Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]([CH3:26])([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])[CH:7]=1)[CH3:5].[OH-].[Na+]>CO.O>[CH3:26][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:17][C:18]=2[CH3:19])[CH:7]=1)([CH3:5])[C:3]([OH:27])=[O:2]
Reactant: COC(=O)C(C)(C)c1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(C(C)(C)C(=O)O)c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a stirred solution of the title B compound, 2-methyl-2-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid methyl ester (3.45 g, 9.45 mmol) in methanol (30 mL) is added sodium hydroxide (1.51 g, 37.81 mmol) in water (10 mL) at RT. The reaction mixture is stirred at 70° C. for 4 h. The reaction mixture is concentrated, poured into water, the aqueous layer is separated, washed with ethyl acetate twice, acidified with concentrated HCl and extracted three times with ethyl acetate. The combined ethyl acetate extract is dried over magnesium sulfate and concentrated to give 2-methyl-2-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid as a white solid.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH2:23][OH:24])[CH:17]=3)[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2(CCC3C=CC(C(C)(C)C#N)=C(F)C=3)CC(O)=CC(=O)O2)CCCC1.[CH3:52][C:53]1[CH:58]=[C:57]([CH3:59])[N:56]2[N:60]=[C:61]([CH:63]=O)[N:62]=[C:55]2[N:54]=1.C(C1NC(C=O)=C(C)N=1)C>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH2:23][OH:24])[CH:17]=3)[O:11][C:10](=[O:12])[C:9]([CH2:63][C:61]3[N:62]=[C:55]4[N:54]=[C:53]([CH3:52])[CH:58]=[C:57]([CH3:59])[N:56]4[N:60]=3)=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CC(=O)OC(CCc2ccc(O)c(CO)c2)(C2CCCC2)C1
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Agent: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(O)=CC(=O)O2)cc1F
Agent: CCc1nc(C)c(C=O)[nH]1
Product: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4ccc(O)c(CO)c4)(C4CCCC4)OC3=O)nc2n1

Procedure:
The title compound was prepared analogously to Example A(97) where 6-Cyclopentyl-6-[2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione (Example A(195)) was substituted in place of 2-{4-[2-(2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile and 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substituted in place of 2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde from that example. 1H NMR (400 MHz, DMSO-d6): δ 1.34–2.09 (m, 11H) 2.0–2.21 (m, 2H), 2.47–2.74 (m, 10H), 3.74 (d, J=16 Hz, 1H), 3.80 (d, J=16 Hz, 1H), 4.44 (s, 2H), 6.65 (d, J=8 Hz, 1H), 6.88 (d, J=8 Hz, 1H), 7.04 (s, 1H), 7.09 (s, 1H), 9.06 (s, 1H). Anal. Calcd. For C27H32N4O5.H2O: C, 62.96; H, 6.75; N, 10.88. Found: C, 62.97; H, 6.57; N, 10.83. MS (ESI): 493.2 (M+H)+.
Reaction SMILES: [CH:1]1([S:6]([C:9]2[CH:10]=[C:11]([C:22]([O:24]C)=[O:23])[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].Cl>O1CCCC1>[CH:1]1([S:6]([C:9]2[CH:10]=[C:11]([C:22]([OH:24])=[O:23])[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[CH:14]=2)(=[O:7])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)cc(S(=O)(=O)C2CCCC2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C(=O)O)cc(S(=O)(=O)C3CCCC3)c2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(cyclopentylsulfonyl)-4′-methylbiphenyl-3-carboxylate (0.34 g, 0.95 mmol) in tetrahydrofuran (15 mL) was added 2.5 M aqueous lithium hydroxide solution (1.0 mL, 2.5 mmol). The reaction mixture was stirred at 60° C. overnight. The aqueous solution was acidified with 15% HCl (aq.) to pH=5, and extracted with EtOAc. The combined organic layers were concentrated in vacuo to afford the title compound as a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1(O)[C:22]2[C:17](=[CH:18][C:19]([O:23][CH2:24][O:25][CH3:26])=[CH:20][CH:21]=2)[O:16][CH2:15][C:14]1([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][O:36][CH3:37])=[CH:30][CH:29]=1)[CH3:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH2:24][O:25][CH3:26])=[CH:20][CH:21]=2)[O:16][CH2:15][C:14]1([C:28]1[CH:29]=[CH:30][C:31]([O:34][CH2:35][O:36][CH3:37])=[CH:32][CH:33]=1)[CH3:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2(O)C#CCCO[Si](C)(C)C(C)(C)C)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 1 h
Yield: 43.4 %

