Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH2:2]1.Cl.[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]([CH2:21][OH:22])[CH2:19][OH:20])=[CH:10][CH:9]=1>O1CCOCC1.O.ClCCl>[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C@@H:18]2[CH2:21][O:22][C@@H:5]([CH2:4][CH2:3][CH2:2][OH:1])[O:20][CH2:19]2)=[CH:10][CH:9]=1
Reactant: C1=COCC1
Reactant: OCC(CO)c1ccc(Cl)c2ccccc12
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: OCCC[C@H]1OC[C@H](c2ccc(Cl)c3ccccc32)CO1
Reaction time: 5 h

Procedure:
0.75 ml (10 mmol) of 2,3-dihydrofuran and then 0.25 ml of a concentrated aqueous hydrochloric acid solution (37%) are added to a solution of 1.18 g (5 mmol) of 2-(4-chloronaphthalen-1-yl)-1,3-propanediol in 10 ml of dioxane. The mixture is allowed to react overnight at ambient temperature and then 5 ml of water are added. The mixture is stirred for 5 hours and is then diluted in 25 ml of water and 50 ml of dichloromethane. The mixture is separated after settling out and the aqueous phase is extracted with 50 ml of dichloromethane. The organic phases are washed with 25 ml of a saturated aqueous sodium chloride solution, drying is carried out over sodium sulfate and concentration is carried out under reduced pressure. The residue is purified by chromatography on silica gel, eluting with a 70/30 and then 60/40 mixture of cyclohexane and ethyl acetate. After recrystallization from diisopropyl ether, 0.557 g of product is obtained, in the form of white crystals.
Reaction SMILES: [Si]([O:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.Cl.Br[C:32]1[CH:33]=[C:34]([CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[CH:35]=[CH:36][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.[Pd]>[CH3:42][N:40]([CH3:41])[CH2:39][CH2:38][C:34]1[CH:33]=[C:32]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C@@H:10]([CH3:21])[C@H:9]([OH:8])[CH2:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:17][CH:16]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Reactant: CN(C)CCc1cccc(Br)c1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C[C@H](Oc1ccc(-c2cccc(CCN(C)C)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 35.9 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-ylbutoxy]benzeneboronic acid (0.2 g, Example 11), [2-(3-bromophenyl)ethyl]dimethylamine hydrochloride (0.21 g, Example 27a)), aqueous sodium carbonate (2M, 0.82 ml) and tertakistriphenylphosphine palladium (0) (0.1 g) in toluene (5 ml) and ethanol (2 ml). The reaction was heated at 100° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure. Concentrated hydrochloric acid (1 ml) was added to a solution of the residue in methanol (5 ml) and stirred at room temperature for 2 hours. After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give the title compound as an oil (0.07 g).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[NH4+:34]>CCO>[NH2:34][C:2]1[N:7]=[N:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=S(=O)(c1ccc(Cl)nn1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)nn1
Temperature: 110 °C
Yield: 60.3 %

Procedure:
To a 2 mL microwave vial was added 2-(4-(4-((6-chloropyridazin-3-yl)sulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (50 mg, 0.099 mmol), EtOH (1.0 mL) and ammonium hydroxide (2.0 mL, 51 mmol). The solution was heated in an Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 110° C. for 1 h and then concentrated. The resulting material was purified by silica gel chromatography (0 to 4% MeOH in CH2Cl2) to afford 2-(4-(4-((6-aminopyridazin-3-yl)sulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (29 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.67 (d, J=9.4 Hz, 1H), 7.47 (d, J=8.6 Hz, 2H), 7.28 (s, 2H), 7.02 (d, J=9.0 Hz, 2H), 6.89 (d, J=9.2 Hz, 1H), 3.29-3.33 (m, 4H), 3.22-3.28 (m, 4H). m/z (ESI, +ve ion) 485.9 (M+H)+. GK-GKRP IC50 (Binding)=0.285 μM; GK-GKRP EC50 (LC MS/MS-2)=0.302 μM.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CCOC(C)=O.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>[CH3:11][O:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)=[CH:3][CH:4]=1
Reactant: OB(O)c1ccncc1
Reactant: COCOc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCOc1ccc(-c2ccncc2)cc1
Temperature: 80 °C
Yield: 74.2 %

