Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20](=[O:24])[CH2:21][CH2:22][CH3:23]>>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([CH:14]([CH:20]([OH:24])[CH2:21][CH2:22][CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC=O
Reactant: CCOC(=O)Cc1nsc(NC(=O)OC(C)(C)C)n1
Product: CCCC(O)C(C(=O)OCC)c1nsc(NC(=O)OC(C)(C)C)n1

Procedure:
1.0 g (3.5 mMol) of product from Example 28 were reacted with 0.9 ml (~10 mMol) of n-butanal for 5 days in the manner described in Example 29 and then purified by chromatography on silica gel. Yield 0.17 g (14% of theory).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=1)[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[CH:22]=[C:23]([C:25]([O:27]C)=[O:26])[S:24][C:17]=12)=[O:11].[OH-].[Na+].O.Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=1)[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[CH:22]=[C:23]([C:25]([OH:27])=[O:26])[S:24][C:17]=12)=[O:11]
Reactant: COC(=O)c1cc2nccc(Oc3cccc(C(=O)Nc4cc(C)ccc4F)c3)c2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(F)c(NC(=O)c2cccc(Oc3ccnc4cc(C(=O)O)sc34)c2)c1
Reaction time: 2.5 h

Procedure:
To a stirred solution of methyl 7-(3-((2-fluoro-5-methylphenyl)carbamoyl)phenoxy)thieno[3,2-b]pyridine-2-carboxylate (170 mg, 0.39 mmol) in 15 ml of MeOH was added 1 ml of 1M NaOH. Reaction was complete within 2.5 hours. The mixture was poured into 100 ml of water and acidified with 2M HCl to pH=5 with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give 7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridine-2-carboxylic acid as white solid. Yield: 150 mg, 91%.
Reaction SMILES: [C:1]1([C:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:8]=2)=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:34]>C(OCC)C>[C:23]12([C:1]3[CH:2]=[CH:3][C:4]([C:7]4[N:11]=[CH:10][N:9]([C:12]5[CH:13]=[CH:14][C:15]([O:18][C:19]([F:20])([F:21])[F:22])=[CH:16][CH:17]=5)[N:8]=4)=[CH:5][CH:6]=3)[O:34][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(C4=CCCCC4)cc3)n2)cc1
Solvent: CCOCC
Product: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(C45CCCCC4O5)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.2 %

Procedure:
To a solution of 3-(2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-4-yl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CB10) (3.11 g, 8.07 mmol) in diethyl ether (60 mL) was added meta-chloroperoxybenzoic acid (70%; 2.79 g, 11.3 mmol) slowly at 0° C. The reaction was stirred and allowed to gradually warm to room temperature, then stirring was continued for 18 hours. The solution was diluted in diethyl ether, washed with sodium bicarbonate, extracted with diethyl ether, washed with water, and extracted again with diethyl ether. The organics were dried, filtered, and concentrated providing the title compound as a white solid (2.5 g, 77%) which was used without further purification: 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.20-8.11 (m, 2H), 7.84-7.77 (m, 2H), 7.52-7.46 (m, 2H), 7.39 (dt, J=8.0, 1.0 Hz, 2H), 3.12 (dd, J=3.1, 1.7 Hz, 1H), 2.34 (ddd, J=14.9, 8.5, 5.3 Hz, 1H), 2.09-1.95 (m, 2H), 1.74-1.45 (m, 4H), 1.42-1.28 (m, 1H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 402 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][N:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[NH2:12])([O-])=O.Cl>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][N:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[NH2:12]
Reactant: NN(Cc1ccccc1[N+](=O)[O-])c1ccc(Cl)cc1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccccc1CN(N)c1ccc(Cl)cc1
Yield: 77.6 %

Procedure:
To a solution of 6.5 g (0.023 m) of 1-[(2-nitrophenyl)methyl]-1-(4-chlorophenyl)hydrazine of Example 12a in 150 ml of 95% ethanol and 25 ml of water, 12.8 g (0.23 g-atom) of iron and 1 ml of concentrated HCl was added. The mixture was refluxed for 0.5 hours, cooled, Celite added and filtered. The filtrate was evaporated and the residual material was partitioned between 10% NaOH and ether. The ether extract was dried (Na2SO4), filtered and evaporated to afford a solid which was triturated with hexane and filtered giving 4.5 g (80%) of 1-[(2-aminophenyl)methyl]-1-(4-chlorophenyl)hydrazine, m.p. 83°-87° C.
Reaction SMILES: [H-].[Na+].O.C(OP([CH2:12]/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])(OCC)=O)C.[CH2:20]([N:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH2:20]([N:27]1[CH2:32][CH2:31][C:30](=[CH:12][CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=CC=C1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 29.2 %

