Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C.[N:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C(NC1[CH:47]=[CH:46][C:45]([C:48](=[O:53])NCCC)=CC=1)=O)C2>>[CH:45]1([C:48]([N:8]2[CH2:9][CH2:10][N:5]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]4[CH2:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:21]4)=[O:19])=[CH:13][CH:12]=3)[CH2:6][CH2:7]2)=[O:53])[CH2:46][CH2:47]1
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)N1Cc2ccccc2C1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Solvent: CC(=O)Cl
Product: O=C(Nc1ccc(N2CCN(C(=O)C3CC3)CC2)cc1)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 278, substituting cyclopropanecarbonyl chloride for acetyl chloride and N-(4-(piperazin-1-yl)phenyl)isoindoline-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.15 (s, 1H), 7.38-7.45 (m, 2H), 7.28-7.39 (m, 4H), 6.87-6.93 (m, 2H), 4.74 (s, 4H), 3.73-3.90 (m, 2H), 3.50-3.70 (m, 2H), 3.02-3.18 (m, 4H), 1.98-2.07 (m, 1H), 0.68-0.77 (m, 4H); MS (ESI(−)) m/e 389 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[CH3:15][O:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([N:20]1[CH2:21][CH2:22][CH:17]([O:16][CH3:15])[CH2:18][CH2:19]1)=[O:14])[CH:6]=[CH:5]2
Reactant: COC1CCNCC1
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Product: COC1CCN(C(=O)c2ccc3cc(O)ccc3c2)CC1

Procedure:
The title compound was synthesised from 6-hydroxy-2-naphtoic acid (commercially available) and 4-methoxy-piperidine (commercially available) according to the procedure described for Example A. MS (m/e): 284.0 (MH−, 100%)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[NH:18][CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4.C(N(CC)CC)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].[Na+].[Cl-]>ClCCl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[N:18]([C:27]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:28])[CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4
Reactant: Oc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(O)cc13
Reaction time: 2 h
Yield: 52.1 %

Procedure:
To a stirred solution of 3-hydroxymorphinan (20 mg, 0.061 mmol) and triethylamine (26 μL, 0.183 mmol) in dry Dichloromethane (0.3 mL) was added benzyl chloroformate (10.5 μL, 0.073 mmol) at 0° C. The mixture was stirred for 2 h, and to the mixture was added sat aq NaCl solution (2 mL) and the mixture was extracted with EtOAc (3 mL×3). The combined organic layer was dried over anhydrous MgSO4, filtered, and concentrated, after column chromatography of the crude product gave 12 mg (51%) of title compound: 1H NMR (300 MHz, CDCl3) δ7.3˜7.5 (5H, m) 6.9 (1H, t); 6.8 (1H, d); 6.6 (1H, t); 5.1 (2H, s); 4.3 (1H, dd); 3.9 (1H, m); 3.1 (1H, m); 2.7 (2H, m); 2.3 (1H, d); 1.0˜1.8 (10H, m).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:20]Br>C(Cl)(Cl)(Cl)Cl>[C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][Br:20])[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccnc(-c2ccccc2)c1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccnc(-c2ccccc2)c1

Procedure:
To a solution of 100 mg of 2-phenyl-4-methylpyridine in 2 mL of carbon tetrachloride was added 300 mg of sodium carbonate and 100 mg of bromine. The reaction mixture was stirred and irradiated with a 500 W lamp for 1 h, filtered and the solvent removed by evaporation under reduced pressure to yield 2-phenyl-4-bromomethylpyridine which was used in the next step without further purification or characterization
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7](Br)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[I-].[Na+]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([NH:31][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1Br
Reactant: NCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1NCc1ccccc1
Yield: 43.8 %

