Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][CH:11]([OH:14])[CH2:12][OH:13])[C:5]([F:19])=[CH:4][N:3]=1.[F:20][C:21]1[CH:22]=[C:23]2[C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][N:27]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[C:24]2=[N:25][CH:26]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O.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]>[F:19][C:5]1[C:6]([NH:8][C@@H:9]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][CH:11]([OH:14])[CH2:12][OH:13])=[N:7][C:2]([C:29]2[C:23]3[C:24](=[N:25][CH:26]=[C:21]([F:20])[CH:22]=3)[N:27]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:40])=[O:41])[CH:28]=2)=[N:3][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Reactant: CC(C)(C)[C@@H](CC(O)CO)Nc1nc(Cl)ncc1F
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H](CC(O)CO)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a solution of (4R)-4-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-5,5-dimethyl-hexane-1,2-diol, 189a, (0.090 g, 0.309 mmol), 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.167 g, 0.401 mmol) and K3PO4 (0.196 g, 0.926 mmol) in 2-Methyl THF (15 mL) and H2O (2 mL) was degassed under a stream of nitrogen for 45 minutes. To the reaction mixture was added X-phos (0.018 g, 0.037 mmol) and Pd2(dba)3 (0.007 g, 0.008 mmol). The reaction mixture was stirred at 120° C. in a pressure tube for 2 hours. The aqueous phase was removed and the organic phase was filtered through a pad of celite and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography (60% EtOAc/Hexanes) to afford 140 mg of the desired product, 191a: 1H NMR (400 MHz, CDCl3) δ 8.51 (dt, J=7.6, 3.8 Hz, 1H), 8.48 (s, 1H), 8.32 (d, J=1.7 Hz, 1H), 8.12 (dd, J=7.2, 5.7 Hz, 3H), 7.30 (d, J=8.1 Hz, 2H), 4.99 (d, J=10.1 Hz, 1H), 4.42-4.28 (m, 2H), 3.72-3.47 (m, 3H), 2.40 (s, 3H), 2.19-2.09 (m, 1H), 1.97-1.83 (m, 1H), 1.49-1.34 (m, 1H), 1.06 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.53 minutes (M+H) 546.49.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]([NH:14][CH:15]3[C:19]4([CH2:23][CH2:22][CH2:21][CH2:20]4)[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]3)[CH:11]=[CH:10][N:9]=2)[CH:4]=[N:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]([NH:14][CH:15]3[C:19]4([CH2:20][CH2:21][CH2:22][CH2:23]4)[CH2:18][NH:17][CH2:16]3)[CH:11]=[CH:10][N:9]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(Nc2nccc(NC3CN(C(=O)OC(C)(C)C)CC34CCCC4)n2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(Nc2nccc(NC3CNCC34CCCC4)n2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 108 %

Procedure:
To a solution of tert-butyl 4-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-2-azaspiro[4.4]nonane-2-carboxylate (550 mg, 1.33 mmol) in DCM (20 mL) was added CF3COOH (5 mL) and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo and adjust to pH=8˜9 with the saturated NaHCO3 aqueous solution, then diluted with H2O (20 mL) and extracted withed EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL), then dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1 to 10/1) to give the product as a yellow solid (450 mg, 100%).
Reaction SMILES: CS(C)=O.Cl[C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]#[C:15][CH3:16])[N:9]=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]([F:31])([C:27]([F:30])([F:29])[F:28])[CH2:25][NH2:26]>C(OCC)(=O)C>[CH2:13]([O:12][C:10]1[CH:11]=[C:6]([NH:26][CH2:25][C:24]([F:31])([F:23])[C:27]([F:30])([F:29])[F:28])[N:7]=[CH:8][N:9]=1)[C:14]#[C:15][CH3:16]
Reactant: NCC(F)(F)C(F)(F)F
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC#CCOc1cc(NCC(F)(F)C(F)(F)F)ncn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 12.4 %

