Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:13](N1C=C(C2C=CC=CC=2)C(C)=N1)[CH2:14][C:15]#[CH:16]>>[CH2:16]([N:6]1[C:2]([CH3:1])=[C:3]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:4]=[N:5]1)[CH2:15][C:14]#[CH:13]
Reactant: C#CCCn1cc(-c2ccccc2)c(C)n1
Reactant: Cc1[nH]ncc1-c1ccccc1
Product: C#CCCn1ncc(-c2ccccc2)c1C
Yield: 42 %

Procedure:
The title compounds were prepared in accordance with the general method of Example 109(D), from 5-methyl-4-phenyl-1H-pyrazole (515 mg, 3.25 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 255 mg (1.21 mmol, 42%) of 1-but-3-ynyl-5-methyl-4-phenyl-1H-pyrazole and 1-but-3-ynyl-3-methyl-4-phenyl-1H-pyrazole.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C@@H:5]1[CH2:9][S:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([N+:19]([O-])=O)[CH:18]=2)[NH:15][C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:13]3)=[N:6]1.[C:29]1(=O)[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:29]1([NH:19][C:17]2[CH:18]=[C:10]([C:7]3[S:8][CH2:9][C@@H:5]([CH2:4][C:3]([OH:2])=[O:28])[N:6]=3)[CH:11]=[C:12]3[C:16]=2[NH:15][C:14]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:13]3)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C1CCCC1
Reactant: COC(=O)C[C@@H]1CSC(c2cc([N+](=O)[O-])c3[nH]c(-c4ccccc4)cc3c2)=N1
Product: O=C(O)C[C@@H]1CSC(c2cc(NC3CCCC3)c3[nH]c(-c4ccccc4)cc3c2)=N1

Procedure:
2-[(R)-2-(7-nitro-2-phenyl-1H-indol-5-yl)-4,5-dihydro-thiazol-4-yl]-acetic acid methyl ester prepared in Step B and cyclopentanone were reacted according to the same procedures as Examples 1 and 30 to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][O-].[Na+].IC>CN(C=O)C>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: Oc1cccnc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cccnc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.9 %

Procedure:
To a stirred solution of 2-chloro-3-hydroxypyridine (25.4 g, 196 mmol) in dry DMF (250 mL), at 0° C., was added sodium methoxide (11.5 g, 213 mmol). After 5 min, the reaction mixture was allowed to warm to RT. After 1 hour, the mixture was cooled to 0° C. and iodomethane (24 mL, 386 mmol) was added. The reaction mixture was stirred at 0° C. for 5 minutes, before allowing to warm to RT. After 2 hours, the reaction mixture was concentrated under reduced pressure. The resultant residue was partitioned between diethyl ether and water. The aqueous phase was isolated and extracted twice with diethyl ether. The combined organic extracts were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (22.2 g, 79%) as an orange solid. LCMS (Method A): RT=2.76 min, [M+H]+=144/146.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([C@H:13]([OH:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1.[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[C:25]1[CH:26]=[N:27][C:28]([CH:31]([NH2:33])[CH3:32])=[N:29][CH:30]=1.O>CS(C)=O>[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[C:25]1[CH:30]=[N:29][C:28]([CH:31]([NH:33][C:2]2[N:7]=[C:6]([N:8]3[C@@H:12]([C@H:13]([OH:15])[CH3:14])[CH2:11][O:10][C:9]3=[O:16])[CH:5]=[CH:4][N:3]=2)[CH3:32])=[N:27][CH:26]=1
Reactant: CC(N)c1ncc(-c2cccc(Cl)c2Cl)cn1
Reactant: C[C@@H](O)[C@H]1COC(=O)N1c1ccnc(F)n1
Solvent: CS(C)=O
Solvent: O
Product: CC(Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)O)n1)c1ncc(-c2cccc(Cl)c2Cl)cn1
Yield: 30.8 %

