Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[S:13][C:14]([C:16]([N:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])[CH3:19])=[O:17])=[CH:15][C:11]=3[CH2:10][CH2:9][O:8][C:7]=2[CH:27]=1.[CH3:28][NH:29][CH3:30]>>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:18]([CH3:19])[C:16]([C:14]1[S:13][C:12]2[C:6]3[CH:5]=[CH:4][C:3]([CH2:2][N:29]([CH3:30])[CH3:28])=[CH:27][C:7]=3[O:8][CH2:9][CH2:10][C:11]=2[CH:15]=1)=[O:17]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(CBr)cc1OCC2)c1ccccc1Cl
Reactant: CNC
Product: CN(C)Cc1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2

Procedure:
8-(Bromomethyl)-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide was reacted with dimethylamine using the procedure of Example 153 for 243 to give 242. MS: (ESI+) 427.0
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][C:8]=1[CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH3:2].[H-].[Na+].[CH3:29]I>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:29])=[CH:9][C:8]=1[CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)COc1ccc(NC(=O)OC(C)(C)C)cc1CCCOC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(N(C)C(=O)OC(C)(C)C)cc1CCCOC
Reaction time: 1 h

Procedure:
To 2.21 g (6.01 mmol) of the above prepared [4-tert-butoxycarbonylamino-2-(3-methoxy-propyl)-phenoxy]-acetic acid ethyl ester, dissolved in 18 ml of abs. DMF, was added at 0° C. 0.313 g of NaH (60% in mineral oil, 1.3 eq.). 5 Min. later, 0.75 ml (2 eq.) of MeI was added and the reaction allowed to proceed for 10 Min. at 0° C. and for 1 h at ambient temperature. Pouring onto crashed ice/KHSO4 solution, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=8/2), yielded 1.55 g of the title compound as light yellow oil.
Reaction SMILES: [N:1]1([C:7](=[O:26])[CH2:8][O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[O:17][C:18]4[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH:35]1[CH2:37][CH2:36]1>CN(C=O)C.C(OCC)(=O)C>[CH:35]1([CH2:34][O:25][C:23]2[CH:22]=[CH:21][C:19]3[N:20]=[C:16]([N:13]4[CH2:12][CH2:11][CH:10]([O:9][CH2:8][C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[O:26])[CH2:15][CH2:14]4)[O:17][C:18]=3[CH:24]=2)[CH2:37][CH2:36]1
Reactant: BrCC1CC1
Reactant: O=C(COC1CCN(c2nc3ccc(O)cc3o2)CC1)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1)N1CCOCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 2-{4-[2-(morpholin-4-yl)-2-oxoethoxy]piperidin-1-yl}-1,3-benzoxazol-6-ol (2.81 g) in DMF (26 mL) were added potassium carbonate (3.22 g) and (bromomethyl)cyclopropane (1.51 mL), and the mixture was stirred at 80° C. overnight. The reaction mixture was allowed to cool to room temperature, and diluted with ethyl acetate. The diluted solution was washed with distilled water 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 (NH, hexane/ethyl acetate) to give the title compound (2.10 g).
Reaction SMILES: [Cl:1][C:2]1[C:12]([NH2:13])=[C:6]2[CH2:7][C:8]([CH3:11])([CH3:10])[O:9][C:5]2=[C:4]([C:14]2[O:18][N:17]=[C:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:15]=2)[CH:3]=1.Br[CH2:26][CH2:27][CH2:28][C:29]#[N:30].C(N(CC)CC)C>CN(C)C=O>[NH2:13][C:12]1[C:6]2[CH2:7][C:8]([CH3:10])([CH3:11])[O:9][C:5]=2[C:4]([C:14]2[O:18][N:17]=[C:16]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:26][CH2:27][CH2:28][C:29]#[N:30])[CH2:23][CH2:24]3)[N:15]=2)=[CH:3][C:2]=1[Cl:1]
Reactant: CC1(C)Cc2c(N)c(Cl)cc(-c3nc(C4CCNCC4)no3)c2O1
Reactant: N#CCCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)Cc2c(N)c(Cl)cc(-c3nc(C4CCN(CCCC#N)CC4)no3)c2O1
Temperature: 70 °C
Reaction time: 2 h
Yield: 39.6 %

