Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1.CC(O)=O>CCO.[Fe]>[NH2:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(Cl)ncc1N
Temperature: 80 °C

Procedure:
2-Chloro-4-methyl-5-nitropyridine (1 g, 5.8 mmol) was dissolved in EtOH (60 mL). AcOH (4 mL) and Fe (5 eq.) were added and the mixture was refluxed at 80° C. overnight. The mixture was filtered through celite and reduced under vacuum to afford the crude 5-amino-2-chloro-4-methylpyridine which was used in the next step with no further purification. The amine was dissolved in conc. HCl (6 mL), transferred to a 3-neck round bottom flask, and cooled to −5° C. A solution of NaNO2/H2O (440 mgs/5 mL) was slowly added and the mixture was allowed to stir for 10 mins. To a second, separate 3-neck round bottom flask was added H2O (12 mL) and cooled to −5° C. Thionyl chloride (4.5 eq.) was then added dropwise. After complete addition the mixture was allowed to warm to room temp. Whereupon CuCl (0.05 eq.) was added and the mixture was then cooled back down to −5° C. The first reaction mixture, containing the amine precursor, was slowly added to the second reaction mixture. A froth formed and was filtered off to afford 6-chloro-4-methyl-pyridine-3-sulfonyl chloride which was used in the next step with no further purification. The title compound was synthesized from 2-[2-(R,S)-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl]-N-(pyrid-4-yl)ethyl acetamide and 6-chloro-4-methyl-pyridine-3-sulfonyl chloride using Method G.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:18]=1)=[O:6]
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Reactant: COc1ccccc1C(=O)Cl
Product: COc1ccccc1C(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Yield: 63.5 %

Procedure:
In a manner similar to that described in Example 3, 2-methoxy-benzoyl chloride (0.060 g, 0.00035 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.052 g of 4-[4-(2-methoxy-benzoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; MS-(AP+) MH+328.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[CH:12]=[C:13]([Br:15])[Br:14])(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[Br:14][C:13]([Br:15])=[CH:12][C:6]1[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=1[OH:4]
Reactant: CC(=O)Oc1cc(C)ccc1C=C(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc(C=C(Br)Br)c(O)c1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
A solution of 2-(2,2-dibromovinyl)-5-methylphenyl acetate (16.5 g, 49.4 mmol) in 100 mL of MeOH was treated with a solution of K2CO3 (10.24 g, 74.1 mmol) dissolved in 5.0 mL of water and stirred at RT. The reaction mixture immediately turned yellow and cloudy. After 30 min the mixture was concentrated under reduced pressure to remove MeOH. The crude material was diluted with water and carefully adjusted to pH˜5-6 via addition of 2M HCl. The crude mixture was extracted with EtOAc×2, dried over MgSO4, filtered, and concentrated under reduced pressure to give an orange oil, 2-(2,2-dibromovinyl)-5-methylphenol (13.5 g). 1H NMR (400 MHz, DMSO-d6) δ 2.21 (s, 3H), 6.65 (d, J=8.2 Hz, 1H), 6.68 (s, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.57 (s, 1H), 9.83 (s, 1H).
Reaction SMILES: F[C@H:2]([C@H:4]1[O:12][C@H:11]2[C@H:7]([N:8]=[C:9]([N:13]([CH3:15])[CH3:14])[S:10]2)[C@@H:6]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C@@H:5]1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH3:3].C(O)(C(F)(F)F)=[O:37]>ClCCl>[CH3:14][N:13]([CH3:15])[C:9]1[S:10][C@H:11]2[O:12][C@H:4]([C:2](=[O:37])[CH3:3])[C@@H:5]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C@H:6]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C@H:7]2[N:8]=1
Reactant: COc1ccc(CO[C@H]2[C@H](OCc3ccc(OC)cc3)[C@H]3N=C(N(C)C)S[C@H]3O[C@@H]2[C@H](C)F)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CO[C@@H]2[C@H]3N=C(N(C)C)S[C@H]3O[C@H](C(C)=O)[C@H]2OCc2ccc(OC)cc2)cc1
Reaction time: 0.17 h
Yield: 24 %

