Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1>O1CCCC1.O.O1CCCC1>[NH2:1][C:2]1[C:7]([NH:8][S:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[CH:11]=2)(=[O:18])=[O:17])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: Nc1cccnc1N
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncccc1NS(=O)(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
2,3-Diaminopyridine (1.97 g, 18 mmol) was dissolved in a tetrahydrofuran/water mixture, followed by the addition of a solution of 1.90 g (9.0 mmol) of 3-chlorobenzenesulfonyl chloride in tetrahydrofuran. The obtained mixture was stirred at room temperature overnight and concentrated, followed by the addition of water and dichloromethane. The organic phase was recovered and put in a vessel and the inside wall of the vessel was scratched to precipitate crystals. The formed crystals were recovered by filtration to give 1.41 g of N-(2-amino-3-pyridinyl)-3-chlorobenzenesulfonamide. 530 mg (1.87 mmol) of the crystals was dissolved in methanol, followed by the addition of a 40% aqueous solution of chloroacetaldehyde (367 mg, 1.87 mmol). The obtained mixture was heated under reflux for 4 hours and concentrated to dryness. A small amount of methanol was added to the residue and the obtained mixture was filtered to give 373 mg of the title compound as a crystal.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:25][C:26]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:31]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=C(O)C=Cc1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccc(F)cc1F
Yield: 99.4 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 2,4-difluorocinnamic acid (2.6 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (4.5 g, 99%) as an oily product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH2:9]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1)[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([CH2:9][CH3:10])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: CCc1ccc(CBr)cc1
Reactant: O=c1ccc(Br)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1ccc(Cn2cc(Br)ccc2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
5-Bromo-1H-pyridin-2-one (1.04 g) and 4-ethylbenzyl bromide (1.43 g) were dissolved in N,N-dimethylformamide (15 ml), and thereto was added potassium carbonate (1.66 g). The mixture was stirred at room temperature overnight, diluted with ethyl acetate, and washed successively with water and brine. The extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1-3:1) to give 5-bromo-1-(4-ethylphenylmethyl)-1H-pyridin-2-one (1.58 g) as colorless crystals. APCI-Mass m/Z 292/294 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].[F:25][C:26]1[CH:31]=[C:30](F)[CH:29]=[CH:28][C:27]=1[S:33]([CH3:36])(=[O:35])=[O:34]>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:4][C:5](=[O:8])[N:6]([C:30]2[CH:29]=[CH:28][C:27]([S:33]([CH3:36])(=[O:34])=[O:35])=[C:26]([F:25])[CH:31]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)[nH]cc2Cl)CC1
Reactant: CS(=O)(=O)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(S(C)(=O)=O)c(F)c3)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.5 %

Procedure:
A suspension of tert-butyl 4-(5-chloro-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (400 mg, 1.22 mmol), sodium hydride (60% wt in mineral oil, 58 mg, 1.5 mmol) and DMF (8 mL) was purged with Argon and then stirred at room temperature for 20 min. To the reaction was added 2,4-difluoro-1-(methylsulfonyl)benzene (351 mg, 1.83 mmol) and then heated at 130° C. for 1 hour. The resulting mixture was quenched with H2O and extracted with EtOAc. The organic layer was concentrated in vacuo to a brown oil. The oil was purified by flash chromatography (SiO2, 0 to 100% EtOAc in CH2Cl2) to yield 321 mg of the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.07-8.14 (m, 1H) 7.35-7.47 (m, 3H) 6.01 (s, 1H) 4.57-4.64 (m, 1H) 3.60-3.69 (m, 2H) 3.44-3.55 (m, 2H) 3.26 (s, 3H) 1.93-2.03 (m, 2H) 1.83-1.93 (m, 2H) 1.49 (s, 9H). MS (ESI) 445 (M−56+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.C(N(CC)C(C)C)(C)C.Br[CH2:37][CH:38]1[CH2:40][CH2:39]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[CH:38]1([CH2:37][NH:26][C:5]2[CH:6]=[CH:7][C:8]([C:9]3[O:10][C:11]([C:14]4[C:15]([C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=5)=[N:16][O:17][C:18]=4[CH3:19])=[N:12][N:13]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:40][CH2:39]1
Reactant: BrCC1CC1
Reactant: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NCC2CC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.8 %