Procedure:
To 4 ml of dimethylsulfoxide were added 365 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 442 mg of potassium carbonate, and 495 mg of 2,2,3,3,3-pentafluoropropylamine, followed by stirring at 80° C. for 4 hours. Then, 596 mg of 2,2,3,3,3-pentafluoropropylamine was further added, and the mixture was stirred at 100° C. for 6 hours. The reaction mixture was then left for cooling to room temperature, diluted with ethyl acetate, and washed twice with an aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 73 mg of 4-(2-butynyloxy)-6-(2,2,3,3,3-pentafluoropropylamino)pyrimidine (the present compound (111)).
Reaction SMILES: CC1(C)[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:5]=2[CH2:4][O:3]1.O>C1COCC1.Cl>[OH:7][C:6]1[C:5]([CH2:4][OH:3])=[C:11]([CH:10]=[CH:9][CH:8]=1)[CH2:12][CH2:13][N:14]1[CH2:15][CH2:16][CH:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][CH2:19]1
Reactant: CCOC(=O)C1CCN(CCc2cccc3c2COC(C)(C)O3)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1CCN(CCc2cccc(O)c2CO)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
To ethyl 1-(2-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-5-yl)ethyl)piperidine-4-carboxylate (100 mg, 0.49 mmol, 1 eq.) in THF (10 mL) were added HCl (6 N, 10 drops) and water (1.0 mL) at rt. The mixture was stirred at 60° C. for 2 h, cooled, and basified with NaHCO3(sat.) solution. The mixture was filtered and concentrated. The residue was bring into THF (10 mL) and filtered. The filtrate was concentrated to give ethyl 1-(3-hydroxy-2-(hydroxymethyl)phenethyl)piperidine-4-carboxylate (85 mg, crude) as a pale brown oil, which was used for next step without purification. LRMS (M+H+) m/z 308.1.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([CH3:15])=[C:8]2[C:3]=1[C:4](=O)[CH2:5][CH:6]=[N:7]2.P(Br)(Br)([Br:19])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Br:19][C:4]1[C:3]2[C:8](=[C:9]([CH3:15])[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:2]=2[CH3:1])[N:7]=[CH:6][CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])c(C)c2c1N=CCC2=O
Reactant: O=P(Br)(Br)Br
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1cc([N+](=O)[O-])c(C)c2c(Br)ccnc12
Temperature: 90 °C

Procedure:
A mixture of 5,8-dimethyl-6-nitro-4-quinolone (7.12 g, 32.7 mmol), phosphorus oxybromide (7.47 g, 26.12 mmol), pyridine (5.3 mL), and toluene (90 mL) is heated at 90° C. for 6 hours. The mixture is filtered hot, and the solid is washed with water and methylene chloride. The filtrate is extracted with methylene chloride (3×100 mL), and the combined organic layers are dried (sodium sulfate) and evaporated to afford 4-bromo-5,8-dimethyl-6-nitroquinoline.
Reaction SMILES: [C:1]([O:9][C:10]1[C:11]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:38]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([O:9][C:10]1[C:11]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][C:13]([CH2:16][Br:38])=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(OC(=O)c2ccccc2)c(OC(=O)c2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Oc1ccc(CBr)cc1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 28.6 %