Procedure:
A mixture of intermediate 5 (4 g), 4-bromobutanenitrile (2.2 g) and triethylamine (4.2 ml) in dimethylformamide (70 ml) was stirred for 2 hours at 70° C. The mixture was cooled and the solvent evaporated. The residue was partitioned between CH2Cl2 and NH3 /H2O. The organic layer was separated, dried over MgSO4, filtered and the solvent evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 /CH3OH 95/5). The pure fractions were collected and the solvent evaporated. The residue was solidified in DIPE at 0° C., filtered and dried, yielding 1.89 g (38%) of 4-[5-(4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofuranyl)-1,2,4-oxadiazol-3-yl]-1-piperidinebutanenitrile (compound 3; mp. 151.4° C.).
Reaction SMILES: CCCC=S.[CH3:6][CH:7]1[CH2:12][CH:11]([O:13][CH2:14][C:15](Cl)=[O:16])[CH:10]([CH:18]([CH3:20])[CH3:19])[CH2:9][CH2:8]1.C[OH:22]>N1C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:6][CH:7]1[CH2:12][CH:11]([O:13][CH2:14][C:15]([OH:22])=[O:16])[CH:10]([CH:18]([CH3:20])[CH3:19])[CH2:9][CH2:8]1
Reactant: CO
Reactant: CC1CCC(C(C)C)C(OCC(=O)Cl)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC=S
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC1CCC(C(C)C)C(OCC(=O)O)C1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
1-L-methoxyacetyloxy-3-methylthiopropene is prepared from 3-methylthiopropionaldehyde, L-menthoxyacetyl chloride, and pyridine catalyst. A 70 mL stainless steel high pressure reactor fitted with a Pyrex glass liner and magnetic stir bar is charged with THF (5 mL), (PPh3)2PdCl2 (0.05 mmol), CH3OH (0.5 mmol), and 1-L-menthoxyacetyloxy-3-methylthiopropene (0.5 mmol). The reactor is sealed, pressurized to 1000 psig with CO, and stirred for 24 hours at 100° C. The product mixture, isolated after removal of gas from the reactor vessel, contains a diastereomeric mixture of methyl 2-L-menthoxyacetyl-4-methylthio-L-2-hydroxybutyrate and methyl 2-L-menthoxyacetyl-4-methylthio-D-2-hydroxybutyrate. The diastereomers are separated by preparative gas chromatography using an SE-30 liquid phase column. Each diastereomer is hydrolyzed separately by treatment with 2N HCI (aq) for 2 hours at 100° C. to give pure L- and D-4-methylthio-2-hydroxybutyric acid (methionine hydroxy analog), methanol, and L-menthoxyacetic acid.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14].[CH2:16](Br)[CH:17]=[CH2:18].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:18][CH:17]=[CH2:16])[C:9]=1[OH:14]
Reactant: C=CCBr
Reactant: Cc1ccccc1Sc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: C=CCc1cccc(Sc2ccccc2C)c1O
Yield: 62.7 %

Procedure:
A mixture of 2-(o-tolylthio)phenol (32.7 g), allyl bromide (27.5 g) and dried potassium carbonate (42 g) in methyl isobutyl ketone (400 ml) was refluxed under heating for 4 hours. The reaction mixture was treated in the same manner as Example 21-(1) to give oily 2-(o-tolylthio)-6-allylphenol (24.3 g), bp. 150°-162° C./0.7-0.8 mmHg.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7])(=[O:3])[CH3:2].[C:11]([NH:16][C@H:17]([C:20]([OH:22])=[O:21])[CH2:18][SH:19])(=[O:15])[CH:12]([CH3:14])[CH3:13].OO>CO>[C:1]([NH:4][C@@H:5]([CH2:6][S:7][S:19][CH2:18][C@H:17]([NH:16][C:11](=[O:15])[CH:12]([CH3:13])[CH3:14])[C:20]([OH:22])=[O:21])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(C)C(=O)N[C@@H](CS)C(=O)O
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Agent: OO
Solvent: CO
Product: CC(=O)N[C@@H](CSSC[C@H](NC(=O)C(C)C)C(=O)O)C(=O)O
Reaction time: 3 h
Yield: 31 %