Procedure:
A solution of (R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (18.6 mg, 0.082 mmol) and 1-(5-(2,3-dichlorophenyl)pyrimidin-2-yl)ethanamine (22 mg, 0.082 mmol) in DMSO (2 mL) was heated at 100° C. for 2 h. The reaction mixture was poured into water (20 mL), and extracted with EtOAc (2×20 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography ((25% MeOH in EtOAc)/Heptane to 100%) provided (4R)-3-(2-(1-(5-(2,3-dichlorophenyl)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (12 mg, approx 1:1 mixture of diastereomers) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.72 (s, 4H), 8.15 (d, J=5.7 Hz, 2H), 7.51 (ddd, J=8.1, 2.8, 1.6 Hz, 2H), 7.40-7.11 (m, 6H), 6.07-5.96 (m, 2H), 5.32 (t, J=7.4 Hz, 1H), 5.09 (s, 1H), 4.81 (s, 1H), 4.68 (s, 1H), 4.43 (dd, J=7.3, 4.8 Hz, 2H), 4.33 (dd, J=9.4, 8.3 Hz, 1H), 4.18 (d, J=9.0 Hz, 2H), 3.62 (s, 1H), 3.23 (s, 1H), 1.62-1.58 (m, 6H), 1.07-0.97 (m, 3H), 0.87-0.77 (m, 3H). HRMS m/z 475.1039 and 475.1042 (M+H)+.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6].N([O-])=[O:17].[Na+]>S(=O)(=O)(O)O>[F:15][C:14]1[CH:13]=[CH:12][C:4]([C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6])=[CH:3][C:2]=1[OH:17]
Reactant: O=N[O-]
Reactant: Nc1cc(C(=O)CCC(=O)O)ccc1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)CCC(=O)c1ccc(F)c(O)c1

Procedure:
3-(3-amino-4-fluorobenzoyl)propionic acid was diazotised in sulphuric acid solution with sodium nitrite and the diazonium salt solution was added dropwise to boiling aqueous sulphuric acid to give 3-(4-fluoro-3-hydroxybenzoyl)propionic acid.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](O)=O)[C:7]([CH3:16])=[CH:6]2)#[N:2].[F:21][C:22]([F:34])([F:33])[C:23]1[N:28]=[CH:27][C:26]([C:29]([NH:31][NH2:32])=[O:30])=[CH:25][CH:24]=1>>[CH3:16][C:7]1[N:8]([CH2:12][C:13]2[O:30][C:29]([C:26]3[CH:27]=[N:28][C:23]([C:22]([F:33])([F:21])[F:34])=[CH:24][CH:25]=3)=[N:31][N:32]=2)[C:9]2[C:5]([CH:6]=1)=[C:4]([C:17]([F:19])([F:18])[F:20])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=2
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=O)O
Reactant: NNC(=O)c1ccc(C(F)(F)F)nc1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1nnc(-c2ccc(C(F)(F)F)nc2)o1

Procedure:
Synthesized as described in Example 35C using [5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]acetic acid and 6-(trifluoromethyl)-3-pyridinecarbohydrazide: 1H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.54 (d, J=8.3 Hz, 1H), 8.11 (d, J=8.3 Hz, 1H), 8.08 (d, J=8.3 Hz, 1H), 7.78 (d, J=8.3 Hz, 1H), 6.66 (s, 1H), 6.03 (s, 2H), 2.58 (s, 3H); MS (ES) m/z 474 (M+Na).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])[CH2:9][N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7]1)=[O:5])[CH3:2].[CH3:23][O:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[C:32](O)=[O:33].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([CH2:11][N:12]([CH:13]([CH3:14])[CH3:15])[C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:29]([O:28][CH2:27][CH2:26][CH2:25][O:24][CH3:23])[CH:30]=2)[CH2:9][N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:7]1)=[O:5])[CH3:2]
Reactant: COCCCOc1cc(C(=O)O)ccc1OC
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CNC(C)C
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN(C(=O)c1ccc(OC)c(OCCCOC)c1)C(C)C

