Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[NH:5][CH:4]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[C:3]=1[C:27]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)=[O:28].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:42][C:43]1[O:44][CH:45]=[C:46]([C:48]([O:50][CH3:51])=[O:49])[N:47]=1>CN(C)C=O>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([CH:4]2[N:5]([CH2:42][C:43]3[O:44][CH:45]=[C:46]([C:48]([O:50][CH3:51])=[O:49])[N:47]=3)[C:6](=[O:18])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:9]=3)[C:2]([CH3:1])=[C:3]2[C:27]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[O:28])=[CH:20][CH:21]=1)#[N:24]
Reactant: COC(=O)c1coc(CCl)n1
Reactant: CC1=C(C(=O)c2cccnc2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1coc(CN2C(=O)N(c3cccc(C(F)(F)F)c3)C(C)=C(C(=O)c3cccnc3)C2c2ccc(C#N)cc2)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred suspension of 4-{6-methyl-2-oxo-5-(pyridin-3-ylcarbonyl)-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzonitrile (Example 21A) (100 mg, 0.22 mmol and potassium carbonate (60 mg, 0.43 mmol) in dimethylformamide (3 ml) is added methyl 2-(chloromethyl)-1,3-oxazole-4-carboxylate (57 mg, 0.32 mmol). The reaction mixture is stirred for 72 hours at room temperature. The crude product is quenched with water (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic phases are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; eluent: acetonitrile/water 30:70→90:10).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[N:9][CH:8]=[N:7][C:6]=2[CH:5]=[N:4]1)[CH3:2].C1C(=O)N([Br:19])C(=O)C1.O>CN(C=O)C>[Br:19][C:5]1[C:6]2[N:7]=[CH:8][N:9]=[CH:10][C:11]=2[N:3]([CH2:1][CH3:2])[N:4]=1
Reactant: CCn1ncc2ncncc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(Br)c2ncncc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
To a solution of 1-ethyl-1H-pyrazolo[4,3-d]pyrimidine (300 mg) in DMF (6 mL) was added NBS (721 mg) at room temperature, and the mixture was stirred at 80° C. overnight. The mixture was poured into water and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (310 mg). 1H NMR (300 MHz, CDCl3) δ 1.62 (3H, t, J=7.3 Hz), 4.54 (2H, q, J=7.3 Hz), 9.14 (1H, s), 9.17 (1H, s).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:26])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])=[CH:7][C:6]=1[Cl:27]>C(NCC)C.CCOC(C)=O>[Cl:27][C:6]1[CH:7]=[C:8]([NH:11][C:12](=[O:26])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])[CH:9]=[CH:10][C:5]=1[CH2:4][CH2:3][CH2:2][N:11]([CH2:12][CH3:13])[CH2:8][CH3:7]
Reactant: O=C(/C=C/c1ccc(C(F)(F)F)cc1Cl)Nc1ccc(CCCBr)c(Cl)c1
Solvent: CCNCC
Solvent: CCOC(C)=O
Product: CCN(CC)CCCc1ccc(NC(=O)/C=C/c2ccc(C(F)(F)F)cc2Cl)cc1Cl

Procedure:
A solution of 0.290 g (0.603 mmol) (E)-N-[4-(3-bromo-propyl)-3-chloro-phenyl]-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylamide (Z45d) in 2 mL diethylamine was heated to 100° C. in a sealed reaction vessel in the microwave for 5 min. The reaction mixture was diluted with EtOAc, the org. phase was washed with water, dried over sodium sulphate and evaporated down i. vac. The residue was triturated with ether, the precipitate was filtered off, washed with ether and dried in a HV.
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:47]=[CH:46][C:45](C4C(C#N)=CSC=4)=[CH:44][CH:43]=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19].[CH3:55][N:56]1[CH2:61][CH2:60][N:59](C2C=CC(O)=CC=2)[CH2:58][CH2:57]1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:47]=[CH:46][C:45]([N:59]4[CH2:60][CH2:61][N:56]([CH3:55])[CH2:57][CH2:58]4)=[CH:44][CH:43]=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19]
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Reactant: CN1CCN(c2ccc(O)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc(OCCCc3sc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)O)cc2)CC1

