9])[CH3:8].[C:26](OCC)(=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O-:33])=[O:32].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][CH:6](/[CH:10]=[CH:11]/[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[CH:7]([NH:9][C:26]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:34])[CH3:8]
Reactant: CCOC(=O)CCCCC(=O)[O-]
Reactant: CC(N)C(/C=C/c1ccc2ccccc2c1)Cc1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(NC(=O)CCCCC(=O)O)C(/C=C/c1ccc2ccccc2c1)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
30 mg of (1RS,2RS,3E)-2-(3,4-dichlorobenzyl)-1-methyl-4-(2-naphthyl)-3-butenylamine was dissolved in 1 ml of methylene chloride, and 18 mg of mono-ethyl adipate, 12 mg of 4-dimethylaminopyridine and 19 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added thereto. The mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate, then sequentially washed with 1N hydrochloric acid, a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was dissolved in 1 ml of methanol, and then 0.5 ml of a 2N sodium hydroxide aqueous solution was added thereto. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and then extracted by an addition of ethyl ether and 1N hydrochloric acid. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel thin layer chromatography (Kieselgel™ 60F254, Art 5744, manufactured by Merck Co.; chloroform/methanol=10/1) to obtain 21 mg (yield: 51%) of the above-identified compound as colorless oily substance.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1>>[CH3:17][C:13]1[CH:12]=[C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Cc1cccc(I)c1
Product: Cc1cccc(-n2ccc3ccccc32)c1

Procedure:
Prepared by Procedure C and Scheme O using 1H-indole and 1-iodo-3-methylbenzene: ESMS m/e: 208.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH2:17])([CH2:14][CH2:15]O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br.Cl[C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44]>ClCCl.O.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([N:17]([C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:44])[CH2:15][CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)(CCO)C1
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC2(CCN2C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of an optically-active compound of 3-amino-3-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (6.46 g), triphenylphosphine (12.5 g) and triethylamine (13.3 ml) in dichloromethane (226 ml) cooled to 0° C. was added carbon tetrabromide (15.8 g). The reaction mixture was stirred at room temperature for 40 minutes and cooled to 0° C. again. Then, thereto were added triethylamine (5.5 ml) and benzyl chloroformate (4.9 ml), and the mixture was stirred for 3.5 hours at room temperature. To the mixture was added water (200 ml), and the mixture was extracted with chloroform (100 ml). The organic layer was washed with saturated aqueous sodium chloride solution, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1) to give the titled compound (5.35 g).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Si:7]([O:14][C@@H:15]1[C@H:19]2[O:20][CH2:21][C:22](=O)[C@H:18]2[O:17][CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.O>[C:10]([Si:7]([CH3:8])([CH3:9])[O:14][C@@H:15]1[CH2:16][O:17][C@@H:18]2[C:22](=[CH2:1])[CH2:21][O:20][C@H:19]12)([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CO[C@@H]2C(=O)CO[C@H]12
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C1CO[C@H]2[C@@H]1OC[C@H]2O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 234.7 %

