Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][C:14](O)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:52]([C:55]1[CH:56]=[CH:57][C:58]([O:73][CH3:74])=[C:59]([C:61]2[CH:66]=[CH:65][C:64]([C:67]([F:70])([F:69])[F:68])=[CH:63][C:62]=2[CH2:71][NH2:72])[CH:60]=1)([CH3:54])[CH3:53]>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([NH:72][CH2:71][C:62]2[CH:63]=[C:64]([C:67]([F:68])([F:69])[F:70])[CH:65]=[CH:66][C:61]=2[C:59]2[CH:60]=[C:55]([CH:52]([CH3:54])[CH3:53])[CH:56]=[CH:57][C:58]=2[O:73][CH3:74])=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNC(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
A solution of 3,5-bis(trifluoromethyl)phenylacetic acid (105.3 mg, 0.387 mmol) in CH2Cl2 (5 mL) was cooled to 0° C. N,N-diisopropylethylamine (169 μL, 0.968 mmol) was added, followed by HATU (139 mg, 0.3667 mmol). The reaction was stirred at 0° C. for 2 minutes and then a solution of 1-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanamine (62.5 mg, 0.193 mmol) in CH2Cl2 (2 mL) was added. The reaction was stirred for 1 hour at 0° C. and then diluted with EtOAc (75 mL). The organics were washed with saturated NaHCO3 and brine (25 mL each), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography with 100% CH2Cl2 gave 2-[3,5-bis(trifluoromethyl)phenyl]-N-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}acetamide. Rf=0.26 (25% EtOAc/hexanes). LCMS=578.2 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.79 (s, 1H), 7.70 (s, 2H), 7.59 (m, 2H), 7.33 (d, J=8.5 Hz, 1H), 7.25 (m, 1H), 6.97 (d, J=2.0 Hz, 1H), 6.91 (d, J=8.5 Hz, 1H), 5.84 (bs, 1H), 4.48 (dd, J=15.1, 6.6 Hz, 1H), 4.20 (dd, J=14.9, 4.3 Hz, 1H), 3.69 (s, 3H), 3.55 (s, 2H), 2.88 (m, 1H), 1.24 (d, J=6.8 Hz, 6H).
Reaction SMILES: Cl.O1CCCCC1[O:8][CH2:9][C:10]1[CH:11]=[C:12]([C:16]2[NH:20][C:19](=[O:21])[O:18][N:17]=2)[CH:13]=[CH:14][CH:15]=1>O1CCCC1.[Cl-].[Na+].O>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:16]2[NH:20][C:19](=[O:21])[O:18][N:17]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: O=c1[nH]c(-c2cccc(COC3CCCCO3)c2)no1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c(-c2cccc(CO)c2)no1
Reaction time: 18 h
Yield: 99 %

Procedure:
Add 10% hydrochloric acid (100 ml) to a solution of 3-[3-(tetrahydro-pyran-2-yloxymethyl)-phenyl]-4H-[1,2,4]oxadiazol-5-one (4.50 g, 16.3 mmol) in tetrahydrofuran (0.1M) and stir. After 18 hours, pour reaction into brine and extract with ethyl acetate. Combine the organic layers, dry with sodium sulfate, filter and concentrate under reduced pressure to yield the title product as a white solid (3.10 g, 99%): 1H NMR (DMSO-d6) δ 4.57 (s, 2H), 7.55 (m, 2H), 7.67 (dt, 1H), 7.81 (m, 1H), 12.95 (bs, 1H).
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[H-].[Na+].[Br:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Br.O>C1COCC1>[Br:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4]
Reactant: BrCc1ccccc1Br
Reactant: CCOP([O-])OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(Cc1ccccc1Br)OCC
Reaction time: 0.08 h