Procedure:
The title compound 82 was prepared as a TFA salt in a similar manner to the synthesis of compound 51 by substituting compound 51A with compound 82A: 1H NMR (DMSO-d6): δ 12.90 (s, 1H), 9.58 (s, 1H), 8.04 (d, J=7.63 Hz, 2H), 7.80 (d, J=7.93 Hz, 2H), 7.67 (d, J=7.63 Hz, 1H), 7.35-7.50 (m, 4H), 6.90-6.92 (m, 2H), 6.82-6.85 (m, 2H), 4.83 (s, 2H), 3.91 (t, J=6.26 Hz, 2H), 3.14-3.17 (m, 2H), 3.03 (t, J=5.95 Hz, 2.82-2.86 (m, 5H), 1.94-2.00 (m, 2H). ESI (+)/MS: 669 (M+H)+.
Reaction SMILES: [CH2:1]([O:13][CH2:14][CH:15]([CH2:21][O:22]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[O:16][C:17]([O:19][CH3:20])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:13][CH2:14][CH:15]([CH2:21][OH:22])[O:16][C:17]([O:19][CH3:20])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(=O)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCOCC(CO)OC(=O)OC
Temperature: 25 °C
Reaction time: 0.13 h
Yield: 107.4 %

Procedure:
To a solution of (rac)-1-O-dodecyl-2-O-methoxycarbonyl-3-O-trityl-glycerol (10.2 g) in methylene chloride (100 ml) was added trifluoroacetic acid (10 ml) in one portion. After the yellow solution was stirred for 8 minutes at ambient temperature, ice water (100 ml) was added. The organic layer was washed with aqueous sodium bicarbonate solution and water, dried, and evaporated under reduced pressure. The residue was treated with n-hexane (50 ml) to remove triphenylmethanol as a white crystal. The filtrate was evaporated to give 6.22 g of (rac)-1-O-dodecyl-2-O-methoxycarbonyl-glycerol as a colorless oil (unstable oil).
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[CH:8]=[C:9]2[C:15]([CH3:16])=[N:14][NH:13][C:10]2=[N:11][CH:12]=1.CN([CH:20]=[O:21])C>C1COCC1>[CH3:16][C:15]1[C:9]2[C:10](=[N:11][CH:12]=[C:7]([CH:20]=[O:21])[CH:8]=2)[NH:13][N:14]=1
Reactant: Cc1n[nH]c2ncc(Br)cc12
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1n[nH]c2ncc(C=O)cc12
Reaction time: 0.08 h
Yield: 14.3 %

Procedure:
80 ml anhydrous THF were charged into a 250 ml round bottom flask and was chilled to −78° C. t-BuLi (1.70 M in THF, 17.6 ml, 30 mmol) was added to the flask via syringe. After stirring for 5 min, 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine (2.12 g, 10 mmol) was added dropwise via syringe. After 30 min, DMF (3.65 g, 50 mmol) in 20 ml THF was added dropwise and the mixture was stirred for overnight. The reaction was quenched by saturated aqueous ammonium chloride. After evaporating the excess THF, the reaction mixture was extracted by ethylacetate twice. The combined organic layer was washed with brine once and dried over sodium sulfate. The crude product was chromatographed with 50% ethylacetate in hexane to afford the desired product (0.23 g, y=20.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[N+:16]([O-])=O.[H][H]>[Ni].O1CCCC1>[NH2:16][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:2]=1[NH2:1])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)c2ccccc2)cc1N
Yield: 100 %