Procedure:
A stirred suspension of methyltriphenylphosphonium bromide (1.84 g, 5.16 mmol) and potassium tert-butoxide (578 mg, 5.16 mmol) in tetrahydrofuran (15 mL) was heated at reflux under an atmosphere of argon for 3 hours then allowed to cool to ambient temperature. A solution of ketone (87) (888 mg, 3.44 mmol) in tetrahydrofuran (7.5 mL) was added then heating at reflux continued for 2.25 hours. The mixture was diluted with water (30 mL) then the product extracted into diethyl ether (2×30 mL). The combined organic layers were washed with brine (25 mL), dried (MgSO4), filtered and reduced in vacuo to leave residue (2.07 g). Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 0:100 to 15:85 gave alkene (88) as a colourless oil (799 mg, 91%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH2:6][NH:7]2.FC1C=CC(N)=C2C=1C=CC=N2>CCOC(C)=O.[Pd]>[F:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][NH:7]2
Reactant: O=[N+]([O-])c1ccc(F)c2c1NCC=C2
Agent: [Pd]
Agent: Nc1ccc(F)c2cccnc12
Solvent: CCOC(C)=O
Product: Nc1ccc(F)c2c1NCCC2
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 5-fluoro-8-nitro-1,2-dihydroquinoline (83.6 mg, 0.43 mmol) in EtOAc (10 mL) was added a slurry of 10% Pd/C (28 mg) in IMS (3 mL) and the reaction mixture was stirred at RT under a hydrogen atmosphere for 22 h. The suspension was then filtered through a pad of Celite® and the filtrate was concentrated in vacuo affording a mixture of the title compound and 5-fluoroquinolin-8-ylamine as a purple oil (70.4 mg, 99%). 1H NMR (CDCl3, 300 MHz) (signals due to title compound): 6.46 (1H, dd, J=8.5, 5.5 Hz), 6.28 (1H, dd, J=9.2, 8.5 Hz), 3.31-3.28 (2H, m), 3.24 (3H, bs), 2.72 (2H, t, J=6.5 Hz), 1.94-1.86 (2H, m)
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([Cl:21])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[Cl:22][C:23](Cl)([Cl:27])[CH2:24][CH2:25]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:22][C:23]([Cl:27])=[CH:24][CH2:25][O:20][C:18]1[CH:19]=[C:2]([Cl:1])[C:3]([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])=[C:16]([Cl:21])[CH:17]=1
Reactant: CC(C)(C)OC(=O)NCCCOc1c(Cl)cc(O)cc1Cl
Reactant: ClCCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Yield: 56.2 %

Procedure:
This compound was prepared in a manner analogous to that of Step D of Example 1, using 3.5 grams (0.0104 mole) of N-[3-(2,6-dichloro-4-hydroxyphenoxy)propyl](tert-butoxy)carboxamide, 2.3 grams (0.0125 mole) of 1,1,1,3-tetrachloropropane and 3.4 grams (0.0250 mole) of potassium carbonate in DMF. The crude product was purified with column chromatography on silica gel using a mixture of 1:3 hexane and methylene chloride as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 2.6 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:14][CH:15]([CH3:17])[CH3:16])[C:11]=1[O:12][CH3:13])[C:5]([O:7]C)=[O:6]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:14][CH:15]([CH3:17])[CH3:16])[C:11]=1[O:12][CH3:13])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(OC)c(OC(C)C)c1
Solvent: CO
Product: COc1c(Cl)cc(C(=O)O)cc1OC(C)C
Yield: 92.7 %

Procedure:
3-Chloro-5-isopropoxy-4-methoxybenzoic acid (5) (0.93 g, 89%) was prepared from methyl 3-chloro-5-isopropoxy-4-methoxybenzoate (4) (1.06 g, 4.10 mmol) using a procedure essentially the same as in step (ii) for AAA-001 except that MeOH instead of water was added dropwise until a solution formed: m/z 243 [M−H]− (ES−).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[CH:9]([C:11]([CH3:13])=[O:12])=[CH2:10].C(N)C.N1C=CN=C1>C(Cl)(Cl)Cl>[CH3:8][C:2]1[CH:1]=[C:6]([CH:5]=[CH:4][CH:3]=1)[O:7][CH2:10][CH2:9][C:11](=[O:12])[CH3:13]
Reactant: Cc1cccc(O)c1
Reactant: C=CC(C)=O
Agent: CCN
Agent: c1c[nH]cn1
Solvent: ClC(Cl)Cl
Product: CC(=O)CCOc1cccc(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To m-Cresol (4.0 g, 37 mmol), methyl vinyl ketone (3.2 mL, 37 mmol) in chloroform (25 mL), was added diispropyl ethyl amine. The mixture was heated at reflux for 16 h, allowed to cool to room temperature and evaporated. The residue has 50% product and 50% starting material. The starting material was separated as t-butyldimethyl silyl ether. The product was isolated via plug filteration using silica gel 50% hexane/ethyl acetate. Yield 4.5 g (68%). As an alternative purification procedure, the crude reaction mixture was evaporated, dissolved in DMF (0.2M) and 0.5 equivalents of imidazole and 0.5 equivalents of tBDMSCI were added. The reaction was stirred for 3 hr at room temperature and then the solvents were removed in vacuo. To the residue was added 75 mL ethyl acetate and 75 mL water (ratio of 1/1). The ethyl acetate layer was separated and dried over Na2SO4. The solvents were removed in vacuo. The crude material was placed on a pad of silical gel and the silylated m-cresol was removed with hexanes. The product was obtained by eluting with 5-10% ethyl acetate in hexanes. The solvents were removed in vacuo to give the desired product. 1H(CDCl3):7.15 (t, 1H), 6.65-6.80(m, 2H), 4.25 (t, 2H), 2.75 (t, 2H), 2.25 and 2.35 (2 s, 3H each).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:22])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)=[CH:8][S:7][CH:6]=1)=[O:4].[OH-].[Na+]>C(O)C>[Cl:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[Cl:20])[O:13][CH2:12][C:11]([NH:10][C:9]1[C:5]([C:3]([OH:4])=[O:2])=[CH:6][S:7][CH:8]=1)=[O:22]
Reactant: COC(=O)c1cscc1NC(=O)COc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(COc1ccc(Cl)c(Cl)c1)Nc1cscc1C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.8 %