Procedure:
To a suspension of 3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine (200 mg, 0.57 mmol) in THF was added N,N-diisopropyl ethyl amine (128 μL, 0.75 mmol) and bromomethyl-cyclopropane (61 μL, 0.63 mmol) and the reaction mixture was stirred for 24 h at ambient temperature. After addition of potassium bis(trimethylsilyl)amide (0.91 M in THF, 0.82 mL, 0.75 mmol) was added stirring was continued for 15 min and further bromomethyl-cyclopropane (78 μL, 0.80 mmol) was added. After stirring for 18 h at ambient temperature further bromomethyl-cyclopropane (0.12 mL, 1.2 mmol) was added and stirring continued for 24 h at this temperature. The reaction mixture was extracted with aqueous sodium carbonate (saturated, 20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers dried over sodium sulfate. Concentration and then purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=40:40:20 to 0:80:20) afforded the title compound (34 mg, 15%) as a light brown solid. MS: m/e=403.4 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH2:9])=[C:4]([F:10])[CH:3]=1.[C:11]([N:14]=[C:15]=[S:16])(=[O:13])[CH3:12].O>CC(C)=O>[C:11]([NH:14][C:15]([NH:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:10])=[S:16])(=[O:13])[CH3:12]
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: CC(=O)N=C=S
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)NC(=S)Nc1c(F)cc(Br)cc1F
Temperature: 72 °C
Reaction time: 1.5 h
Yield: 91.8 %

Procedure:
4-bromo-2,6-difluorobenzenamine (2.514 g, 12.1 mmol) was dissolved in acetone (75 ml) and ethanoyl isothiocyanate (1.30 ml, 14.8 mmol) was added. The reaction flask was fit with a reflux condensor and placed in a preheated oil bath (70-74° C.) and the reaction was stirred under nitrogen for 90 minutes. The reaction was then cooled to room temperature and poured into water (200 ml), and the resultant suspension was filtered. The solid was washed with water, collected, and dried under high vacuum in water bath (60° C.) to afford 1-acetyl-3-(4-bromo-2,6-difluorophenyl)thiourea (3.435 g, 93% purity, 85% yield). MS (ESI pos. ion) m/z: 309 (MH+, 79Br), 311 (MH+, 81Br). Calculated exact mass for C9H7BrF2N2OS 308 (79Br), 310 (81Br).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5]P(OCC)(OCC)=O)[CH3:2].[H-].[Na+].[O:17]=[C:18]1[C:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:26]=2)=[C:22]([CH2:39][CH2:40][CH3:41])[N:21]2[N:42]=[CH:43][N:44]=[C:20]2[N:19]1[CH:45]1[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]1>O1CCCC1>[CH2:1]([O:3][C:4](=[O:14])[CH:5]=[C:48]1[CH2:47][CH2:46][CH:45]([N:19]2[C:18](=[O:17])[C:23]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]#[N:38])=[CH:27][CH:26]=3)=[C:22]([CH2:39][CH2:40][CH3:41])[N:21]3[N:42]=[CH:43][N:44]=[C:20]23)[CH2:50][CH2:49]1)[CH3:2]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=CC(=O)OCC)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a solution (10 mL) of ethyl(diethoxyphosphoryl)acetate (1.2 g) in tetrahydrofuran was added sodium hydride (0.21 g), and the mixture was stirred at room temperature for 1 hr. A solution (10 mL) of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (2 g) in tetrahydrofuran was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was extracted with 1 N hydrochloric acid and ethyl acetate, and the obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.9 g, 86%). 1H NMR (300 MHz, CHLOROFORM-d) δ1.06 (t, J=7.4 Hz, 3H), 1.28 (t, J=7.2 Hz, 3H), 1.66-1.80 (m, 2H), 1.87-1.98 (m, 2H), 1.99-2.12 (m, 2H), 2.33-2.51 (m, 2H), 2.65-2.89 (m, 2H), 2.98-3.08 (m, 2H), 4.02 (s, 2H), 4.07-4.19 (m, 2H), 5.23-5.38 (m, 1H), 5.71 (s, 1H), 7.35-7.52 (m, 6H), 7.58-7.67 (m, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.90 (s, 1H)
Reaction SMILES: [OH:1][C:2]([CH3:41])([CH3:40])[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[C:37](C)[N:38]=[C:12]23)[CH2:7][CH2:6]1.C([Sn](=O)CCCC)CCC.[N:52]([Si](C)(C)C)=[N+:53]=[N-:54].C1(C)C=CC=CC=1>C(OCC)(=O)C>[OH:1][C:2]([CH3:41])([CH3:40])[CH2:3][O:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:54][N:53]=[N:52][N:32]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)[CH2:9][CH2:10]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2nc(C)nn12
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ncnn12
Temperature: 110 °C
Reaction time: 48 h

