Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:36])[C:7]([CH3:35])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][NH:17][C:18]2[N:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)=[CH:20][N:19]=2)[N:14]=1)[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:35][C:7]([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][NH:17][C:18]2[N:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][C:31]([F:34])([F:32])[F:33])=[CH:28][CH:29]=3)=[CH:20][N:19]=2)[N:14]=1)([CH3:8])[C:6]([OH:36])=[O:5]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ncc(-c3ccc(OC(F)(F)F)cc3)cn2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Sc1nc(CCNc2ncc(-c3ccc(OC(F)(F)F)cc3)cn2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.6 %

Procedure:
2-Methyl-2-({4-[2-({5-[4-(trifluoromethoxy)phenyl]pyrimidin-2-yl}amino)ethyl]-1,3-thiazol-2-yl}thio)propionic acid tert-butyl ester (370 mg) obtained in Example 162-2 was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (the objective compound was extracted in the ethyl acetate layer). The ethyl acetate layer was washed with aqueous 10% citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1 to 1:1) to give the title compound (297 mg) as a white solid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C[O:6][C:7]([C:9]1[N:10]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:11]2[C:16]([C:17]=1[C:18](=[O:29])[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=1)=[CH:15][CH:14]=[C:13]([O:30]C)[CH:12]=2)=[O:8]>CCS.C(Cl)Cl>[F:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[F:27])[CH2:20][NH:19][C:18]([C:17]1[C:16]2[C:11](=[CH:12][C:13]([OH:30])=[CH:14][CH:15]=2)[N:10]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:9]=1[C:7]([OH:8])=[O:6])=[O:29]
Reactant: COC(=O)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC)cc2n1Cc1ccccn1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: O=C(NCc1ccc(F)c(F)c1)c1c(C(=O)O)n(Cc2ccccn2)c2cc(O)ccc12
Reaction time: 2 h

Procedure:
General Procedure M. To a solution of AlCl3 (1.8 g, 13.5 mmol) in EtSH (25 ml) at room temperature was added a solution of methyl3-(3,4-difluorobenzylcarbamoyl)-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (Compound 93, 1.26 g, 2.7 mmol) in CH2Cl2 (75 ml). The reaction was stirred for 2 h and was quenched with ice. The mixture was concentrated in vacuo, and the resulting white suspension in aqueous solution was acidified with 1M HCl and filtered. The cake was washed with H2O (×3), taken in MeOH, dried over MgSO4, and concentrated in vacuo to yield the title compound as a crude yellowish white solid contaminated with unknown inorganic product. The crude was used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[C:10]([NH:11][CH2:12][C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])=[CH:9][CH:8]=[CH:7][N:6]2[C:21]=1[CH3:22].[C-:23]#[N:24].[K+].CS(C)=O.C(Cl)Cl>O>[C:23]([CH2:2][C:3]1[N:4]=[C:5]2[C:10]([NH:11][CH2:12][C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])=[CH:9][CH:8]=[CH:7][N:6]2[C:21]=1[CH3:22])#[N:24]
Reactant: [C-]#N
Reactant: Cc1cccc(C)c1CNc1cccn2c(C)c(CCl)nc12
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: Cc1cccc(C)c1CNc1cccn2c(C)c(CC#N)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.2 %

Procedure:
2-chloromethyl-8-(2,6-dimethylbenzylamino)-3-methylimidazo[1,2-a]pyridine (2.4 mmol) and potassium cyanide (2.4 mmol) were added to dimethyl sulfoxide (25 ml) and stirred for 2 h. at room temperature. Methylene chloride and water were added to the reaction mixture and the organic layer was separated, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by by column chromatography on silica gel using methylene chloride:methanol (10:1) as eluent. Crystallization from acetonitrile gave 0.25 g (34%) of the title compound.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[NH:12][C:11]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([C:27]([O:29]CC5C=CC=CC=5)=[O:28])=[N:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][CH:16]=3)=[N:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].C(O)C>[CH:1]1([CH2:7][C:8]2[NH:12][C:11]([CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]4[C:22]([C:27]([OH:29])=[O:28])=[N:23][CH:24]=[CH:25][CH:26]=4)=[CH:19][CH:20]=3)=[N:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(OCc1ccccc1)c1ncccc1-c1ccc(CCc2ncc(CC3CCCCC3)[nH]2)cc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1ncccc1-c1ccc(CCc2ncc(CC3CCCCC3)[nH]2)cc1
Reaction time: 2 h

