Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.O.[C:3]([OH:8])(=[O:7])[C:4]([OH:6])=[O:5].[CH3:9][CH:10]([CH3:45])[CH2:11][C@H:12]([NH:34][C:35]([C@H:37]1[O:39][C@@H:38]1[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[O:36])[C:13]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[C:23]=2[O:32][CH3:33])[CH2:17][CH2:16]1)=[O:14]>CC(C)=O>[C:3]([O-:8])(=[O:7])[C:4]([O-:6])=[O:5].[CH3:9][CH:10]([CH3:45])[CH2:11][C@H:12]([NH:34][C:35]([C@H:37]1[O:39][C@@H:38]1[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[O:36])[C:13]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[C:23]=2[O:32][CH3:33])[CH2:17][CH2:16]1)=[O:14]
Reactant: O=C(O)C(=O)O
Agent: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N1CCN(Cc2ccc(OC)c(OC)c2OC)CC1
Solvent: O
Solvent: CC(C)=O
Product: O=C([O-])C(=O)[O-]
Yield: 590.1 %

Procedure:
An acetone solution (2 ml) of oxalic acid dihydrate (0.25 g) was added to an acetone solution (6 ml) of ethyl (2S,3S)-3-[(s)-3-methyl-1-{4-(2,3,4-trimethoxyphenylmethyl)-piperazine-1-yl carbonyl}butylcarbamoyl]oxirane-2-carboxylate (1.04 g), and the crystal which had precipitated was collected by filtration and dried to yield 1.03 g of an oxalate of ethyl (2S,3S)-3-[(s)-3-methyl-1-{4-(2,3,4-trimethoxyphenylmethyl)piperazine-1-yl carbonyl}butylcarbamoyl]oxirane-2-carboxylate as a colorless crystal (yield: 84%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[Cl:10][C:11]1[CH:12]=[C:13]([Br:18])[CH:14]=[CH:15][C:16]=1F>>[Br:18][C:13]1[CH:14]=[CH:15][C:16]([O:9][C:3]2[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=2[NH2:1])=[C:11]([Cl:10])[CH:12]=1
Reactant: Nc1ccc(Cl)cc1O
Reactant: Fc1ccc(Br)cc1Cl
Product: Nc1ccc(Cl)cc1Oc1ccc(Br)cc1Cl

Procedure:
The subtitle compound was prepared by the method of example 3 step viii) using 2-amino-5-chlorophenol and 3-chloro-4-fluorobromobenzene. Yield 2.05 g.
Reaction SMILES: CO[CH:3](OC)[CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:13][C:12]=3[N:23]([CH3:33])[S:24]([C:27]2[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=2)(=[O:26])=[O:25])=[N:6][CH2:5]1.FC(F)(F)C(O)=O.S(=O)(=O)(O)O.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.O>[CH3:22][O:21][CH2:20][CH2:19][O:18][C:14]1[CH:15]=[C:16]2[C:11](=[C:12]([N:23]([CH3:33])[S:24]([C:27]3[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=3)(=[O:25])=[O:26])[CH:13]=1)[NH:10][C:9]([C:7]1[S:8][CH:4]([CH2:3][N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)[CH2:5][N:6]=1)=[CH:17]2
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2nccn2C)c2[nH]c(C3=NCC(C(OC)OC)S3)cc2c1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COCCOc1cc(N(C)S(=O)(=O)c2nccn2C)c2[nH]c(C3=NCC(CN4CCOCC4)S3)cc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
To a mixture of N-[2-[5-(dimethoxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]-5-(2-methoxyethoxy)-1H-indol-7-yl]-N,1-dimethyl-1H-imidazole-2-sulfonamide (580 mg), trifluoroacetic acid (7 mL) and water (14 mL) was added concentrated sulfuric acid (7 mL), and the mixture was stirred at 60° C. for 3 hr. The excess trifluoroacetic acid was evaporated under reduced pressure, and the residue was neutralized with sodium hydrogencarbonate. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The obtained crude product was dissolved in tetrahydrofuran (15 mL), morpholine (0.1 mL) was added, and the mixture was stirred at room temperature for 15 min. Sodium triacetoxyborohydride (466 mg) was added, and the mixture was stirred for 1 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (ethyl acetate:hexane=10:90-80:20) to give the title compound (183.5 mg, yield 30%) as a white solid.
Reaction SMILES: [NH:1]([C:21]([O:23]CC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([NH2:20])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH2:3][C:4](=[O:6])[OH:5].[CH3:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>ClCCl>[NH2:39][CH2:38][C:21]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:18]([NH2:20])=[O:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])[CH2:3][C:4](=[O:6])[OH:5])=[O:23].[CH3:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1
Reactant: NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: NCC(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(N)=O