Procedure:
A mixture of N-acetyl-L-cysteine (0.652 g, 4 mmol) and N-isobutyryl-L-cysteine (0.764 g, 4 mmol) in 10 mL of MeOH was stirred while hydrogen peroxide (30%, 0.60 mL, 5 mmol) was added dropwise. The stirring was continued for 3 hours at room temperature, after which the solvent was removed on the rotary evaporator. Addition of 25 mL of acetone and repeated evaporation afforded 1.5 g of crude material as an oil which solidified on standing. The desired title compound was isolated from this mixture by preparative HPLC as described in Example 17.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH3:24])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=1>>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=2)[C:9]2[C:10]([CH3:24])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: Cc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(O)C1CCCCC1
Product: Cc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1

Procedure:
Using cyclohexyl{3-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (0.75 g) synthesized in Example 1(6) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.80 g) synthesized in Example 2(2) and in the same manner as in Example 1 (7), the title object compound (0.74 g, 65%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.[C:12]1([N:18]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:21](=O)[C:19]2=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:10][C:8]1[S:9][C:5]2[CH:4]=[CH:3][C:2]([N:1]=[C:21]3[C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:18]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:19]3=[O:20])=[CH:11][C:6]=2[N:7]=1
Reactant: O=C1C(=O)N(c2ccccc2)c2ccccc21
Reactant: Cc1nc2cc(N)ccc2s1
Product: Cc1nc2cc(N=C3C(=O)N(c4ccccc4)c4ccccc43)ccc2s1
Temperature: 140 °C
Yield: 32.3 %

Procedure:
5-amino-2-methylbenzothiazole (52.2 mg, 0.31 mmol) was mixed with 1-phenylisatin (69.7 mg, 0.31 mmol) and heated at 140° C. for 3 h. The resulting crude product was purified by preparative TLC using ethyl acetate/hexane (6:4) as the eluent to give the desired product as a yellow solid (36.9 ma, 32.3%). 1H NMR Data: δ 7.9-6.7 (m, 12H), 2.9 (s, 3H). ESI-MS m/z found 370 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:11][C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[CH:4][C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1.CCN(C(C)C)C(C)C.Cl[CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34]>C1COCC1>[Cl:1][C:2]1[C:3]([S:11][C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34])[C:6]=2[CH:10]=1
Reactant: Cc1cccc(Sc2cc3nc[nH]c3cc2Cl)c1
Reactant: COCCOCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCn1cnc2cc(Sc3cccc(C)c3)c(Cl)cc21
Temperature: 23 °C
Yield: 66.9 %