Procedure:
To 4-[2-(3,4-dichloro-phenoxy)-acetylamino]-thiophene-3-carboxylic acid methyl ester (80 mg, 0.222 mmol) in suspension in ethanol was added an aqueous solution of sodium hydroxide (1N, 0.333 mL, 0.333 mmol) and the reaction mixture was stirred at room temperature for 48 hours. After such time the reaction mixture was filtered and the filtrate was neutralized by addition of an aqueous solution of hydrochloric acid (1N, 0.335 mL). The precipitate was then isolated by filtration, washed with water and dried in vacuo to yield the title compound as a white solid (62.1 mg, 80%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:12][CH2:11][C:10]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[CH2:9]2)[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:32]Br>ClCCl>[Br:32][C:7]1[C:2]([CH3:1])=[N:3][C:4]([N:8]2[CH2:12][CH2:11][C:10]([C:17]3[CH:18]=[C:19]([Cl:25])[C:20]([Cl:24])=[C:21]([Cl:23])[CH:22]=3)([C:13]([F:14])([F:16])[F:15])[CH2:9]2)=[CH:5][CH:6]=1
Reactant: Cc1cccc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1Br
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a dichloromethane (200 ml) solution of 2-methyl-6-[3-(3,4,5-trichlorophenyl)-3-(trifluoro-methyl)pyrrolidin-1-yl]pyridine (3.4 g), an aqueous solution (100 ml) of sodium carbonate (1.2 g) was added. Under ice cooling, a dichloromethane solution of bromine (1.4 g) was added dropwise. Upon the completion of the dropwise addition, the stirring was continued for 1 hour at 0° C. The dichloromethane layer was separated and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to obtain 3-bromo-2-methyl-6-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]pyridine (3.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH2:11])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:12](Cl)(=[O:15])[CH2:13][CH3:14].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: NC1(c2ccc(Br)cc2)CC1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)NC1(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 79.2 %