Procedure:
1-Bromo-6-methoxy-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (120 mg, 0.32 mmol) obtained in Example 18 was dissolved in THF (10 mL), and benzylamine (102.87 mg, 0.11 mL, 0.93 mmol) and sodium iodide (9.60 mg, 0.06 mmol) were added thereto, followed by refluxing for 6 hrs. The resulting mixture washed with saturated saline and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 56 mg of the titled compound (yield: 44%).
Reaction SMILES: [OH-:1].[K+].CCCCCC.[CH3:9][CH:10]([CH2:15][C:16](N)=[O:17])[CH2:11][CH2:12][CH2:13][CH3:14].N>C(O)C>[CH3:9][CH:10]([CH2:15][C:16]([OH:17])=[O:1])[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC(C)CC(N)=O
Reactant: [OH-]
Agent: N
Agent: [K+]
Solvent: CCO
Solvent: CCCCCC
Product: CCCCC(C)CC(=O)O

Procedure:
In this preparation 2 ml. of 30% aqueous potassium hydroxide is admixed with 0.1 mole of exobicyclo[3.1.0]hex-2-yl acetamide in 20 ml. of ethanol and warmed to 70° C and stirred at this temperature until no more ammonia evolves. The ethanol solvent is then removed by evaporation under vacuum and the residue poured into 100 ml. of water and extracted three times with ethyl ether. The aqueous solution is acidified to about pH 2 with 5N aqueous hydrochloric acid and then extracted three times with ethyl ether. The ethyl ether extracts are combined and dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under vacuum to remove the ethyl ether, affording exobicyclo[3.1.0]hex-2-yl acetic acid as a residue.
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1>O1CCCC1>[N:6]1([CH2:2][C:3]([OH:5])=[O:4])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: O=C(O)CBr
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: O=C(O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Bromoacetic acid (2 g, 14.4 mole) was dissolved in tetrahydrofuran (50 mL) and added dropwise to a stirred solution of morpholine (3.76 g, 43.2 mole) in tetrahydrofuran (THF, 20 mL). The solution was stirred at room temperature for three days. The white solid (4.17 g) was filtered, washed with THF (100 mL), and recrystallised from hot ethanol (EtOH), Yield: 2.59 g: IR:1740 cm−1. For the two different isobaric versions of morpholine acetic acid, either bromoacetic-1-13C acid (Aldrich PN 27,933-1) or bromoacetic-2-13C acid (Aldrich PN 27,935-8) was substituted for bromoacetic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:16][C:9]=23)[CH:7]=1.[Br:32]N1C(=O)CCC1=O>CN(C)C=O.O.C(OCC)(=O)C>[Br:32][C:16]1[C:9]2[C:10](=[N:11][CH:12]=[CH:13][C:8]=2[C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:30][CH3:31])[NH:14][C:15]=1[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19][CH2:18]1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3CCN(C(=O)OC(C)(C)C)CC3)cc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3CCN(C(=O)OC(C)(C)C)CC3)c(Br)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Example 17F (300 mg, 0.705 mmol) in N,N-dimethylformamide (3 mL) at 0° C. was added N-bromosuccinimide (188 mg, 1.058 mmol) and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with water and ethyl acetate and the ethyl acetate layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (silica gel, 15% ethyl acetate in hexane) afforded the title compound. LCMS: 506 (M+3)+.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@H:11]1[CH:19]=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+].[O:23]=[C:24]([CH2:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:25]P(=O)(OC)OC.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.O1CCCC1>[C:1]([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@H:11]1/[CH:19]=[CH:25]/[C:24](=[O:23])[CH2:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COP(=O)(CC(=O)COc1ccccc1)OC
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1)COc1ccccc1
Temperature: -20 °C
Yield: 50.6 %