Procedure:
Under an atmosphere of nitrogen, 0.583 g of sodium hydride (as a 50% w/w dispersion in mineral oil) were added to a 4 ml of tetrahydrofuran and the mixture was cooled with water. A solution of 3.04 g of ethyl 4-(diethylphosphono)crotonate in 5 ml of tetrahydrofuran was added dropwise to the cooled mixture, which was then stirred for 30 minutes. At the end of this time, a solution of 1.84 g of 1-benzyl-4-piperidone in 2 ml of tetrahydrofuran was added to the mixture over a period of 30 minutes, whilst the mixture was kept at 0° C. by ice-cooling, and the mixture was stirred at 0° C. for 1 hour. The reaction mixture was then stirred at room temperature for 2 hours, after which it was concentrated by evaporation under reduced pressure. The residue was extracted with ethyl acetate, and the extract was washed with water. The solvent was then removed by distillation under reduced pressure. The red brown residue was subjected to column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to afford 0.81 g (29% yield) of the title compound as a pale yellow oil.
Reaction SMILES: Cl.[CH:2]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]1[N:17]=[C:18]([CH2:21][NH2:22])[S:19][CH:20]=1.C(N(CC)CC)C.[CH3:30][O:31][C:32](Cl)=[O:33]>O1CCOCC1>[CH:2]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]1[N:17]=[C:18]([CH2:21][NH:22][C:32](=[O:33])[O:31][CH3:30])[S:19][CH:20]=1
Reactant: NCc1nc(-c2ccc3c(c2)Nc2ccccc2S3)cs1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)NCc1nc(-c2ccc3c(c2)Nc2ccccc2S3)cs1
Temperature: 0 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
The compound of Example 362 (0.622 g; 2.0 mmol) is dissolved in dioxane (100 ml) cooled down to 0° C. Triethylamine is added, then, dropwise, methylchloroformate (2.5 mmol). The reaction medium is then stirred for 3 hours at ambient temperature before being poured into ice-cold water and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and concentrated under vacuum. The expected product is purified on a silica column (eluent: 10% acetone in dichloromethane). The pure fractions are combined and the solvents are evaporated off in order to produce an off-white solid with a yield of 46.0%. Melting point: 151-153° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.[CH2:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:17]>>[CH2:19]([N:18]([CH2:16][CH3:17])[C:13]([C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:15])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Reactant: CCNCc1ccccc1
Product: CCN(Cc1ccccc1)C(=O)c1cnoc1-c1ccccc1Cl

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and N-ethylbenzylamine (8.1 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (8.4 mg). Calcd for C19H17ClN2O2: 340.0979, found 340.0978.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17](Cl)=[O:18].Cl.[C:21]1([C:27]2([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:35][CH:34]=[C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[O:42][CH3:43])[C@H:32]3[C@@H:28]2[CH2:29][NH:30][CH2:31]3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:44]1([C:27]2([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:35][CH:34]=[C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[O:42][CH3:43])[C@H:32]3[C@@H:28]2[CH2:29][N:30]([C:17](=[O:18])[CH2:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH3:8])[CH2:31]3)[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: COc1ccccc1CC(=O)Cl
Reactant: COc1ccccc1C1=CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@@H]12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1CC(=O)N1C[C@H]2C(c3ccccc3OC)=CCC(c3ccccc3)(c3ccccc3)[C@H]2C1
Temperature: 0 °C
Reaction time: 15 h
Yield: 20 %