Procedure:
To a cooled solution (0° C.) of 6-chloro-5-m-tolylsulfanyl-1H-benzoimidazole (2.14 g, 7.78 mmol) and THF (39 mL) was added DIPEA (2.71 mL, 15.6 mmol). 1-Chloromethoxy-2-methoxy-ethane (0.977 mL, 8.56 mmol) was added dropwise, and the reaction mixture was allowed to warm to 23° C. over 16 h. The reaction mixture was concentrated. The residue was purified (FCC) (0-100% EtOAc/hexanes) to yield the titled compound (1.89 g, 67%) as a 1:1 mixture of regioisomers. MS (ESI/CI): mass calcd. for C18H19ClN2O2S, 362.1; m/z found, 363.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.95 (s, 1H), 7.92 (s, 1H), 7.88 (s, 1H), 7.64 (s, 1H), 7.59 (s, 1H), 7.41 (s, 1H), 7.22-7.18 (m, 3H), 7.16-7.13 (m, 2H), 7.11-7.05 (m, 3H), 5.56 (s, 2H), 5.47 (s, 2H), 3.57-3.54 (m, 2H), 3.52-3.49 (m, 2H), 3.48-3.45 (m, 2H), 3.44-3.42 (m, 2H), 3.35 (s, 3H), 3.30 (s, 3H), 2.30 (s, 6H).
Reaction SMILES: [CH2:1]([C:5]1[N:6](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:7]([C:14]#[N:15])=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]>C(O)(=O)C>[CH2:1]([C:5]1[NH:6][C:7]([C:14]#[N:15])=[C:8]([C:10]([OH:13])([CH3:11])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C(C)(C)O)c(C#N)n1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Product: CCCCc1nc(C(C)(C)O)c(C#N)[nH]1
Temperature: 50 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
A mixture of 1.3 g of 2-butyl-5-cyano-4-(1-hydroxy-1-methylethyl)-1-tritylimidazole [prepared as described in step (i) above] and 26 ml of 75% v/v aqueous acetic acid was stirred at 50° C. for 3 hours, and then the solvent was removed by distillation under reduced pressure. The resulting residue was washed with carbon tetrachloride and purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, and the product was crystallized in carbon tetrachloride, to give 0.6 g of the title compound as colorless crystals, melting at 171°-172° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[C:8]([O:15][CH2:16][CH3:17])=[N:9][O:10][C:11]=1[C:12]([OH:14])=[O:13])[C:3]([OH:5])=[O:4].Cl.[CH2:19](O)[CH3:20]>>[NH2:1][CH:2]([CH2:6][C:7]1[C:8]([O:15][CH2:16][CH3:17])=[N:9][O:10][C:11]=1[C:12]([OH:14])=[O:13])[C:3]([O:5][CH2:19][CH3:20])=[O:4]
Reactant: CCOc1noc(C(=O)O)c1CC(N)C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(N)Cc1c(OCC)noc1C(=O)O

Procedure:
A mixture of (RS)-2-amino-3-(5-carboxy-3-ethoxyisoxazol-4-yl)propionic acid (2.0 g, 8.2 mmol) and a solution of HCl in ethanol (35 mL) was boiled under reflux for 3 h to give ethyl (RS)-2-amino-3-(5-carboxy-3-ethoxyisoxazol-4-yl)propionate. Ethyl (RS)-2-Amino-3-(5-carboxy-3-ethoxyisoxazol-4-yl)propionate (0.6 g) was added a dilute solution of NaOH, and the aqueous phase was extracted with ethyl acetate. The organic extracts were washed with brine, dried (MgSO4), filtered and evaporated to dryness in vacuo. The residue was dissolved in acetone (6 mL) and added a solution of oxalic acid (0.14 g, 1.6 mmol) in acetone (6 mL), and the formed precipitate was collected by filtration (110 mg, 10%): mp 159-161° C.; 1H NMR (DMSO-d6) δ1.11 (t, 3 H), 1.32 (t, 3 H), 1.36 (t, 3 H), 3.02 (dd, 1 H), 3.11 (dd, 1 H), 3.98-4.16 (m, 3 H) 4.32 (q, 2 H), 4.37 (q, 2 H); MS ((M+H)+) m/z 301. Anal. calcd, C, 46.15; H, 5.69; N, 7.18; found, C, 46.38; H, 5.69; N, 7.36.
Reaction SMILES: Br[CH:2](Br)[CH3:3].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[Cl:13][C:14]1[C:15]([F:32])=[C:16]([F:31])[CH:17]=[C:18]2[C:23]=1[N:22]=[C:21]([SH:24])[C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:19]2[OH:30]>CN(C)C=O>[Cl:13][C:14]1[C:15]([F:32])=[C:16]([F:31])[CH:17]=[C:18]2[C:23]=1[N:22]1[CH:2]([CH3:3])[S:24][C:21]1=[C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:19]2=[O:30]
Reactant: CCOC(=O)c1c(S)nc2c(Cl)c(F)c(F)cc2c1O
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2n(c3c(Cl)c(F)c(F)cc3c1=O)C(C)S2