Procedure:
A 4-L reactor equipped with a mechanical stirrer, under nitrogen, was charged with (3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate (Cayman Chemical Catalog #70030, 99.2 g, 0.362 mol) in dichloromethane and lithium chloride (16.7 g, 0.398 mol) dissolved in tetrahydrofuran. Dimethyl 2-oxo-3-phenoxypropylphosphonate (102.7 g, 0.398 mol) is added neat and rinsed with dichloromethane (50 mL). Some lithium chloride precipitated from solution when the THF and DCM solutions were mixed. The mixture was stirred under nitrogen and cooled to −20° C. After adding the phosphonate and subsequent stirring and cooling, the precipitated lithium chloride dissolved. After stirring for 2.5 hours, triethylamine (40.2 g, 0.398 mol) was added neat via addition funnel and the temperature was held at −5° C. and stirred at this temperature for 19 hours. The temperature was adjusted to 0° C. and treated with 5% aqueous citric acid and the layers were separated. The organic layer was dried over magnesium sulfate and filtered. The crude product was purified on silica gel, eluted with ethyl acetate-hexanes (1:1). The desired product precipitated from the product-rich fractions as a white fluffy solid. After further purification of mixed fractions, all the purified product crystallized from MTBE to afford the title intermediate (74.4 g, 50.6%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CN(C=O)C>O>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([OH:12])([CH3:14])[CH2:13][N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C[C@@](C)(O)Cn2cc([N+](=O)[O-])nc2Cl)CC1
Temperature: 57.5 °C
Reaction time: 9 h
Yield: 81.1 %

Procedure:
A mixture of (S)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 18 (440 mg, 2.02 mmol), tert-butyl piperazine-1-carboxylate (414 mg, 2.22 mmol) and DMF (4 ml) was stirred at 55-60° C. for 9 hours. The reaction mixture was allowed to return to room temperature, then diluted with water (24 ml), and the solution was extracted with ethyl acetate (10 ml) twice. The organic phases were combined, washed with water (20 ml) three times and a saturated saline solution (10 ml), dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue treated with diethyl ether to afford tert-butyl (R)-4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]piperazine-1-carboxylate (662 mg, yield 81%) as a light yellow powder.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)=[O:4].[Cl:15][C:16]1[N:21]=[N:20][C:19](/[N:22]=[CH:23]/N(C)C)=[CH:18][CH:17]=1.CN(C=O)C>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:2]([C:3]([C:5]3[CH:6]=[C:7]4[C:12](=[CH:13][CH:14]=3)[N:11]=[CH:10][CH:9]=[CH:8]4)=[O:4])=[CH:23][N:22]=2)[N:21]=1
Reactant: O=C(CBr)c1ccc2ncccc2c1
Reactant: CN(C)/C=N/c1ccc(Cl)nn1
Solvent: CN(C)C=O
Product: O=C(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Temperature: 105 °C
Yield: 61.4 %

Procedure:
A 100 mL RB flask was charged with 2-bromo-1-(quinolin-6-yl)ethanone (0.7011 g, 2.80 mmol), (E)-N′-(6-chloropyridazin-3-yl)-N,N-dimethylformamidine (0.518 g, 2.80 mmol), and DMF (10.0 ml, 129 mmol), equipped with a reflux condenser, then heated at 105° C. for 3 hours. The reaction mixture was concentrated, then triturated with MeOH to yield (6-chloroimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone (0.530 g, 1.72 mmol, 61%) as a brown solid.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([OH:13])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[N:8][CH:7]=1.[CH3:14][C@@:15]12[C@@H:23](O)[CH2:22][CH2:21][C@H:20]1[C@@H:19]1[CH2:25][CH2:26][C:27]3[C@@:33]([CH3:34])([C@H:18]1[CH2:17][CH2:16]2)[CH2:32][CH2:31][C:29](=[O:30])[CH:28]=3>>[CH3:14][C@@:15]12[C@@H:23]([O:12][C:5]([C:6]3[CH:11]=[CH:10][CH:9]=[N:8][CH:7]=3)=[O:13])[CH2:22][CH2:21][C@H:20]1[C@@H:19]1[CH2:25][CH2:26][C:27]3[C@@:33]([CH3:34])([C@H:18]1[CH2:17][CH2:16]2)[CH2:32][CH2:31][C:29](=[O:30])[CH:28]=3
Reactant: O=C(O)c1cccnc1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Solvent: O=S(Cl)Cl
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC(=O)c1cccnc1
Reaction time: 3 h