Procedure:
The title compound was synthesized by solid-phase methodology on a ACT90 automated peptide synthesizer (Advanced ChemTec, Louisville, Ky.) using tritylchloride-polystyrene(1%)divinylbenzene (TCP; loading: 0.96 mmol/g; PepChem, Tubingen) and Fmoc-Asp-Phe-NH2 (NovaBiochem, Laufelfingen) as starting materials. The Fmoc-protected dipeptide amide (320.4 mg; 0.72 mmol) was dissolved in 4 ml dichloromethane. After 1 eq N-methyl-morpholin (NM1) was added the solution was given to 444 mg (0.48 mmol) dry TCP resin. After 5 min an additional volume of 130 ul NNM was added yielding a total amount of 1.80 mmol NMM in solution. The mixture was shaken for further 60 min. Then the residual tritylchloride groups were capped by the addition of 0.5 ml methanol. After further 20 min the resin was filtered off and washed with dichloromethane, DMF and methanol. The resin was dried under reduced pressure. Loading of the resin was determined to be 0.057 mmol/g. The Fmoc group was removed by treatment with piperidine/dimethylformamide (1:1 v/v) for 2×10 min. Afterwards Fmoc-Gly-OH was coupled within 30 min in 30-fold excess in a double coupling procedure using 1 eq TBTU and 1 eq NMM as activing agents. After removal of the Fmoc group by the same procedure as described above Boc-Ada(Boc2)-OH was coupled manually in DMF within 17 h by using a 2.5-fold excess of the protected amino acid and equimolar amounts of TBTU and NMM for activation. Cleavage from the resin and deprotection of the peptide was performed according to example 8f). Instead of heptane trifluoroethanol (2 ml) was used to dissolve the deprotected peptide. From this solution the crude peptide was precipitated by the addition of 16 ml diethylether. After centrifugation the supernatant was discarded and the precipitate lyophilized from tert.-butanol/water (1:1 v/v). Ada-Gly-Asp-Phe-NH2.HCl (28 mg) was obtained as white lyophilisate.
Reaction SMILES: [OH:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][CH2:7][CH2:8][N:9]([CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1>Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][N:9]([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=2)[C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:15]=2)=[CH:33][CH:34]=1
Reactant: COC(=O)CCCc1ccc(N(CCOc2ccc(O)cc2)CCOc2ccc(O)cc2)cc1
Agent: Cl
Product: O=C(O)CCCc1ccc(N(CCOc2ccc(O)cc2)CCOc2ccc(O)cc2)cc1
Yield: 84.6 %

Procedure:
Compound 27 (60 mg, 0.13 mmol) was refluxed in concentrated hydrochloric acid for 2 hours. The reaction was concentrated, quenched with 50 mL of water, and neutralized with ammonium hydroxide to pH 7. The mixture was then extracted with EtOAc and the combined organic layer was washed with water, then brine, and dried over Na2SO4. The solvent was evaporated to yield the compound 28 (50 mg, 0.11 mmol, 85% yield). 1H NMR (CDCl3, 400 MHz) δ12.00 (bs, 1H), 8.92 (bs, 2H), 6.98 (d, J=8.0 Hz, 2H), 6.66-6.77 (m, 10H), 3.99-5.05 (m, 4H), 3.72 (t, J=5.6 Hz, 4H), 2.44 (t, J=7.2 Hz, 2H), 2.17 (t, J=7.2 Hz, 2H), 1.72 (q, J=7.2, 7.6 Hz, 2H); HRMS (ESI, positive) m/z calcd. for C26H30NO6 [M+H]+: 452.2073, found: 452.2007.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH3:19])=[C:6]([CH:18]=1)[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][OH:17])[CH2:12][CH2:11]1)=[O:8].N1C=CC=CC=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[Cl:1][C:2]1[CH:18]=[C:6]([C:7]([NH:9][C@H:10]2[CH2:11][CH2:12][C@H:13]([CH2:16][O:17][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:14][CH2:15]2)=[O:8])[C:5]([CH3:19])=[N:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ncc(Cl)cc1C(=O)N[C@H]1CC[C@H](CO)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ncc(Cl)cc1C(=O)N[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of trans-5-chloro-N-(4-hydroxymethyl-cyclohexyl)-2-methyl-nicotinamide (Intermediate E, step 2) (100 mg, 0.354 mmol) and pyridine (3.6 ml) in dry DCM (3.5 ml) under nitrogen was cooled to approx. 0° C. using an ice-water bath. Methanesulfonyl chloride (0.030 ml, 0.389 mmol) was added dropwise. The reaction mixture was allowed to warm to room temp and stirred at this temp for 4 hours. The reaction was quenched by the addition of sat. NH4Cl at room temp and then extracted with diethyl ether (3×20 ml). The Et2O extracts were combined, washed with sat brine (20 ml), dried (MgSO4), filtered and evaporated to give the title compound as a colourless solid. LCMS 361.2/363.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.52 (1H, d), 7.65 (1H, d), 5.68 (1H, br d), 4.09 (2H, d), 3.96 (1H, m), 3.04 (3H, s), 2.65 (3H, s), 2.21 (2H, m), 1.96 (2H, m), 1.79 (1H, m), 1.27 (4H, m).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]([OH:7])=[O:6].[CH2:8]([O:24][CH2:25][CH:26]([OH:50])[CH2:27][O:28]C(C1C=CC(OC)=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].O>C1(C)C=CC=CC=1>[CH2:8]([O:24][CH2:25][CH:26]([CH2:27][OH:28])[O:50][CH2:4][C:5]([OH:7])=[O:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccc(OC)cc1
Reactant: O=C(O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCOCC(CO)OCC(=O)O
Yield: 53.5 %