Procedure:
To a degassed solution of 1-bromo-4-(methoxymethoxy)benzene (360 mg, 1.66 mmol), pyridin-4-ylboronic acid (307 mg, 2.50 mmol), and Cs2CO3 (1.09 g, 3.35 mmol) in THF (5 mL) was added Pd(PPh3)4 (190 mg, 0.16 mmol). The reaction mixture was heated at 80° C. overnight and diluted with EtOAc (50 mL). It was washed with H2O (2×25 mL), dried over Na2SO4, and concentrated. Purification on a silica gel column gave the desired product as a white solid (265 mg). NMR (CDCl3): 8.63 (d, 2H), 7.67 (d, 2H), 7.47 (d, 2H), 7.16 (d, 2H), 5.24 (s, 2H), 3.52 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[NH:4][C:5]([C@@H:7]1[CH2:11][C:10](=[N:12][O:13][CH3:14])[CH2:9][N:8]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=O.C(=O)(O)[O-].[Na+]>ClCCl.C(O)(=O)C>[NH:4]1[C:3]2[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=2[N:1]=[C:5]1[C@@H:7]1[CH2:11][C:10](=[N:12][O:13][CH3:14])[CH2:9][N:8]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CON=C1C[C@@H](C(=O)Nc2ccccc2N)N(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CON=C1C[C@@H](c2nc3ccccc3[nH]2)N(C(=O)OC(C)(C)C)C1
Yield: 97.4 %

Procedure:
A solution of the anilide compound from the previous step, e.g. tert-butyl (2S,4EZ)-2-[(2-aminoanilino)carbonyl]-4-(methoxyimino)-1-pyrrolidinecarboxylate (0.8 g, 2.3 mmol) in dichloromethane (30 ml) and acetic acid (3 ml) was stirred at room temperature for 3 days. Saturated aqueous sodium bicarbonate (7 ml) was added to the reaction, the organic phase collected and dried over magnesium sulfate before filtering and removal of solvent in vacuo to give the desired product, e.g. tert-butyl (2S,4EZ)-2-(1H-benzimidazol-2-yl)-4-(methoxyimino)-1-pyrrolidinecarboxylate (740 mg, 97%) as an off-white foam.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([CH3:16])([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:17])[CH:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([CH3:16])([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:17])[CH:3]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(c1ccccc1)N1CCC(O)C(c2ccccc2)C1=O
Solvent: c1ccncc1
Product: CC(=O)OC1CCN(C(C)(C)c2ccccc2)C(=O)C1c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3.6 g (0.0117 mol) of 4-hydroxy-1-(α,α-dimethylbenzyl)-3-phenyl-2-piperidone prepared by the method of Reference Example 19 and 10 ml of acetic anhydride were dissolved in 20 ml of pyridine, and the mixture was stirred at room temperature for one day and night. After completion of the reaction, the reaction solution was poured into ice water, extracted with ethyl acetate, washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 4.1 g (quantitatively) of the desired compound.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5](=O)[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:3]1=[O:20].O.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:5]1[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:3](=[O:20])[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN1C(=O)CC(=O)N(c2cccc(C(F)(F)F)c2)C1=O
Solvent: O
Product: Cn1c(=O)cc(Cl)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 0 °C

Procedure:
To a solution of 1-methyl-3-(3-(trifluoromethyl)phenyl)pyrimidin-2,4,6(1H, 3H, 5H)-trione (2.74 g) (prepared in Reference Example 55) in phosphorus oxychloride (22 ml) was added water (0.55 ml) slowly and the resulting mixture was stirred with heating under reflux for one hour. After concentration under reduced pressure, the reaction solutions were cooled to 0° C. and to the residue was added water (50 ml) slowly with stirring. The resulting mixture was extracted with ethyl acetate (50 ml×3), and the resulting extracts were dried and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 6-chloro-3-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (1.54 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]([N:20]3[CH2:25][CH2:24][N:23](C(OOC(C)(C)C)=O)[CH2:22][CH2:21]3)=[O:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1>C(OCC)(=O)C>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:13][CH2:14][CH:15]([C:18]([N:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)=[O:19])[CH2:16][CH2:17]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OOC(=O)N1CCN(C(=O)C2CCN(S(=O)(=O)c3ccc(Cl)cc3)CC2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(C1CCN(S(=O)(=O)c2ccc(Cl)cc2)CC1)N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl acetate saturated with gaseous HCl was added to a solution of 1-(4-chlorophenylsulphonyl)-4-[1-(t-butoxyoxycarbonyl)piperazine-4-ylcarbonyl]piperidine (1.10 g) in ethyl acetate (25 ml). The reaction was stirred at room temperature for 2 hours. Solvent was removed by evaporation to give the crude 1-(4-chlorophenylsulphonyl)-4-(4-piperazinylcarbonyl)piperidine hydrochloride.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH2:17])=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])[CH3:2]>C(O)(=O)C.OO>[CH2:1]([C:3]1[C:4]2[C:5](=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[O:7][N:17]=2)[CH:14]=[CH:15][CH:16]=1)[CH3:2]
Reactant: CCc1cccc(C(=O)c2ccccc2)c1N
Agent: OO
Solvent: CC(=O)O
Product: CCc1cccc2c(-c3ccccc3)onc12
Temperature: 0 °C

