Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:25]([F:26])=[CH:24][C:10]3[NH:11][C:12]([O:14][CH:15]4[CH2:18][CH:17]([C:19]([O:21]CC)=[O:20])[CH2:16]4)=[N:13][C:9]=3[C:8]=2[F:27])=[CH:3][CH:2]=1.O([Si](C)(C)C)[K]>C1COCC1.CCOC(C)=O>[C:1]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:2]=[CH:3][C:4]([C:7]2[C:25]([F:26])=[CH:24][C:10]3[NH:11][C:12]([O:14][CH:15]4[CH2:18][CH:17]([C:19]([OH:21])=[O:20])[CH2:16]4)=[N:13][C:9]=3[C:8]=2[F:27])=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CC(Oc2nc3c(F)c(-c4ccc(-c5ccccc5)cc4)c(F)cc3[nH]2)C1
Agent: C[Si](C)(C)O[K]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)C1CC(Oc2nc3c(F)c(-c4ccc(-c5ccccc5)cc4)c(F)cc3[nH]2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 3-{[5-(biphenyl-4-yl)-4,6-difluoro-1H-benzimidazol-2-yl]oxy}cyclobutane carboxylate (0.046 g, 0.102 mmol) was dissolved in 1 mL of THF and treated with KOTMS (0.039 g, 0.308 mmol). The reaction mixture was stirred at ambient temperature overnight, and then diluted with EtOAc and washed with 2 N HCl. The aqueous layer was further extracted with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound. LCMS: calculated for C24H18F2N2O3 420.41, observed m/e 420.9 (M+H)+ (Rt 2.07/4 min). 1H NMR (500 MHz, d6-DMSO): δ7.77 (d, 2H), 7.73, (d, 2H), 7.55-7.47 (m, 4H), 7.39 (m, 1H), 7.15 (br, 1H), 5.23 (m, 1H), 2.82-2.70 (m, 2H), 2.32-2.25 (m, 2H), 1.98 (m, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.Cl.[CH3:14][C:15]1([NH:21][C:22](=[O:24])[CH3:23])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C>[I-].[K+].CN(C)C=O>[F:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:18]2[CH2:19][CH2:20][C:15]([NH:21][C:22](=[O:24])[CH3:23])([CH3:14])[CH2:16][CH2:17]2)=[CH:7][CH:8]=1
Reactant: Fc1ccc(OCCCCl)cc1
Reactant: CC(=O)NC1(C)CCNCC1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)NC1(C)CCN(CCCOc2ccc(F)cc2)CC1
Temperature: 70 °C
Yield: 39.6 %

Procedure:
A mixture of 35.84 g of 1-(3-chloropropoxy)-4-fluorobenzene, 33 g of N-(4-methyl-4-piperidinyl)acetamide monohydrochloride, 54 ml of N,N-diethylethanamine, 0.1 g of potassium iodide and 1000 ml of N,N-dimethylformamide was stirred and heated for 1.5 hours at 70° C. The reaction mixture was cooled and the solvent was evaporated. The residue was taken up in a sodium carbonate solution in water and the product was extracted with dichloromethane. The extract was washed successively twice with water, twice with a sodium carbonate solution in water and again with water, dried, filtered and evaporated. The residue was purified by column chromatography (CHCl3 :CH3OH 95:5 by volume). The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried in vacuo at 50° C., yielding 20.93 g of N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]acetamide; mp. 103.4° C. (interm. 2).
Reaction SMILES: [O-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[C:9](=[O:13])([O-:12])[O:10]C.C(=O)(OCC)OC/C=C/C1C=CC=CC=1>CCOCC>[O-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](=[O:10])([O-:13])[O-:12]
Reactant: COC(=O)[O-]
Agent: CCOC(=O)OC/C=C/c1ccccc1
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: CCOCC
Product: O=C([O-])[O-]

Procedure:
Alkali metal phenoxides as nucleophiles proved to be superior to the combination of phenol and amine base. Sodium phenoxide furnished the corresponding allylation product with high regio- and enantioselectivity (Table 6, entries 4-6). Reaction of sodium phenoxide with methyl carbonate 1a formed the alkylation product at room temperature in a modest 40% yield because of competing trans-esterification (entry 4), but reactions with the more hindered and less reactive (E)-cinnamyl ethyl carbonate (1b of Table 6) occurred without significant competing transesterification. This combination of phenoxide and carbonate gave the branched ether in good yields with excellent regio- and enantioselectivities after 35 h at room temperature or 17 h at 50° C. (Table 6, entries 5 and 6).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[CH2:18]([C:21]1[N:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:24]=[C:23]([CH:32]=O)[CH:22]=1)[CH2:19][CH3:20]>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][NH:17][CH2:32][C:23]2[CH:22]=[C:21]([CH2:18][CH2:19][CH3:20])[N:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:24]=2)[CH2:13][CH2:14]1
Reactant: CCCc1cc(C=O)nn1-c1ccccc1
Reactant: Cc1cccc(N2CCN(CCN)CC2)c1C
Product: CCCc1cc(CNCCN2CCN(c3cccc(C)c3C)CC2)nn1-c1ccccc1
Yield: 69.2 %