Procedure:
To a suspension of 13.1 g of 50% sodium hydride in 200 ml of toluene was add a solution of 12.6 g of chloroacetic acid in 50 ml of toluene over a 45 minute period. A solution of 65.5 g of 1-(hexadecyloxy)-3-[(4-methoxyphenyl)diphenylmethoxy]-2-propanol in 100 ml of toluene was added over 30 minutes. The mixture was refluxed for 65 hours, poured into water and acidified to pH 4. The mixture was extracted with ether. The ether solution was dried and evaporated. The residue was purified by chromatography giving 22.3 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C:9]1[N:10]([CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28])[CH:11]=[C:12](Br)[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8].[CH2:34]([Sn](CCCC)(CCCC)CC=C)[CH2:35][CH2:36]C>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>[Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C:9]1[N:10]([CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28])[CH:11]=[C:12]([C:35]([CH3:36])=[CH2:34])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8]
Reactant: COC(Cn1cc(Br)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=C(C)c1cn(CC(OC)OC)c(C(=O)NCc2cccc(Cl)c2)c(OCc2ccccc2)c1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 69.5 %

Procedure:
To a solution of 3-benzyloxy-5-bromo-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (138 mg) obtained in Example 161, Step 2 in dioxane (2.5 ml) were added tributyl-2-propenyltin (245 mg) and tetrakis(triphenylphosphine)palladium(0) (60 mg), and the mixture was stirred at 100° C. for 4 hr. The solvent was evaporated, toluene was added, and the mixture was concentrated again. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3) to give 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-isopropenyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (89 mg).
Reaction SMILES: [OH-].[K+].CO.[C:5]([C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].[C:16]([N:20]=[N:21][C:22](Cl)([CH2:24][C:25]([CH3:33])([O:27][O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:26])[CH3:23])([CH3:19])([CH3:18])[CH3:17]>O>[C:16]([N:20]=[N:21][C:22]([S:15][C:12]1[CH:11]=[CH:10][C:9]([C:5]([CH3:8])([CH3:6])[CH3:7])=[CH:14][CH:13]=1)([CH2:24][C:25]([CH3:26])([O:27][O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:33])[CH3:23])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1ccc(S)cc1
Reactant: CC(C)(C)N=NC(C)(Cl)CC(C)(C)OOC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)N=NC(C)(CC(C)(C)OOC(C)(C)C)Sc1ccc(C(C)(C)C)cc1
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a stirred solution of 1.38 g (0.021 moles) of 85% potassium hydroxide in 25 ml. of methanol in a 125 ml. erlenmeyer flask was added dropwise 3.66 grams (0.022 moles) of p-t-butylthiophenol. The reaction was stirred an additional 30 minutes and then 6.0 grams (0.0205 moles) of 2-(t-butylazo)-2-chloro-4-methyl-4-(t-butylperoxy)pentane from Example 23 was added dropwise over 30 minutes, holding the reaction temperature at 15° C with a cold water bath. The reaction was stirred an additional hour at room temperature and poured into 100 ml. of water. The product was extracted with 50 ml. of pentane, the pentane solution washed with water, dried over anhydrous sodium sulfate, filtered and the pentane evaporated on a flash evaporator. The residue weighed 8.65 g (72% yield) and its infrared spectrum was in agreement with that of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[CH:7]=[C:8]([CH3:10])[O:9][C:4]=2[CH:3]=1.N1CCCCC1.[Cl:20][CH2:21][CH:22]1[O:24][CH2:23]1>>[Cl:20][CH2:21][CH:22]([OH:24])[CH2:23][O:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[CH:7]=[C:8]([CH3:10])[O:9][C:4]=2[CH:3]=1
Reactant: Cc1cc(=O)c2ccc(O)cc2o1
Reactant: ClCC1CO1
Solvent: C1CCNCC1
Product: Cc1cc(=O)c2ccc(OCC(O)CCl)cc2o1