Procedure:
To a solution of 1-(4-bromophenyl)-cyclopropylamine (Intermediate 116, 84 mg, 0.4 mmol) in 4 mL CH2Cl2 at room temperature was added propionyl chloride (43.0 mg, 0.47 mmol) and pyridine (56.0 mg, 0.71 mmol). After stirring 17 hours at room temperature the reaction was quenched by the addition of H2O and extracted with EtOAc. The combined extracts were washed with 10% aqueous HCl, saturated aqueous NaHCO3, and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound 85.0 mg (67%), was isolated by column chromatography (20-50% EtOAc-hexanes) as a colorless solid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[O:3].[H-].[Na+].[CH3:10][O:11][C:12](=[O:23])[C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16](Cl)=[N:15][CH:14]=1>O1CCOCC1>[CH3:10][O:11][C:12](=[O:23])[C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16]([O:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])=[N:15][CH:14]=1
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)COc1ncc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
A solution of ethyl glyoxalate (2.80 g) in dry dioxan (100 mL), cooled in ice, was treated with sodium hydride (60% dispersion in oil; 1.30 g) and the mixture was heated at 50° C. for 30 minutes and cooled in ice. A solution of 6-chloro-5-nitro-nicotinic acid methyl ester (5.25 g) [prepared as described by A. H. Berrie et al. J. Chem. Soc. 2590-2594 (1951)] in dioxan (40 mL) was added and the solution was stirred at 0° C. for 30 minutes and then at room temperature overnight. The reaction mixture was evaporated to dryness, sodium bicarbonate solution was added to pH 7, and the mixture extracted with chloroform, dried (anhydrous sodium sulfate) and evaporated to afford a semi-solid that was chromatographed on silica gel [dichloromethane-hexane (1:1) then dichloromethane] to afford the product (4.70 g).
Reaction SMILES: [CH:1]([CH:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)[C:4]#[N:5])=O.Cl.[NH2:20][NH:21][C:22]([NH2:24])=[O:23].[OH-].[Na+].Cl>O.CO>[NH2:5][C:4]1[N:21]([C:22](=[O:23])[NH2:24])[N:20]=[CH:1][C:3]=1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1
Reactant: NNC(N)=O
Reactant: N#CC(C=O)c1ccc(Cc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=O)n1ncc(-c2ccc(Cc3ccccc3)cc2)c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.5 %

Procedure:
A mixture of α-formyl-4-benzylphenylacetonitrile (152.22 g), semicarbazide hydrochloride (72.24 g), methanol (400 ml) and water (80 ml) was stirred at room temperature, and after 18 hours, maintained pH to about 10 with 5N sodium hydroxide aqueous solution. When heat was generated, the reaction mixture was cooled with ice-water. After stirring at room temperature for 1 hour, the reaction mixure was neutralized with 10% hydrochloric acid, and water (1 l) was added. After stirring for 1 hour, the precipitate was separated by filtration, washed with water, and dried to give the title compound (165.52 g).
Reaction SMILES: [CH2:1]([C:8]1[NH:12][C:11]([C:13]([O:15]CC)=[O:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([C:8]1[NH:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(Cc2ccccc2)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(Cc2ccccc2)[nH]1

Procedure:
A mixture of Ethyl 5-benzylpyrrole-2-carboxylate (0.7 g, 3.05 mmol; Elder et al., Synthetic Communications, 19, 763-767 (1989)), ethanol (20 ml) and 1M sodium hydroxide (9.2 ml, 9.2 mmol) was stirred and heated under reflux for 3 h. The major part of the ethanol was removed and the remaining liquid was diluted with water, washed with ether, cooled in ice and acidified with concentrated hydrochloric acid. The mixture was extracted with ether. The combined extracts were washed with brine, dried (Na2SO4) and concentrated to afford 0.567 g (92%) of an off white solid: mp. 130°-134° C.; 1H NMR (CDCl3) δ 8.87 (1H, brs), 7.37-6.95 (5H, m), 6.97 (1H, m), 6.07 (1H, m), 4.00 (2H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11]\[OH:12])[CH:5]=[CH:6][CH:7]=1.[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:9]/[C:10](/[C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)=[N:11]\[OH:12])[CH:3]=2)=[CH:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: O/N=C(\CC(c1ccccc1)c1cccc(Br)c1)c1ccncc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CS(=O)(=O)c1ccc(-c2cccc(C(C/C(=N\O)c3ccncc3)c3ccccc3)c2)cc1

Procedure:
In analogy to example 22, from (E)-3-(3-bromo-phenyl)-3-phenyl-1-pyridin-4-yl-propan-1-one oxime (example 12) and (4-methylsulfonylphenyl)boronic acid was prepared the title compound as a colorless oil, MS (ESI+): m/z=457.3 ([M+H]+).