Procedure:
Diethyl phosphite (0.77 mL, 6.0 mmol) was dissolved in dry THF (10 mL) in a dry schlenk tube under an argon atmosphere. The solution was cooled on an ice bath and NaH (0.24 g, 60% in oil, 6.0 mmol) was added and stirred for 5 min. 2-bromo-benzylbromide (1.0 g, 4.0 mmol) dissolved in 2 mL dry THF was added and the reaction mixture was refluxed overnight. H2O (20 mL) was added and the water phase was extracted with EtOAc (3×10 mL). The combined organic phases were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash chromatography using EtOAc as the eluent to afford the title compound as a colourless oil.
Reaction SMILES: [CH:1](=[C:8]([CH2:13][OH:14])[C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[C].[Pd]>[OH:14][CH2:13][CH:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: [H][H]
Reactant: COC(=O)C(=Cc1ccccc1)CO
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(CO)Cc1ccccc1
Yield: 99.2 %

Procedure:
Methyl 2-benzylidene-3-hydroxypropionate (847.2 mg, 4.408 mmols) was dissolved in 8 ml of methanol, and 21.7 mg (water content 2.7%) of 5% palladium-carbon were added thereto to conduct catalytic reduction in a hydrogen atmosphere for 140 minutes. After the completion of the reaction, the reaction solution was filtered with Celite to remove the palladium-carbon. The resulting solution was concentrated under reduced pressure to obtain 849.2 mg of a crude product of the above title compound.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:10]1([CH2:18][NH2:19])[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH2:17])[CH:11]=1>C(O)(C)C.[Ni]>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH2:1][NH:17][CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:18][NH:19][CH2:1][C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[OH:4])[CH:11]=1
Reactant: O=Cc1ccccc1O
Reactant: NCc1cccc(CN)c1
Agent: [Ni]
Solvent: CC(C)O
Product: Oc1ccccc1CNCc1cccc(CNCc2ccccc2O)c1
Yield: 3.2 %

Procedure:
34.4 g of a bisazomethine prepared from 2 mols of salicylaldehyde and 1 mol of m-xylylenediamine and having a melting point of 61°-63° C. are hydrogenated for 7 hours in 170 ml of isopropanol in an autoclave in the presence of 4 g of Raney nickel at 85° C. and under a pressure of 60 atmospheres. The catalyst is filtered off and the filtrate is concentrated in a rotary evaporator to give 35.8 g of crude product. 25.7 g are recrystallised from 77 ml of isopropanol and the bulk of the product separates out on cooling in a refrigerator. The precipitate is collected by filtration, washed off with cold isopropanol and dried in vacuo at 40° C., affording 11.0 g (41.8% of theory) of N,N'-bis-(2-hydroxybenzyl)-m-xylylenediamine with a melting point of 67°-68° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:22])[C:7]=1[N:8]1[CH2:11][CH:10]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:14]=3[N:13]=2)[CH2:9]1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:22][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:7]=1[N:8]1[CH2:11][CH:10]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:14]=3[N:13]=2)[CH2:9]1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc2[nH]c(C3CN(c4c(Cl)cncc4Cl)C3)nc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2[nH]c(C3CN(c4c(Cl)cncc4-c4ccccc4)C3)nc2c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 12.1 %

Procedure:
The mixture of 2-[1-(3,5-dichloro-pyridin-4-yl)-azetidin-3-yl]-5-methyl-1H-benzoimidazole (200 mg, 0.60 mol), phenylboronic acid (80 mg, 0.66 mmol), K2CO3 (166 mg, 1.2 mmol) and Pd(dppf)Cl2 (44 mg, 0.06 mmol) in toluene (10 mL) and H2O (3 mL) was stirred at 100° C. under N2 for 12 h. The mixture was then poured into H2O and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated to give the crude product and purified by column chromatography and followed by preparative HPLC to afford pure product 2-[1-(3-chloro-5-phenyl-pyridin-4-yl)-azetidin-3-yl]-5-methyl-1H-benzoimidazole (30 mg, 14%) as white solid. [M+1] 375. IC50 (uM) 0.022.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].CC1C=CC=C(C)N=1.ClCCCl.[Cl:33][C:34]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][C:44](=[O:57])[NH:45][C@@H:46]([CH:54]2[CH2:56][CH2:55]2)[C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([F:53])[CH:48]=2)[C:35]=1[C:36](O)=[O:37]>>[CH:54]1([C@H:46]([NH:45][C:44]([C:43]2[C:39]3[C:35](=[C:34]([Cl:33])[CH:42]=[CH:41][CH:40]=3)[C:36](=[O:37])[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]=2[CH2:11][CH:8]2[CH2:7][CH2:6][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]2)=[O:57])[C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([F:53])[CH:48]=2)[CH2:56][CH2:55]1
Reactant: CC(C)(C)N1CCC(CC(=O)Nc2ccccc2)CC1
Reactant: O=C(Cc1cccc(Cl)c1C(=O)O)N[C@H](c1cccc(F)c1)C1CC1
Solvent: ClCCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)N1CCC(Cc2c(C(=O)N[C@H](c3cccc(F)c3)C3CC3)c3cccc(Cl)c3c(=O)n2-c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 15.8 %