Procedure:
4-[4-(t-butyl dimethylsilyloxy)-1-butynyl]4-hydroxy-7-methoxymethoxy-3-(4-(methoxymethoxy)phenyl)-3-methylchroman (1.6 g, 2.95 mmol) was dissolved in ethyl acetate (30 ml), and then 10% Pd/C (0.6 g) was added thereto. The reaction suspension was stirred under hydrogen for 1 hour, filtered, and concentrated. The residue was subjected to silica gel column chromatography (n-hexane:ethyl acetate=20:1) to give the title compound (680 mg, yield 44%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][C:13]1[C:21]([CH3:22])=[C:20]2[C:16]([CH2:17][CH2:18][NH:19]2)=[CH:15][CH:14]=1.N1C=CC=CC=1>C(O)(C)C>[CH3:12][C:13]1[C:21]([CH3:22])=[C:20]2[C:16]([CH2:17][CH2:18][N:19]2[C:2]2[C:3]3[CH:11]=[CH:10][N:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:15][CH:14]=1
Reactant: Clc1ncnc2cnccc12
Reactant: Cc1ccc2c(c1C)NCC2
Solvent: c1ccncc1
Solvent: CC(C)O
Product: Cc1ccc2c(c1C)N(c1ncnc3cnccc13)CC2
Yield: 17.9 %

Procedure:
To 4-chloro-pyrido[3,4-d]pyrimidine (200 mg, 1.21 mmol) in isopropanol (3 mL) was added 6,7-dimethylindoline (211 mg, 1.44 mmol) and pyridine (190 mg, 2.41 mmol). The mixture was heated to reflux under an atmosphere of dry N2(g) for 6hours. Solvent was removed in vacuo and the residue was dissolved in CHCl3 and washed with saturated aqueous Na2CO3. The organic phase was dried over Na2SO4, concentrated in vacuo, and flash chromatographed on silica in 45% acetone/hexanes to afford 60 mg of 4-(6,7dimethyl-2,3-dihydro-indol-1-yl)-pyrido[3,4-d]pyrimidine (LC-MS: 278 (MH+). This material was dissolved in a minimum volume of 10% MeOH in CH2Cl2, and 1 mole equivalent of HCl in diethyl ether was added dropwise with stirring. The mixture was diluted with diethyl ether (4 volumes) and the precipitated HCl salt of the product was filtered and dried in vacuo (58 mg): MP: 248° C.; GEMS: 277 (M+); anal. RP-HPLC: 4.06 minutes.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([OH:20])[C:13]3[CH:14]=[CH:15][N:16]([CH3:19])[C:17]=3[CH:18]=2)=[CH:4][N:3]=1.[CH3:21][CH:22]([CH3:28])[CH2:23][S:24](Cl)(=[O:26])=[O:25]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][N:16]3[CH3:19])=[C:12]([O:20][S:24]([CH2:23][CH:22]([CH3:28])[CH3:21])(=[O:26])=[O:25])[CH:11]=2)=[CH:4][N:3]=1
Reactant: Cn1ccc2c(O)cc(Cc3cnc(N)nc3N)cc21
Reactant: CC(C)CS(=O)(=O)Cl
Product: CC(C)CS(=O)(=O)Oc1cc(Cc2cnc(N)nc2N)cc2c1ccn2C

Procedure:
This compound was produced by reaction of 6-(2,4-diamino-pyrimidin-5-ylmethyl)-1-methyl-1H-indol-4-ol (Example 4,269 mg, 1.00 mmol) with 2-methylpropane-1-sulfonyl chloride (188 mg, 1.20 mmol), following the procedure detailed in Example 5c. Yield: 58 mg (15%). White solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=O)=[C:10]([CH3:16])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19].N1C=CC=CC=1>CO>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[N:18][OH:19])=[C:10]([CH3:16])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2ccc(O)cc2)ccc1C=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: Cc1cc(-c2ccc(O)cc2)ccc1C=NO
Yield: 53.3 %

