Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[N:13]=[C:12]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:11]=[C:10]([NH:20][S:21]([CH:24]=[CH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([OH:34])=[O:33])=[CH:28][CH:27]=2)(=[O:23])=[O:22])[C:9]=1[O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[O:42][CH3:43].[CH3:44]O>>[CH3:6][O:7][C:8]1[N:13]=[C:12]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:11]=[C:10]([NH:20][S:21]([CH:24]=[CH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([O:34][CH3:44])=[O:33])=[CH:30][CH:31]=2)(=[O:22])=[O:23])[C:9]=1[O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[O:42][CH3:43]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)C=Cc2ccc(C(=O)O)cc2)nc(-c2ncccn2)nc1OC
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C=CS(=O)(=O)Nc2nc(-c3ncccn3)nc(OC)c2Oc2ccccc2OC)cc1
Reaction time: 8 h

Procedure:
Concentrated sulfuric acid (0.1 ml) was added to a solution of 150 mg of N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(4-carboxyphenyl)ethenesulfonamide in 10 ml of methanol followed by stirring overnight under a refluxing condition. The reaction mixture was concentrated in vacuo, 1N hydrochloric acid was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with a saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo and the resulting solid was recrystallized form ethyl acetate to give 102 mg of N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-(4-methoxycarbonylphenyl)ethenesulfon-amide.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)[CH3:2].[NH:12]1[CH2:15][CH:14]([NH:16][C:17](=[O:34])[CH2:18][NH:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:13]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([O:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([N:12]2[CH2:13][CH:14]([NH:16][C:17](=[O:34])[CH2:18][NH:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]([F:31])([F:33])[F:32])[CH:28]=4)[N:23]=[CH:22][N:21]=3)[CH2:15]2)[CH2:7][CH2:6]1)[CH3:2]
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: CCOCC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCOCC1CCC(N2CC(NC(=O)CNc3ncnc4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
Reaction of 4-(ethoxymethyl)cyclohexanone with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product.
Reaction SMILES: [OH:1][C:2]1([CH3:16])[CH2:5][CH:4]([NH:6]C(=O)OC(C)(C)C)[C:3]1([CH3:15])[CH3:14].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:6][CH:4]1[CH2:5][C:2]([CH3:16])([OH:1])[C:3]1([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NC1CC(C)(O)C1(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(O)CC(N)C1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (3-hydroxy-2,2,3-trimethylcyclobutyl)carbamate (1.0 equiv.) in anhydrous DCM (0.5 M) was added trifluoroacetic acid (1.0 M) at 0° C. and the mixture was stirred at room temperature for 30 min. After removal of the volatile solvents, the residue was neutralized by ammonia MeOH solution and the final resulting mixture was concentrated to give the crude title product which was used for the next step without further purification. MS (ESI) m/z 130.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[NH2:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]3[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=3)=[CH:30][C:25]=2[N:24]=[C:23]1[OH:38]>>[CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][N:22]2[C:26]3[CH:27]=[CH:28][C:29]([C:31]4[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=4)=[CH:30][C:25]=3[N:24]=[C:23]2[OH:38])=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: NCCn1c(O)nc2cc(C3=NNC(=O)CC3)ccc21
Reactant: CC(C)COCCc1ccc(OCC2CO2)cc1
Product: CC(C)COCCc1ccc(OCC(O)CNCCn2c(O)nc3cc(C4=NNC(=O)CC4)ccc32)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2- isobutoxy-ethyl)phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)-2-hydroxy-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][OH:8].N1C=CC=CC=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C(Cl)(Cl)Cl>[C:17]([O:8][CH2:7][C:6]1[CH:9]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[Cl:10])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OCc1cc(Br)ccc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(OCc1cc(Br)ccc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-2-chlorobenzylalcohol (1.0 g) and pyridine (0.44 mL) in chloroform (40 mL) was added benzoyl chloride (0.58 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1N HCl under ice-cooling, and the mixture was extracted with chloroform. The organic layer was washed successively with water, an aqueous saturated sodium hydrogencarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. The resultant residue was triturated with diisopropylether to give 5-bromo-2-chlorobenzyl benzoate (753 mg) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]2[S:31][C:30]([O:32][CH3:33])=[N:29][CH:4]2[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]([C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[O:8][C:7]2=[O:28].