Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)=[O:9])([CH3:6])[C:3]([O-:5])=O.C([O-])([O-])=O.[K+].[K+].[Cl:28][C:29]1[CH:34]=[C:33]([CH2:35]Cl)[CH:32]=[CH:31][N:30]=1>CN(C=O)C>[Cl:28][C:29]1[CH:34]=[C:33]([CH2:35][N:7]2[C:2]([CH3:1])([CH3:6])[C:3](=[O:5])[N:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[C:8]2=[O:9])[CH:32]=[CH:31][N:30]=1
Reactant: CC(C)(NC(=O)Nc1ccc(SC(F)(F)F)cc1)C(=O)[O-]
Reactant: ClCc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(c2ccc(SC(F)(F)F)cc2)C(=O)N1Cc1ccnc(Cl)c1

Procedure:
5,5-Dimethyl-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione 3 (1 g, 3.29 mmol) is dissolved in 10 ml of DMF, 1.36 g of K2CO3 (3 eq, 9.87 mmol) and 909 mg of 2-chloro-4-chloromethylpyridine (3.95 mmol, 1.2 eq) are added, and the mixture is refluxed for 20 hours. The solvent is removed under vacuum and the residue is dissolved in CH2Cl2 and treated three times with active charcoal. After removing the solvent, the product 1-(2-chloropyrid-4-ylmethyl)-5,5-dimethyl-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione is obtained (3.2 g; 56%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][N:5]=[N:4][C:3]=1NN.[OH-].[Na+]>O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][N:5]=[N:4][CH:3]=1
Reactant: CN1CCN(c2cnnc(NN)c2Cl)CC1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CN1CCN(c2cnncc2Cl)CC1
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
[4-Chloro-5-(4-methylpiperazin-1-yl)pyridazin-3-yl]hydrazine (145 mg, 0.5974 mmol) and copper sulfate pentahydrate (522.1 mg, 2.091 mmol) were dissolved in water (9 mL) and stirred at 95° C. for ˜30 minutes. The brown suspension was allowed to cool and 15 wt % NaOH (2 mL) was added. The resulting suspension was heated to 95° C. for ˜5 mins, allowed to cool to RT and filtered through a pre-wetted (10% MeOH in DCM) celite cartridge (10 g). The cartridge was washed with 10% MeOH in DCM and the filtrate was partitioned with water. The aqueous layer was extracted with further 10% MeOH in DCM (3×10 mL) and the combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (7.5% MeOH/1% NH 40H in DCM, ˜75 mL silica) to give 4-chloro-5-(4-methylpiperazin-1-yl)pyridazine as an off-white solid (100.6 mg, 79% Yield).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17](=[O:21])[C:18]([OH:20])=[O:19])=[CH:8]1>>[CH:12]1[CH:11]=[C:10]2[C:9]([CH2:16][C@@:17]([OH:21])([C:18]([OH:20])=[O:19])[CH2:3][C@H:2]([NH2:1])[C:4]([OH:6])=[O:5])=[CH:8][NH:7][C:15]2=[CH:14][CH:13]=1
Reactant: O=C(O)C(=O)Cc1c[nH]c2ccccc12
Reactant: C[C@H](N)C(=O)O
Product: N[C@@H](C[C@@](O)(Cc1c[nH]c2ccccc12)C(=O)O)C(=O)O

Procedure:
The addition of alanine to indole-3-pyruvic acid produces monatin, and this reaction can be performed synthetically with a Grignard or organolithium reagent.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]2[C:17]2[CH:22]=[CH:21][C:20](OS(C(F)(F)F)(=O)=O)=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:31]([O:35][CH3:36])(=[O:34])[CH:32]=[CH2:33]>CC#N>[CH3:36][O:35][C:31](=[O:34])[CH:32]=[CH:33][C:20]1[CH:19]=[CH:18][C:17]([CH:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:15][CH2:16][CH:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:22][CH:21]=1
Reactant: O=S(=O)(Oc1ccc(C2c3ccccc3CCC2c2ccccc2)cc1)C(F)(F)F
Reactant: C=CC(=O)OC
Solvent: CC#N
Product: COC(=O)C=Cc1ccc(C2c3ccccc3CCC2c2ccccc2)cc1