Procedure:
A solution of 7.5 g (0.033 mole) of 3-ethyl-2-aminobenzophenone in 150 ml of acetic acid and 40 ml of 30% hydrogen peroxide was let stand at ambient temperature for 72 hr. The solution was poured into ice water and a solid gradually crystallized. The solid was collected by filtration, washed with water and dried. The solid was then slurried with 20 ml of carbon tetrachloride and the mixture was filtered.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[CH:20]([CH:22]1[NH:27][CH2:26][CH2:25][NH:24][CH2:23]1)=[CH2:21]>N1C=CC=CC=1>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:24]4[CH2:25][CH2:26][NH:27][CH:22]([CH:20]=[CH2:21])[CH2:23]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: C=CC1CNCCN1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Solvent: c1ccncc1
Product: C=CC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1
Temperature: 140 °C
Yield: 12.7 %

Procedure:
A mixture of 1.3 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.9 g of 3-ethenylpiperazine and 15 ml of pyridine is heated at 140° C. in a pressure bottle for 18 hours and then purified as described in Example 101, giving 210 mg of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:10]=2[C:18](=[O:20])[CH3:19])=[CH:5][CH:4]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][C:6]2[CH:21]=[CH:22][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]=1[C:18](=[O:20])[CH3:19]
Reactant: COc1ccc(COc2cccc([N+](=O)[O-])c2C(C)=O)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1ccc(COc2cccc(N)c2C(C)=O)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 175.5 %

Procedure:
To a stirred suspension of 1-{2-[(4-methoxybenzyl)oxy]-6-nitrophenyl}ethanone (0.50 g, 1.659 mmol) in ethanol was added a solution of ammonium chloride (0.10 g, 1.825 mmol) in water (5 mL) followed by iron powder (0.75 g). The mixture was stirred at 100° C. for 1 hr. The reaction mixture was filtrated on Celite®. The filtrate was diluted with ethyl acetate and washed with water. The separated organic phase was washed with brine and dried over Na2SO4, filtrated and concentrated under reduced pressure to give 1-{2-amino-6-[(4-methoxybenzyl)oxy]phenyl}ethanone as a yellow solid (0.790 g, yield; 108%). The residue was used for the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[N:22]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[N:26][C:21]2=[N:20][CH:19]=1)CCC>>[CH:8]1([C:4]2[N:3]=[C:2]([C:18]3[N:22]4[CH:23]=[CH:24][C:25]([C:27]([F:28])([F:29])[F:30])=[N:26][C:21]4=[N:20][CH:19]=3)[CH:7]=[CH:6][CH:5]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Brc1cccc(C2CCCC2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: FC(F)(F)c1ccn2c(-c3cccc(C4CCCC4)n3)cnc2n1
Yield: 10.5 %