Procedure:
A mixture of 4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.2 g), dibutyltin oxide (0.046 g), azidotrimethylsilane (1.3 g) and toluene (15 mL) was stirred at 110° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium fluoride solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (10 mL). Tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 0.93 mL) was added and the mixture was stirred at 70° C. for 1 hr. Ethyl acetate and 1 N hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.033 g, 15%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[CH2:9]([NH:11][CH2:12][C:13]([CH2:19][NH:20][C:21]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][N:25]2[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([OH:18])[C:14]([F:17])([F:16])[F:15])[CH3:10]>>[CH2:9]([N:11]([CH2:12][C:13]([OH:18])([CH2:19][NH:20][C:21]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][N:25]2[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:14]([F:17])([F:16])[F:15])[C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:8])[CH3:10]
Reactant: O=C(O)c1ccsc1
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F
Product: CCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccsc1

Procedure:
Prepared similarly to Example 11 from 3-thiophenecarboxylic acid and 3-(ethylamino)-1,1,1-trifluoro-2-{[(6-methyl-1-phenyl-1H-indazol-4-yl)amino]methyl}-2-propanol.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.[H-].[Na+].[Cl:13][CH2:14][CH2:15][CH2:16]I.[Na+].[Cl-]>CN(C=O)C.O>[O:2]1[C:3]2[CH:9]=[CH:8][C:7]([O:10][CH2:16][CH2:15][CH2:14][Cl:13])=[CH:6][C:4]=2[O:5][CH2:1]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: ClCCCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCOc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, a solution of sesamol (2.00 g, 14.48 mmol) in DMF (15 mL) was slowly added over 5 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.65 g of an 80% dispersion in mineral oil, 21.67 mmol) in DMF (10 mL). The mixture was allowed to warm to ambient temperature and further stirred for 1 h. To this slurry was added drop-wise over 5 min, 1-chloro-3-iodopropane (3.55 g, 1 7.37 mmol), and the resulting brown mixture was stirred at ambient temperature for 4 h. Cold water (25 mL) was carefully added, followed by saturated NaCl solution (25 mL). The resulting mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (MgSO4), filtered, concentrated by rotary evaporation to a residue that was dried briefly under high vacuum producing a brown oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=4[F:24])[CH:15]=3)[N:10](C(OC(C)(C)C)=O)[CH:9]=2)[CH:5]=[N:4][CH:3]=1.CC[N:34]([CH2:37][CH3:38])[CH2:35][CH3:36].[CH3:39][N:40]1C(=O)CCC1>C(Cl)Cl.O>[F:23][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([F:24])[C:17]=1[C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[C:6]1[N:7]=[C:2]([N:34]2[CH2:35][CH2:36][CH:39]([NH2:40])[CH2:38][CH2:37]2)[CH:3]=[N:4][CH:5]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)n1cc(-c2cncc(Cl)n2)c2cc(-c3c(F)cccc3F)ccc21
Reactant: CN1CCCC1=O
Solvent: O
Solvent: ClCCl
Product: NC1CCN(c2cncc(-c3c[nH]c4ccc(-c5c(F)cccc5F)cc34)n2)CC1
Temperature: 150 °C

Procedure:
A glass microwave reaction vessel was charged with tert-butyl 3-(6-chloropyrazin-2-yl)-5-(2,6-difluorophenyl)-1H-indole-1-carboxylate (50.0 mg, 0.113 mmol) and 4-boc-amino-1-piperidine (34.0 mg, 0.170 mmol) in NMP (0.6 mL), followed by Et3N (0.047 mL, 0.339 mmol). The reaction mixture was stirred and heated in an oil bath at 150° C. for 16 h, and then the mixture was diluted with DCM and water. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was dissolved in DCM (2 mL) and treated with TFA (0.5 mL). The reaction mixture was stirred at RT for 2 h, and solvent was removed. The residue was purified with RP-HPLC to give 1-(6-(5-(2,6-difluorophenyl)-1H-indol-3-yl)pyrazin-2-yl)piperidin-4-amine as a brown solid. MS (ESI, pos. ion) m/z: 406 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.C(#N)C.[CH2:13]([NH2:16])[CH2:14][CH3:15].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:16][CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1
Reactant: CCCN
Reactant: ClCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CCCNCc1ccc(Cl)cc1
Reaction time: 0.75 h