Procedure:
To a cold (ice bath) mixture of 2-(1-tert-butyl-piperidin-4-yl)-N-phenyl-acetamide (250 mg, 0.91 mmol) and 2,6-dimethylpyridine (0.139 ml, 1.2 mmol) in 1,2-dichloroethane (8 ml) oxalyl chloride (0.07 ml, 0.8 mmol) was added and stirred at 0° C. for 15 min. 2-Chloro-6-({[(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-methyl)-benzoic acid (70 mg, 0.2 mmol) was added and the reaction mixture was stirred in a sealed vessel at 90° C. for 15 hours. It was partitioned between 0.5 M aq. NaOH (40 ml) and ethyl acetate (200 ml), the organic phase washed with water, dried and evaporated. The residue was purified by flash chromatography (SiO2, ethyl acetate-methanol) to give 19 mg of the title compound. LC-MS (m/z) 600.6 (MH+); tR=1.1. 1H NMR (500 MHz, r.t., DMSO-d6): broad signals, a mixture of two atropisomers.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH3:23])[CH:16]=1)=[N:7][CH:6]=[C:5]2[CH:24]=[O:25].C(=O)([O-])[O-].[K+].[K+].[Br:32][CH2:33][CH2:34]Br>CN(C)C=O>[CH2:22]([O:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][C:8]1[C:9]2[C:4](=[CH:3][C:2]([O:1][CH2:34][CH2:33][Br:32])=[C:11]([O:12][CH3:13])[CH:10]=2)[C:5]([CH:24]=[O:25])=[CH:6][N:7]=1)[CH3:23]
Reactant: BrCCBr
Reactant: CCOc1cccc(Cc2ncc(C=O)c3cc(O)c(OC)cc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccc(Cc2ncc(C=O)c3cc(OCCBr)c(OC)cc23)c1
Temperature: 85 °C

Procedure:
To a stirred solution of 6-hydroxy-7-methoxy-1-(3-ethoxy-benzyl)-isoquinoline-4-carbaldehyde (90 mg, 0.25 mmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (352 mg, 2.50 mmol) and 1,2-dibromoethane (0.129 μL, 1.25 mmol) at room temperature. The reaction mixture was heated 85° C. for 2 hrs. The solvent was evaporated and the residue was purified on a flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) to afford product 1-(3-ethoxy-benzyl)-6-(2-bromo-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde as a colorless oil. The crude product was used without further purification. To a stirred solution of 1-(3-ethoxy-benzyl)-6-(2-bromo-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde in acetic acid (2 mL) was added selenium dioxide (278 mg, 2.50 mmol). The reaction mixture was heated at 120° C. for 1 hr. The solvent was evaporated and the residue was diluted with dichloromethane (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL), saturated aqueous sodium chloride solution (20 μL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded 1-(3-ethoxy-benzoyl)-6-(2-bromo-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde as a major product (80 mg, 100% yield).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:28])[C@@H:7]1[C@:23]2([CH3:24])[CH:10]([CH:11]3[C:20](=[CH:21][CH2:22]2)[C@:19]2([CH3:25])[C:14](=[CH:15][C:16](=[O:26])[CH:17]=[CH:18]2)[CH2:13][CH2:12]3)[CH2:9][C@H:8]1[CH3:27])(=[O:3])[CH3:2].C([SiH](CC)CC)C>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C(Cl)Cl>[C:1]([O:4][CH2:5][C:6](=[O:28])[C@@H:7]1[C@:23]2([CH3:24])[CH:10]([CH:11]3[C:20](=[CH:21][CH2:22]2)[C@:19]2([CH3:25])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][C@H:8]1[CH3:27])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)[C@H]1[C@H](C)CC2C3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@@]21C
Agent: [Rh]
Agent: CC[SiH](CC)CC
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)OCC(=O)[C@H]1[C@H](C)CC2C3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Temperature: 40 °C
Yield: 30 %