Procedure:
2-Bromo-6-cyclopentylpyridine (479 mg, 2.1 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.4 mmol) by the method of Example 1 to give 3-(6-cyclopentylpyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (49 mg) as a white solid: δH (400 MHz, DMSO) 1.70-1.87 (6H, m), 2.10-2.16 (2H, m), 7.29 (1H, d, J 7.4), 7.80 (1H, d, J 7.0), 7.87 (1H, t, J 7.8), 7.95-7.97 (1H, m), 8.84 (1H, s), 10.50 (1H, d, J 6.7); m/z (ES+) 332 (M++H).
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:5](/[CH:14]=[CH:15]/[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[C:18]([N:26]3[CH2:32][CH2:31][CH2:30][C:29]4[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=4[CH2:27]3)[CH:17]=2)[CH2:4][O:3]1>[OH-].[Pd+2].[OH-].C(O)C>[CH3:1][C:2]1([CH3:37])[N:6]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@@H:5]([CH2:14][CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[C:18]([N:26]3[CH2:32][CH2:31][CH2:30][C:29]4[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=4[CH2:27]3)[CH:17]=2)[CH2:4][O:3]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](/C=C/c2cc(N3CCCc4ccccc4C3)nc3ccccc23)COC1(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2cc(N3CCCc4ccccc4C3)nc3ccccc23)COC1(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
The mixture of tert-butyl (4S)-2,2-dimethyl-4-{(E)-2-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]ethenyl}-1,3-oxazolidine-3-carboxylate (380 mg, 0.76 mmol), palladium hydroxide (20% on carbon, 50 mg) and ethanol (15 mL) was stirred at room temperature for 4 hours under hydrogen. The solid was filtered by a pad of silica gel and the filtrate was concentrated in vacuo to give 340 mg of product as a white solid (yield was 89%). MS obsd. (ESI+) [(M+H)+] 502.
Reaction SMILES: Cl[C:2]1[C:7](Cl)=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(OC(C)(C)C)=O>>[CH3:2][C:7]1[C:13]([N:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: Cc1cc(C(F)(F)F)cnc1N1CCNCC1
Yield: 22.5 %

Procedure:
Using 2,3-dichloro-5-trifluoromethylpyridine (25 g) and 1-Boc-piperazine (23.84 g) and by the reaction and treatment in the same manner as in Preparation Example 79, the title compound (6.38 g) was obtained.
Reaction SMILES: [F:1][C:2]([F:9])([C:5]([F:8])([F:7])[F:6])[CH2:3]O.CCN(C(C)C)C(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[C:34]([S:53][CH2:54][C@@H:55]([C:57]([OH:59])=[O:58])[NH2:56])([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[F:1][C:2]([F:9])([C:5]([F:8])([F:7])[F:6])[CH2:3][NH:56][C@@H:55]([CH2:54][S:53][C:34]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:57]([OH:59])=[O:58]
Reactant: OCC(F)(F)C(F)(F)F
Reactant: N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NCC(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a −78° C. methylene chloride solution (75 mL) of 2,2,3,3,3-pentafluoropropan-1-ol (1.5 g, 10.0 mmol) and DIPEA (6.1 mL, 35.0 mmol) was added triflic anhydride (1.78 mL, 10.5 mmol). After 2.5 h, S-tritylcysteine was added all at once and the reaction mixture was stirred at 0° C. for 80 min. The reaction mixture was stirred at RT for 18 h and then concentrated on the rotovap. Ethyl acetate was added and the reaction mixture was washed with 1N HCl. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (3 hexanes/1 ethyl acetate+1% acetic acid) to provide 2(R)-(2,2,3,3,3-pentafluoropropylamino)-3-tritylsulfanylpropionic acid (3.29 g).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([C:21]1[NH:25]N=C[CH:22]=1)[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[S:33]1C=C(B(O)O)N=[CH:34]1>>[C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([C:21]1[N:25]=[CH:34][S:33][CH:22]=1)[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: OB(O)c1cscn1
Reactant: Cc1cc2nc(-c3ccn[nH]3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2nc(-c3cscn3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reaction time: 1.5 h