Procedure:
A solution of (3aR,5S,6S,7R,7aR)-5-((S)-1-fluoroethyl)-6,7-bis(4-methoxybenzyloxy)-N,N-dimethyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-amine (240 mg, 0.48 mmol) in dichloromethane (20 mL) was treated with TFA (2 mL) for 1 h at room temperature. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by Prep-HPLC under the following conditions [(Agilent 1200 prep HPLC): Column, SunFire Prep C18, 19*50 mm 5 um; mobile phase, water with 0.03% NH4OH and CH3CN (10% CH3CN up to 45% in 10 min); Detector, UV 220 nm] to afford compound 51 (Example 9) as a white solid (30 mg, 24%). (ES, m/z): [M+H]+ 265.0; 1H NMR (300 MHz, D2O) δ 6.23-6.25 (d, J=6.0 Hz, 1H), 4.93-4.99 (m, 0.5H), 4.77-4.84 (m, 0.5H), 4.17 (t, J=6.0 Hz, 1H), 4.00 (t, J=6.0 Hz, 1H), 3.71-3.74 (m, 1H), 3.36-3.49 (m, 1H), 2.94 (s, 1H), 1.25-1.35 (dd, J=6.6 Hz, 6.3 Hz, 3H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14])[CH:2]=[CH2:3].C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].N1CCCCC1.Cl>N1C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:17][C:18]([OH:20])=[O:19])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14])[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: C=CCOc1ccc(C=CC(=O)O)cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 70.3 %

Procedure:
4-Allyloxy-3-nitrobenzaldehyde (5 g, 24.1 mM) was dissolved in pyridine (100 ml) and malonic acid (5.02 g, 48.3 mM) and piperidine (0.48 ml, 4.8 mM) added. The mixture was heated to reflux with stirring for 2 hours, cooled, and poured onto a mixture of concentrated hydrochloric acid and ice. Organics were extracted into ethyl acetate, the organic layer washed with 2M hydrochloric acid, and product back-extracted into aqueous NaHCO3. The aqueous solution was then re-acidified (concentrated hydrochloric acid), and organics extracted into ethyl acetate, washed with brine, and dried (MgSO4), to give title compound (4.23 g).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>FC(F)(F)S(O)(=O)=O>[NH:18]1[CH2:19][CH2:20][CH:15]([CH:13]2[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH2:7][N:8]3[CH:12]=[CH:11][N:10]=[C:9]23)[CH2:16][CH2:17]1
Reactant: OC(c1nccn1Cc1ccccc1)C1CCNCC1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: c1ccc2c(c1)Cn1ccnc1C2C1CCNCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
A mixture of α-[1-(phenylmethyl)-1H-imidazol-2-yl]-4-piperidinemethanol (5.4 g) in trifluoromethanesulfonic acid (25 ml) was stirred overnight at 100° C. The reaction mixture was cooled, poured out onto ice, then alkalized with NaOH and this mixture was extracted with DCM. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/(CH3OH/NH3) 95/5, upgrading to 90/10). The pure fractions were collected and the solvent was evaporated, yielding 2.5 g (50%) of 5,10-dihydro-10-(4-piperidinyl)-imidazo[1,2-b]isoquinoline (intermediate 10).
Reaction SMILES: [C:1]([P:5](Cl)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].[CH:11](Cl)([CH3:13])[CH3:12].[Mg].S(=O)(=O)(O)O>O1CCCC1.[Cu]Cl.C1(C)C=CC=CC=1>[C:1]([P:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH:11]([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Reactant: CC(C)Cl
Agent: Cl[Cu]
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)P(C(C)(C)C)C(C)(C)C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
In a 300 ml four-necked flask thoroughly purged with nitrogen, 9.0 g (0.05 mol) of di-tert-butylphosphinous chloride, 0.05 g (0.001 mol (corresponding to 1% by mol)) of copper(I) chloride and 30 ml of tetrahydrofuran were placed. To the contents of the flask, a Grignard reagent solution previously prepared from 4.7 g (0.060 mol) of isopropyl chloride and 1.7 g (0.072 mol) of metallic magnesium in 50 ml of tetrahydrofuran was dropwise added over a period of 1 hour with maintaining the temperature at 25° C. to 30° C. After the dropwise addition was completed, stirring was conducted at the same temperature for 3 hours. After the temperature of the reaction solution was returned to room temperature, disappearance of di-tert-butylphosphinous chloride was confirmed by gas chromatography. Thereafter, 20 ml of toluene and 30 ml of a 5% sulfuric acid aqueous solution were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent and a low-boiling component were distilled off under reduced pressure to obtain 8.2 g (purity: 95.0%) of the aimed di-tert-butylisopropylphosphine as an oily substance. The yield was 92.7%.
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)#[N:2].[CH2:16](O)[CH2:17][OH:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:1]([C:3]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:4][CH2:5][C:6]2([O:18][CH2:17][CH2:16][O:9]2)[CH2:7][CH2:8]1)#[N:2]
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC1(c2ccccc2)CCC2(CC1)OCCO2
Reaction time: 20 h