Procedure:
A mixture of 3.3 g (8.6 mM) of 2-oxo-2-((10S,13S,16R,17S)-10,13,16-trimethyl-3-oxo-6,7,8,10,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-17-yl)ethyl acetate, chlorotris(triphenylphosphine)rhodium(I) (Wilkinson's Catalyst, 480 mg, 0.52 mM), triethylsilane (1.4 mL, 1.0 g, 8.8 mM) and methylene chloride (15 mL) was warmed to 40° C. and stirred until most of the starting material was gone, as determined by thin layer chromatography. The reaction was evaporated in vacuo and chromatographed on fine silica gel (600 g) in 10-15% ethyl acetate in methylene chloride. One fraction of 700 mL was collected, followed by twelve 200 mL fractions. A 1.0 g quantity of desired product (30% yield) was obtained by evaporation of fractions 6-12. (Starting material was obtained from fraction 13, 0.7 g, 20% recovery). NMR (500 MHz, CDCl3, TMS): δ 0.68 (s, 3H), 0.98 (d, 3H, J=6.5 Hz), 1.12 (m, 1H), 1.33 (s, 3H), 1.47 (m, 1H), 1.57 (m, 1H), 1.69 (m, 1H), 1.99 (m, 1H), 2.18 (s, 3H), 2.07-2.29 (m, 6H), 2.36 (d, 1H), 2.50 (m, 3H), 2.79 (m, 1H), 4.48 (d, 1H, J=17 Hz), 4.73 (d, 1H, J=17 Hz), 5.50 (s, 1H), 5.75 (s, 1H).
Reaction SMILES: [CH2:1]([N:7](CCCCCC)C1C=CC(N)=CC=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].FC1C=CC([N+]([O-])=O)=CC=1.[CH2:31]([N:37]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>CS(C)=O>[N+:44]([C:41]1[CH:40]=[CH:39][C:38]([N:37]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:47]2[CH:52]=[CH:51][C:50]([NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:49][CH:48]=2)=[CH:43][CH:42]=1)([O-:46])=[O:45]
Reactant: CCCCCCN(CCCCCC)c1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCN(CCCCCC)c1ccc(N)cc1
Agent: O=[N+]([O-])c1ccc(F)cc1
Solvent: CS(C)=O
Product: CCCCCCNc1ccc(N(CCCCCC)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 100 °C

Procedure:
To a flask equipped with a magnetic stirrer, reflux condenser, and a nitrogen inlet was added N,N-di-n-hexylbenzene1,4-diamine (22.3 grams 0.09 moles), 1-fluoro-4-nitrobenzene (4.3 grams. 0.03 moles) and anhydrous methyl sulfoxide (40 ml). The contents of the flask were heated at 100° C. for 3 days; cooled to room temperature; partitioned between ethyl acetate (200 ml) and water (100 ml). The ethyl acetate extract was washed with water (4×100 ml) followed by brine (50 ml). The ethyl acetate extract was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield a dark brown oil containing excess N,N-di-n-hexyl-N-(4-nitrophenyl)amine. The dark brown oil was chromatographed on silica gel, eluting with hexane/ethyl acetate gradient to afford 11.8 grams of the desired product as a dark purple color oil. 1H NMR (DMSO-d4) δ 8.95(bs, 1H), 8.0(d, 2H), 7.0(d, 2H), 6.8(d, 2H), 6.6(d, 2M), 3.25(t, 4H), 1.5(pent, 4H), 1.2-1.4(m, 12H), 0.9(t, 6H),
Reaction SMILES: [ClH:1].[NH2:2][C:3]([CH3:12])(/[CH:7]=[CH:8]\[CH2:9][C:10]#[N:11])[C:4]([OH:6])=[O:5].[BH4-].[Na+].Cl>CO>[ClH:1].[ClH:1].[NH2:2][C:3]([CH3:12])(/[CH:7]=[CH:8]\[CH2:9][CH2:10][NH2:11])[C:4]([OH:6])=[O:5]
Reactant: CC(N)(/C=C\CC#N)C(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(N)(/C=C\CCN)C(=O)O