Procedure:
A mixture of benzyl 3-(4-{2-[5-(cyclohexylmethyl)-1H-imidazole-2-yl]ethyl}phenyl)pyridine-2-carboxylate (70 mg, 0.146 mmol), palladium on carbon (7 mg) and ethanol (3 mL) was stirred under a hydrogen atmosphere for 2 hours. The mixture was filtered, and the filtrate was concentrated to afford 3-(4-{2-[5-(cyclohexylmethyl)-1H-imidazole-2-yl]ethyl}phenyl)pyridine-2-carboxylic acid. LCMS: m/e 390 (M+H)+. 1HNMR (CD3OD, 500 MHz): δ 7.79 (1H, d, J=7.5 Hz), 7.42 (1H, d, J=7.5 Hz), 7.08 (1H, 7.5 Hz), 7.01 (1H, s), 3.11 (2H, t, J=6.0 Hz), 2.97 (2H, t, J=6.5 Hz), 2.45 (2H, d, J=7.5 Hz), 1.65 (4H, m), 1.51 (1H, m), 1.16 (4H, m), 0.90 (2H, m).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:7]=1[Br:15])(=O)C.[OH-].[Na+]>O1CCOCC1>[Br:15][C:7]1[C:8]([CH:12]([CH3:14])[CH3:13])=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][OH:4]
Reactant: CC(=O)OCc1cccc(C(C)C)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)c1cccc(CO)c1Br
Yield: 99.7 %

Procedure:
116 g (0.43 mole) of 2-bromo-3-isopropylbenzyl acetate in 770 ml of dioxane and 255 g of 8% strength sodium hydroxide solution are hydrolyzed and worked up similarly to Example 1, Paragraph c. 98.2 g (quantitative) of 2-bromo-3-isopropylbenzyl alcohol of boiling point 110°-112° C./0.2 mbar are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[S:18][C:19]3[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][C:20]=3[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Sn]Cl.Cl.[OH-].[Na+]>CCO.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[S:18][C:19]3[CH:25]=[C:24]([NH2:26])[CH:23]=[CH:22][C:20]=3[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc3ccc([N+](=O)[O-])cc3s2)CC1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2nc(N3CCN(C(=O)OCc4ccccc4)CC3)sc2c1
Temperature: 70 °C
Yield: 76.5 %

Procedure:
A mixture of 4-(6-nitrobenzothiazol-2-yl)piperazine-1-carboxylic acid benzyl ester (1.13 g, 2.84 mmol), SnCl2 (2.56 g, 11.3 mmol), and conc. HCl (0.35 mL, 4.25 mmol) in EtOH was heated at 70° C. overnight, diluted with water, neutralized with 1 N NaOH to pH 10, and extracted with CH2Cl2. The combined extracts were filtered through a pad of silica gel. The filtrate was concentrated in vacuo to provide the title compound (0.80 g, 77%), characterized by NMR and mass spectral analyses.
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:10]=[N:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH2:2][CH3:3].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:18][CH:17]=1)=O.C(=O)([O-])O.[Na+]>C(O)C>[CH3:26][O:25][CH2:24][CH2:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:11]=[C:8]3[CH:7]=[CH:6][C:5]([S:4][CH2:1][CH2:2][CH3:3])=[N:10][N:9]3[CH:13]=2)=[CH:21][CH:20]=1
Reactant: COCCOc1ccc(C(=O)CBr)cc1
Reactant: CCCSc1ccc(N)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCSc1ccc2nc(-c3ccc(OCCOC)cc3)cn2n1