Procedure:
4-cyano-4-phenylcyclohexanone (5.97 g, 30 mmole) was taken up in toluene (200 ml) and ethylene glycol (4 ml, 71.6 mmole) was added. After addition of p-toluenesulfonic acid (86 mg, 0.5 mmole) the reaction mixture was heated to the boil in a water separator. The course of the reaction was followed by thin layer chromatography. After 20 hours no starting product could be detected any longer by thin layer chromatography. After cooling, the toluene solution was extracted by shaking with water (5×30 ml) and saturated aqueous NaCl solution (3×20 ml) and dried over Na2SO4. After removing the solvent on a rotary evaporator the desired ketal was obtained in a yield of 6.8 g (94%) as a white solid with a melting point of 108°-110° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([F:9])=[C:6]([F:8])[F:7].[C:10](Cl)(Cl)=[S:11].C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:9][C:5](=[C:6]([F:8])[F:7])[CH2:4][CH2:3][N:2]=[C:10]=[S:11]
Reactant: S=C(Cl)Cl
Reactant: NCCC(F)=C(F)F
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: FC(F)=C(F)CCN=C=S
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.5 %

Procedure:
To a stirred solution of 0.4 gram (0.0027 mole) of 4-amino-1,1,2-trifluoro-1-butene hydrochloride in 15 ml of chloroform was added 0.3 gram (0.003 mole) of thiophosgene, followed by 0.7 ml (0.009 mole) of triethylamine. Upon completion of addition the reaction mixture was stirred at ambient temperature for three hours. The reaction mixture was then washed in succession with one 25 ml portion of water, two 25 ml portions of aqueous 5% sodium hydroxide, and, finally, one 25 ml portion of water. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 0.3 gram of (3,4,4-trifluoro-3-butenyl) isothiocyanate as an oil. The ir spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl.[NH2:23][OH:24].C(O)C>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12](=[N:23][OH:24])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(N2CCC(=O)CC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(N2CCC(=NO)CC2)cc1

Procedure:
A mixture of 1-(p-methoxyphenyl)-4-piperidinone (prepared following the procedure reported in: Scherer, T. et al., Recl. Trav. Chim. Pays-Bas (1993), 112(10), 535-48.) (5.13 g, 25 mmol), K2CO3 (6.22 g, 45 mmol), hydroxylamine hydrochloride (2.606 g, 37.5 mmol) and ethanol was refluxed for 20 min. After cooling H2O (50 ml) was added and white crystals of 1-(4-methoxy-phenyl)-piperidin-4-one oxime (4.56 g, 83%, Mp. 116-119°, MS: m/e=220 (M+)) was collected.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]2[S:8][CH2:9][CH2:10][N:11]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[CH:5]=1)([O-])=O.I.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](SC)=[NH:28]>C(O)C.ClCCl.[Pd]>[N:14]1([CH2:13][CH2:12][N:11]2[CH2:10][CH2:9][S:8][C:7]3[CH:19]=[CH:20][C:4]([NH:1][C:27]([C:23]4[S:22][CH:26]=[CH:25][CH:24]=4)=[NH:28])=[CH:5][C:6]2=3)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc2c(c1)N(CCN1CCCC1)CCS2
Reactant: CSC(=N)c1cccs1
Agent: [Pd]
Agent: I
Solvent: ClCCl
Solvent: CCO
Product: N=C(Nc1ccc2c(c1)N(CCN1CCCC1)CCS2)c1cccs1
Reaction time: 3 h
Yield: 53.2 %