Procedure:
The (3Z)-2-amino-5-cyano-2-methylpent-3-enoic acid hydrochloride product of Example 1k is taken up in MeOH. To this is added Co(II)Cl2.6H2O in one portion with stirring under argon during which the reaction mixture is expected to turn purple. This is followed by the cautious addition of NaBH4 in 6 portions over 15 min. at 25° C. during which the reaction mixture is expected to turn black. HCl is then added carefully and the reaction mixture is stirred until the reaction becomes a light purple color. It is then concentrated under reduced pressure and the residue is subjected to BioRad ‘H’ form ion exchange resin. Elution with 1% NH4OH/H2O gives the desired fraction. This is concentrated to drive off excess NH3 at <55° C. on a rotary evaporator and then acidified to pH 4.5 with conc. HCl before it is concentrated to dryness to afford the desired title product.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH:15]1[CH2:20][CH:21]([C:27](OCC)=[O:28])[C:22](OCC)=[O:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>C1COCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH:15]1[CH2:20][CH:21]([CH2:27][OH:28])[CH2:22][OH:23])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(CC1COCCN1Cc1ccccc1)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCC(CO)CC1COCCN1Cc1ccccc1
Temperature: 30 °C
Yield: 53.8 %

Procedure:
LiAlH4 (0.35 g, 9.32 mmol) in a dried flask was cooled to 0° C., and then anhydrous THF (15 mL) was added. The mixture was stirred thoroughly and a solution of diethyl 2-((4-benzylmorpholin-3-yl)methyl)malonate (0.93 g, 2.66 mmol) in anhydrous THF (5 mL) was added, then the mixture was stirred at 70° C. for 6 hours and cooled to 30° C. To the reaction mixture were added water (0.5 mL), sodium hydroxide aqueous solution (10%, 0.5 mL) and water (3 mL) in turn, then the mixture was stirred at 25° C. for 10 minutes and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=3/1) to give the title compound as colorless oil (0.38 g, 54%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([C:3]1[C:4]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:5][C:6]2[C:11]([C:12]=1[CH:13]([CH3:15])[CH3:14])=[CH:10][CH:9]=[CH:8][CH:7]=2)#[CH:2].[I:23]I>C([SnH](CCCC)CCCC)CCC.CCOCC.CC(N=NC(C#N)(C)C)(C#N)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:4]2[C:3](/[CH:1]=[CH:2]/[I:23])=[C:12]([CH:13]([CH3:15])[CH3:14])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:17][CH:18]=1
Reactant: C#Cc1c(-c2ccc(F)cc2)nc2ccccc2c1C(C)C
Reactant: II
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CCOCC
Product: CC(C)c1c(/C=C/I)c(-c2ccc(F)cc2)nc2ccccc12
Temperature: 110 °C
Reaction time: 4.5 h
Yield: 94.7 %