Procedure:
Prepared by Heck coupling 7b and methyl acrylate in accordance with the general method described in Example IV. Yield (76%); APcI m/z: 410 (M+H+CH3CN+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[CH:31]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:31]1([NH:37][C:12]2[N:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[CH3:30])[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1C
Reactant: NC1CCCCC1
Product: Cc1cc(F)ccc1-c1nc(NC2CCCCC2)nc2c1ccc(=O)n2-c1ccccc1C
Yield: 48.1 %

Procedure:
Following the general procedure outlined in Example 126, the product of Example 121 (200 mg, 0.47 mmol), and cyclohexylamine (0.27 mL, 2.36 mmol) were reacted to give the crude material, which was purified as described in Example 198 to give the desired product 100 mg (48%). LC-MS: 443.4 (MH+, m/z), 2.79 (Rt, min).
Reaction SMILES: F/[C:2](=[CH:5]\[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1)/[CH:3]=[O:4].[CH3:17][Mg]I.[Mg].CI>CCOCC>[Cl:16][C:11]1[CH:10]=[C:9]([C@@H:7]2[CH2:8][C@H:6]2/[CH:5]=[CH:2]\[CH:3]([OH:4])[CH3:17])[CH:14]=[CH:13][C:12]=1[Cl:15]
Reactant: O=C/C(F)=C/[C@@H]1C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: C[Mg]I
Agent: [Mg]
Solvent: CCOCC
Solvent: CI
Product: CC(O)/C=C\[C@@H]1C[C@H]1c1ccc(Cl)c(Cl)c1
Reaction time: 18 h

Procedure:
(±)-(2Z)-2-Fluoro-3-[trans-2-(3,4-dichlorophenyl)cyclopropyl]prop-2-enal (2.59 g) (example 19) in ehter (10 ml) was treated at 0° under nitrogen with methyl magnesium iodide, prepared from magnesium turning (0.26 g) and methyl iodide (0.7 ml) in ether (20 ml). After 18 hours at 25° the mixture was worked up as usual. Purification by chromatography (silica, ether/hexane) gave (±)-(3Z)-4-[trans-2-(3,4-dichlorophenyl)cyclopropyl]but-3-en-2-ol (2.0 g). NMR 1H: 7.23(1H,d), 7.05(1H,d), 6.90(1H,dd), 4.52(1H,m), 4.23(1H,m), 3.0(1H,s), 1.80(2H,m), 1.35(3H,d), 1.18(2H,m).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH:15][C:16](=O)[CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].B#B.C1COCC1.C([O-])(O)=O.[Na+]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([NH:15][CH2:16][CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[S:13][CH:14]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(-c2csc(NC(=O)Cc3cccs3)n2)cc1
Agent: B#B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1ccc(-c2csc(NCCc3cccs3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.7 %

Procedure:
To N-[4-(4-isopropyl-phenyl)-thiazol-2-yl]-2-thiophen-2-yl-acetamide (270 mg, 0.79 mmol) was added diborane in THF (1.6 mL, 1M solution, 1.58 mmol). The mixture was stirred at room temperature for 2 h. Saturated NaHCO3 solution was added, and the mixture was extracted into ethyl acetate (3×5 mL). Combined ethyl acetate extracts were dried over Na2SO4, concentrated and purified on silica gel column to afford [4-(4-isopropyl-phenyl)-thiazol-2-yl]-(2-thiophen-2-yl-ethyl)-amine (103 mg). LCMS m/z: 330 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][N:13]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:12](=[O:23])[C:11]=2[C:10]([CH3:24])=[CH:9]1.C1C(=O)N([Br:32])C(=O)C1.O>CN(C=O)C>[Br:32][C:9]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:16]2[CH2:15][CH2:14][N:13]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[C:12](=[O:23])[C:11]=2[C:10]=1[CH3:24]
Reactant: Cc1cn(-c2ccccc2Cl)c2c1C(=O)N(N1CCCCC1)CC2
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c2c(n(-c3ccccc3Cl)c1Br)CCN(N1CCCCC1)C2=O
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To as solution of 1-(2-chlorophenyl)-3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-4-one (0.93 g, 2.70 mmol) in DMF (30 ml) was added NBS (0.50, 2.84 mmol) at 0° C. The reaction mixture was stirred at this temperature for one hour and then water was added. The mixture was extracted with ether (×3). The combined ether extracts were dried (Na2SO4), filtered and concentrated to give 0.92 g (84%) of the title compound after flash chromatography (heptane:EtOAc gradient).
Reaction SMILES: C[O:2][C:3](=[O:34])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:33])=[O:25])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[Cl:15])=[O:7].O[Li].O.C(O)(=O)C>C1COCC1.O>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([NH:5][C@H:4]([C:3]([OH:34])=[O:2])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24]([C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:33])=[O:25])=[CH:21][CH:22]=2)=[O:7])=[C:9]([Cl:15])[CH:10]=1
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1ccc(N)cc1Cl
Agent: [Li]O
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)c(Cl)c1
Temperature: 25 °C
Yield: 62.6 %