Procedure:
A mixture of (3S*,4R*)-4-(isopropylamino-methyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (2.58 g, 8.2 mmol), 3-(3-methoxy-propoxy)-4-methoxy-benzoic acid (1.93 g, 8.04 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (2.3 g, 9.02 mmol) and triethylamine (4.57 μL, 32.81 mmol) in CH2Cl2 (50 mL) is refluxed for 2 h and then quenched by the addition of aqueous NaHCO3 solution. The organic layer is separated, and the aqueous phase is extracted 3 times with AcOEt. The combined organic extracts are dried (Na2SO4), and the solvent is removed in vacuo. The crude product is purified by flash chromatography on silica gel (eluent: c-hexane/AcOEt 50:50 to 0:100 and then AcOEt/MeOH 95:5) to give the title product. TLC, Rf (CH2Cl2/MeOH 95:5)=0.3. tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 5.76 min.
Reaction SMILES: [C:1]([C:4]([CH2:21][CH:22]=[CH:23][CH:24]([O:30]C(=O)C)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])C(OCC)=O)(=[O:3])[CH3:2].[OH-].[Na+]>O.C(O)C>[C:1]([CH:4]([CH2:21]/[CH:22]=[CH:23]/[CH:24]([OH:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:3])[CH3:2]
Reactant: CCCCCC(C=CCC(CCCCCCC(=O)OCC)(C(C)=O)C(=O)OCC)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCC(O)/C=C/CC(CCCCCCC(=O)O)C(C)=O

Procedure:
A solution of diethyl 2-acetyl-2-(4-acetoxy-2-nonen-1-yl)azelate (22.9 g., 0.049 mole) and sodium hydroxide (15.7 g., 0.392 mole) in water (150 ml.) and ethanol (150 ml.) is boiled under reflux for 2 hours. Solvents are removed under reduced pressure, the residue is dissolved in water, and the solution extracted with ether. The aqueous layer is acidified with concentrated hydrochloric acid to the Congo Red endpoint. The crude product separates as an oil, weight 18.9 g. 8-Acetyl-12-hydroxy-(E)-10-heptadecenoic acid is isolated in pure condition from the crude product by chromatography on silica gel with 4% methanol in chloroform as the eluant. There is obtained 3.5 g. of yellow oil showing a single spot, Rf 0.63, in thin layer chromatography (silica gel, 1% acetic acid in ether); pmr (CDCl3) δ 0.88 (3H,t), 2.10 (3H,s, CH3C=O), 4.03 (1H,m HCO), 5.50 (2H,m, HC=CH), 6.58 (2H,s COOH, OH).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[CH2:18][CH2:17][CH2:16]2.CN(P(N(C)C)(N(C)C)=O)C.[CH2:35](Br)[CH:36]=[CH2:37]>C1COCC1>[CH2:37]([CH:18]1[CH2:17][CH2:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([O:12][CH3:11])[CH:14]=2)[C:19]1=[O:23])[CH:36]=[CH2:35]
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: C=CCC1CCc2cc(OC)ccc2C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
To a solution of LiHMDS (1.04 g, 6.24 mmol), in THF (40 mL) cooled at −78° C. is added slowly a solution of 6-methoxy-1-tetralone (1.0 g, 5.67 mmol) in anhydrous THF (40 mL). After the addition is complete, the solution is stirred at −78° C. for 30 minutes, then HMPA (1.97 mL, 11.3 mmol) is slowly added and the mixture is stirred for other 5 minutes followed by the addition of a solution of allyl bromide (0.74 mL, 8.5 mmol) in anhydrous THF (5 mL). The mixture is left to warm slowly to room temperature (2-3 h) and quenched at 0° C. with aqueous 1N HCl (20 mL), then extracted with diethylether. The organic phase is dried over MgSO4 and concentrated to dryness. The residue is purified by column chromatography on SiO2 (Petroleum Ether/EtOAc=95:5) to afford the title compound 53 as a colorless oil (Yield 0.56 g, 45%).
Reaction SMILES: [BH4-].[Li+].C([C@@H]1COC(=O)N1[C:16](=[O:41])[C@H:17]([CH3:40])[C@@H:18]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)C1C=CC=CC=1.CO>C1COCC1>[Si:33]([O:32][C@@H:18]([CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[C@@H:17]([CH3:40])[CH2:16][OH:41])([C:36]([CH3:38])([CH3:39])[CH3:37])([CH3:34])[CH3:35]
Reactant: COc1ccc(COCCC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(COCCC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CO)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 77.4 %