Procedure:
Fifty grams of 4-amino-3-nitrobenzophenone were hydrogenated at room temperature in 945 ml. of tetrahydrofuran with 15 g. of Raney nickel at 2.74×106 dynes/cm.2. After 4 hours three equivalents of hydrogen were absorbed. The catalyst was filtered and the filtrate was evaporated in vacuo to a solid residue. The residue was chromatographed over silica gel using ethyl acetate as eluant. Fractions 5-9 were combined to yield 43.6 g. (100 percent yield) of 3,4-diaminobenzophenone.
Reaction SMILES: [CH:1]1([N:4]([CH3:22])[C:5]2[C:6]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=4[S:15][C:7]=3[N:8]=[C:9]([CH2:11][C:12](O)=[O:13])[N:10]=2)[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.C[CH2:34][N:35]=[C:36]=NCCCN(C)C.Cl>C1COCC1.O>[CH:1]1([N:4]([CH3:22])[C:5]2[C:6]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=4[S:15][C:7]=3[N:8]=[C:9]([CH2:11][C:12]([N:35]([CH3:36])[CH3:34])=[O:13])[N:10]=2)[CH2:2][CH2:3]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CN(c1nc(CC(=O)O)nc2sc3c(c12)CCCC3)C1CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)Cc1nc(N(C)C2CC2)c2c3c(sc2n1)CCCC3
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To 2-(4-(cyclopropyl(methyl)amino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)acetic acid (100 mg, 0.000315 mol) in anhydrous THF (10 ml) 2M dimethyl amine in THF (0.017 g, 0.000378 mol) and HOBt (0.051 g, 0.000378 mol) were added. This mixture was cooled to 0° C. and then treated with EDC HCl (0.120 g, 0.00063 mol). The reaction mixture was allowed to warm to room temperature and kept stirred for 16 h. After completion, the reaction was diluted with water (50 ml) and extracted with ethyl acetate (25 ml×3). Combined organic extracts were washed with water (50 ml), dried over anhydrous Na2SO4 and concentrated under vacuum to get crude compound. It was then purified by column chromatography by using 100-200 mesh silica gel. Pure compound was eluted in 1-2% MeOH: DCM to afford 2-(4-(cyclopropyl(methyl)amino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)-N,N-dimethylacetamide as a pale yellow oil. Yield—50 mg, (46.29%); 1H-NMR: (400 MHz, CDCl3); δ=3.97 (s, 2H), 3.04 (s, 3H), 3.01 (s, 3H), 2.97 (s, 3H), 2.89-2.80 (m, 5H), 1.92-1.86 (m, 2H), 1.77-1.71 (m, 2H), 0.72-0.67 (m, 2H), 0.45-0.41 (m, 2H); LC-MS [M+H]=345.3; HPLC purity=98.78%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([N:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:32]4[N:36]([CH3:37])[N:35]=[CH:34][CH:33]=4)[CH:29]=3)[C:24]2=[O:38])[CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])[CH:5]=[C:6]([F:8])[CH:7]=1.[Br:39]N1C(=O)CCC1=O>O1CCCC1>[Br:39][C:33]1[CH:34]=[N:35][N:36]([CH3:37])[C:32]=1[C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[C:24](=[O:38])[N:23]([C@@H:10]([CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[CH2:11][N:12]1[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]1=[O:22])[CH2:31]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1nccc1-c1ccc2c(c1)CN([C@@H](Cc1cc(F)cc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Solvent: C1CCOC1
Product: Cn1ncc(Br)c1-c1ccc2c(c1)CN([C@@H](Cc1cc(F)cc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
To a solution of 2-{(2S)-3-(3,5-difluorophenyl)-2-[5-(1-methyl-1H-pyrazol-5-yl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]propyl}-1H-isoindole-1,3(2H)-dione (200.0 mg, 0.39 mmol) [prepared in Example 40] in tetrahydrofuran (5 mL) was added N-bromosuccinimide (72.0 mg, 0.404 mmol). The solution was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was purified by combi-flash chromatography eluting with EtOAc/hexane (50-100%). The purification afforded 177 mg (77% yield) of the desired product as white solid. LC/MS found: 591.0 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19](Br)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.[NH:25]1[C:33]2[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[C:28]=2[CH:27]=[N:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19]([C:29]4[CH:30]=[CH:31][CH:32]=[C:33]5[C:28]=4[CH:27]=[N:26][NH:25]5)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C
Reactant: OB(O)c1cccc2[nH]ncc12
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: O
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(-c3cccc4[nH]ncc34)c2n1C
Temperature: 140 °C
Yield: 39.6 %