Procedure:
Thionyl chloride (2 ml) was added to 0.7 g (5.7 mmol) of nicotinic acid and the mixture was refluxed for 3 hrs. Excess thionyl chloride was distilled under vacuum. To the cold residue 10 ml of dry pyridine was added followed with 1.44 g (5.0 mmol) of testosterone. The mixture was heated while stirring over a boiling water bath for 3 hrs. Pyridine was distilled under vacuum and 5 ml of methanol was added to the oily residue. The mixture was cooled and the solid crystallized out was filtered and recrystallized from methanol/acetone mixture. Yield, 1.4 g (71%), m.p. 187°-188°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9])#N.CCCCCC.[H-].C([Al+]CC(C)C)C(C)C.[O:34]1CCCC1>>[CH:13]1([NH:12][C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:34])=[CH:11][C:7]=2[C:8]([OH:10])=[O:9])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCOC1
Reactant: N#Cc1ccc(NC2CCCC2)c(C(=O)O)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Product: O=Cc1ccc(NC2CCCC2)c(C(=O)O)c1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a solution of 5-cyano-2-(cyclopentylamino)benzoic acid (40.0 mg) in anhydrous tetrahydrofuran (2 mL) was added 1.5 M diisobutylaluminium hydride hexane solution (0.34 mL) under dry ice-acetone cooling, and the mixture was stirred for an hour at −78° C. and then for 4 hours at ambient temperature. The reaction was quenched by addition of methanol and an aqueous saturated ammonium chloride solution. After stirring at ambient temperature for a half hour, the mixture was partitioned with 5% sulfuric acid and chloroform. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a preparative silica gel chromatography with 10% methanol in chloroform to give 2-(cyclopentylamino)-5-formylbenzoic acid (25.0 mg) as pale orange powders.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][CH:31]=2)=[O:29])[CH2:24][CH:23]1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([C:30]2[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:38][CH:39]=2)=[O:29])[CH2:24][CH:23]1[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(C(=O)N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](c1cccc2ccccc12)N(CC1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 55 mg of methyl 4-{[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]carbonyl}benzoate were added 2.0 mL of THF, 1.0 mL of methanol, and 1.00 mL of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature overnight. It was neutralized by addition of 1.1 mL of 1 M hydrochloric acid, and then extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and dried to obtain 4-{[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]carbonyl}benzoic acid as a crude product(colorless foamy substance, 57.5 mg).
Reaction SMILES: [Na].[CH2:2]([OH:4])[CH3:3].Br[C:6]1[CH:7]=[N:8][CH:9]=[C:10]([Br:12])[CH:11]=1.CN(C=O)C>O>[Br:12][C:10]1[CH:11]=[C:6]([O:4][CH2:2][CH3:3])[CH:7]=[N:8][CH:9]=1
Reactant: Brc1cncc(Br)c1
Reactant: CCO
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cncc(Br)c1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, sodium (4.60 g, 200.0 mmol) was added to absolute ethanol (100 mL) at 0-5° C., and the stirring mixture was allowed to warm to ambient temperature over 18 h. To the resulting solution was added 3,5-dibromopyridine (31.50 g, 133.0 mmol), followed by DMF (100 mL). The mixture was heated at 70° C. for 48 h. The brown mixture was cooled, poured into water (600 mL), and extracted with ether (3×500 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation, producing 46.70 g of an oil. Purification by vacuum distillation afforded 22.85 g (85.0%) of an oil, bp 89-90° C. at 2.8 mm Hg, (lit. bp 111° C. at 5 mm Hg, see K. Clarke et al., J. Chem. Soc. 1885 (1960)).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1([CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:13].C([O-])(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[CH3:3][C:4]1([CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:1])[CH:11]=2)[NH:6][C:5]1=[O:13]
Reactant: BrBr
Reactant: CC1(C)C(=O)Nc2ccccc21
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1(C)C(=O)Nc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of bromine (1.98 g) in acetic acid (10 cm3) was added dropwise to a stirred solution of 3,3-dimethyl-indol-2-one (2.0 g) and sodium acetate (1.01 g) in acetic acid (10 cm3). The mixture was stirred at room temperature for 30 minutes, poured onto water (20 cm3), basified to pH9 with sodium carbonate, and extracted with ethyl acetate (3×50 cm3). The combined and dried (MgSO4) organic extracts were evaporated in vacuo and the residue chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with methanol:hexane:dichloromethane, 1:10:40 by volume. Combination and evaporation of the appropriate fractions gave the title compound, m.p. 166°-166.5° (2.15 g).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.[F-].[K+].O1CCOCC1.CCCC[Sn]([C:45]1[N:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)(CCCC)CCCC>C(Cl)Cl.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>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C@H:12]([O:11][C:10]1[C:5]2[O:4][CH:3]=[C:2]([C:49]3[CH:48]=[CH:47][CH:46]=[CH:45][N:50]=3)[C:6]=2[CH:7]=[N:8][C:9]=1[NH2:23])[CH3:13]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H](Oc1c(N)ncc2c(-c3ccccn3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 100 °C