Procedure:
Lithium borohydride (2.0 M in THF, 5 mL, 10 mmol) was added dropwise to a stirred solution of 11 (2.77 g, 5 mmol) and methanol (0.4 mL, 10 mmol) in anhydrous THF (20 mL) under an atmosphere of N2 at 0° C. The mixture was stirred for 20 min at 0° C. and then warmed to ambient temperature. After 3 h at room temperature, the reaction was quenched with aqueous NH4Cl (100 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried over anhydrous MgSO4, evaporated and chromatographed (hexane/EtOAc 7:3) to yield the alcohol (1.48 g, 78%) as a colorless oil: IR (CHCl3) 2948, 2856, 2302, 1612, 1265 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.27 (d, 2H, J=8.5 Hz), 7.00 (d, 2H, J=8.5 Hz), 4.43 (s, 2H), 3.78 (s, 3H), 3.67 (dd, 1H, J=8.6, 10.5 Hz), 3.51–3.41 (m, 3H), 2.78 (br s, 1H), 1.94 (m, 1H), 1.72–1.49 (m, 4H), 0.90 (s, 9H), 0.81 (d, 3H, J=7.0 Hz), 0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (75 MHz, CDCl3) 159.2, 130.6, 129.3, 113.8, 75.4, 72.6, 70.1, 65.8, 55.9, 55.3, 39.7, 29.1, 26.6, 25.9, 18.0, 12.1, −4.28, −4.38; LRMS (ESI) 405.2 (M+Na).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[CH:11][N:10]=1)[CH3:8].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[N:1]1([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[CH:11][N:10]=2)[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CC(Br)c1ccc(-c2ccc([N+](=O)[O-])cc2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(c1ccc(-c2ccc([N+](=O)[O-])cc2)cn1)n1ccnc1
Temperature: 50 °C

Procedure:
To a stirred solution of 1H-imidazole (13 mg, 0.19 mmol) in DMF (2 mL) was added 2-(1-bromoethyl)-5-(4-nitrophenyl)pyridine (50 mg, 0.1 mmol) and K2CO3. The reaction was heated at 50° C. for about 1 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine solution (10 mL), organic layer was dried over Na2SO4 and concentrated under vacuum to obtain crude product. The crude product was purified by flash chromatography (silica gel, 100-200μ) using 2% methanol in DCM eluent to afford 2-(1-(1H-imidazol-1-yl)ethyl)-5-(4-nitrophenyl)pyridine as off white solid (50 mg, 58% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.97 (s, 1H), 8.31 (d, 2H), 8.22 (dd, 1H), 8.01 (d, 2H), 7.82 (s, 1H), 7.30 (t, 2H), 6.91 (s, 1H), 5.71-5.65 (m, 1H), 1.84 (d, 3H), LC-MS m/z calcd for [M+H]+ 295.11. found 295.4.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:2]=1.Cl.[C:17](Cl)(Cl)=[S:18]>CCOCC.C(Cl)(Cl)Cl>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]2[CH:2]=[CH:1][C:6]([N:7]=[C:17]=[S:18])=[CH:5][CH:4]=2)=[CH:10][CH:11]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: S=C=Nc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 77.9 %