[CH:34]1([CH2:37][NH2:38])[CH2:36][CH2:35]1>>[CH:34]1([CH2:37][NH:38][C:7]([C:6]2[C:11]([NH:10][C:9]([C:12]3[N:13]([C:21]4[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=4)[N:14]=[C:15]([C:17]([F:19])([F:20])[F:18])[CH:16]=3)=[O:8])=[C:2]([Cl:1])[CH:3]3[S:31][C:30]([O:32][CH3:33])=[N:29][CH:4]3[CH:5]=2)=[O:28])[CH2:36][CH2:35]1
Reactant: NCC1CC1
Reactant: COC1=NC2C=c3c(nc(-c4cc(C(F)(F)F)nn4-c4ncccc4Cl)oc3=O)=C(Cl)C2S1
Product: COC1=NC2C=C(C(=O)NCC3CC3)C(NC(=O)c3cc(C(F)(F)F)nn3-c3ncccc3Cl)=C(Cl)C2S1

Procedure:
See step f) of example H2 using 4-chloro-6-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-2-methoxy-3a,9a-dihydro-7-oxa-3-thia-1,5-diaza-cyclopenta[b]naphthalen-8-one as starting material and cyclopropanemethylamine. After overnight reaction and chromatography column purification, the expected product is obtained within 34%; LC/MS: 585/587 (M+1)+; m.p.: 199-201° C.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=4[F:51])[CH:34]=3)[O:32][C@@:10]1([C:52]([OH:54])=[O:53])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:60](=O)(O)[O-].[Na+].O>CO>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=4[F:51])[CH:34]=3)[O:32][C@@:10]1([C:52]([O:54][CH3:60])=[O:53])[CH2:11][O:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(=O)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(=O)OC)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 40 °C
Reaction time: 7 h
Yield: 62 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl) methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-carboxylic acid 24a (507 mg, 0.67 mmol) in methanol (10 mL) was added concentrated sulphuric acid (0.04 mL, 0.74 mmol) at room temperature. The mixture was warmed up to 40° C. and stirred for 7 hours. The reaction mixture was cooled to room temperature and adjusted with saturated aqueous sodium bicarbonate to pH 7. To the mixture was added 10 mL of water and the resulting mixture was extracted with ethyl acetate (15 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=15/1 to give the title compound 24b as colorless oil (320 mg, 62%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.39 (m, 10H), 7.20 (m, 6H), 6.89 (d, 2H), 6.63 (t, 1H), 6.51 (t, 1H), 4.83 (m, 3H), 4.63 (d, 1H), 4.53 (d, 1H), 4.30 (d, 1H), 4.20 (d, 2H), 4.08-3.97 (m, 5H), 3.90 (d, 1H), 3.75 (m, 1H), 3.71 (s, 3H), 1.44 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:17](=[O:28])[CH2:18][N:19]4[CH:23]=[C:22]([C:24]([NH2:27])=[N:25][OH:26])[CH:21]=[N:20]4)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:29]C1C=CC(S(O)(=O)=O)=CC=1.O>C(OC)(OC)OC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:17](=[O:28])[CH2:18][N:19]4[CH:23]=[C:22]([C:24]5[N:27]=[CH:29][O:26][N:25]=5)[CH:21]=[N:20]4)[C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: NC(=NO)c1cnn(CC(=O)N2CCCc3c2cnn3-c2ccc(F)cc2)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(OC)OC
Product: O=C(Cn1cc(-c2ncon2)cn1)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 100 °C
Yield: 93.2 %

Procedure:
A mixture of 1-[2-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-2-oxo-ethyl]-N′-hydroxy-pyrazole-4-carboxamidine (0.115 g, 0.30 mmol) and p-TsOH.H2O (0.030 g, 0.15 mmol) in HC(OMe)3 (3 mL) was heated at 100° C. for 1.5 hrs. It was then cooled to rt. The mixture was partitioned between IPA/CHCl3 (1:2, 50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified by reverse phase HPLC to afford the desired product (0.055 g, 21%). 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 7.65-8.50 (m, 3H), 7.44 (dd, J=8.4, 4.6 Hz, 2H), 7.17 (dd, J=9.2, 7.6 Hz, 2H), 5.27 (m, 2H), 3.85 (m, 2H), 2.85 (m, 2H), 2.14 (m, 2H); MS: (ES) m/z calculated for C19H16FN7O2 [M+H]+ 394.1, found 394.1.