Procedure:
A solution of 6-propylsulfanylpyridazin-3-amine (169 mg, 1 mmol) and 2-bromo-1-[4-(2-methoxyethoxy)phenyl]ethanone (273 mg, 1 mmol) in ethanol (10 mL) was refluxed for 3 h. Sodium hydrogen carbonate (84 mg, 1 mmol) was then added and the mixture was refluxed for a further 3 h. The solvent was evaporated and the organic residue was extracted with chloroform. The chloroform extract was washed with water, dried (sodium sulfate) and evaporated. The residue was purified by radial chromatography on silica gel. Elution with 2-3% methanol in dichloromethane afforded Compound 65 (57 mg). 1H n.m.r. (CDCl3) δ 1.12, t, J=6 Hz, 3H; 1.75-1.95, m, 2H; 3.16-3.22, m, 2H; 3.27, s, 3H; 3.75-3.82, m, 2H; 4.15-4.22, m, 2H; 6.88-7.08, m, 3H; 7.80-7.995, m, 3H; 8.06, s, 1H.
Reaction SMILES: [CH3:1][O:2][C@:3]1([C@@H:22]2[CH2:26][S:25][C:24](=[O:27])[N:23]2[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH2:19][C@H:18]2[CH2:20][C@@H:5]([CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:21])[O:17]2)[O:4]1.CO[C@]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@H]2C[C@@H](CCCC=CCCC(C)=CC(=O)O2)O1>>[CH3:1][O:2][C@:3]1([C@@H:22]2[CH2:26][S:25][C:24](=[O:27])[N:23]2[CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[CH2:19][C@H:18]2[CH2:20][C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:21])[O:17]2)[O:4]1
Reactant: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCCCCC(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C/CCCCCC(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCC/C(C)=C\C(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCC(C)=CC(=O)O3)O2)cc1
Product: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCCCCCCCCC(=O)O3)O2)cc1

Procedure:
Application of the method shown in Example 41, with the modification that (R)-4-((1R,14R,16R,E)-16-methoxy-3-oxo-2,15-dioxa-bicyclo[12.3.1]octadec-9-en-16-yl)-3-(4-methoxybenzyl)thiazolidin-2-one was substituted for (R)-4-((1R,4Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, afforded the title compound.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[CH:29]=[CH:28][CH:27]=[CH:26][C:7]=1[O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][N:16]=2)[CH2:10]1)[CH3:4]>O1CCCC1.O>[CH2:3]([O:5][C:6]1[CH:29]=[CH:28][CH:27]=[CH:26][C:7]=1[O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:25]=[CH:24][C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=2)[CH2:10]1)[CH3:4]
Reactant: CCOC(=O)c1ccc(N2CCC[C@@H](Oc3ccccc3OCC)C2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ccc(C(=O)O)cn2)C1
Temperature: 60 °C
Yield: 98.8 %

Procedure:
Aqueous 1N sodium hydroxide solution (27.1 mL, 27.0 mmol) was added to a stirred solution of ethyl (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)nicotinate (2.5 g, 6.8 mmol) in tetrahydrofuran (20 mL) at 0° C. The reaction mixture was heated to 60° C. for 18 h. The mixture was then diluted with water (25 mL) and was washed with ethyl acetate (2×50 mL). The aqueous layer was acidified with citric acid solution (pH-2) and was extracted with ethyl acetate (3×50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. The crude solid material was purified by washing with ether and hexane to afford (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)nicotinic acid (2.3 g) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 8.57 (d, 1H), 7.87 (dd, 1H), 7.03 (dd, 1H), 6.90 (m, 3H), 6.79 (d, 1H), 4.29 (m, 1H), 4.16 (m, 1H), 3.91 (m, 2H), 3.76 (m, 1H), 3.59 (m, 2H), 2.01 (m, 1H), 1.81 (m, 2H), 1.51 (m, 1H), 1.23 (t, 3H). MS (ES+) 343.2 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][C:5]2([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C.[CH3:25][Si:26]([CH2:29][CH2:30][O:31][CH2:32]Cl)([CH3:28])[CH3:27]>C(Cl)Cl>[CH3:12][O:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([CH3:15])([CH3:14])[CH2:6][C:7]2=[O:13])=[CH:3][C:2]=1[O:1][CH2:32][O:31][CH2:30][CH2:29][Si:26]([CH3:28])([CH3:27])[CH3:25]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1cc2c(cc1O)C(C)(C)CC2=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2c(cc1OCOCC[Si](C)(C)C)C(C)(C)CC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
To a solution of 5-hydroxy-6-methoxy-3,3-dimethyl-indan-1-one (40.0 g, 0.194 mol, see preparation in J. Chem. Soc. Perkin Trans. I 1982, p2013-2017) in CH2Cl2 (400 mL) were added diisopropylethylamine (35.5 mL, 0.204 mol) and SEMCl (34.9 mL, 0.198 mol). The reaction mixture was stirred at room temperature for 3 hours and concentrated. The residue was purified by flash chromatography eluted with EtOAc/hexane (2:8) to give 60.5 g (93%) of the desired product as brown oil. MS (DCI/NH3) m/z: 337.1 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm 0.00 (s, 9H) 0.96 (t, J=8.10 Hz, 2H) 1.39 (s, 6H) 2.56 (s, 2H) 3.83 (t, J=8.10 Hz, 2H) 3.90 (s, 3H) 5.39 (s, 2H) 7.15 (s, 1H) 7.20 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:16][NH2:17])[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1)=[O:4].C(N(CC)CC)C.[CH2:25]([O:27][C:28](=[O:33])[CH2:29][C:30](Cl)=[O:31])[CH3:26].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([CH2:16][NH:17][C:30](=[O:31])[CH2:29][C:28]([O:27][CH2:25][CH3:26])=[O:33])[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:6]1)=[O:4]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: COC(=O)C1(CN)CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)NCC1(C(=O)OC)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C