Procedure:
A mixture of 4′-hydroxy-3-methyl[1,1′-biphenyl]-4-carbaldehyde (310 mg, 1.46 mmol), hydroxylamine hydrochloride (203 mg, 2.92 mmol) and pyridine (236 ul, 2.92 mmol) in 15 mL absolute methanol was refluxed for 2.5 h. The solvent was removed under reduced pressure and the mixture was dissolved in ethyl acetate and water, extracted with ethyl acetate (×3), washed with brine, dried over sodium sulfate, and filtered. Evaporation of the solvent and purification by recrystallization (ethyl acetate, acetone and hexane) gave 177 mg (53%) of the title compound as a yellowish solid: mp 195-197° C.;
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([F:19])[CH:11]=2)C)[CH:5]=[CH:4][N:3]=1.[CH:20]1([C:23]([NH2:25])=[O:24])[CH2:22][CH2:21]1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O>[F:19][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[N+:16]([O-:18])=[O:17])[NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:25][C:23]([CH:20]2[CH2:22][CH2:21]2)=[O:24])[CH:7]=1
Reactant: CN(c1ccnc(Cl)c1)c1ccc([N+](=O)[O-])c(F)c1
Reactant: NC(=O)C1CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(Nc2ccc([N+](=O)[O-])c(F)c2)ccn1)C1CC1
Temperature: 25 °C
Yield: 74.4 %

Procedure:
Add 2-chloro-N-(3-fluoro-4-nitro-phenyl)-N-methyl-pyridin-4-amine (190 mg, 0.68 mmol), cyclopropanecarboxamide (85 mg, 2.03 mmol), Cs2CO3 (440 mg, 1.35 mmol), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP, 43 mg, 0.05 mmol) and tris(dibenzylideneacetone)dipalladium [Pd2(dba)3, 42 mg, 0.07 mmol] in 1,4-dioxane (6 mL) under N2. Heat the reaction at 125° C. for 16 hrs. TLC (EtOAc:PE=2:1) shows the reaction is complete. Cool to room temperature, filter, and concentrate the filtrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=2:1) affords the target compound (160 mg, 71.7%). MS: (M+1): 331.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]=1.[C:12]1(=O)[O:17][C:15](=[O:16])[CH:14]=[CH:13]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[C:15](=[O:16])[CH:14]=[CH:13][C:12]2=[O:17])[CH:2]=1
Reactant: NCCCOc1cccnc1
Reactant: O=C1C=CC(=O)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=C1C=CC(=O)N1CCCOc1cccnc1

Procedure:
From 2 to 3 mmol of the appropriate 3-(pyridin-3-yloxy)propylamine in 5 ml of THF are admixed in succession with 500 mg of maleic anhydride (molecular mass: 98.06; 5.1 mmol) and 200 mg of p-toluenesulphonic acid hydrate (molecular mass: 190.22; 1.0 mmol). The solution is refluxed for 24 hours and concentrated to dryness. The residue is chromatographed on silica gel to give the desired 1-[3-(pyridin-3-yloxy)propyl]-pyrrole-2,5-dione derivative.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].CC([C@@H]1N=C(C2C=CC=C(C3OC[C@H](C(C)C)N=3)N=2)OC1)C>CC([C@H]1N=C(C2C=CC=C(C3OC[C@@H](C(C)C)N=3)N=2)OC1)C.CC(N(C)C)=O.C1COCC1.[Zn].Cl[Ni]Cl.C(COC)OC.IC1C=CC(CCCCCCCCCCCCCCCCCCO)=CC=1>[O:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)CCCCCCCCCCBr
Reactant: ICCCCCCOC1CCCCO1
Agent: Cl[Ni]Cl
Agent: CC(C)[C@@H]1COC(c2cccc(C3=N[C@H](C(C)C)CO3)n2)=N1
Agent: CC(C)[C@H]1COC(c2cccc(C3=N[C@@H](C(C)C)CO3)n2)=N1
Solvent: COCCOC
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCCCCCCCCCCCCCCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71 %