Procedure:
Compound 16 was prepared using the same method as that of Example 1 except that 4-(2,3-dimethylphenyl)piperazin-1-ylethylamine and 5-propyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4]([CH2:5][C@@H:6]([OH:29])[C@@H:7]3[C@@H:22]2[CH2:21][C@H:20](O)[C@@:19]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1.C(O)=C>>[OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4]([CH2:5][C@@H:6]([OH:29])[C@@H:7]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: C=CO
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 96 h

Procedure:
To 50 ml. of a medium comprising Brewer modified throgylcollate broth (Baltimore Biological Laboratories), a stock culture of Clostridium perfringens ATCC 19574 is inoculated under anaerobic conditions. The medium is incubated under anaerobic conditions, at 37° C for a period of 96 hours and the resultant culture is employed to inoculate 1 liter of the same medium. At the time of inoculation, 2 gm. of 3α, 7α, 12α-trihydroxy-5β-cholanic acid dissolved in 15 ml. of ethenol and sterilized through a Seitz pad is added. The flask is incubated anaerobically for 72 hours and the broth is then filtered on a Buchner funnel with the aid of filter cel and the filtrate is then acidified to pH 1-2 with HCl, extracted 3 times with ether and the combined ether extracts washed with water, dried over sodium sulfate, and evaporated to dryness in vacuo. The residue is then crystalized from ethyl acetate-heptane to yield crude 3α, 7α,-dihydroxy-5β-cholanic acid. If further purification is required, the resultant product may be further treated in accordance with the procedures set forth in my copending application, Ser. No. 417,170, filed Nov. 19, 1973.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([C:19]([OH:21])=O)[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:22][C:23]1[N:24]=[N:25][C:26]([N:29]([CH3:31])[NH2:30])=[CH:27][CH:28]=1>>[Cl:22][C:23]1[N:24]=[N:25][C:26]([N:29]([CH3:31])[NH:30][C:19]([C:9]2[CH:10]=[N:11][C:12]([O:13][CH2:14][C:15]([F:18])([F:16])[F:17])=[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:8]=2)=[O:21])=[CH:27][CH:28]=1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Reactant: CN(N)c1ccc(Cl)nn1
Product: CN(NC(=O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1)c1ccc(Cl)nn1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid (example 12c) and 3-chloro-6-(1-methylhydrazinyl)-pyridazine (CAN 76953-33-8) as starting materials; LC-MS (UV peak area/ESI) 100.0%, 444.1408 (M+H)+.
Reaction SMILES: I[C:2]1([O:9][CH3:10])[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH2:3]1>CC(C)=O.O.[Pd].[Zn]>[CH3:10][O:9][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[O:9][CH3:10]
Reactant: COC1(I)C=C(C)C=CC1
Agent: [Pd]
Agent: [Zn]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(C)ccc1-c1ccc(C)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
Bdb was synthesized according to FIG. 15. Briefly, 1-iodo-5-methylanisole (100 mg, 0.4 mmol) was added in to a mixture of 10% Pd on carbon (100 mg) and zinc powder (100 mg, 1.5 mmol) suspended in 5.2 mL of acetone/water (1:1), and the mixture was stirred at room temperature overnight. The solution was extracted with diethyl ether and the ether layer was collected and dried over anhydrous Na2SO4. The ether was removed under reduced pressure and the residue was applied to a flash column chromatography to afford 2,2′-dimethoxy-4,4′-dimethyl biphenyl as a yellow solid (42 mg, 46%). The conversion of 2,2′-dimethoxy-4,4′-dimethyl biphenyl to 4,4′-bis-bromomethyl-2,2′-dimethoxy-biphenyl was accomplished by following a previously reported procedure and resulted in a 31% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Cl.Cl.[N:52]1[CH:57]=[CH:56][CH:55]=[N:54][C:53]=1[N:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1>>[CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[CH:32][C:33]([C:34]([N:61]6[CH2:62][CH2:63][N:58]([C:53]7[N:52]=[CH:57][CH:56]=[CH:55][N:54]=7)[CH2:59][CH2:60]6)=[O:35])=[CH:37][CH:38]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Agent: Cl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCN(c5ncccn5)CC4)cc3)cn2)cc1
Yield: 178.8 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (60.0 mg, 0.0909 mmol) obtained in Step A in Example 1-D-19 and 1-(2-pyrimidyl)piperazine dihydrochloride (43.1 mg, 0.182 mmol) instead of 3-(aminomethyl)pyridine, amidation was carried out in the same manner as Step B in Example 1-D-19, to obtain a crude product of {4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-phenyl}-(4-pyrimidin-2-yl-piperazin-1-yl)-methanone as a brown solid (131 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-284) as a yellow powder (40.7 mg, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH2:12][C:11](=[O:14])[N:10]([C@@H:15]([CH2:21][CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C@@H:9]2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:30](Br)[CH:31]=[CH2:32].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH2:32]([C@H:12]1[CH2:13][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C@@H:9]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[N:10]([C@@H:15]([CH2:21][CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]1=[O:14])[CH:31]=[CH2:30]
Reactant: C=CCBr
Reactant: CCOC(=O)[C@H](CC)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)OCC)C1=O
Temperature: 25 °C