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(thiazol-4-yl)quinolin-6-yl)acetic acid (76) was prepared following the procedure for (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(1H-pyrazol-5-yl)quinolin-6-yl)acetic acid of Example 70 except that thiazol-4-ylboronic acid was used instead of 1H-pyrazol-5-ylboronic acid and the in the final step the reaction was stirred for 1.5 hours. 1H-NMR: 400 MHz, (CD3CN) δ: 9.07 (d, J=2.0 Hz, 1 H), 8.58 (d, J=2.0 Hz, 1 H), 8.17 (d, J=9.2 Hz, 1 H), 8.02 (s, 1 H), 7.93 (d, J=9.2 Hz, 1 H), 7.59 (m, 3 H), 7.35 (d, J=7.6 Hz, 1 H), 5.25 (s, 1H), 2.64 (s, 3 H), 0.98 (s, 9 H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:59]1[N:64]=[C:63]([N:65]2[CH2:70][CH2:69][CH:68]([N:71]3[C:79]4[C:74](=[N:75][CH:76]=[CH:77][CH:78]=4)[NH:73][C:72]3=[O:80])[CH2:67][CH2:66]2)[CH:62]=[C:61]([C:81]([C:83]2[CH:93]=[C:92]([CH3:94])[C:86]3[N:87]([CH3:91])[C:88](=[O:90])[O:89][C:85]=3[CH:84]=2)=[O:82])[CH:60]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:5]([O:4][C:3](=[O:9])[N:2]([C:59]1[N:64]=[C:63]([N:65]2[CH2:70][CH2:69][CH:68]([N:71]3[C:79]4[C:74](=[N:75][CH:76]=[CH:77][CH:78]=4)[NH:73][C:72]3=[O:80])[CH2:67][CH2:66]2)[CH:62]=[C:61]([C:81]([C:83]2[CH:93]=[C:92]([CH3:94])[C:86]3[N:87]([CH3:91])[C:88](=[O:90])[O:89][C:85]=3[CH:84]=2)=[O:82])[CH:60]=1)[CH3:1])([CH3:8])([CH3:7])[CH3:6]
Reactant: Cc1cc(C(=O)c2cc(Cl)nc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)c2)cc2oc(=O)n(C)c12
Reactant: CNC(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)nc(N(C)C(=O)OC(C)(C)C)c2)cc2oc(=O)n(C)c12

Procedure:
Under an argon atmosphere 13 mg (0.96 mmol) tert-butyl methyl-carbamate, 11 mg (0.019 mmol) Xantphos, 8.8 mg (0.010 mmol) Pd2 dba3 and 47 mg (0.15 mmol) caesium carbonate were added to 50 mg (0.10 mmol) 1-[6′-chloro-4′-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-one in 1.00 mL dioxane and the mixture was refluxed for 15 h with stirring. The reaction mixture was evaporated down i. vac. and the residue obtained was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][CH3:14])[N:8]=2)[S:5][CH:6]=1.[I:15]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[I:15][C:11]1[C:7]([C:4]2[S:5][CH:6]=[C:2]([CH3:1])[CH:3]=2)=[N:8][N:9]([CH2:12][CH2:13][CH3:14])[CH:10]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CCCn1ccc(-c2cc(C)cs2)n1
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1cc(I)c(-c2cc(C)cs2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution of 3-(4-methyl-2-thienyl)-1-propyl-1H-pyrazole (6.2 mmol) in 16 mL dry N,N-dimethylformamide under argon atmosphere was added N-iodosuccinimide (6.6 mmol) in small portions at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. 5% aqueous sodium thiosulfate solution and saturated aqueous sodium carbonate solution were added and the mixture was stirred at room temperature for 1 h, then extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (cyclohexane:dichloromethane 100:0 to 0:100) to afford 1.77 g 4-iodo-3-(4-methyl-2-thienyl)-1-propyl-1H-pyrazole (85% yield).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([CH3:18])(=[O:17])=[O:16])[C:10]=2[F:19])[CH2:5][CH2:4]1)[CH3:2].C(O)=O>[Pd].C(O)(C)C>[CH2:1]([N:3]1[CH2:4][CH2:5][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([CH3:18])(=[O:17])=[O:16])[C:10]=2[F:19])[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CC=C(c2cccc(S(C)(=O)=O)c2F)CC1
Agent: [Pd]
Solvent: O=CO
Solvent: CC(C)O
Product: CCN1CCC(c2cccc(S(C)(=O)=O)c2F)CC1
Reaction time: 20 h
Yield: 69.3 %

Procedure:
A mixture of 1-ethyl-4-[2-fluoro-3-(methylsulfonyl)phenyl]-1,2,3,6-tetrahydropyridine (5 g, 17.7 mmol), formic acid (3.4 ml, 90 mmol) and palladium on carbon (1.1 g) in isopropanol (50 ml) was shaken in a parr apparatus for 20 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated and evaporated to dryness. Aqueous sodium carbonate (10%, 200 ml) was added and the mixture was extracted with ethyl acetate (3×100 ml). The combined organic phases was dried (MgSO4) and evaporated to dryness. Flash column chromatography (ethylacetate/methanol, 1:1) gave the title compound (3.5 g, 70%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 280.2° C. MS m/z (relative intensity, 70 eV) 285 (M+, 12), 270 (bp), 57 (19), 84 (15) 133 (9).