Procedure:
1.5 cm3 of triethylamine and then 1.6 g of (2-methoxyphenyl)-acetyl chloride are added to a solution of 1.5 g of (3aS,7aR)-4,4-diphenyl-7-(2-methoxyphenyl)-2,3,3a,4,5,7a-hexahydro-isoindole hydrochloride in 20 cm3 of methylene chloride, cooled to 0° C. The mixture is stirred at room temperature for 15 hours; the reaction mixture is washed with twice 40 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed over a Merck silica gel column (particle size 0.04-0.06 mm, diameter 3.6 cm, height 25 cm) by eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (75/25 by volume) and collecting fractions of 25 cm3. Fractions 14 to 28 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The yellow foam obtained is recrystallised from 10 cm3 of cyclohexane to give 0.38 g of (3aS,7aR)-4,4-diphenyl-2-[(2-methoxyphenyl)-acetyl]-7-(2-methoxyphenyl)-2,3,3a,4,5,7a-hexahydro-isoindole in the form of a beige solid which melts at 142° C.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@@H:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=5)=[CH:21][CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:4].[Li+].[OH-].Cl>C1COCC1.CO>[C:38]([O:37][C:35]([N:6]1[C@H:5]([C:3]([OH:4])=[O:2])[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@@H:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=5)=[CH:21][CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7]1)=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: COC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Reaction time: 0.25 h

Procedure:
(3R,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester 8-methyl ester (1.0 g) was dissolved in 60 mL of THF-MeOH (1:4) and the mixture cooled on an ice bath. 2 N aqueous LiOH (5 eq.) was added and the mixture was stirred on ice for 15 minutes and then at room temperature for 14 hours. The pH of the mixture was adjusted to about 2 with 1N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. DCM was added and mixture was again concentrated (900 mg). LCMS: m/z 587.
Reaction SMILES: [C:1]([O:4][CH2:5]Br)(=[O:3])[CH3:2].[C:7]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:12]=[CH:11][C:10]([CH2:13][C@@H:14]([NH:23]C(OC(C)(C)C)=O)[CH2:15][C@:16]([CH2:21][OH:22])([CH3:20])[C:17]([OH:19])=[O:18])=[CH:9][CH:8]=1.CCN(CC)CC>CC(C)=O>[C:1]([O:4][CH2:5][O:19][C:17](=[O:18])[C@@:16]([CH2:21][OH:22])([CH3:20])[CH2:15][C@H:14]([NH2:23])[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@](C)(CO)C(=O)O
Reactant: CC(=O)OCBr
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)OCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1

Procedure:
Bromomethyl acetate (38 μL, 387 μmol) was added to a mixture of (2S,4R)-5-biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (100 mg, 242 μmol) and Et3N (35 μL, 254 μmol) in acetone (10 mL). The mixture was refluxed for 24 hours and the reaction monitored for completion. When the reaction was complete, the product was purified ((Interchim reverse phase chromatography column) the solvent was removed under vacuum to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid acetoxymethyl ester.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:19][C@H:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[S:28][C:29]4[C:34]([N:35]=3)=[CH:33][CH:32]=[C:31]([C:36]3([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[CH2:38][CH2:37]3)[N:30]=4)=[CH:23][CH:22]=2)[CH2:17][C@H:16]1[C:45]([OH:47])=[O:46])=O)(C)(C)C>C(Cl)Cl>[C:39]1([C:36]2([C:31]3[N:30]=[C:29]4[S:28][C:27]([C:24]5[CH:25]=[CH:26][C:21]([O:20][C@H:18]6[CH2:19][NH:15][C@H:16]([C:45]([OH:47])=[O:46])[CH2:17]6)=[CH:22][CH:23]=5)=[N:35][C:34]4=[CH:33][CH:32]=3)[CH2:37][CH2:38]2)[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](Oc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)cc2)C[C@H]1C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H]1C[C@@H](Oc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)cc2)CN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,2,2-Trifluoroacetic acid (0.5 mL, 6.49 mmol) was added to a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-(4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenoxy)pyrrolidine-2-carboxylic acid (130.0 mg, 0.233 mmol) in DCM (4.5 mL) and the resulting solution was stirred at 25° C. for 2 h. The reaction mixture was then concentrated in vacuo, and the residue was taken up in DMSO (2.0 mL) and purified by rpHPLC (10-100% CH3CN/H2O+0.1% TFA) to provide (2S,4R)-4-(4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenoxy)pyrrolidine-2-carboxylic acid as a white solid. MS (ESI) m/z: Calculated: 457.1; Observed: 458.1 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:20][CH2:21][O:22][CH3:23])[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[C:8](=[O:19])[CH2:7]1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1([CH2:20][CH2:21][O:22][CH3:23])[CH2:11][CH2:10][NH:9][C:8](=[O:19])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CCOC)CCN(C(=O)OC(C)(C)C)C(=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(CCOC)CCNC(=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.6 %