Procedure:
3-Aminomethyl-azetidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (3.11 g; 12.7 mmol) and triethylamine (1.95 ml; 14.01 mmol) in CH2Cl2 (55 ml) are cooled to 0° C. under stirring. Chlorocarbonyl-acetic acid ethyl ester (1.9 g; 12.74 mmol) in CH2Cl2 (15 ml) is added dropwise within 15 minutes. The reaction mixture is warmed to room temperature and stirred for 30 minutes, poured on 10% aqueous NaHCO3 and extracted with CH2Cl2 three times. The combined organic phases are dried over Na2SO4, filtered, evaporated and purified via chromatography (SiO2; TBME/MeOH 97:3) to yield the title compound as colorless resin (3.8 g; 77%), which crystallizes slowly.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[C:23]([O:30][CH3:31])[CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=3)[N:3]=2)=[C:23]([O:30][CH3:31])[CH:22]=1
Reactant: COc1cc(Cl)ccc1B(O)O
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: COc1cc(Cl)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Example 32 was prepared under similar conditions as described in the preparation of Example 30 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and (4-chloro-2-methoxyphenyl)boronic acid (ABCR GmbH & CO. KG). The batch was purified by preparative HPLC.
Reaction SMILES: [OH:1][CH:2]([C:6]([O:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].CN(C=O)C.[H-].[Na+].[CH3:39][O:40][C:41]1[CH:46]=[C:45]([CH3:47])[N:44]=[C:43](S(C)(=O)=O)[N:42]=1>O>[CH3:39][O:40][C:41]1[CH:46]=[C:45]([CH3:47])[N:44]=[C:43]([O:1][CH:2]([C:6]([O:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]([OH:5])=[O:4])[N:42]=1
Reactant: COc1cc(C)nc(S(C)(=O)=O)n1
Reactant: COc1ccc(CCOC(c2ccccc2)(c2ccccc2)C(O)C(=O)O)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C)nc(OC(C(=O)O)C(OCCc2ccc(OC)c(OC)c2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.25 h
Yield: 52.3 %

Procedure:
1 g (2.3 mmol) of 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionic acid was introduced into 10 ml of DMF, and 340 mg of NaH (50% suspension) were added. After the mixture had been stirred for 15 minutes, 526 mg of 4-methoxy-6-methyl-2-methylsulfonylpyrimidine were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the mixture, which was then extracted with ether. The aqueous phase was acidified with 1 N aqueous HCl, extracted with ether and dried over magnesium sulfate. The solvent was distilled off, the residue was purified by MPLC, and 655 mg (52%) of colorless powder were isolated after recrystallization from ether/n-hexane.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([N:12]([CH3:37])[C@H:13]([C:17]([N:19]([CH3:36])[C@H:20]([C:33]([NH2:35])=[O:34])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:23]=1)=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H]>CO.[C].[Pd]>[NH2:1][C@H:2]([C:10]([N:12]([CH3:37])[C@H:13]([C:17]([N:19]([CH3:36])[C@H:20]([C:33]([NH2:35])=[O:34])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([C:29]([CH3:30])([CH3:32])[CH3:31])[CH:23]=1)=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@@H](N)Cc1ccccc1

Procedure:
A mixture of Z-Phe-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (610 mg) and 10% palladium carbon (100 mg) in methanol (15 ml) was stirred at room temperature in a hydrogen atmosphere for 17 hours. The reaction mixture was filtered and washed with methanol. The solvent was distilled off under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate) to yield Phe-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 in the amount of 431 mg (89%).
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[CH:8][CH2:9][NH2:10])=[CH:3][CH:2]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>C(O)(=O)C>[C:14]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:16][C:11]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:6][CH:5]=2)=[CH:8][CH2:9][NH:10][C:29](=[O:31])[CH3:30])=[CH:12][CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCC=C(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1
Solvent: CC(=O)O
Product: CC(=O)NCC=C(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1