Procedure:
To a stirred solution of 6-nitro-4-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine (649 mg, 2.212 mmol) in ethanol (5 mL) was added palladium, 10 wt. % on activated carbon (235 mg, 0.221 mmol) as a suspension in ethanol (5 mL). The resulting suspension was stirred under an atmosphere of hydrogen (balloon pressure) for 3 hours (yellow color disappears). The balloon was removed, and methyl thiophene-2-carbimidothioate hydroiodide (1.262 g, 4.42 mmol) was added to the mixture. The resulting mixture was stirred under argon overnight at room temperature. The mixture was then diluted with dichloromethane and filtered through Celite. The filtrate was then diluted with saturated sodium carbonate and extracted with dichloromethane (2×). The combined organics were dried, filtered, concentrated, and then chromatographed in 1:19 (2M NH3 in methanol):ethyl acetate, giving the desired product 25 (438 mg, 53.1%). 1H NMR (DMSO-d6) δ 7.71 (d, J=3.3 Hz, 1H), 7.58 (d, J=5.1 Hz, 1H), 7.10-7.06 (m, 1H), 6.83 (d, J=8.1 Hz, 1H), 6.38 (brs, 2H), 6.19 (s, 1H), 6.08 (d, J=1H), 3.63-3.58 (m, 2H), 3.40-3.33 (m, 2H), 3.01-2.97 (m, 2H), 2.61 (t, J=6.8 Hz, 2H), 2.49-2.42 (m, 4H), 1.70-1.61 (m, 4H); ESI-MS (m/z, %): 373 (MH+, 62), 276 (100); HRMS calculated for C19H25N4S2 (MH+), calculated: 373.1515, observed: 373.1512; HPLC purity: 97% by area.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=2)[CH2:10][CH:9]1[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:10][CH:9]1[CH3:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CN(c2ccc([N+](=O)[O-])nc2)CCN1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Product: CC1CN(c2ccc(N)nc2)CCN1C(=O)OC(C)(C)C
Yield: 122.4 %

Procedure:
By repeating procedures described in Example B, 2-methyl-4-(6-nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (600 mg, 1.52 mmol) is hydrogenated over Pd—C on an H-cube (Thales) (instead of under an atmosphere of hydrogen) to give 4-(6-amino-pyridin-3-yl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (544 mg, 98%). MS(ESI) m/z 293 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=2Cl)[C:9]([C:21]([O:23][CH3:24])=[O:22])=[C:8]([CH3:25])[N:7]([CH3:26])[C:6]=1[CH3:27])=[O:4].[Na].[CH2:29]([O:31][C:32](=[O:35])[CH2:33][SH:34])[CH3:30]>CCOCC>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=2[S:34][CH2:33][C:32]([O:31][CH2:29][CH3:30])=[O:35])[C:9]([C:21]([O:23][CH3:24])=[O:22])=[C:8]([CH3:25])[N:7]([CH3:26])[C:6]=1[CH3:27])=[O:4]
Reactant: COC(=O)C1=C(C)N(C)C(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1Cl
Reactant: CCOC(=O)CS
Agent: [Na]
Solvent: CCOCC
Product: CCOC(=O)CSc1ccc([N+](=O)[O-])cc1C1C(C(=O)OC)=C(C)N(C)C(C)=C1C(=O)OC

Procedure:
A solution of 19.7 g of 1,2,6-trimethyl-(2-chloro-5-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (melting point 190°C) in 200 ml of alcohol is heated to reflux and 60 ml of a solution of 2.3 g of sodium in 100 ml of alcohol, together with 13.2 g of mercaptoacetic acid ethyl ester, are added thereto. The mixture is refluxed for 15 hours and thereafter filtered and evaporated. The precipitate obtained after adding a little ether is recrystallized from methanol to yield yellow crystals of melting point 118°C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])[NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:28][O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH:10]([NH:11][C@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[CH3:13])[C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccccc1C(N[C@@H](C)c1cccc(F)c1)c1cccc([N+](=O)[O-])c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccccc1C(N[C@@H](C)c1cccc(F)c1)c1cccc(N)c1
Yield: 29.3 %

Procedure:
In a similar manner to that described in Example (1b), a solution of N-[(3-nitrophenyl)-(2-methoxyphenyl)methyl]-N-[(S)-1-(3-fluorophenyl)ethyl]amine (2.96 g) [prepared as described in step (a) above] in methanol (50 ml), nickel chloride hexahydrate (3.70 g) and sodium borohydride (1.24 g) were reacted, and the crude product was purified by reverse phase HPLC using a 40:60 by volume mixture of acetonitrile and an acetic acid buffer solution (water/acetic acid/triethylamine=1000:2:2) as the eluant, to afford isomer A of the title compound (540 mg) as a yellow oil and isomer B of the title compound (800 mg) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(Cl)[Cl:14]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([Cl:14])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: ClC(Cl)Cl
Product: O=C(Cl)Cc1ccc(Cl)c(Cl)c1