Procedure:
A solution of N-[(4-amino-2-chlorophenyl)carbonyl]-4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester (66 mg, 0.126 mmol) in THF (3 mL) was treated with a solution of LiOH.H2O (20 mg, 0.48 mmol) in water (0.5 mL) and the mixture was stirred over night at room temperature. Acetic acid (0.5 mL) was added and the mixture was purified directly by RP-HPLC (5-95-35-214) to give 40 mg of a white solid. HRMS: (C23H18Cl3N3O4): Obs. Mass 506.0461. Calcd. Mass 506.0441 (M+H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O)#[N:6].[CH2:16]([O:22][C:23]1[CH:24]=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl>[N+](C1C=CC=CC=1)([O-])=O>[CH3:29][C:25]1[CH:24]=[C:23]([O:22][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:28]=[CH:27][C:26]=1[C:10]([C:9]1[CH:8]=[C:7]([CH:15]=[CH:14][CH:13]=1)[C:5]#[N:6])=[O:12]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: CCCCCCOc1cccc(C)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCCCOc1ccc(C(=O)c2cccc(C#N)c2)c(C)c1
Temperature: 0 °C
Yield: 32 %

Procedure:
Anhydrous aluminium chloride (38.35 g) is added to a solution of the acid chloride prepared from 3-cyanobenzoic acid (36.3 g) as described in Example 26 and nitrobenzene (200 ml). A solution of 3-n-hexyloxytoluene (39.5 g) in nitrobenzene (50 ml) is added and the resulting mixture heated to 110°-120° C. for 3 hours. The reaction mixture is cooled and poured into a mixture of ice water (1,000 ml) and concentrated hydrochloric acid (100 ml). The mixture is extracted with ether (3×300 ml) and the combined extracts concentrated and the nitrobenzene removed by steam distillation. The resulting residue is dissolved in ether, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue is chromatographed on silica gel (hexanes:ether; 70:30) to yield 3-(2-methyl-4-n-hexyloxybenzoyl)benzonitrile (21.1 g) as a dark brown oil and 3-(2-hydroxy-4-methylbenzoyl)benzonitrile, which is recrystallized from ethanol to give 5.78 g as a yellow solid (m.p. 126°-128°C.). The 3-(2-methyl-4-n-hexyloxybenzoyl)benzonitrile thereby obtained is heated under reflux in a mixture of acetic acid (160 g) and a solution of 75% sulfuric acid (160 g) for 1 hour. The cooled mixture is then poured into ice water (500 ml) and extracted with ether (3×200 ml). The extract is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue is chromatographed on silica gel (hexanes:ether:acetic acid; 50:50:1). The main fraction is collected and concentrated in vacuo. The residual yellow solid is crystallized from heptane to yield 3-(4-n-hexyloxy-2-methylbenzoyl)benzoic acid (9.62 g) as yellow needles m.p. 136°-138° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[O:6][C:7]1[CH:8]=[C:9]([C:16]([N+:19]([O-])=[O:20])=[CH:17][CH:18]=1)[CH2:10][C@@H:11]([C:13](O)=[O:14])[NH2:12])#[N:2].[ClH:25]>O1CCOCC1.CCOCC>[ClH:25].[NH2:12][C@H:11]1[CH2:10][C:9]2[C:16](=[CH:17][CH:18]=[C:7]([O:6][C:5]3[CH:4]=[C:3]([CH:24]=[CH:23][CH:22]=3)[C:1]#[N:2])[CH:8]=2)[N:19]([OH:20])[C:13]1=[O:14]
Reactant: N#Cc1cccc(Oc2ccc([N+](=O)[O-])c(C[C@H](N)C(=O)O)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: N#Cc1cccc(Oc2ccc3c(c2)C[C@H](N)C(=O)N3O)c1
Reaction time: 1.5 h
Yield: 97 %