Reaction SMILES: [C:1]([N:5]1[CH2:31][CH2:30][CH2:29][C:8]2[C:9](Br)=[C:10]3[C:19]4[CH:18]=[C:17]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)[C:16]([O:26][CH3:27])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:32])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:38]1[O:39][CH:40]=[CH:41][N:42]=1)CCC>C1(C)C=CC=CC=1.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>[C:1]([N:5]1[CH2:31][CH2:30][CH2:29][C:8]2[C:9]([CH:38]3[NH:42][CH2:41][CH2:40][O:39]3)=[C:10]3[C:19]4[CH:18]=[C:17]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)[C:16]([O:26][CH3:27])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: COc1cc2c(cc1-c1cccnc1)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCC3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1-c1cccnc1)-c1c(C3NCCO3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCC3
Yield: 31.1 %

Procedure:
A solution of 49 mg of 13d, 50 mg of 2-tributylstannyl oxazole and 10 mg of Pd(PPh3)4 in 3 ml of degassed toluene was heated under N2 at 100° C. for 48 hr. The reaction mixture was cooled and applied to a silica gel column and eluted with a gradient of toluene/ethyl acetate. The product obtained was triturated with diethyl ether to provide 15 mg of 13f as white crystalline material; Mp 218-220° C. Rf 0.20 (toluene/ethyl acetate 1/1). MS-ESI: [M+1] 482.23.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]([CH2:18][CH:19]=[CH2:20])[C:5]=1[OH:21])[CH:2]=[CH2:3].[CH3:22][C:23]1[O:27][C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:25][C:24]=1[CH2:34][CH2:35]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]([CH2:18][CH:19]=[CH2:20])[C:5]=1[O:21][CH2:35][CH2:34][C:24]1[N:25]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:27][C:23]=1[CH3:22])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(OCc2ccccc2)cc(CC=C)c1O
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCc1cc(OCc2ccccc2)cc(CC=C)c1OCCc1nc(-c2ccccc2)oc1C
Yield: 83.8 %

Procedure:
A mixture of 2,6-diallyl-4-benzyloxy-phenol (520 mg, 1.85 mmol), toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)ethyl ester (Japan Tobacco Inc WO 9518125) (828 mg, 2.32 mmol), and Cs2CO3 (604 mg, 1.85 mmol) was heated at 55° C. in DMF (5 mL) for 20 h. Additional toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)ethyl ester (300 mg, 0.839 mmol) and CS2CO3 (200 mg, 0.614 mmol) were added, and the mixture was heated for 18 h. The reaction mixture was cooled and partitioned between EtOAc (40 mL) and H2O (10 mL). The organic layer was washed with brine (15 mL), dried (Na2SO4), and concentrated. The crude product was purified by radial chromatography using hexanes:ethyl acetate (8:1) to give a colorless oil (722 mg, 83%): 1H NMR (400 MHz, CDCl3) δ 2.38 (s, 3H), 2.95 (t, 2H, J=6.3 Hz), 3.33 (d, 2H, J=6.3 Hz), 4.01 (t, 2H, J=6.3 Hz), 4.96 (s, 2H), 4.97-5.02 (m, 2H), 5.03 (s, 2H), 5.84-5.94 (m, 1H), 6.65 (s, 2H), 7.28-7.45 (m, 8H), 7.99 (dd, 2H, J=2.0, 7.8 Hz).
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[N:22]=[C:23]([C:26]5[CH:31]=[N:30][CH:29]=[CH:28][N:27]=5)[S:24][CH:25]=4)=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:8]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[N:22]=[C:23]([C:26]5[CH:31]=[N:30][CH:29]=[CH:28][N:27]=5)[S:24][CH:25]=4)=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4cnccn4)n3)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2ccc(OCc3csc(-c4cnccn4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
A mixture of ethyl 3-[4-phenyl-1-[4-[2-(2-pyrazinyl)-4-thiazolylmethoxy]benzyl]-3-pyrrolyl]propionate (629 mg), 1N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature overnight and 1N hydrochloric acid (2.5 ml) was added, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[4-phenyl-1-[4-[2-(2-pyrazinyl)-4-thiazolylmethoxy]benzyl]-3-pyrrolyl]propionic acid (523 mg, yield: 88%) as colorless crystals. This was recrystallized from ethanol. Melting point: 137–138° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][C:23](=[O:31])[CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@H:14](OS(C)(=O)=O)[CH2:13]1)[CH:6]=[CH:5]2.[C-:32]#[N:33].[Li+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([NH:22][C:23](=[O:31])[CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@@H:14]([C:32]#[N:33])[CH2:13]1)[CH:6]=[CH:5]2
Reactant: [C-]#N
Reactant: CS(=O)(=O)O[C@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Agent: [Li+]
Solvent: CN(C)C=O
Product: N#C[C@@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1

Procedure:
Prepared according to the method of example 96, using N-[6-chloro-2-[(3S)-3-[(methylsulfonyl)oxy]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide (example 33 (a)) (0.33 g) and lithium cyanide in N,N-dimethylformamide (6 mL, 0.5M). Purification (SiO2, isohexane:ethyl acetate 60:40, as eluant) gave the sub-title compound as a solid (0.066 g).