Procedure:
3,4-Dichlorophenylacetyl chloride is prepared according to the method described in Example 8, using 3,4-dichlorophenylacetic acid (2.62 g, 12.8 mmol) to give a yellow oil which is dissolved in chloroform (15 mL). This solution is refluxed for 9 hours with a solution of (±)-trans-[2-(4-morpholinyl)]cyclohexanol (2.25 g, 12.2 mmol) in chloroform (10 mL) under nitrogen. The solvent is removed in vacuo, and the residue is partitioned between 1M hydrochloric acid (75 mL) and ether (75 mL). The ether layer is separated and the aqueous is washed with more ether (2×30 mL), and then basified to pH14 by the addition of 50% sodium hydroxide solution. This is then extracted with ether (4×30 mL), and the combined ether extracts are washed with water until GC shows no unreacted aminoalcohol in the ether. The ether containing the product is then dried over sodium sulfate, and the solvent is removed to leave the crude free ester. The residue is dissolved in ether (20 mL) and treated with HCl in ether to precipitate the salt. It is washed with ether and recrystallised from hot methanol to yield the title compound.
Reaction SMILES: Cl.Cl.[C:3]([O:7][C:8]([N:10]([C@@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[C:11]1[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[CH2:30][C:31]1[N:32]=[C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[S:34][CH:35]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:3]([O:7][C:8]([N:10]([C@@H:24]1[CH2:28][CH2:27][N:26]([CH2:30][C:31]2[N:32]=[C:33]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[S:34][CH:35]=2)[CH2:25]1)[C:11]1[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCNC2)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(Cc3csc(-c4ccccc4)n3)C2)nc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a mixture of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate dihydrochloride (110 mg), 4-(chloromethyl)-2-phenyl-1,3-thiazole (53.1 mg), and DMF (2.5 mL) was added K2CO3 (123 mg). After stirring for 2 hours at 60° C., the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo to give ethyl (2E)-3-[6-((tert-butoxycarbonyl){(3R)-1-[(2-phenyl-1,3-thiazol-4-yl)methyl]-3-pyrrolidinyl}amino)-3-pyridyl]acrylate (133 mg).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=O)[CH:5]([CH:9]([CH3:11])[CH3:10])[CH2:4]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH:9]([CH:5]1[CH2:6][NH:7][C@@H:3]([CH2:2][OH:1])[CH2:4]1)([CH3:11])[CH3:10]
Reactant: CC(C)C1C[C@H](CO)NC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)C1CN[C@@H](CO)C1
Temperature: 75 °C
Reaction time: 18 h
Yield: 80.2 %

Procedure:
To a solution of (5R)-5-(hydroxymethyl)-3-isopropylpyrrolidin-2-one (2.251 g, 14.32 mmol) in THF (25 mL) was added lithium aluminium hydride, 1.0 M solution in THF (20.05 mL, 20.05 mmol) at room temperature dropwise slowly. The resulting mixture was then refluxed at 75° C. for 2 h. Additional lithium aluminium hydride, 1.0 M solution in THF (20.05 mL, 20.05 mmol) was added and the mixture was refluxed overnight. After 18 h, the reaction mixture was allowed to cool to 0° C. The reaction was quenched by adding saturated aqueous solution of Rochelle's salt. The reaction mixture was stirred vigorously for 1 h and the layers were separated. The aqueous layer was extracted with EtOAc twice and the organics were combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to provide ((2R)-4-isopropylpyrrolidin-2-yl)methanol (1.645 g, 11.49 mmol, 80% yield) as a light yellow oil. The crude material was used in the next step without further purification. m/z (ESI, +ve) 144 (M+H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:14]([N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc2nc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc2c(c1)ncn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.2 %

Procedure:
A mixture of 2.8 g of methyl 5-benzimidazolecarboxylate (prepared as described in Preparation 26), 3.52 g of benzyl bromide, 3 g of potassium carbonate and 50 ml of acetone was stirred for 3 days at room temperature. At the end of this time, the solvent was removed by evaporation under reduced pressure and the residue was mixed with an aqueous solution of sodium chloride, after which it was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was then recrystallized from a mixture of ethyl acetate and hexane, to give 0.94 g of the title compound, melting at 156°-162° C.