Procedure:
A solution of 48.3 g. 4-chlorobenzyl chloride in 40 ml. acetonitrile was added to a mixture of 18 g. propylamine, 12.6 g. sodium hydroxide, 50 ml. acetonitrile and 30 ml. water. The mixture was shaken intermittently for 45 minutes. An exothermic reaction occurred and a white solid separated in the lower phase. After a period of 4 days the reaction mixture was poured into a liter of water and the organic phase isolated with ether. Distillation of the ethereal extract gave an oily product N-4-chlorobenzyl-N-propylamine, b.p. 101°-106° C./1.7-2.5 mm. Hg.
Reaction SMILES: [I:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].O=[CH:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CO.C(OCC)(=O)C>[CH2:10]([N:9]([CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:8][CH2:7][O:6][C:5]1[CH:22]=[CH:23][C:2]([I:1])=[CH:3][CH:4]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCOC(=O)CCC=O
Reactant: CCCCCCCCCCCCNCCOc1ccc(I)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCCCCCCN(CCCC(=O)OCC)CCOc1ccc(I)cc1
Temperature: 22 °C
Reaction time: 24 h
Yield: 88.7 %

Procedure:
To a mixture of N-2-[4-iodophenoxy]ethyldodecylamine ( 4.0 g, 9.3 mmol) and sodium cyanoborohydride (1.45 g, 23 mmol) in methanol (80 ml) was added dropwise a solution of ethyl 4-oxobutyrate (Fournet, G. ; Balme, G.; Barieux, J. J. and Gore, J. Tetrahedron, 1988, 44, 5821) (2.4 g, 18 mmol) in methanol (20 ml) over a period of 10 min. The resulting mixture was stirred at 22° C. for 24 h, and then diluted with ethyl acetate (600 ml), washed with brine (3×250 ml). The aqueous phase was extracted with ethyl acetate (150 ml), and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (Hexane/ethyl acetate 8:1 to 6:1) to afford the title compound (4.5 g, 89%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH:9]1[C:10]([C:15]1[C:16]([CH2:23][CH2:24][O:25][Si](C(C)(C)C)(C)C)=[CH:17][C:18]([O:21][CH3:22])=[N:19][CH:20]=1)=[CH:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CCOC(C)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH:9]1[C:10]([C:15]1[C:16]([CH2:23][CH2:24][OH:25])=[CH:17][C:18]([O:21][CH3:22])=[N:19][CH:20]=1)=[CH:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(CCO[Si](C)(C)C(C)(C)C)c(C2=CC3CCC2N3C(=O)OC(C)(C)C)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(CCO)c(C2=CC3CCC2N3C(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.9 %