Procedure:
To a solution of 19.94 g (0.06 mol) of 4-methyl-benzene-1,2-diol dibenzoate in 350 mL of carbon tetrachloride was added a catalytic amount of 2,2'-azobisisobutyronitrile, followed by 10.68 g (0.06 mol) of N-bromosuccinimide. The reaction mixture was stirred at room temperature for several days and was then filtered. The filtrate was dried over MgSO4, filtered and evaporated to dryness in a rotary evaporator. Purification of the crude material (24.76 g) by HPLC gave 7.05 g of product which was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12]O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].P(Br)(Br)[Br:15]>C(OCC)C.O>[Br:15][CH2:12][C:4]1[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([F:1])[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(CO)cc1F
Reactant: BrP(Br)Br
Solvent: O
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(CBr)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of (3-fluoro-4-methanesulfonyl-phenyl)-methanol (0.269 g, 1.31 mmol) in diethyl ether (5 ml) under an inert atmosphere of Argon is added dropwise phosphorus tribromide (46 μl, 0.434 mmol). After stirring at room temperature overnight, the reaction mixture is diluted with water (2 ml) and the diethyl ether layer separated. This organic portion is placed over NaOH pellets and after 20 minutes, is used as a reagent in solution in diethyl ether.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1>C(O)C>[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH:9]=[CH:8][N:7]=[CH:6]2)=[O:16])=[CH:13][CH:12]=1
Reactant: NCCCn1ccnc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: CCO
Product: O=C(NCCCn1ccnc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(3-Aminopropyl)imidazole (2.39 ml, 0.02 mol) was added to a solution of 4-bromobenzoyl chloride (4.0 g, 0.018 mol) in ethanol (250 ml). The mixture was stirred at ambient temperature for 18 hours. The volatiles were removed by evaporation and the residue was purified by chromatography eluting with hexane/dichloromethane (50:50) increasing in polarity to dichloromethane/methanol (80:20) to give the title compound. NMR: 1.95 (m, 2H), 3.20 (q, 2H), 4.0 (t, 2H), 6.87 (s, 1H), 7.19 (s, 1H), 7.64 (d, 2H), 7.68 (s, 1H), 7.78 (d, 2H), 8.58 (t, 1H); m/z: 308 [MH]+.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][C:4]#[CH:5].[CH3:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:1](=[O:7])[CH2:2][CH2:3][C:4]#[CH:5])[CH2:11][CH2:10]1
Reactant: C#CCCC(=O)O
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C#CCCC(=O)N1CCN(C)CC1
Yield: 28.3 %

Procedure:
4-Pentynoic acid (1.03 g) and N-methylpiperazine (1.0 g) was dissolved in 30 mL of DMF, 1.6 g of HOBt was added to the solution at ice temperature under stirring. After the mixture was stirred at same temperature for 15 minutes, additionally 2.3 g of WSC was added, and the solution was stirred at room temperature overnight. The DMF was removed under reduced pressure from the reaction mixture, then water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was removed. The residue was purified by chromatography on silica gel (methylene chloride-methanol-triethylamine 600:20:1) to give 510 mg of 1-(4-methylpiperazin-1-yl)pent-4-yn-1-one as a colorless oil.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C@@H:10]([OH:22])[CH2:11][C@@H:12]([C:18]([OH:21])([CH3:20])[CH3:19])[C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=O)(C)(C)C.C(OC(N[C@@H](CC1CCCCC1)[C@@H](O)C[C@@H](C(O)(C)C)C(NC)=O)=O)(C)(C)C.[C:58]([O:62][C:63]([NH:65][C@H:66]([C:73]([OH:75])=O)[CH2:67][C:68]1[N:69]=[CH:70][S:71][CH:72]=1)=[O:64])([CH3:61])([CH3:60])[CH3:59].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>>[C:58]([O:62][C:63]([NH:65][C@H:66]([C:73]([NH:8][C@@H:9]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C@@H:10]([OH:22])[CH2:11][C@@H:12]([C:18]([OH:21])([CH3:20])[CH3:19])[C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[O:75])[CH2:67][C:68]1[N:69]=[CH:70][S:71][CH:72]=1)=[O:64])([CH3:59])([CH3:60])[CH3:61]
Reactant: CN(C)C(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(C)(C)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Agent: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(C)(C)O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Yield: 71.9 %

Procedure:
A procedure similar to that described in Example 9(a) was repeated, except that 152 mg of (2S, 4S, 5S)- 5-(t-butoxycarbonylamino)-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N,N-dimethylhexanamide (prepared as described in Preparation 25) were used instead of the (2S, 4S, 5S)-5-(t-butoxycarbonylamino)-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-methylhexanamide, and that 109 mg (0.4 mmoles) of N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine, 0.23 ml (1.66 mmoles) of triethylamine, and 0.064 ml (0.4 mmoles) of diethyl cyanophosphate were also used, to obtain 150 mg of the title compound as a white amorphous substance.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[N:13]=[CH:12][C:11]3[CH:10]=[C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:8](=[O:20])[NH:7][C:6]=3[N:5]2[N:21]=1.[I:22]N1C(=O)CCC1=O>CN(C=O)C>[I:22][C:3]1[C:2]([CH3:1])=[N:21][N:5]2[C:6]3[C:11](=[CH:10][C:9]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)=[C:8]([OH:20])[N:7]=3)[CH:12]=[N:13][C:4]=12
Reactant: Cc1cc2ncc3cc(-c4ccccc4)c(=O)[nH]c3n2n1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Cc1nn2c(ncc3cc(-c4ccccc4)c(O)nc32)c1I
Reaction time: 2 h