Procedure:
17.6 g 7-hydroxy-2-methyl-4H-1-benzopyrane-4-one-[J.Org. Chem. 24, 683, (1959)], 0.1 cm3 piperidine and 60 cm3 1-chloro-2,3-epoxy-propane were stirred for 9 hours at a temperature of 90° C. The mixture was worked up according to example 5 (b) and 19.0 g 1-chloro-3-(2-methyl-4H-1-benzopyrane-4-one-7-yloxy)-2-propanol was obtained (m.p. 104°-106° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)[CH2:8][CH2:9][NH:10]C(=O)C(F)(F)F)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CO>O>[C:1]([O:5][C:6](=[O:29])[N:7]([CH2:8][CH2:9][NH2:10])[CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCCc1ccc([N+](=O)[O-])cc1)CCNC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N(CCN)CCCc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C

Procedure:
Add [3-(4-Nitro-phenyl)-propyl]-[2-(2,2,2-trifluoro-acetylamino)-ethyl]carbamic acid tert-butyl ester (16 g, 33 mmol), potassium carbonate (23 g, 170 mmol), methanol (100 mL) and water (45 mL) to a 500 mL flask. Heat to 50° C. for 1 hr. Cool the reaction and filter off any solids. Add dichloromethane and water, stir and separated the layers. Extract the aqueous layer with dichloromethane. Combine the organic layers, wash with brine, dry over MgSO4 and concentrate under reduced pressure to obtain the title compound as an oily residue. The title compound was used without purification. 1H NMR (CDCl3, 500.0 MHz): δ 8.13 (d, 2H, J=9 Hz), 7.32 (d, 2H, J=8.5 Hz), 3.24 (br m, 4H), 2.82 (br m, 2H), 2.69 (t, 2H, J=7.5 Hz), 1.87 (p, J=7.5 Hz), 1.48 (br s, 2H), 1.43 (s, 9H).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[N:10][C:9]([OH:12])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:20]Cl>CN(C)C=O>[C:1]1([N:7]2[C:11]([Cl:20])=[N:10][C:9]([OH:12])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCl
Reactant: Oc1ncn(-c2ccccc2)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Oc1nc(Cl)n(-c2ccccc2)n1

Procedure:
32.2 g of 1-phenyl-3-hydroxy-1,2,4-triazole and 40.5 g of triethylamine in 300 ml of dimethyl formamide. While cooling with ice, 21.3 g of chlorine gas are passed in at 20° to 30°C. Subsequently the resulting triethylamine hydrochloride is filtered off and the solvent is distilled off in vacuo. The residue is taken up in 300 ml of water and extracted 4 times with 200 ml of ether. The combined ethereal extracts are dried over sodium sulphate and, after the solvent has been filtered off, concentrated in vacuo. The residue is recrystallised from acetonitrile. Yield: 15.0 g (38.4 % of theory); m.p. 146°-147°C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:25]=[CH:26][C:27]([C:30](=[O:31])[NH:39][CH2:38][C:37]5[CH:40]=[CH:41][C:34]([F:33])=[CH:35][CH:36]=5)=[CH:28][CH:29]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Product: O=C(NCc1ccc(F)cc1)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 72.6 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 4-fluorobenzylamine (available from Aldrich Chemical Company, Inc.; 78 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(4-fluoro-benzylcarbamoyl)-biphenyl-2-carboxylic acid (88 mg, 84%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.17 (br s, 1H), 9.11 (t, J=5.8 Hz, 1H), 8.46 (s, 1H), 8.38 (s, 1H), 8.33 (s, 1H), 8.24 (d, J=7.8 Hz, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.96 (d, J=8.0 Hz, 2H), 7.76 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 2H), 7.35-7.41 (m, 2H), 7.16 (t, J=8.7 Hz, 2H), 4.50 (d, J=5.8 Hz, 8H).
Reaction SMILES: C(N)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[CH3:18][O:19][C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:21].[Cl:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Cl)=[CH:38][CH:37]=1.[Cl-].[NH4+]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:18][O:19][C:20]([C:22]1([CH2:40][C:39]2[CH:42]=[CH:43][C:36]([Cl:35])=[CH:37][CH:38]=2)[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]1)=[O:21]
Reactant: ClCc1ccc(Cl)cc1
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(C)N
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.3 %