Procedure:
To a solution of 0.62 g (1.4 mmol) of (S)-ethyl 2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)butanoate (Example 9, Step A) and allyl bromide (0.14 ml, 1.7 mmol) in THF (6.0 mL, 0.25 M) was added lithium bis(trimethylsilyl)-amide (1M solution in THF, 1.5 ml, 1.5 mmol) at −78° C. The reaction was allowed to warm to R.T., then was quenched (sat. aqueous NH4Cl) and extracted with EtOAc. The combined organic layers were washed with water and sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (15 to 20% EtOAc/Hex, gradient elution) provided the title compound as the slower eluting isomer as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:26][CH:25]3[CH:20]([N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:23][CH2:24]3)[CH2:19]2)[C:5]2[CH2:12][CH2:11][O:10][C:9]3[CH:13]=[C:14](I)[CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=1.[C:34]1(B(O)O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:26][CH:25]3[CH:20]([N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:23][CH2:24]3)[CH2:19]2)[C:5]2[CH2:12][CH2:11][O:10][C:9]3[CH:13]=[C:14]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC2CN(c3nc(N)nc4c3CCOc3cc(I)ccc3-4)CC21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCCC2CN(c3nc(N)nc4c3CCOc3cc(-c5ccccc5)ccc3-4)CC21
Temperature: 90 °C

Procedure:
The product from Example 102A (32 mg, 0.057 mmol) was treated with phenylboronic acid (10 mg, 0.085 mmol), Pd(PPh)4 (6.6 mg, 5.7 μmol), and 2 M Na2CO3 (63 μl, 0.12 mmol) in 1,2-dimethoxyethane (170 μl), heated overnight at 90° C., cooled, diluted with CH2Cl2 (25 mL) and washed with 1 M NaOH (10 mL). The layers were separated and the aqueous was extracted with CH2Cl2 (25 mL). The combined CH2Cl2 layers were dried (MgSO4), filtered, concentrated and purified by chromatography on silica gel eluting with a gradient of 5:1 to 1:2 hexane:EtOAc to provide the title compound. 1H NMR (CDCl3) δ 1.32-1.46 (m, 2H), 1.49 (s, 9H), 1.52-1.82 (m, 3H), 2.15-2.28 (m, 1H), 2.64-2.89 (m, 3H), 3.35 (d, J=10.5 Hz, 1H), 3.54 (t, J=9.2 Hz, 1H), 3.72 (t, J=10.0 Hz, 1H), 3.87 (dd, J=10.7, 5.6 Hz, 1H), 4.00-4.09 (m, 1H), 4.72 (s, 3H), 4.72 (s, 2H), 7.32-7.40 (m, 1H), 7.41-7.50 (m, 3H), 7.61-7.66 (m, 2H), 8.14 (d, J=8.1 Hz, 1H); MS (M+H)+ m/z at 514.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=CC=CC=2)[CH:3]=[CH:2]1.C([N:17]1[C:29]2[C:28]([OH:30])=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Cl:46])[CH:22]=2)(OC(C)(C)C)=O.O[C@@H]1CCN(C(OC(C)(C)C)=O)C1>>[Cl:38][C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:27]1[C:28]([O:30][C@@H:3]3[CH2:4][CH2:9][NH:1][CH2:2]3)=[C:29]3[NH:17][C:18]4[CH:19]=[CH:20][C:21]([Cl:46])=[CH:22][C:23]=4[C:24]3=[CH:25][C:26]2=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Cl)cc2c2cc3c4cc(Cl)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Agent: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Product: Clc1ccc2[nH]c3c(O[C@@H]4CCNC4)c4[nH]c5ccc(Cl)cc5c4cc3c2c1