Procedure:
To a solution of Compound [IV] (0.2 g, 0.73 mmol, 1 eq.) in DMF (10 mL) was added N-iodosuccinimide (0.18 g, 0.8 mmol, 1.1 eq.) and the mixture stirred for 2 hours and concentrated. The residue was purified by silica gel chromatography using CHCl3/MeOH (10%) as eluant to give Compound [XCVII]: LCMS ink 403 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 7.33-7.40 (m, 1H) 7.44 (t, J=7.42 Hz, 2H) 7.69 (d, J=7.22 Hz, 2H) 8.37 (s, 1H) 8.83 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:28]([N:30]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:31](Cl)=[O:32])[CH3:29].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([CH2:25][CH3:26])[C:31]([N:30]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:28][CH3:29])=[O:32])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCN(Cc1ccccc1)C(=O)Cl
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(Cc1ccccc1)C(=O)N(CC)Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC

Procedure:
(2′-Ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.130 g, 0.34 mmol), N-ethyl-N-benzylcarbamoyl chloride (0.081 g, 0.41 mmol), 4-dimethylaminopyridine (0.010 g, 0.08 mmol), and triethylamine (0.12 mL, 0.85 mmol) were combined in CH2Cl2 (5 mL) and stirred at reflux overnight. The mixture was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give [2′-(3-Benzyl-1,3-diethyl-ureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester. The ethyl ester was then hydrolyzed with 1N aqueous LiOH in THF at room temperature to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:10]3([CH2:23][C:13]4=[N:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:17]=[C:12]4[CH2:11]3)[C:9](=[O:24])[NH:8][C:5]2=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:32][Si:33]([CH3:40])([CH3:39])[CH2:34][CH2:35][O:36][CH2:37]Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C@:10]3([CH2:23][C:13]4=[N:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:17]=[C:12]4[CH2:11]3)[C:9](=[O:24])[N:8]([CH2:37][O:36][CH2:35][CH2:34][Si:33]([CH3:40])([CH3:39])[CH3:32])[C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncc(Br)cc21
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)N(COCC[Si](C)(C)C)c2ncc(Br)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl (6S)-5′-bromo-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylate (3.00 g, 7.73 mmol) in THF (30 mL) at 0° C. was added triethylamine (1.29 mL, 9.28 mmol). The resulting mixture was stirred for 10 min, then 2-(trimethylsilyl)ethoxymethyl chloride (1.64 mL, 9.27 mmol) was added dropwise. The reaction mixture was allowed to warm slowly to ambient temperature and stirring was continued for 4 h. The reaction mixture was poured into saturated aqueous sodium bicarbonate (50 mL) and the mixture was extracted with EtOAc (2×75 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc-100:0 to 50:50, to give the title compound. MS: m/z=520.3 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH3:28])[CH2:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH2:16][CH:17]3O)[N:9]=1)[CH3:2].[NH2:29][C@H:30]([CH3:33])[CH2:31][OH:32]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH3:28])[CH2:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH2:16][CH:17]3[NH:29][C@H:30]([CH3:33])[CH2:31][OH:32])[N:9]=1)[CH3:2]
Reactant: CCOc1ccc(Cc2nc(-c3cccc4c3CCC4O)no2)cc1OCC
Reactant: C[C@@H](N)CO
Product: CCOc1ccc(Cc2nc(-c3cccc4c3CCC4N[C@H](C)CO)no2)cc1OCC