Procedure:
A mixture of 3-Ethynyl-2-(4-fluorophenyl)-4-(1-methylethyl)-quinoline (1.000 gm, 3.64 mmol) (the preparation of which is described in Example 5) and AIBN (13 mg) in 140 ml of tri-n-butylstannyl hydride was rapidly heated to 110° C. After 5 minutes of heating, the mixture was treated with additional Bu3SDE (0.4 ml) and the temperature of the reaction was raised to 130° C. Approximately 10 mg of AIBN was added to the reaction mixture every 0.5 hours. After 4.5 hours, the mixture was cooled to room temperature, diluted with Et2O (25 ml) and treated with solid I2 (3.08 gm, 12.2 mmol). The dark reaction mixture was stirred for 1 hour, then quenched with 10% Na2SO3 in saturated NaHCO3. The layers were shaken and separated. The ethereal layer was washed with brine, dried (Na2SO4), filtered and stripped to yield a yellow oil which was triturated with cold hexane to give a precipitate. Recrystallization of the solid from hot hexane gave 1.438 gm (E)-2-(4-Fluorophenyl)-3-(2-iodoethenyl)-4-(1-methylethyl)quinoline (917 mg, 64%) as light yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([CH:8]([O:18][C:19](OC2C=CC=CC=2)=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:34].C(O)(=O)C>O>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]2[NH:34][C:19](=[O:20])[O:18][C:8]=2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCCC(OC(=O)Oc1ccccc1)C(=O)c1ccc(Cl)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CCCCc1oc(=O)[nH]c1-c1ccc(Cl)cc1
Yield: 70.9 %

Procedure:
Ethyl 6-(4-chlorobenzoyl)-6-phenoxycarbonyloxyhexanoate (32.3 g), ammonium acetate(29.7 g) and acetic acid(150 ml) was stirred for 1 hour under reflux. Water was added to the reaction mixture to give ethyl 5-[4-(4-chlorophenyl)-2-oxo-4-oxazolin-5-yl)pentanoate(17.7 g, 71%). This was recrystallized from acetone-isopropyl ether to give colorless needls. mp 143-144° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:34])[C@@H:12]([NH:20][C:21](=[O:33])[CH:22]([NH2:32])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([CH3:31])[CH:24]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4].C(N(C(C)C)CC)(C)C.[O:44]=[C:45](Cl)OC(Cl)(Cl)Cl.O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:34])[C@@H:12]([N:20]2[C:21](=[O:33])[CH:22]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([CH3:31])[CH:24]=3)[NH:32][C:45]2=[O:44])[CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)C(N)c2ccc(OC)c(C)c2)n1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)N2C(=O)NC(c3ccc(OC)c(C)c3)C2=O)n1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-{(S)-2-[2-amino-2-(4-methoxy-3-methyl-phenyl)-acetylamino]-3-phenyl-propionylamino}-thiazole-4-carboxylic acid methyl ester (0.40 g , 0.83 mmol) and diisopropylethylamine (0.72 mL, 4.14 mmol) in dichloromethane (20 mL) was added to a solution of diphosgene (0.07 mL, 0.58 mmol) in dichloromethane (20 mL) at −10° C. The mixture was stirred at −10° C. for 0.5 hours. Water was added to quench the reaction, then the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography over silica gel eluted with ethyl acetate to give 2-{(S)-2-[4-(4-methoxy-3-methyl-phenyl)-2,5-dioxo-imidazolidin-1-yl]-3-phenyl-propionylamino}-thiazole-4-carboxylic acid methyl ester as an off white foam (0.29 g, 69%).
Reaction SMILES: [NH2:1][C:2]1[C:12](Br)=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(C)C=CC=CC=1.O1CCCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I.C(N(CC)CC)C>[NH2:1][C:2]1[C:12]([C:21]#[C:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(N)c(Br)c1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc(N)c(C#Cc2ccccc2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A mixture of ethyl 6-amino-5-bromonicotinate (245 mg, 1 mmol), phenylacetylene (220 mg, 2.2 mmol), (dppf)PdCl2 (40 mg), CuI (15 mg), toluene (2 mL), tetrahydrofuran (1 mL) and triethylamine (1 mL) was stirred at 80° C. under argon for 2 h. After cooling to RT, the mixture was washed with water, dried and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with ethyl acetate in heptanes (1:1) to provide ethyl 6-amino-5-(2-phenylethynyl)nicotinate (205 mg, 77%) as a solid. LC/MS; (M+H)+=267.2