Procedure:
3-(3-Cyanophenoxy)-6-nitro-L-phenylalanine (87) N-(tert-Butoxycarbonyl)-3-(3-cyanophenoxy)-6-nitro-L-phenylalanine (86) (1.6 g, 3.8 mmol) was dissolved in a solution of HCl in dioxane (4 N, 70 mL). After 1.5 h, the reaction mixture was diluted with Et2O (200 mL) and filtered. The solid was washed with Et2O and dried at 50° C. under vacuum to afford the title compound as a white solid (1.3 g, 97%). LCMS m/z 328.1 (M+1). 1H NMR (400 MHz, CD3OD) δ 3.41 (dd, J=13.8, 7.5 Hz, 1H), 3.66 (dd, J=13.8, 7.4 Hz, 1H), 4.34 (t, J=7.4 Hz, 1H), 7.12-7.15 (m, 2H), 7.43-7.49 (m, 1H), 7.52-7.54 (m, 1H), 7.63-7.68 (m, 2H), 8.22-8.25 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:19]=[CH:18][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=3)[C:4]=2[CH:3]=1.NC1C=CC=C(C)C=1.ClC1C2C=C(F)N=CC=2N=CN=1.C[O:41][C:42]1C=CC(CN)=[CH:44][CH:43]=1.FC(F)(F)C(O)=O.C(Cl)(=O)C=C>CN(C1C=CN=CC=1)C.O.CCN(CC)CC>[CH3:17][C:13]1[CH:12]=[C:11]([NH:10][C:9]2[C:4]3[CH:3]=[C:2]([NH:1][C:42](=[O:41])[CH:43]=[CH2:44])[N:19]=[CH:18][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cccc(Nc2ncnc3cnc(N)cc23)c1
Reactant: COc1ccc(CN)cc1
Agent: C=CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Fc1cc2c(Cl)ncnc2cn1
Solvent: CCN(CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)Nc1cc2c(Nc3cccc(C)c3)ncnc2cn1
Temperature: 20 °C
Reaction time: 3 h
Yield: 24 %

Procedure:
To a stirred solution of 6-amino-4-[(3-methylphenyl)amino]pyrido[3,4-d]pyrimidine, made from m-toluidine and 4-chloro-6-fluoropyrido[3,4-d]pyrimidine, followed by p-methoxybenzylamine and trifluoroacetic acid, as described in the previous example (140 mg, 0.56 mmol), DMAP (14 mg) and Et3N (excess, 0.5 mL) at 0° C. under N2 was added acryloyl chloride (2.7 mol eq., 123 μL) dropwise over 3 hours. The reaction was then stirred at 20° C. for 1 hour, diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure before being chromatographed on silica gel eluting with CH2Cl2/EtOAc (1:1) to MeOH/CH2Cl2/EtOAc (2:48:50), to give N-[4-[(3-methylphenyl)amino]pyrido[3,4-d]pyrimidin-6-yl]acrylamide (41 mg, 24%) as a cream powder, mp (EtOAc/hexane) 221-223° C. (decomp).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=1)\[CH2:4][C@H:5]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].[NH2:29][CH2:30][C@@H:31]([OH:33])[CH3:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[OH:1]/[N:2]=[C:3](/[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=1)\[CH2:4][C@H:5]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:29][CH2:30][C@@H:31]([OH:33])[CH3:32])=[O:18])=[CH:20][CH:21]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12]
Reactant: C[C@H](O)CN
Reactant: Cc1cc(/C(C[C@H](c2ccc(C(=O)O)cc2)c2ccccc2C)=N/O)ccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(/C(C[C@H](c2ccc(C(=O)NC[C@H](C)O)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 207, step 2, 4-[(R)-3-[(E)-hydroxyimino]-3-(2-methyl-pyridin-4-yl)-1-o-tolyl-propyl]-benzoic acid (example 272) was coupled with (S)-1-aminopropan-2-ol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as a yellow solid, MS (ESI+): m/z=432.4 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>O1CCCC1>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34](=[O:35])[O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9][N:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:14]=1
Reactant: O=C=Nc1ccccc1Cl
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1Cl)Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 35 °C