Procedure:
Prepared using General Procedure 14 from 4-(5-(3,4-diethoxybenzyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ol 60 and (R)-2-aminopropan-1-ol.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:8]([O:21][CH2:22][CH2:23][OH:24])=[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[CH:6]=1)C.[CH3:36][NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[CH3:36][N:37]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:4](=[O:3])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)[C:8]([O:21][CH2:22][CH2:23][OH:24])=[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=2)[CH:6]=1
Reactant: CNCCCCCCCCc1ccccc1
Reactant: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Product: CN(CCCCCCCCc1ccccc1)C(=O)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
N-methyl-N-(8-phenyloctyl)-3,5-bis(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzamide was prepared as a white solid (0.238 g, 67%) from 3,5-bis-(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzoic acid ethyl ester and N-methyl-N-(8-phenyloctyl)amine using a procedure similar to step 2 of Example 175. 1H NMR (CDCl3) δ 7.94 (s, 2H); 7.84 (d, 2H); 7.68-7.56 (m, 4H); 7.44 (s, 2H); 7.30-7.12 (m, 5H); 3.24 (t, 2H); 3.52 and 3.33 (2bt, 2H); 3.40 (t, 2H); 3.08 (2s, 3H); 2.58 (bt, 2H); 1.60 (m, 4H); 1.42-1.12 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][NH:12][C:13](=[O:27])[CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]3)=S)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:27][C:13]([CH2:14][O:15][C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]4)=[N:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(COc1ccc2c(c1)CCC(=O)N2)NNC(=S)Nc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=C1CCc2cc(OCc3nnc(Nc4ccc(Cl)cc4)o3)ccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
To a stirred solution of N-(4-chlorophenyl)-2-(2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yloxy)acetyl)hydrazinecarbothioamide (0.2 g, 0.49 mmol) in dry DMF (10 mL) at room temperature, EDC HCl (0.189 g, 0.98 mmol) and TEA (0.148 g 1.4 6 mmol) were added. The reaction was stirred at room temperature overnight and monitored by LCMS. The solvent was removed under vacuum and then water (20 mL) was added to the residue. The solid which formed was filtered, dried, and the crude product (0.15 g) was recrystallized in a mixture of ethanol/ACN to afford 6-((5-(4-chlorophenylamino)-1,3,4-oxadiazol-2-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (70 mg, 38%) as an off white solid. 1H NMR: 400 MHZ, DMSO-d6: δ 2.41 (t, J=7.20 Hz, 2H), 2.85 (t, J=8.00 Hz, 2H), 5.23 (s, 2H), 6.80 (d, J=8.40 Hz, 1H), 6.87 (dd, J=2.80, 8.40 Hz, 1H), 6.94 (d, J=2.40 Hz, 1H), 7.42 (dd, J=2.00, 6.80 Hz, 2H), 7.58 (dd, J=2.40, 6.80 Hz, 2H), 9.96 (s, 1H), 10.77 (s, 1H). LCMS: RT 1.50 min, LCMS (ES-API), m/z 371.0 (M+H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13](OS(C)(=O)=O)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Br-:22].[Na+].O>CN(C)C=O>[Br:22][CH:13]([C:5]1[CH:4]=[C:3]([C:2]([F:21])([F:20])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1)[CH3:14]
Reactant: [Br-]
Reactant: C[C@@H](OS(C)(=O)=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
With reference to Japanese Patent No. 3938651, a solution of (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (optical purity, >99.5% ee; 1.6 g; 6.20 mmol) in dichloromethane (20 mL) was added with methanesulfonyl chloride (0.58 mL, 7.44 mmol), triethylamine (1.30 mL, 9.3 mmol), and dimethylaminopyridine (76 mg, 0.62 mmol) with stirring under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was added with 1 N hydrochloric acid and chloroform at the same temperature, and the organic layer was separated. The aqueous layer was extracted with chloroform (20 mL×3), and the organic layers were combined, washed with saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (R)-methanesulfonic acid 1-[3,5-bis(trifluoromethyl)phenyl]ethyl ester (2.23 g) as colorless oil. Then, a solution of the resulting (R)-methanesulfonic acid 1-[3,5-bis(trifluoromethyl)phenyl]ethyl ester (2.23 g) in N,N-dimethylformamide (20 mL) was added with sodium bromide (1.26 g, 12.25 mmol), and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was added with water (30 mL) at room temperature, and the mixture was extracted with hexane (30 mL×3). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 1.85 g of 1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane as colorless oil. On the basis of the specific rotation, it was confirmed that the resulting 1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane was obtained after racemization.