Procedure:
4-(2-Methoxy-ethyl)-2-oxo-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (8.7 g) dissolved in dichloromethane (300 ml) under an argon atmosphere was treated with trifluoroacetic acid (60.32 g, 39.11 ml) and stirred for 3 hours at RT. The reaction mixture was then concentrated in vacuo, the residue dissolved in AcOEt, which was then washed with 3M aqueous NaOH, brine and dried over magnesium sulphate. The solvent was removed in vacuo and the residue was chromatographed on silica gel (acetone/CH2Cl2, gradient 0 to 10%) to give the desired product as light brown viscous oil (1.49 g). MS (ESI): 230.13 (MH+).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][N:20]2[CH:24]=[C:23](/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:22]=[N:21]2)=[CH:17][CH:16]=1.C(O)C>[C].[Pd].O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:22]=[N:21]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)/C=C/c1cnn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCc1cnn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
A mixture of ethyl(E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propenoate (1.78 g), 5% palladium-carbon (2.0 g), ethanol (20 ml), and tetrahydrofuran (20 ml) was stirred at room temperature for one hour under a hydrogen atmosphere. After removal of the catalyst by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (1.57 g, yield: 88%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][C:29]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:36][C:37]([Si:40]([CH3:54])([CH3:53])[O:41][CH2:42][C@@H:43]1[CH2:52][N:51]2[C@H:46]([CH2:47][O:48][CH2:49][CH2:50]2)[CH2:45][NH:44]1)([CH3:39])[CH3:38].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:44]3[C@H:43]([CH2:42][O:41][Si:40]([C:37]([CH3:39])([CH3:38])[CH3:36])([CH3:53])[CH3:54])[CH2:52][N:51]4[C@H:46]([CH2:47][O:48][CH2:49][CH2:50]4)[CH2:45]3)=[CH:22][C:23]=2[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][C:29]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1ccncc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CN2CCOC[C@@H]2CN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccncc1-c1cc(N2C[C@H]3COCCN3C[C@H]2CO[Si](C)(C)C(C)(C)C)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 130 °C
Yield: 74.9 %

Procedure:
The 2-[3,5-bis(trifluoromethyl)phenyl]-N-(6′-chloro-4-methyl-3,4′-bipyridin-3′-yl)-N,2-dimethylpropanamide (D52, 77 mg, 0.15 mmol), (7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)octahydropyrazino[2,1-c][1,4]oxazine (D51, 51.5 mg, 0.18 mmol), sodium t-Butoxide (18 mg, 0.19 mmol) were degassed together in dry toluene (1.5 mL) for 5 mins before adding Bis(dibenzyleneacetone) Palladium (9 mg, 0.015 mmol) and 2-Dicyclohexylphosphino-2′-(N′N′-dimethylamino)biphenyl (15 mg, 0.038 mmol) and heating under microwave conditions at 130° C. for 30 mins. Diluted with EtOAC, washed with sat. NaHCO3×1, brine ×1, dried (MgSO4). Filtered. Solvent evaporated. Residue purified eluting with Pent to EtOAc. No Fractions isolated clean. Mixed fractions combined, solvent evaporated and residue re-purified on a 2 g SCX column, washing with MeOH (2×10 mL) before eluting the compound off with NH3 in MeOH (3×10 mL). Solvent evaporated under reduced pressure to afford a gummy solid (86 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:14][N:15]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].[CH3:37]I>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:14][N:15]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[CH:18][CH:17]=3)=[CH:10][N:11]2[CH3:37])=[CH:7][CH:6]=1)=[O:4]
Reactant: CI
Reactant: COC(=O)c1ccc2c(CN(C(=O)OC(C)(C)C)c3ccc(N4CCOCC4)cc3)c[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(CN(C(=O)OC(C)(C)C)c3ccc(N4CCOCC4)cc3)cn(C)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the ester 124 (473 mg, 1.02 mmol) in DMF (15 ml) was added 60% NaH (45 mg, 1.12 mmol). The solution was stirred for one hour at room temperature under nitrogen, cooled to 0° C., treated with MeI (170 μl, 1.12 mmol), warmed to room temperature and stirred overnight under nitrogen. The mixture was partitioned between water and AcOEt, organic layer was collected, dried over MgSO4 and concentrated in vacuo to yield 454 mg (93%). 1H-NMR (DMSO) δ: 7.99 (m, 1H), 7.56 (dd, J=1.4, 8.2 Hz, 1H); 7.47 (m, 1H); 7.27 (s, 1H); 6.86 (d, J=8.8 Hz, 2H); 6.75 (d, J=9.0 Hz, 2H); 4.86 (s, 2H); 3.83 (s, 3H); 3.76 (s, 3H); 3.67 (t, J=4.8 Hz, 4H); 3.01 (t, J=4.8 Hz, 4H); 1.37 (s, 9H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:4]=1[O:5][C@H:6]1[C@@H:10]([OH:11])[CH2:9][N:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:7]1=[O:18].[Cl:27][C:28]1[CH:33]=[N:32][C:31](Cl)=[CH:30][N:29]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:27][C:28]1[N:29]=[CH:30][C:31]([N:15]2[CH2:14][CH2:13][CH:12]([N:8]3[CH2:9][C@H:10]([OH:11])[C@H:6]([O:5][C:4]4[CH:19]=[CH:20][C:21]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:22][C:3]=4[F:2])[C:7]3=[O:18])[CH2:17][CH2:16]2)=[N:32][CH:33]=1
Reactant: Clc1cnc(Cl)cn1
Reactant: CS(=O)(=O)c1ccc(O[C@@H]2C(=O)N(C3CCNCC3)C[C@@H]2O)c(F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(O[C@@H]2C(=O)N(C3CCN(c4cnc(Cl)cn4)CC3)C[C@@H]2O)c(F)c1
Temperature: 100 °C
Yield: 7.7 %