Procedure:
Unless otherwise indicated, all thioureas, isothiocyanates, thioamides and amines were purchased from Maybridge Chemical Co. Ltd.(Cornwall, U.K.), Transworld Chemical Co. (Rockville, Md.), or Aldrich Chemical Co., (Milwaukee, Wis.). (a) 4-Amino-4′-chlorodiphenylether (TCI America, Portland Oreg., 520 mg, 2.03 mmol) was slurried in 10 mL of ether and treated with ca. 1 mL of ether saturated with HCl gas. After 5 min. the solvent was removed in vacuo. To a stirring biphasic solution amine-HCl salt in 20 mL CHCl3-sat'd NaHCO3 (1:1, v/v) at ambient temperature was added thiophosgene (1.2 equiv, 2.4 mmol) in 5 mL of CHCl3 dropwise via an addition funnel. The reaction was vigorously stirred for 1 h (TLC, 50% ethyl acetate-hexanes indicates clean conversion to a higher Rf spot), at which time the layers were separated, the aqueous layer extracted with CHCl3 (1×20 mL), and the combined organic layers washed with brine (1×20 mL) and dried (Na2SO4). Concentration of the solvent in vacuo yielded the crude 4-(4-chlorophenoxy)-phenylisothiocyanate (414 mg). (b) The 4-(4-chlorophenoxy)-phenylisothiocyanate was transferred to an Ace Glass pressure tube equipped with a Teflon coated stir bar and treated with a 2.0 M solution of NH3 in 5 ml methanol (Aldrich Chemical Co., Milwaukee, Wis.)). The tube was sealed and immersed in a 80° C. oil bath. After 2 h, the reaction was cooled to 0° C. in an ice bath. The precipitates were filtered and dried under vacuum to yield amino{[4-(4-chlorophenoxy)phenyl]amino}methane-1-thione (328 mg, 79%). 1H NMR (DMSO-d6, 300 MHz) 7.02 (m, 4H), 7.41 (m, 4H), 9.65 (s, 1H); Mass Spectrum (ESI) m/z calcd. for C13H11ClN2OS, 278.8 (M+H), found 279.4.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:26][S:27][C:28]1[S:29][C:30]2[CH:36]=[C:35]([CH:37]=O)[CH:34]=[CH:33][C:31]=2[N:32]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:37][C:35]2[CH:34]=[CH:33][C:31]3[N:32]=[C:28]([S:27][CH3:26])[S:29][C:30]=3[CH:36]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CSc1nc2ccc(C=O)cc2s1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1nc2ccc(CNc3ccc(Br)cc3[N+](=O)[O-])cc2s1
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
To a stirred mixture of 4-bromo-2-nitroaniline (694 mg, 3.2 mmol) in TFA (5 mL) at −15° C. under argon was added NaBH(OAc)3 (1.1 g, 5.3 mmol) portionwise. The mixture was stirred for 10 min. To the stirred mixture was added dropwise 2-(methylthio)benzo[d]thiazole-6-carbaldehyde (735 mg, 3.5 mmol) from Step 1 of this Example in CH2Cl2 (3 mL). The mixture was stirred for 1 h and then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 100% hexanes to 100% EtOAc to afford 4-bromo-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline (1.0 g, 77%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.84 (t, J=6.0 Hz, 1H), 8.19 (d, J=2.4 Hz, 1H), 7.98 (s, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.56 (dd, J=2.4, 9.3 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H), 6.88 (d, J=9.2 Hz, 1H), 4.75 (d, J=6.0 Hz, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 410 and 412 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:21][C:22]1[C:27]([OH:28])=[C:26]([CH:29]=[O:30])[C:25]([CH2:31][OH:32])=[CH:24][N:23]=1.Cl.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:21][C:22]1[C:27]([OH:28])=[C:26]([CH:29]=[O:30])[C:25]([CH2:31][O:32][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:24][N:23]=1
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)Cl
Reactant: Cc1ncc(CO)c(C=O)c1O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCc1cnc(C)c(O)c1C=O