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dichloro-6-hydroxyindolo[2,3-b]carbazole and the reagent is (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate. 1H-NMR (400 MHz, CD3OD) δ ppm 8.51 (s, 1 H), 8.14-8.11 (m, 2H), 7.44 (dd, J=8.4, 0.6 Hz, 2 H), 7.31 (dd, J=8.4, 2.2 Hz, 2 H), 5.41 (t, J=4.6 Hz, 1 H), 3.91-3.72 (m, 2 H), 3.56-3.45 (m, 2 H), 2.48-2.40 (m, 1 H), 1.28-1.16 (m, 1 H); MS (ESI) m/z 408.2 (M−H)−; MS (ESI) m/z 410.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:24][C:25](=[O:30])[C:26]([NH:28][NH2:29])=[O:27])[CH2:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C1C[O:34][CH2:33]C1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:24][C:25]([C:26]3[O:27][C:33](=[O:34])[NH:29][N:28]=3)=[O:30])[CH2:16][C@@H:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)C(=O)NN
Reactant: C1CCOC1
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1n[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (4S)-ethyl 5-(3′-chlorobiphenyl-4-yl)-4-(2-hydrazinyl-2-oxoacetamido)-2-methylpentanoate, intermediate 26, (542 mg, 1.25 mmol) in THF (16 mL) is added CDl (244 mg, 1.50 mmol) at room temperature. After stirring for 18 hour at room temperature, the reaction is quenched with H2O and 1M HCl and diluted in EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O(0.1% TFA)/CH3CN) and by Chiral-HPLC (OJ-H 21×250 mm, EtOH(0.1% TFA)/Heptane=30/70) to give (2R,4S)-ethyl 5-(3′-chlorobiphenyl-4-yl)-2-methyl-4-(5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-carboxamido)pentanoate (333 mg). HPLC retention time=1.74 minutes (condition A); MS 458.2 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (d, J=7.1 Hz, 3H) 1.12 (t, J=7.1 Hz, 3H) 1.58-1.74 (m, 1H) 1.76-1.91 (m, 1H) 2.45-2.50 (m, 1H) 2.77 (dd, J=13.7, 7.9 Hz, 1H) 2.86 (dd, J=13.7, 7.9 Hz, 1H) 4.00 (q, J=7.1 Hz, 2H) 4.06-4.22 (m, 1H) 7.28 (d, J=8.1 Hz, 2H) 7.37-7.42 (m, 1H) 7.47 (t, J=7.8 Hz, 1H) 7.58-7.66 (m, 3H) 7.67-7.73 (m, 1H) 8.86 (d, J=8.8 Hz, 1H) 12.95 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][CH3:15])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][NH:21][C:22]2=[O:28].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>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]>[CH3:27][C:26]1[C:17]([NH:16][C:2]2[C:7]([C:8]3[CH:9]=[C:10]([NH:14][CH3:15])[N:11]=[CH:12][N:13]=3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:28])[NH:21][CH:20]=[CH:19]2
Reactant: Cc1ccc2c(=O)[nH]ccc2c1N
Reactant: CNc1cc(-c2cccnc2Cl)ncn1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CNc1cc(-c2cccnc2Nc2c(C)ccc3c(=O)[nH]ccc23)ncn1
Temperature: 150 °C
Yield: 25.9 %

Procedure:
6-(2-chloropyridin-3-yl)-N-methylpyrimidin-4-amine (897 mg, 4.1 mmol), 5-amino-6-methylisoquinolin-1(2H)-one (779 mg, 4.5 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (128 mg, 0.33 mmol) and tris(dibenzylideneacetone)dipalladium (0) (149 mg, 0.16 mmol) were added to a microwave tube. The tube was capped and flushed with nitrogen, and then lithium bis(trimethylsilyl)amide (16.9 mL, 1.0 M solution in THF) was added. The mixture was heated in a microwave reactor at 150° C. for 15 min. The reaction mixture was quenched with saturated aqueous sodium bicarbonate then extracted with DCM. The DCM extracts were conccentrated and purified by flash chromatography (0-10% 2 M ammonia in methanol) to give the title compound (380 mg, 26%). MS (M+H)+ 359.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:4]([NH2:12])[CH:3]=1.[CH:13]1([CH:19]=O)[CH2:18][CH2:17][CH:16]=[CH:15][CH2:14]1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[S:8](=[O:9])(=[O:10])[NH:11][CH:19]([C:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=3)[NH:12][C:4]=2[CH:3]=1
Reactant: O=CC1CC=CCC1
Reactant: Nc1cc(Cl)ccc1S(N)(=O)=O
Solvent: CC#N
Product: O=S1(=O)NC(C2=CCCCC2)Nc2cc(Cl)ccc21