Reaction SMILES: C([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:25])[CH2:17][C:18]([CH3:24])([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)=O.Cl>CO>[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:25])[CH2:17][C:18]([CH3:23])([CH3:24])[C:19]([O:21][CH3:22])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)C(C)(C)CC(=O)c1ccc(-c2ccc(NC=O)cc2)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)C(C)(C)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a suspension of methyl 4-[4′-(formylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoate (2.40 g, 7.07 mmol) in 20 mL methanol, was added 7 mL concentrated hydrochloric acid at below rt. The reaction mixture was stirred at rt overnight. The mixture was concentrated under reduced pressure and saturated aqueous sodium bicarbonate solution was slowly added until pH>8.0. The aqueous layer was then extracted with methylene chloride (2×25 mL), and the combined organic layer was dried over sodium sulfate. The mixture was concentrated under reduced pressure to afford methyl 4-(4′-amino-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate as a light red solid (2.1 g, 95%). 1H NMR (CDCl3) δ 7.96 (d, J=9Hz, 2H), 7.60 (d, J=9Hz, 2H), 7.46 (d, J=9Hz, 2H), 6.76 (d, J=9Hz, 2H), 3.85 (br s, 2H), 3.69 (s, 3H), 3.32 (s, 2H), 1.35 (s, 6H); ESI-MS m/z 312.4 (MH+); HRMS m/z calcd for MH+ 312.1594, found 312.1597.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([SH:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[C:28](=[O:41])[CH:29]=[C:30]([CH2:33][O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[O:31][CH:32]=1>CN(C=O)C.O>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]3[C:28](=[O:41])[CH:29]=[C:30]([CH2:33][O:34][CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][O:36]4)[O:31][CH:32]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=c1cc(COC2CCCCO2)occ1OCCCCCCCBr
Reactant: FC(F)(F)c1ccc2c(S)ccnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(COC2CCCCO2)occ1OCCCCCCCSc1ccnc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-Trifluoromethyl-4quinoline-thiol (320 mg, 1.4 mmol) was charged in a 50 mL round-bottomed flask equipped with a magnetic stirrer and under inert atmosphere. Anhydrous DMF (10 mL) and NaH 60% dispersion in oil (55 mg, 1.4 mmol) were successively added at 4° C. After 30 min a solution of 5-(7-bromo-heptyloxy)-2-(tetrahydro-pyran-2-yloxymethyl)-4H-pyran-4-one 4 (520 mg, 1.3 mmol) in DMF (6 mL) was added at room temperature. The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was poured in 150 mL of H2O, extracted with EtOAc (3×80 mL). The organic layer was washed with brine (2×20 mL), dried over MgSO4, filtered and evaporated to dryness. The crude compound was purified by column chromatography (SiO2; CH2Cl2:MeOH=95:5 to 98:2) to give 5-(7-(7-(trifluoromethyl)quinolin-4-ylthio)heptyloxy)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-4-one EHT 8883 (310 mg, 43% yield) as an oil.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[C:10]([C:12]([CH2:15][CH3:16])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[OH:17])([CH2:4][CH3:5])([CH3:3])[CH3:2].Br[C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]>N1C=CC=CC=1.C(OCC)C.[Cu]Cl>[C:1]([C:6]1[CH:11]=[C:10]([C:12]([CH2:15][CH3:16])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[O:17][C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)c1ccc(O)c(C(C)(C)CC)c1
Reactant: COC(=O)c1ccccc1Br
Agent: Cl[Cu]
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCC(C)(C)c1ccc(Oc2ccccc2C(=O)OC)c(C(C)(C)CC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