Procedure:
A solution of z,z,z-octadeca-6,9,12-trienoyl chloride (800 mg, 2.7 mmol) in methylene chloride (10 ml) was added slowly dropwise to a mixture of pyridoxal hydrochloride (500 mg, 2.45 mmol), triethylamine (1 ml, 7.2 mmol) and 4-(N,N-dimethylamino)pyridine (few mg, catalytic amount) in methylene chloride (20 ml) at 0° C. under nitrogen. On completion, as indicated by tlc, the mixture was concentrated and purified by flash chromatography (ethyl acetate/hexane), yielding 2-methyl-3-hydroxy-4-formyl-5-(z,z,z-octadeca-6,9,12-trienoyloxy)methyl pyridine as a colourless oil which subsequently solidified.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH:19]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:22]1([C:28]2[CH2:29][CH2:30][NH:31][CH2:32][CH:33]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH2:19][N:31]2[CH2:30][CH:29]=[C:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:33][CH2:32]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: O=CC1CN(Cc2ccccc2)CC1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: C1=C(c2ccccc2)CCN(CC2CN(Cc3ccccc3)CC2c2ccccc2)C1
Yield: 77.9 %

Procedure:
The title compound was prepared from 20 mg of 1-Benzyl-3-(SR)-formyl-4-(SR)-phenylpyrrolidine, 16 mg of 4-phenyl-1, 2, 3, 6-tetrahydropyridine-hydrochloride, 0.013 mL of DIEA and 23 mg of sodium triacetoxyborohydride using a procedure analogous to that described in Example 9, Step B to provide 24 mg of the title compound. RF: 0.37 (50% EtOAc in hexanes). 1H NMR (300 MHz, CDCl3): δ2.40-2.71 (m, 9H), 2.91-3.16 (m, 5H), 3.67 (ABq, J=13 Hz, 2H), 5.98-6.00 (m, 1H ), 7.07-7.41 (m, 15H). Mass Spectrum (ESI): 409.1 (M+H).
Reaction SMILES: [CH2:1]([C:5]1[C:10]([CH3:11])=[C:9](Cl)[N:8]=[C:7]([NH2:13])[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:14]([NH2:19])[CH2:15][CH2:16][CH2:17][CH3:18]>>[NH2:13][C:7]1[N:8]=[C:9]([NH:19][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([CH3:11])=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=1
Reactant: CCCCc1nc(N)nc(Cl)c1C
Reactant: CCCCCN
Product: CCCCCNc1nc(N)nc(CCCC)c1C
Yield: 42.7 %

Procedure:
A mixture of 4-butyl-6-chloro-5-methylpyrimidine-2-ylamine (93.5 mg, 0.47 mmol) and amylamine (1.5 ml) was refluxed for 8 hours. After reaction, the procedure according to pro-treatment of Example 7 was carried out to give the object compound (50 mg, 42.7%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH3:66][O:67][C:68](=[O:77])[C:69]1[CH:74]=[CH:73][C:72]([CH2:75][NH2:76])=[CH:71][CH:70]=1>C(Cl)Cl>[CH3:66][O:67][C:68](=[O:77])[C:69]1[CH:74]=[CH:73][C:72]([CH2:75][NH:76][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:30])=[CH:71][CH:70]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)c1ccc(CN)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CNC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (150 mg, 0.26 mmol) in methylene chloride (10 mL), HATU (Aldrich, 177 mg, 0.46 mmol) was added followed by the addition of DIPEA (0.36 mL, 2.06 mmol) and 4-aminomethyl-benzoic acid methyl ester hydrochloride salt (Aldrich, 104 mg, 0.52 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 5-15% EtOAc/hexanes) to give a white solid. 119 mg.