Procedure:
To a suspension of 13.7 g of 1,1-dibromoethane, 5.7 g of potassium iodide and 9.5 g of potassium carbonate in 60 ml of N,N-dimethylformamide, a solution of 11.1 g of ethyl 8-chloro-6,7-difluoro-4-hydroxy-2-mercaptoquinoline-3-carboxylate in 240 ml of N,N-dimethylformamide was added dropwise at from 110° C. to 115° C. during 2 hours with stirring. After stirring for 30 minutes at the same temperature, the reaction mixture was concentrated in vacuo and water was added to the residue. The precipitate was collected by filtration and chromatographed on silica gel using chloroform. The eluent was recrystallized from a mixture of chloroform and diethyl ether to give colorless needles, m.p. 191°-194° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C@@H:15]2[C@:10]([CH3:22])([CH2:11][CH2:12][C:13]3[C:20](Br)=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:29](/B(O)O)=[CH:30]/[CH3:31]>COCCOC.C(O)C.O>[CH2:1]([N:8]1[CH2:16][C@@H:15]2[C@:10]([CH3:22])([CH2:11][CH2:12][C:13]3[C:20](/[CH:29]=[CH:30]\[CH3:31])=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CCc3c(Br)cccc3[C@@H]1CN(Cc1ccccc1)C2
Reactant: C/C=C\B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: C/C=C\c1cccc2c1CC[C@]1(C)CN(Cc3ccccc3)C[C@@H]21
Temperature: 160 °C
Yield: 67.4 %

Procedure:
trans-2-Benzyl-6-bromo-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (0.561 mmol, 200 mg) was dissolved in DME (1 ml) and ethanol (0.5 ml). 2 N sodium carbonate solution (1 ml) was added along with (Z)-prop-1-enylboronic acid (0.842 mmol, 72.3 mg) and tetrakis(triphenylphosphine)Pd(0) (0.028 mmol, 32.4 mg). The reaction mixture was heated to 160° C. for 15 minutes in a microwave reactor and then diluted with water. The resulting mixture was extracted with DCM (3×) and the combined organic extracts were dried over Na2SO4 and concentrated in vacuo to afford a crude residue that was purified by silica column chromatography (eluting with 10% EtOAc in heptane) to afford trans-2-benzyl-3a-methyl-6-((Z)-prop-1-enyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (120 mg), m/z: 318.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][NH:27][CH2:28][CH:29]([C:31]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[C:33]([F:39])[CH:32]=1)[OH:30].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:27]([CH2:28][CH:29]([OH:30])[C:31]4[CH:32]=[C:33]([F:39])[C:34]([F:38])=[C:35]([F:37])[CH:36]=4)[CH3:26])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CNCC(O)c1cc(F)c(F)c(F)c1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(CN(C)CC(O)c2cc(F)c(F)c(F)c2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 6 h
Yield: 50.4 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 2-(methylamino)-1-(3,4,5-trifluorophenyl)ethanol (Preparation 46)(77 mg, 0.38 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 6 hours at that temperature. After cooling to room temperature, the solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (30 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (71 mg) as a white solid.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:31][CH3:32].C(OCC)(=O)C>CN(C)C=O>[C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:31][CH3:32])[CH:15]=3)[N:10]([C:18](=[O:23])[C:19]([F:21])([F:22])[F:20])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC2(C1)CN(C(=O)C(F)(F)F)c1ccc(O)cc12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccc2c(c1)C1(CCN(C(C)=O)C1)CN2C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.2 %