Procedure:
A mixture of 4-amino-6-[(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile, (0.10 g, 0.26 mmol), 1H-indazole-4-boronic acid (0.054 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.013 mmol) and caesium carbonate (0.17 g, 0.51 mmol) in dioxane (3 mL) and water (1.5 mL) was placed in a sealed tube and degassed with nitrogen for 5 minutes, then heated for 30 min at 140° C. by microwave irradiation. 1H-indazole-4-boronic acid (0.054 g, 0.33 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.01 mmol) were added and the resultant mixture heated for 30 min at 140° C. by microwave irradiation. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge then washed with MeOH and the product eluted with 2M NH3/MeOH and concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 78 min gradient 20-98% 0.1% HCO2H in acetonitrile/water) to give 426 as a white solid (0.044 g, 40%). LCMS (Method K): RT 2.82, 2.99 min [M+H]+ 428.1. 1H NMR (DMSO-d6, 400 MHz): δ 13.30 (1H, s), 8.23-7.98 (1H, m), 7.77-7.60 (4H, m), 7.51-7.48 (1H, m), 7.36-7.24 (2H, m), 7.23-7.08 (2H, m), 5.59-5.54 (1H, m), 3.00 (3H, d, J=8.05 Hz), 1.57 (3H, dd, J=6.69, 1.65 Hz). Signals split due to presence of rotamers/tautomers
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[O:45]1[CH2:50][CH2:49][CH:48]([CH2:51][NH2:52])[CH2:47][CH2:46]1.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:52][CH2:51][CH:48]3[CH2:49][CH2:50][O:45][CH2:46][CH2:47]3)=[O:12])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1
Reactant: NCC1CCOCC1
Reactant: COc1cc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2O)ccn1
Yield: 81.7 %

Procedure:
Combined 6-(5-hydroxy-4-(2-methoxypyridin-4-yl)-1H-pyrazol-1-yl)nicotinic acid (30 mg, 0.096 mmol), EDCI (27.6 mg, 0.144 mmol), HOBT (19.47 mg, 0.144 mmol), and DMF (961 μl), then added (tetrahydro-2H-pyran-4-yl)methanamine (17.66 μl, 0.144 mmol) and Hunig's base (68.3 μl, 0.384 mmol) and stirred at room temperature overnight. The reaction mixture was purified via preparative HPLC to give the title compound (32.1 mg, 82%) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ ppm 1.35 (qd, J=12.38, 4.55 Hz, 2H) 1.71 (d, J=12.88 Hz, 2H) 1.84-1.99 (m, 1H) 3.42 (td, J=11.68, 1.64 Hz, 2H) 3.95 (d, J=3.28 Hz, 1H) 3.98 (s, 3H) 4.19 (s, 3H) 7.76 (d, J=6.57 Hz, 1H) 7.84 (s, 1H) 8.03 (d, J=6.57 Hz, 1H) 8.28-8.47 (m, 2H) 8.55 (br. s., 1H) 8.85 (br. s., 1H). MS m/z [M+H]+410.1.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=1.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K].O>CN(C)C=O>[C:15]1(=[O:25])[N:19]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=2)[C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(=O)c1ccc(OCCCBr)cc1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
p-(3-Bromopropoxy)acetophenone (5.14 g.) and potassium phthalimide (3.75 g.) were dissolved in anhydrous N,N-dimethylformamide (50 ml.), and the solution was stirred at 70° C. for 2.5 hours. After the reaction mixture was allowed to cool, water (300 ml.) was poured thereto. The aqueous solution was extracted three times with ethyl acetate, and the extract was washed with ethyl acetate and then dried over magnesium sulfate. The ethyl acetate was removed by evaporation from the solution under reduced pressure, and the resultant residue was treated with ether to give p-(3-phthalimidopropoxy)acetophenone (5.75 g.).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[F:13][C:14]([F:28])([F:27])[CH2:15][CH2:16][CH2:17][C:18]([C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1)=[O:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[F:13][C:14]([F:27])([F:28])[CH2:15][CH2:16][CH2:17][C:18]([C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)=[O:19]
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=C(CCCC(F)(F)F)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CCCC(F)(F)F)c1cccc(OCc2ccc3ccccc3n2)c1
Yield: 62 %