Procedure:
From (38) and (76). Zinc powder (166 mg, 2.55 mmol) was dried at 70° C. for 30 min in a sealed tube, then DMA (2.5 ml) and solid 12 (22 mg, 0.09 mmol) were added. After stirring for 10 min, neat ethyl 11-bromoundecanoate (500 mg, 1.7 mmol) was added and the reaction mixture was stirred in the sealed tube for 10 h at 80° C. In a 10-ml flask, NiCl2-glyme (29 mg, 0.13 mmol) and (R)-(i-Pr)-Pybox (or (S)-(i-Pr)-Pybox) (51 mg, 0.17 mmol) were dissolved in DMA (1.5 ml) and THF (0.5 ml), then neat I(CH2)6OTHP 38 (410 mg, 1.31 mmol) was added. This mixture was cooled to 0° C. and organozinc solution 76 was added via cannula. The reaction mixture was allowed to warm to the room temperature over period of 12 h and stirred at room temperature for additional 12 h. The reaction was quenched by addition of aqueous NH4Cl, extracted with EtOAc, the extract was dried over Na2SO4 and evaporated. The crude product was purified by silica gel chromatography in hexane-EtOAc (98:2, 97:3, 96:4) to afford the product ethyl 17-(tetrahydropyran-2-yl-oxy)-heptadecanoate 78 (369 mg, 71%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:21][C:22](C)([O-])[CH3:23].[K+].IC(C)C>C1COCC1>[CH3:21][CH:22]([O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2O)CC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)I
Solvent: C1CCOC1
Product: CC(C)Oc1ccccc1C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To a solution of 1-(tert-Butyloxycarbonyl)-4-(2-hydroxyphenyl)piperidine 5a (5 g) in dry THF (100 ml) was added potassium tert-butoxide (2.2 g). After stirring for 5 minutes 2-iodopropane (9 g) was added and the mixture was refluxed for 3 hours. Additionally 1.1 g of potassium tert-butoxide was added and reflux was continued overnight. After cooling to room temperature inorganic salts were filtered off and the solvents evaporated in vacuo. The remaining oil was purified by filtering through silica gel (eluted with a 7:3 mixture of heptane and ethyl acetate). Yield: 4.5 g of 1-(tert-butyloxycarbonyl)-4-[2-(2-propyloxy)phenyl]piperidine all of which was dissolved in a mixture of dichloromethane (90 ml) and trifluoroacetic acid (40 ml). After stirring for one hour at room temperature all volatile material was evaporated in vacuo. To the remaining oil was added ethyl acetate (200 ml) and water (200 ml). pH was adjusted to >10 by addition of diluted aqueous NH4OH. The organic phase was separated and washed with brine (2×50 ml). Work-up of the organic phase as above yielded 2.6 g of 4-[2-(2-propyloxy)phenyl]piperidine. A mixture of the thus isolated 1-unsubstituted piperidine (2.5 g), 1-(4-chloro-1-butyl)-3-(4-fluorophenyl)-2-imidazolidinone 2a (3.0 g), potassium carbonate (1.6 g), and potassium iodide (0.5 g) in MIBK (50 ml) was refluxed overnight. Inorganic salts were filtered off and MIBK evaporated in vacuo. The remaining crude product was purified by column chromatography on silica gel (eluted with 4% triethylamine in ethyl acetate). Pure title compound 6a crystallized from ethyl acetate. Yield: 2.6 g, mp: 130-131° C. 1H NMR (CDCl3) δ 1.45 (d, 6H); 1.60 (t, 4H); 1.70-1.90 (m, 4H); 2.00-2.15 (m, 2H); 2.40 (t, 2H); 2.90-3.05 (m, 3H); 3.35 (t, 2H); 3.45 (t, 2H); 3.75 (t, 2H); 4.55 (h, 2H); 6.80-6.90 (m, 2H); 7.00 (t, 2H); 7.10 (dt, 1H); 7.15 (dd, 1H); 7.50 (dd, 2H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:12]3[NH:16][N:15]=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.N12CCCN=C1CCCCC2.[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH:43]([C:48](=O)[CH2:49][CH2:50][CH2:51][CH3:52])[C:44](OC)=[O:45])=[CH:38][CH:37]=1)#[N:29].C(OCC)(=O)C>CCN(C1C=CC=CC=1)CC.O>[CH2:49]([C:48]1[N:16]2[N:15]=[CH:14][CH:13]=[C:12]2[N:11]([CH:8]2[CH2:7][CH2:6][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:10][CH2:9]2)[C:44](=[O:45])[C:43]=1[CH2:42][C:39]1[CH:38]=[CH:37][C:36]([C:31]2[C:30]([C:28]#[N:29])=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:41][CH:40]=1)[CH2:50][CH2:51][CH3:52]
Reactant: c1cc(NC2CCC3(CC2)OCCO3)[nH]n1
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ccnn12
Yield: 69.9 %