Procedure:
The 1-(1′-acetyl-5-hydroxyspiro[indoline-3,3′-pyrrolidin]-1-yl)-2,2,2-trifluoroethanone (40 mg, 0.122 mmol) obtained in Step 2 of Example 198 was dissolved in N,N-dimethylformamide (0.5 mL). Thereafter, cesium carbonate (52 mg, 0.159 mmol) and iodoethane (23 mg, 0.146 mmol) were added to the above obtained solution, and the thus obtained mixture was then stirred at room temperature for 18 hours. Thereafter, ethyl acetate was added to the reaction solution, and the reaction mixture was then washed with water and brine. The resultant was dried over anhydrous sodium sulfate. The solvent was distilled away, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate) to obtain 1-(1′-acetyl-5-ethoxyspiro[indoline-3,3′-pyrrolidin]-1-yl)-2,2,2-trifluoroethanone (24 mg, 54%) in the form of a colorless oily product.
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([OH:46])=O)=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.[N:50]1[CH:55]=[CH:54][CH:53]=[N:52][C:51]=1[CH2:56][NH2:57]>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([NH:57][CH2:56][C:51]4[N:52]=[CH:53][CH:54]=[CH:55][N:50]=4)=[O:46])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:48][CH:49]=1
Reactant: NCc1ncccn1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ncccn1
Yield: 70 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with pyrimidin-2-ylmethanamine, the title compound was obtained as a colorless solid in 70% yield: mp 205-207° C. (dichloromethane/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.76 (d, J=4.8 Hz, 2H), 8.42-8.38 (m, 1H), 7.41-7.7.34 (m, 3H), 7.23-7.17 (m, 2H), 4.58 (d, J=5.7 Hz, 2H), 4.43 (s, 2H), 4.04-3.99 (m, 2H), 3.49-3.43 (m, 2H), 2.50 (s, 3H); MS (ES+) m/z 427.2 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])[CH3:15])=[CH:8][C:7]=1[CH3:34].[OH-].[Na+].Cl>O1CCCC1.C(OCC)(=O)C>[CH3:34][C:7]1[CH:8]=[C:9]([O:12][CH2:13][CH:14]([C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])[CH3:15])[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]([OH:35])=[O:2]
Reactant: COC(=O)CCc1ccc(OCC(C)c2nc(-c3ccc(-c4ccccn4)cc3)oc2C)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(OCC(C)c2nc(-c3ccc(-c4ccccn4)cc3)oc2C)ccc1CCC(=O)O
Temperature: 25 °C

Procedure:
3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-2-yl-phenyl)-oxazol-4-yl]-propoxy}-phenyl)-propionic acid methyl ester from step A is dissolved in tetrahydrofuran (1 mL) and 5N sodium hydroxide (1 mL) solution is added with stirring at room temperature. The reaction is heated to reflux and monitored by HPLC. Upon complete conversion, the reaction is allowed to cool to room temperature and neutralized with 5N hydrochloric acid (1 mL), diluted with ethyl acetate, and extracted. The organic layer is washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The pure 3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-2-ylphenyl)oxazol-4yl]propoxy}phenyl)propionic acid (400 mg, 0.875 mmol) may also be obtained by recrystalization from ethyl acetate. 70% yield 2 steps, MS (ES): 457.2 (M++1).
Reaction SMILES: C1(C2C=CC=CC=2)C=CC([C:7](=[O:15])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=CC=1.Br[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30]>>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C:7](=[O:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cc1ccccc1)c1ccc(-c2ccccc2)cc1
Reactant: Fc1ccc(Br)c(F)c1
Product: O=C(Cc1ccccc1)c1ccc(F)cc1F
Yield: 19 %

Procedure:
Prepared following the procedure described in Intermediate 14, starting from 1-bromo-2,4-difluorobenzene, where the crude product was purified by column chromatography (PE:EtOAc=50:1) to afford Intermediate 21 (250 mg, yield 19%).