First, methyl 2,4-di-(tert-amyl)phenoxybenzoate was prepared. To a stirred suspension under argon of sodium hydride (60% dispersion in mineral oil, 1.1 g, 46.5 mmol, washed with ligroin to remove the oil) in pyridine (60 mL) was added dropwise a solution of 2,4-di-(tert-amyl)phenol (12.0 g, 51.2 mmol) in 20 mL of pyridine. The mixture was stirred for 2 h at room temperature and then treated dropwise with a solution of methyl 2-bromobenzoate (10 g, 46.5 mmol) in 10 mL of pyridine. Copper (I) chloride (1.15 g, 11.6 mmol) was added, and the mixture was heated at reflux 16 h and then cooled to ambient. The mixture was diluted with diethyl ether, washed successively with 10% aqueous HCl, water, and brine, and then dried over Na2SO4. The solvent was removed at reduced pressure to deposit dark brown oil. This crude product was purified by column chromatography to give 25.5 g, 78% of theory) of a light brown oil. 1H NMR (CDCl3): δ 0.70 (t, 6H), 1.3 (s, 6H), 1.4 (s, 6H), 1.63 (q, 2H), 1.85 (q, 2H), 3.85 (s, 3H), 6.68 (d, 1H), 6.82 (d, 1H), 7.05 (m, 2H), 7.3 (br s, 1H), 7.35 (t, 1H), 7.9 (dd, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)[C:4]1[C:5]([CH3:17])=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7](O)=[O:8])[CH3:2].Cl.[NH2:26][CH2:27][C:28]1[C:29](=[O:38])[NH:30][C:31]([CH3:37])=[CH:32][C:33]=1[CH2:34][CH2:35][CH3:36].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[CH2:1]([N:3]([CH:18]1[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]1)[C:4]1[C:5]([CH3:17])=[C:6]([CH:10]=[C:11]([C:13]([F:15])([F:14])[F:16])[CH:12]=1)[C:7]([NH:26][CH2:27][C:28]1[C:29](=[O:38])[NH:30][C:31]([CH3:37])=[CH:32][C:33]=1[CH2:34][CH2:35][CH3:36])=[O:8])[CH3:2]
Reactant: CCN(c1cc(C(F)(F)F)cc(C(=O)O)c1C)C1CCN(C)CC1
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(C(F)(F)F)cc(N(CC)C2CCN(C)CC2)c1C
Temperature: 23 °C
Reaction time: 20 h
Yield: 22.4 %

Procedure:
To a stirred solution of 3-[ethyl(1-methylpiperidin-4-yl)amino]-2-methyl-5-(trifluoromethyl)benzoic acid (crude material, 680 mg, 1.97 mmol) and 3-(aminomethyl)-6-methyl-4-propyl-1,2-dihydropyridin-2-one HCl salt (642 mg, 2.96 mmol) in DMSO (7 mL) was added PyBOP (1.85 g, 3.55 mmol) and hunig base (764 mg, 5.91 mmol). The reaction mixture was stirred at 23° C. for 20 hours. The reaction mixture was quenched with water and resulting precipitate was collected. The solid was purified by silica gel column chromatography (NH—SiO2 ethylacetate/MeOH=20/1) to give the titled compound as a white solid (224 mg, 22% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.31 (s, 1H), 7.26 (s, 1H), 7.16 (m, 1H), 5.94 (s, 1H), 4.55 (d, J=5.9 Hz, 2H), 3.08 (q, J=7.0 Hz, 2H), 2.82 (m, 2H), 2.66-2.73 (m, 3H), 2.33 (s, 3H), 2.24 (s×2, 6H), 1.79-1.98 (m, 2H), 1.67-1.75 (m, 4H), 1.59-1.66 (m, 2H), 1.02 (t, J=7.2 Hz, 3H), 0.84 (t, J=7.0 Hz, 3H); MS (ES) [M−H] 505.2; HPLC 98.1% purity.
Reaction SMILES: O[N:2]=[C:3]([C:11](=O)[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]2[NH:26][C:11]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[N:2]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)c1ccncc1
Reactant: COc1ccc(CN)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nc(C(=O)OC(C)(C)C)c(-c3ccncc3)[nH]2)cc1
Yield: 33.2 %

Procedure:
tert-Butyl 2-hydroxyimino-3-oxo-3-(4-pyridyl)propionate (3.0 g) and 4-methoxybenzylamine (1.7 g) were dissolved in toluene (80 ml), and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 10 to give tert-butyl 2-(4-methoxyphenyl)-5-(4-pyridyl)imidazole-4-carboxylate (1.4 g), melting point 211-212° C.