Procedure:
A solution of N-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-5-amine (2.2 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) and methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (7.0 g) in diethylaniline (10 mL) was stirred at 180° C. for 2 hr. The mixture was allowed to cool, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (3.6 g, 69%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][SH:8])[NH2:6].C(=O)([O-])O.[Na+].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCOCC>CO>[CH3:2][O:3][C:4]([CH:5]1[CH2:7][S:8][CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:6]1)=[O:9]
Reactant: COC(=O)[C@@H](N)CS
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C1CSC(c2ccccc2)N1
Temperature: 25 °C
Reaction time: 40 h
Yield: 76.3 %

Procedure:
1.72 g of L-cysteine methylester hydrochloride was neutralized by addition of 0.84 g of sodium hydrogen carbonate. The resulting ester was dissolved in 2 ml of methanol, and to this solution was added a solution of 0.94 g of benzaldehyde in 3 ml of methanol. The mixture was then stirred at room temperature for 40 hours under a nitrogen atmosphere. Ether was added to the reaction mixture, and then the mixture was extracted with diluted hydrochloric acid. The extract was neutralized by addition of sodium hydrogen carbonate and then extracted with ether. The organic portion was dried over anhydrous sodium sulfate and placed under reduced pressure for distilling off the solvent. There was obtained 1.51 g of 4-methoxycarbonyl-2-phenylthiazolidine as a colorless oil.
Reaction SMILES: [CH:1]12[N:8]([C:9](Cl)=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[F:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][NH2:20])=[N:17][CH:18]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][NH:20][C:9]([N:8]2[CH:5]3[CH2:6][CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4]3)=[O:10])=[N:17][CH:18]=1
Reactant: NNc1ccc(F)cn1
Reactant: O=C(Cl)N1C2CCCC1CC2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NNc1ccc(F)cn1)N1C2CCCC1CC2
Reaction time: 120 h
Yield: 46.6 %

Procedure:
To a solution of Intermediate 122a (240 mg, 1.38 mmol) and (5-fluoro-pyridin-2-yl)-hydrazine (176 mg, 1.38 mmol) in DCM (10 mL) was added DIPEA (721 μL, 4.15 mmol) and the reaction stirred for 5 days. The reaction was then partitioned between DCM and water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% MeOH in DCM to give the title compound (170 mg, 47%). LCMS (Method 3): Rt 2.31 min, m/z 265 [MH+].
Reaction SMILES: Cl[C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:12])[C:5]([CH3:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH:16]([NH2:19])([CH3:18])[CH3:17]>>[CH:16]([NH:19][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[C:4]([CH3:12])[C:3]=1[N+:13]([O-:15])=[O:14])([CH3:18])[CH3:17]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C
Reactant: CC(C)N
Product: Cc1cc([N+](=O)[O-])c(NC(C)C)c([N+](=O)[O-])c1C
Yield: 79.9 %