Procedure:
1, 1 - di (4 - biphenylyl) -3 - amino - prop -1 -ene (1g) was added to a mixture of anhydrous sodium acetate (1g), acetic acid (10 ml) and acetic anhydride (1 ml) and the mixture was refluxed for one hour then evaporated in vacuo. The residue was washed with water and dried and recrystallised from n - propanol to give 1, 1- di (4-biphenylyl) -3 - acetamido - prop -1 - ene. (m.p. 246°- 249°C). This compound was reduced in a similar manner to the method described in Example 43 to yield 1, 1 - di (4-biphenylyl) -3 - ethylamino - prop -1 - ene.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]([OH:13])[C@@H:5]([OH:12])[C@H:6]([OH:11])[C@H:7]([OH:10])[CH2:8][OH:9].[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][CH2:26][NH:27][C:28](=[O:42])[C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][N:38]=[C:37](Cl)[N:36]=4)=[CH:31][CH:30]=3)[CH:23]=2)[NH:18][CH:17]=1)#[N:15]>>[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][CH2:26][NH:27][C:28](=[O:42])[C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][N:38]=[C:37]([N:2]([CH3:1])[CH2:3][C@H:4]([OH:13])[C@@H:5]([OH:12])[C@H:6]([OH:11])[C@H:7]([OH:10])[CH2:8][OH:9])[N:36]=4)=[CH:31][CH:30]=3)[CH:23]=2)[NH:18][CH:17]=1)#[N:15]
Reactant: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: CN(C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)c1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1

Procedure:
Using N-methyl-(2 (S),3 (R),4 (R),5 (R),6-pentahydroxy-hexyl)-amine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=3)=[CH:16][C:15]=2[CH3:30])=[CH:12][C:11]([C:31]([O:33]C)=O)=[N:10]1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=3)=[CH:16][C:15]=2[CH3:30])=[CH:12][C:11]([C:31]([N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:33])=[N:10]1
Reactant: C1CCNC1
Reactant: COC(=O)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2C)n(-c2c(Cl)cccc2Cl)n1
Product: Cc1cc(-c2cccc(S(C)(=O)=O)c2)ccc1-c1cc(C(=O)N2CCCC2)nn1-c1c(Cl)cccc1Cl
Temperature: 180 °C
Yield: 13.5 %

Procedure:
Methyl 1-(2,6-dichlorophenyl)-5-(3-methyl-3′-(methylsulfonyl)biphenyl-4-yl)-1H-pyrazole-3-carboxylate (102 mg, 0.20 mmol) was suspended in pyrrolidine (0.6 mL, 7.2 mmol) and heated in the microwave at 180° C. for 10 minutes. The dark reaction mixture was concentrated under reduced pressure and azeotroped with toluene to remove most of the pyrrolidine. The resulting crude product was purified by preparative reverse phase HPLC eluting with MeCN/H2O with 0.05% TFA. The product fractions from the HPLC were made basic by the careful addition of saturated aqueous NaHCO3. The resulting mixture was concentrated to remove most of the MeCN. The resulting aqueous suspension was extracted with CH2Cl2 (3×), and the combined extracts were dried over Na2SO4 overnight, filtered and concentrated under reduced pressure to afford (1-(2,6-dichlorophenyl)-5-(3-methyl-3′-(methylsulfonyl)biphenyl-4-yl)-1H-pyrazol-3-yl)(pyrrolidin-1-yl)methanone (15 mg, 14% yield) as a brown solid. 1H NMR (400 MHz CDCl3): δ 8.10 (1H, m), 7.91 (1H, m), 7.83 (1H, m), 7.62 (1H, t), 7.49 (1H, d), 7.42-7.34 (2H, m), 7.33-7.21 (2H, m), 7.13 (1H, d), 7.06 (1H, s), 3.99 (2H, t), 3.71 (2H, t), 3.08 (3H, s), 2.50 (3H, s), 2.03-1.86 (4H, m). MS(ES): 554 [M+H]+.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[N:12]([S:26]([C:23]4[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=4)(=[O:28])=[O:27])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C1=C(c2c[nH]c3ncccc23)CC2CCCN2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(C3=CCN4CCCC4C3)c3cccnc32)cc1

Procedure:
from 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-7-Azaindole (10 mg, 0.0418 mmol), 4-methyl-benzenesulfonyl chloride (20 mg, 0.105 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.