Procedure:
To a stirred solution of 7-tert-butoxycarbonyl-2-{4-[2-(tert-butyldimethylsilanyloxy)ethyl]-2-methoxy-5-pyridinyl}-7-azabicyclo[2.2.1]hept-2-ene (360 mg, 0.78 mmol) in anhydrous THF (8 mL) was added 1.56 mL (1.56 mmol) of 1 M tetrabutylammonium fluoride in THF. The reaction solution was stirred at room temperature for 6 h, and then poured into a mixture of water (10 mL) and EtOAc (60 mL). The organic layer was separated and washed with brine, dried (Na2SO4), and concentrated. The residue was purified by chromatography with hexane/EtOAc (2:1) to afford 7-tert-butoxycarbonyl-2-[4-(2-hydroxyethyl)-2-methoxy-5-pyridinyl]-7-azabicyclo[2.2.1]hept-2-ene as a syrup (270 mg, 100%). 1H NMR (CDCl3) δ 7.82 (s, 1H), 6.66 (s, 1H), 6.20 (s, 1H), 4.91 (s, 1H), 4.78 (s, 1H), 3.91 (s, 3H), 3.77 (br s, 2H), 3.20-2.85 (m, 2H), 2.40 (br s, 1H), 2.10-1.89 (m, 2H), 1.44 (s, 9H), 1.36-1.16 (m, 2H); 13C NMR (CDCl3) δ 164.05, 156.36, 149.36, 145.98, 144.61, 132.12, 123.75, 111.27, 80.38, 62.92, 62.28, 61.45, 53.33, 36.88, 28.16, 25.83, 23.46. MS m/z (%): 346 (M+, 1), 318 (8), 262 (100), 218 (12), 199 (21). Anal. Calcd for (C19H26N2O4. 1/3H2O) C, 64.75; H, 7.63; N, 7.95. Found: C, 64.55; H, 7.29; N, 7.64.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:32]=[CH:31][C:18]3[N:19]([CH3:30])[C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[N:21][C:17]=3[CH:16]=2)[CH:11]=[CH:10][N:9]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O.O>[F:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:20]2[N:19]([CH3:30])[C:18]3[CH:31]=[CH:32][C:15]([O:14][C:12]4[CH:11]=[CH:10][N:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:13]=4)=[CH:16][C:17]=3[N:21]=2)=[CH:24][CH:25]=1
Reactant: Cn1c(Nc2ccc(F)cc2)nc2cc(Oc3ccnc(C(=O)OC(C)(C)C)c3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cn1c(Nc2ccc(F)cc2)nc2cc(Oc3ccnc(C(=O)O)c3)ccc21

Procedure:
A stirring solution of 4-[2-(4-Fluoro-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylic acid tert-butyl ester in trifluoroacetic acid was treated with two drops of water at room temperature for 3-4 hours or when the reaction was determined to be complete by HPLC. The reaction was evaporated under reduced pressure and then ether was added to the residue, which was then sonicated for 30 minutes. Filtration and washing with ether yields the desired acid in quantitative yield. LCMS m/z 379.4 (MH+), tR=1.74 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17]([CH2:20][CH2:21][CH2:22][CH2:23]Cl)(=[O:19])=[O:18])[C:9]([N+:25]([O-:27])=[O:26])=[C:8]([CH3:28])[NH:7][C:6]=1[NH2:29])=[O:4].[I-].[Na+].[C:32](=[O:35])(O)[O-].[Na+].[CH3:37][N:38]([CH:40]=O)[CH3:39]>>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17]([CH2:20][CH2:21][CH2:22][CH2:23][N:7]2[CH2:8][CH2:40][N:38]([C:39]3[CH:12]=[CH:11][CH:10]=[CH:5][C:3]=3[O:35][CH3:32])[CH2:37][CH2:6]2)(=[O:19])=[O:18])[C:9]([N+:25]([O-:27])=[O:26])=[C:8]([CH3:28])[NH:7][C:6]=1[NH2:29])=[O:4]
Reactant: CN(C)C=O
Reactant: O=C([O-])O
Reactant: COC(=O)C1=C(N)NC(C)=C([N+](=O)[O-])C1c1ccccc1S(=O)(=O)CCCCCl
Agent: [I-]
Agent: [Na+]
Product: COC(=O)C1=C(N)NC(C)=C([N+](=O)[O-])C1c1ccccc1S(=O)(=O)CCCCN1CCN(c2ccccc2OC)CC1

Procedure:
0.89 g of 2-amino-1,4-dihydro-4-{2-[(4-chlorobutyl)sulfonyl]phenyl}-6-methyl-5-nitro-3-pyridinecarboxylic acid methyl ester was treated with 0.60 g of sodium iodide, 0.34 g of sodium bicarbonate and 0.42 g of 2-methoxyphenyl-1-piperazine in 25 ml of DMF using the procedure as described for Example 3. Purification via column chromatography on silica gel, eluting with 60:35:5 toluene:ethyl acetate:methanol gave 0.10 g of product, m.p. 145°-147° C. 1H-NMR (d6 -DMSO) δ 1.57-1.63(m,2H); 1.80-1.87(m,2H); 2.36(t,2H,J=7 Hz); 2.45(s,3H); 2.49(s,4H); 2.94(s,4H); 3.35(m,2H); 3.40(s,3H); 3.77(s,3H); 6.50(s,1H); 6.88-6.92(m,6H); 7.35-7.81(m,4H); 9.50(br s,1H). Mass spectrum: 600 (M+H).