Procedure:
A mixture of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (800 mg, 3.34 mM) and triethylamine (0.6 mL) in dry tetrahydrofuran (THF, 5 ml) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, 2-chiorophenyl isocyanate (604 mg/ml, 5.01 mM) was added at once and then the reaction mixture was further stirred for 62 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chloroform-hexane (1:9) to give 8e. Yield: 1.02 g, 77.66%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([N:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=2)N)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC[N:45](CC)CC.ClC(Cl)(Cl)C(Cl)(Cl)Cl.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C1COCC1.C(Cl)Cl.CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[N:15]3[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]3=[N:18][N:45]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)N(N)c2ccc(F)cn2)C1
Reactant: CCN(CC)CC
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2nnc3ccc(F)cn23)C1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 72.2 %

Procedure:
To a brown solution Intermediate 90a (1.37 g, 4.22 mmol), Ph3P (2.22 g, 8.45 mmol) and Et3N (2.35 mL, 16.9 mmol) in THF (25 mL) at 0° C. was added hexachloroethane (2.00 g, 8.45 mmol) in 3 portions at 1 min intervals. The solution was stirred at 0° C. for 30 min and at RT for 3.5 h. The suspension was filtered and the filter-cake washed with THF (10 mL). The combined organics were applied to an SCX-2 cartridge (50 g), then washed with DCM-MeOH (1:1, 50 mL) and MeOH (50 mL). The product was eluted with 2M NH3 in MeOH (75 mL); concentration in vacuo gave a brown oil that solidified on standing. The solid was dissolved in DCM (10 mL) then Et3N (0.580 mL, 4.16 mmol) and BOC anhydride (454 mg, 2.08 mmol) added sequentially. The solution was stirred at RT for 45 min, then water (10 mL) was added and the aqueous extracted with DCM (5 mL). The combined organics were passed through a hydrophobic frit and concentrated in vacuo to leave a brown gum. FCC, using 2.5-3% MeOH in DCM, gave the title compound as a pale brown solid (933 mg, 73%). LCMS (Method 3): Rt 2.94 min, m/z 207 [MH+—C5H9O2].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:23]1([NH:22][C:4]2[C:5]([CH3:21])=[C:6]([C:7]([NH:9][CH2:10][C:11]3[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])=[O:8])[CH:20]=[C:2]([C:33]3[CH:34]=[CH:35][C:30]([CH:28]=[O:29])=[CH:31][CH:32]=3)[CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(NC3CCCC3)c2C)c(=O)[nH]1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)cc3)cc(NC3CCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 5-bromo-3-(cyclopentylamino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.), (4-formylphenyl)boronic acid (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane (4 mL) was purged with argon for 10 min. Then, 2 M Na2CO3 solution (3.6 equiv.) was added to it and argon was purged again for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After cooling to room temperature water was added to the mixture and then product was extracted with DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel (60-120 mesh size) to afford 5-(cyclopentylamino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4′-formyl-4-methyl-[1,1′-biphenyl]-3-carboxamide.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:24](OC(=O)C)(=[O:26])[CH3:25].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccc(CN)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(CNC(C)=O)cc1
Temperature: 25 °C
Reaction time: 69 h

Procedure:
To a room temperature mixture of 15 g of product from Example 99, 0.229 g of 4-N,N-dimethylaminopyridine and 50 ml of methylene chloride is added 5 ml of acetic anhydride. An additional 50 ml of methylene chloride is added and the solution is stirred at room temperature for 69 hours. The reaction is poured into half saturated sodium bicarbonate and extracted with methylene chloride. The combined organic layers are washed with half saturated sodium bicarbonate, water and saturated sodium chloride. The dried methylene chloride layer is concentrated in vacuo and purified by chromatography (silica gel: 5% methyl alcohol/chloroform) to give 16.29 g of the desired product as colorless prisms.