Procedure:
4-chloro-2-aminobenzenesulfonamide (20 g.) and 12 g. of 3-cyclohexene carboxaldehyde are combined in 150 ml. of acetonitrile and refluxed 41/2 hours. The precipitate which forms during refluxing and on cooling is collected by filtration and washed with cold acetonitrile. The crude (17.4 g) is recrystallized from dimethylformamide-water to give a white product melting at 252°-4°. Analysis calculated for C13H15ClN2O2S: C% 52.26, H% 5.06. Found: C% 52.39; H% 5.00.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][C:17]([OH:19])=O)[CH2:11]2)=[O:8])=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]2=[O:42])=[CH:32][C:31]=1[F:43].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(#N)C.CN(C=O)C>[F:43][C:31]1[CH:32]=[C:33]([N:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]2=[O:42])[CH:34]=[CH:35][C:30]=1[NH:29][C:17]([CH2:16][N:12]1[CH2:13][CH2:14][CH2:15][CH:10]([NH:9][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:8])[CH2:11]1)=[O:19]
Reactant: O=C(O)CN1CCCC(NC(=O)c2ccc(Cl)s2)C1
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCCC(NC(=O)c2ccc(Cl)s2)C1)Nc1ccc(-n2ccccc2=O)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.4 %

Procedure:
9.3 To a stirred suspension of 300 mg {3-[(5-chloro-thiophene-2-carbonyl)-amino]-piperidin-1-yl}-acetic acid (containing 2 mol equivalents of sodium chloride) at r.t. in 5 ml acetonitrile and 0.5 ml DMF under an argon atmosphere were added 0.5 ml N-ethyldiisopropylamine, 175 mg 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (CAS 536747-52-1, prepared according to WO 2003045912) and 365 mg BOP-Cl. The compact slurry was then stirred at r.t. for 18 h. The mixture was concentrated. The residue was taken up with CH2Cl2, washed with 1 N NaOH, H2O and brine, dried (MgSO4), filtered and concentrated. The crude product was purified by chromatography (silica gel; gradient: cyclohexane to EtOAc) to give 98 mg 5-chloro-thiophene-2-carboxylic acid (1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-piperidin-3-yl)-amide. White solid. MS 489.5 ([M+H]+)
Reaction SMILES: [ClH:1].Cl.O[NH:4][C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[N:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[NH2:22])=[NH:6]>[Ni].CO.O>[ClH:1].[ClH:1].[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[N:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[NH2:22])(=[NH:4])[NH2:6]
Reactant: N=C(NO)c1cccc2c1CCC2=Nn1ccnc1N
Agent: [Ni]
Agent: Cl
Solvent: O
Solvent: CO
Product: N=C(N)c1cccc2c1CCC2=Nn1ccnc1N

Procedure:
0.3 g of Raney nickel is added to a solution of 0.8 g (2.33 mmol) of 1-[4-(N-hydroxy-amidino)-2,3-dihydro-1H-inden-1-ylideneamino]-2-amino-imidazole dihydrochloride in 60 ml of methanol/water (1:1), and hydrogenation is carried out at room temperature and under normal pressure until the absorption of hydrogen has ceased. The filtrate is adjusted to pH 3 with a small amount of 3N methanolic hydrochloric acid and is concentrated by evaporation in vacuo. Recrystallization of the residue from methanol/water yields the title compound, m.p. >260° C., 1H-NMR (D2O): δ=8.15 (d, 1H); 7.82 (d, 1H); 7.58 (t, 1H); 7.17 (d, 1H); 6.90 (d, 1H); 3.29-3.35 (m, 2H); 3.12-3.18 (m, 2H).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[C:35]1([OH:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH3:33][C:8]1[CH:9]=[C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:24][C:23]=3[O:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:15]=2)[CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][C:4]([OH:3])=[O:34]
Reactant: CCOC(=O)CCc1ccc(Oc2ccc(C)c(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: Oc1ccccc1
Product: Cc1cc(Oc2ccc(C)c(Oc3ccc(C(F)(F)F)cc3Oc3ccccc3)c2)ccc1CCC(=O)O
Yield: 57 %

Procedure:
The compound of 3-{4-[3-(2-Bromo-4-trifluoromethyl-phenoxy)-4-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester is reacted with phenol as in Example 45 to afford 0.256 g (57%) of the title compound. 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C30H26O5F3 523.1732, found 523.1749.