Procedure:
This material was synthesized by refluxing a mixture of 2-chloromethyl quinoline (2.6 g, 14.5 mmol), 3-(5,5,5-trifluoropentanoyl)phenol (3.7 g, 15.9 mmol), powdered potassium carbonate (6.0 g, 43.5 mmol) and a catalytic amount of potassium iodide (0.1 g) in dry acetone (50 ml) for 14 hours. After this period, the mixture was filtered, and the filtrate was concentrated. The residue was dissolved in ether, and the ethereal solution was washed with brine, dried over MgSO4, and then concentrated in vacuo. The pure desired ketone was isolated by chromatography on silica gel using 20% ethyl acetate in hexanes as eluent. The product was obtained in 62% yield (3.4 g), had a melting point 80°-82° C. and was a yellowish solid.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C1COCC1.[CH3:14][N:15]([CH2:17][CH:18]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:19]1)[CH3:16].[C:32]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=1>O>[C:32]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:33]=[CH:34][C:35]([CH2:38][CH2:31][S:28]([N:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:27][CH:18]([CH2:17][N:15]([CH3:14])[CH3:16])[CH2:19]2)(=[O:29])=[O:30])=[CH:36][CH:37]=1
Reactant: CN(C)CC1Cc2ccccc2N(S(C)(=O)=O)C1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CC1Cc2ccccc2N(S(=O)(=O)CCc2ccc(-c3ccccc3)cc2)C1
Yield: 10.7 %

Procedure:
LDA (1.9 M/THF, 1.2 ml) was added dropwise to a THF solution of 3-(N,N-dimethylamino)methyl-1-methylsufonyl-1,2,3,4-tetrahydroquinoline (0.24 g). The reaction mixture was stirred under ice-cooling for 30 minutes. A THF (1 ml) solution of 4-biphenylylmethyl bromide (0.16 g) was added to the reaction mixture, which was stirred at room temperature for 3 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water, Lil then dried and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate), which was further recrystallized from hexane-ethyl acetate to give the entitled compound (30 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([C:7](OCC)=[O:8])[CH2:5][NH:4][C:3]1=[O:12].[NH3:13]>CO>[CH3:1][CH:2]1[CH:6]([C:7]([NH2:13])=[O:8])[CH2:5][NH:4][C:3]1=[O:12]
Reactant: N
Reactant: CCOC(=O)C1CNC(=O)C1C
Solvent: CO
Product: CC1C(=O)NCC1C(N)=O

Procedure:
A solution of ethyl 3-methyl-2-oxo-4-pyrrolidinecarboxylate [Chem. Pharm. Bull., 24, 1362 (1976)] (5 g) in methanol (100 ml) saturated with ammonia gas left at room temperature for 4 days. After the reaction mixture was concentrated and the residue was recrystallized from ethanol to give 3-methyl-2-oxo-4-pyrrolidinecarboxamide (3.4 g), mp 169°-171° C.
Reaction SMILES: C([CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17](=[O:32])[CH:18]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])[C:11]=1[F:33])[C:6]([OH:8])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([CH:18]([CH:19]([CH3:24])[C:20]([F:23])([F:21])[F:22])[C:17]([NH:16][C:12]2[C:11]([F:33])=[C:10]([CH2:9][CH2:5][C:6]([OH:8])=[O:7])[CH:15]=[CH:14][CH:13]=2)=[O:32])=[CH:30][CH:29]=1
Reactant: CC(C(C(=O)Nc1cccc(CC(C(=O)O)C(C)(C)C)c1F)c1ccc(Cl)cc1)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C(C(=O)Nc1cccc(CCC(=O)O)c1F)c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
270 mg (0.553 mmol) of tert-butyl (+/−)-3-(3-{[2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-2-fluorophenyl) propanoic acid (diastereomer 1, Example 102A) were dissolved in 0.2 ml of dichloromethane, and 0.85 ml of trifluoroacetic acid was added at RT. The reaction mixture was stirred at RT for 4 h and then concentrated under reduced pressure. The residue was purified by preparative RP-HPLC (acetonitrile/water mixture). This gave 188 mg (78.7% of theory) of the target compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:15][C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[F:24])[CH2:10][C:11]([O:13]C)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[OH-].[Na+].Cl>O>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:15][C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[F:24])[CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Temperature: 60 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a clean flask, 34.73 g (R)-methyl 3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butyrate, 100 ml toluene, 160 ml water and 4.8 g sodium hydroxide were added. The mixture was warmed to 60° C. and kept at this temperature for 3 hours. 4.73 g hydrochloric acid was added dropwisely. After completion, the resulting mixture was kept at 20-30° C. for 2 hours and filtrated to obtain 30.66 g (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)n-butyric acid (yield: 92%).