Procedure:
(3S,4S)-3-(2-fluoro-4-(methylsulfonyl)phenoxy)-4-hydroxy-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride (0.03 g, 0.073 mmol) was dissolved in DMF (2 mL) and 2,5-dichloropyrazine (0.012 g, 0.081 mmol) and Hunig's base (0.040 mL, 0.22 mmol) were added. The reaction was heated at 100° C. for 4 hours. The reaction was cooled and concentrated. The residue was purified by reverse phase chromatography (5 to 95% ACN in water) to afford (3S,4S)-1-(1-(5-chloropyrazin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenoxy)-4-hydroxypyrrolidin-2-one (0.0027 g, 0.0056 mmol, 7.6% yield). Mass spectrum (apci) m/z=485.2 (M+H).
Reaction SMILES: [OH:1][C:2]1([CH2:12][NH:13][C:14]([C:16]2[C:17]3[CH:18]=[CH:19][C:20](Cl)=[N:21][C:22]=3[CH:23]=[CH:24][C:25]=2[Cl:26])=[O:15])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([F:11])([F:10])[F:9])[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:37][N:38]([CH3:44])[C@@H:39]1[CH2:43][CH2:42][NH:41][CH2:40]1>>[OH:1][C:2]1([CH2:12][NH:13][C:14]([C:16]2[C:17]3[CH:18]=[CH:19][C:20]([N:41]4[CH2:42][CH2:43][C@@H:39]([N:38]([CH3:44])[CH3:37])[CH2:40]4)=[N:21][C:22]=3[CH:23]=[CH:24][C:25]=2[Cl:26])=[O:15])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([F:9])([F:10])[F:11])[CH2:3]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: O=C(NCC1(O)CCCC(C(F)(F)F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)[C@@H]1CCN(c2ccc3c(C(=O)NCC4(O)CCCC(C(F)(F)F)C4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (1-hydroxy-3-trifluoromethyl-cyclohexylmethyl)-amide, DIPEA and (R)-3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.76 (s, 1H), 3.83 (t, 1H), 3.75 (m, 2H), 3.46 (m, 2H), 3.26 (m, 2H), 2.84 (m, 1H), 2.22 (s, 6H), 2.12 (m, 2H), 1.85-1.72 (m, 4H), 1.27 (t, 1H), 1.07 (t, 1H), 0.83 (d, 3H). m/z: 499 [M+H]