Procedure:
To a solution of isopropylamine (3.71 ml, 26.45 mmol) in THF (110 ml) at 0° C. was added n-butyllithium (10.1 ml of a 2.5M solution in hexanes, 25.25 mmol). The resulting LDA solution was added via cannula to a solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (5.85 g, 24.04 mmol) in THF (110 ml) and HMPA (20 ml) at −78° C. and stirring was continued for 1 hour. 4-Chlorobenzyl chloride (6.4 ml, 50.49 mmol) in THF (20 ml) was added and the solution was warmed to room temperature over 2 hours. After stirring for 18 hours, saturated aqueous ammonium chloride (500 ml) was added and the aqueous phase was extracted with diethyl ether (2×200 ml). The organic phases were combined, dried over magnesium sulphate and concentrated to dryness. Purification by silica column chromatography (0.5% methanol in DCM) gave the ester as an oil (3.03 g, 34%). LC-MS (LCT1) m/z 390 [M+Na+], Rt 8.02 min.
Reaction SMILES: [Li]N([Si](C)(C)C)[Si](C)(C)C.[C:11]([CH:15]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:34]3=[N:35][C:36]([CH3:40])=[CH:37][C:38]([CH3:39])=[C:33]3[N:32]=[C:31]2[CH2:41][CH3:42])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([O:13][CH3:14])=[O:12].[CH:43](Br)([CH3:45])[CH3:44]>>[C:11]([CH:15]([N:22]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:34]3=[N:35][C:36]([CH3:40])=[CH:37][C:38]([CH3:39])=[C:33]3[N:32]=[C:31]2[CH2:41][CH3:42])=[CH:25][CH:24]=1)[CH:43]([CH3:45])[CH3:44])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([O:13][CH3:14])=[O:12]
Reactant: CC(C)Br
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NC(C(=O)OC)c2ccccc2)cc1
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(N(C(C)C)C(C(=O)OC)c2ccccc2)cc1

Procedure:
Using the general procedure for the alkylation of secondary amines with LiN(TMS)2 described in Step A of Example 29, 3-[4-(N-(1-carbomethoxy -1-phenylmethyl)amino)phenylmethyl]-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine (Step A, Example 28) was alkylated with isopropyl bromide. Standard workup and purification by flash chromatography afforded the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:19]([NH:21][C@H:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]3[OH:28])=[O:20])[CH:10]=2)=[CH:4][CH:3]=1.[CH3:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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].O1CCOCC1>[OH:28][C@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27][C@@H:22]1[NH:21][C:19]([C:11]1[CH:10]=[C:9]([CH2:8][C:5]2[CH:6]=[N:7][C:2]([C:33]3[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=3)=[CH:3][CH:4]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)=[O:20]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(Cc2ccc(Cl)nc2)c2ccccc2n1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc(Cc3cc(C(=O)N[C@H]4CCCC[C@@H]4O)nc4ccccc34)cn2)cn1
Temperature: 140 °C

Procedure:
To a microwave vial containing 4-[(6-chloropyridin-3-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide (A) (100 mg, 0.25 morel), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrazole (63 mg, 0.30 mmol), Pd2(dba)3 (2.3 mg, 2.5 μmol), and tricyclohexylphosphine (1.7 mg, 6.1 mop was added 0.84 mL of dioxane and 0.34 mL 1.7 M aqueous tribasic potassium phosphate. The reaction was heated to 140° C. in a microwave reactor for 1 h. The reaction mixture was extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated. The resultant residue was subjected to purification via reverse phase HPLC to afford the title compound that gave a mass ion (ES+) of 442.2241 for M+H+. 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=2.0 Hz, 1H), 8.27 (d, J=7.3 Hz, 1H), 8.19 (s, 1H), 8.14 (d, J=8.6, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.88 (d, J=9.7 Hz, 2H), 7.75 (t, J=7.1 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.39 (dd, J=2.0, 8.1 Hz, 1H), 7.33 (d, J=8.2 Hz, 2H), 4.48 (s, 2H), 3.94 (s, 3H), 3.91-3.84 (m, 1H), 3.58 (m, 1H), 3.38 (br s, 1H) 2.16-2.13 (m, 2H), 1.92-1.79 (m, 2H), 1.52-1.31 (m, 4H).