Procedure:
A mixture of 3-bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-furo[3,2-c]pyridin-6-ylamine (49.0 mg, 0.117 mmol), KF (44 mg, 0.75 mmol), and Pd(PPh3)4 (13 mg, 0.011 mmol) in 1,4-dioxane (1.0 mL, 13 mmol) in a microwave reactor vial was evacuated and refilled with nitrogen (3×). 2-(1,1,1-Tributylstannyl)pyridine (90% pure; 60 μL, 0.17 mmol) was added, and the reaction mixture was heated to 100° C. for 45 min. Further 2-(1,1,1-tributylstannyl)pyridine (90% pure; 30 μL, 0.083 mmol) was added, and the reaction mixture was heated to 100° C. for a total of 2 h. The reaction mixture was diluted with DCM and washed with water. The DCM solution was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was redissolved in MeOH and pre-purified by passing through a thiol SPE cartridge (500 mg/6 mL, PL-Thiol MP SPE+). The material from the thiol SPE treatment was chromatographed on a SCX column (1 g/6 mL cartridge), and the fraction that eluted with NH3/MeOH was concentrated and chromatographed on silica gel [10 g/70 mL cartridge, eluting with DCM→10% EtOAc in DCM→15% EtOAc in DCM→20% EtOAc in DCM→30% EtOAc in DCM]. Fractions containing product were combined and concentrated in vacuo to give the title compound as a foam. 1H NMR (CDCl3, 400 MHz): δ=8.69 (d, J=5.6 Hz, 1H), 8.68 (s, 1H), 7.94 (s, 1H), 7.75 (dd, J=7.6, 7.6 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.29 (dd, J=8.4, 4.4, Hz, 1H), 7.23 (dd, J=7.2, 5.6 Hz, 1H), 7.05 (dd, J=8.4, 8.0 Hz, 1H), 6.56 (q, J=6.8 Hz, 1H), 4.78 (brs, 2H), 1.89 (d, J=6.8 Hz, 3H). MS (ES+): m/z=417.94/419.91/421.93 (100/80/15) [MH+], 228.03 (19) [MH+−3-F-2,6-di-Cl-Ph-CH═CH2]. HPLC: tR=3.27 min (polar—5 min, ZQ3).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[CH:5]1([CH:10]=O)[CH2:9][CH2:8][CH2:7][CH2:6]1.C([BH3-])#N.[Na+].Cl>O.CO>[CH2:1]([NH:4][CH2:10][CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: O=CC1CCCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=CCNCC1CCCC1

Procedure:
To 100 mL of methanol is added 5.7 g (0.1 mol) of 2-propen-1-amine, 9.8 g (0.1 mol) of cyclopentanecarboxaldehyde and 12 g (0.2 mol) of sodium cyanoborohydride. Adjust the pH to 6 with concentrated HCl and monitor the reaction with thin-layer chromatography. Upon completion add concentrated HCl until gas evolution ceases. Add 300 mL of H2O and extract once with 200 mL of ether. Add 1N NaOH to the aqueous solution until it is basic and extract twice with 200 mL of ether. Dry the organic phase over Na2SO4. Filter off the drying agent and remove the solvent in vacuo to obtain the title compound.