Procedure:
4-Chloro-3,5-dinitro-o-xylene (10.0 grams, 0.043 mole) and i-propylamine (10.1 grams, 0.17 mole) are mixed and refluxed for 12 hours using an efficient reflux condenser. The mixture is then cooled and poured into 100 ml. of 5% hydrochloric acid and extracted with diethyl ether. The ether extract is dried over magnesium sulfate. Removal of the drying agent and solvent leaves an orange oil which readily solidifies. The product is recrystallized from methanol to give 8.7 grams (80%) of an orange solid with melting point 69° C. to 70° C.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3].C(N(CC)C(C)C)(C)C.[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=2)=[CH:30][CH:29]=1)=[O:26]>O.CN(C=O)C.C(#N)C>[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[C:25]([NH:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[CH:39]=[CH:38][C:37]([S:40]([NH:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3])(=[O:42])=[O:41])=[CH:36][CH:35]=2)=[CH:32][CH:33]=1)=[O:26]
Reactant: C[C@@H](N)C(=O)O
Reactant: O=C(Nc1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1)c1cc2ccccc2o1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: C[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3cc4ccccc4o3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of D-alanine (0.15 mmol, 14 mg) in water (0.5 mL) and DMF (0.1 mL) was added N,N-diisopropylethylamine (52 uL, 0.3 mmol) and 4′-[(benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonyl chloride (0.1 mmol, 41 mg) as a solution in acetonitrile (0.4 mL). The resulting solution was shaken at room temperature for 4 hours and purified by semi-preparative RP-HPLC (Gilson Preparative HPLC conditions: Gilson Preparative HPLC system; YMC Pro C18, 20 mm×50 mm ID, 5 uM column; 2 mL injection; Solvent A: 0.02% TFA/water; Solvent B: 0.02% TFA/acetonitrile; Gradient: Time 0: 95% A; 2 min: 95% A; 14 min: 10% A, 15 min: 10% A, 16 min: 95% A; Flow rate 22.5 mL/min; Detection: 254 nm DAD.) to provide N-({4′-[(1-benzofuran-2-ylcarbonyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)-D-alanine.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:15]=1[O:16][C:17]1[CH:29]=[CH:28][C:20]([C:21]([NH:23][CH2:24][CH2:25][O:26][CH3:27])=[O:22])=[CH:19][CH:18]=1>>[Cl:34][C:32]1[CH:31]=[CH:30][C:15]([O:16][C:17]2[CH:29]=[CH:28][C:20]([C:21]([NH:23][CH2:24][CH2:25][O:26][CH3:27])=[O:22])=[CH:19][CH:18]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:33]=1
Reactant: COCCNC(=O)c1ccc(Oc2ccc(Cl)cc2N)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: COCCNC(=O)c1ccc(Oc2ccc(Cl)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 7d (111 mg, 0.62 mmol) was reacted with the product from Example 34e (200 mg, 0.62 mmol) for 18 h following the procedure from Example 7g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (89.4 mg, 25%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.73 (s, 3 H) 3.25 (s, 3 H) 3.32-3.50 (m, 4 H) 6.72 (d, J=6.99 Hz, 1 H) 6.97 (d, J=8.82 Hz, 2 H) 7.30 (d, J=8.82 Hz, 1 H) 7.61 (dd, J=8.82, 2.57 Hz, 1 H) 7.70-7.80 (m, 4 H) 8.42 (t, J=5.15 Hz, 1 H) 8.53 (d, J=6.99 Hz, 1 H) 8.82 (d, J=8.82 Hz, 1 H) 10.90 (s, 1 H) 14.54 (s, 1 H); MS (ESI+) m/z 463 (M+H−TFA)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:20]([O-])=O)[N:13]=2)=[CH:5][CH:4]=1>[Pd].CCO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH2:20])[N:13]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc(-c3ccccc3[N+](=O)[O-])c[nH]2)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(-c2nc(-c3ccccc3N)c[nH]2)cc1
Reaction time: 0.75 h
Yield: 102.4 %

Procedure:
2-(4-Methoxyphenyl)-4-(2-nitrophenyl)imidazole (10 g) is mixed with EtOH (80 ml) and 5% Pd-C (wet, 2 g). The mixture is shaken under hydrogen at 50 psi for 45 min. then filtered through Celite. The filtrate is evaporated under reduced pressure to yield 2-(4-methoxyphenyl)-4-(2-aminophenyl)imidazole (9.2 g) as a brown solid which is used in the next step without further purification.