Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH3:29][N:30]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH:24]1([N:22]([CH3:23])[C:4]2[C:5]([CH3:21])=[C:6]([CH:20]=[C:2]([C:33]3[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=3)[CH:3]=2)[C:7]([NH:9][CH2:10][C:11]2[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=2[CH3:17])=[O:8])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Reactant: Cn1cc(B(O)O)cn1
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: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnn(C)c3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A solution of 5-bromo-3-(cyclopentyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.), (1-methyl-1H-pyrazol-4-yl)boronic acid (1.2 equiv.) and Pd (PPh3)4 (0.1 equiv.) in 1,4-dioxane (4 mL) was purged with argon for 10 min. Then, 2 M Na2CO3 solution (3.6 equiv.) was added to it and the mixture was purged again for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After reaction completion, water was added and extraction was carried out using DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel (60-120 mesh size) to afford the title compound (0.07 g, 70%) LCMS: 448.25 (M+1)+; HPLC % 98.34 (@254 nm) (Rt; 4.578; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.44 (s, 1H), 8.11 (s, 1H), 8.05 (t, 1H), 7.80 (s, 1H), 7.29 (s, 1H), 7.09 (s, 1H), 5.85 (s, 1H), 4.26 (d, 2H, J=3.2 Hz), 3.83 (s, 3H), 3.49 (m, 1H), 2.20 (s, 3H), 2.16 (s, 3H), 2.10 (s, 3H), 1.69 (m, 2H), 1.60 (m, 2H), 1.42-1.49 (m, 4H). [3H merged in solvent peak].
Reaction SMILES: NCC(O)=O.[OH-].[Na+].[C@@H:8]1([CH2:16][OH:17])[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14][OH:15].COC1C=CC(C=O)=CC=1>O.CC(C)=O.C(O)C.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)([O-])=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.C(OCC)(=O)C.C(Cl)Cl>[C@H:9]12[CH2:14][O:15][C:16](=[O:17])[C@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10]2
Reactant: OC[C@@H]1CCCC[C@@H]1CO
Agent: COc1ccc(C=O)cc1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)([O-])OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: NCC(=O)O
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CCO
Product: O=C1OC[C@@H]2CCCC[C@H]12
Yield: 87.4 %

Procedure:
Glycine (18.8 grams) is dissolved in 2 liters of deionized water, and the pH is adjusted by the addition of 10% sodium hydroxide to 9.0. Cis-1,2-cyclohexane dimethanol (10.0 grams) is dissolved in 150 ml of acetone added to the glycine solution with stirring, followed by the addition of β-NAD+ (Sigma, 0.5 grams). To the resulting solution is added horse liver alcohol dehydrogenase (Sigma, 250 mg, approximately 400 units). After the enzyme has dissolved the pH is readjusted to 9.0 with 10% sodium hydroxide, and the reaction mixture is stirred at 30° C. During the reaction, the pH is maintained at 9.0 with a pH-stat by the addition of 10% sodium hydroxide. Progress of the reaction is monitored by thin layer chromatography (Silica gel plates, eluent 1:1 ethyl acetate-methylene chloride; visualization by dipping in a solution of 5% anisaldehyde in ethanol and heating). When the reaction is complete as judged by thin layer chromatography, the reaction mixture is adjusted to a pH of 13 with 10 M sodium hydroxide and then extracted 3 times with 250 ml of methylene chloride. The pH of the aqueous mixture is then adjusted to 3 with concentrated HCl, followed by continuous extraction with 1 liter of ethyl acetate for 24 hours. The ethyl acetate extract is dried over anhydrous magnesium sulfate and evaporated under reduced pressure to yield (1R,6S)-(+)-8-oxabicyclo[4.3.0]nonan-7-one (8.5 grams) as a yellowish oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C@@H:8]([NH:11][C:12]([C:14]2[C:15]3[CH:22]=[N:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:16]=3[CH:17]=[N:18][CH:19]=2)=[O:13])[CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1.Cl.CN.C[CH2:34][N:35](C(C)C)C(C)C>CS(C)=O.C(=O)(O)[O-].[Na+]>[CH3:34][NH:35][C:2]1[CH:7]=[C:6]([C@@H:8]([NH:11][C:12]([C:14]2[C:15]3[CH:22]=[N:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:16]=3[CH:17]=[N:18][CH:19]=2)=[O:13])[CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(Br)c1
Agent: CN
Agent: Cl
Agent: O=C([O-])O
Solvent: CS(C)=O
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(NC)c1
Temperature: 160 °C
Reaction time: 16 h

Procedure:
A sealed tube charged with 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid[(S)-1-(2-bromopyridin-4-yl)-propyl]-amide (0.10 g, 0.22 mmol), methylamine hydrochloride (45 mg, 0.67 mmol) and DIPEA (203 μL, 1.17 mmol) in DMSO (2 mL) was warmed at 160° C. After 16 hours, the reaction was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with dichloromethane (5×10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography eluting with 10% methanol in dichloromethane to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:41][C@H:42]([OH:52])[C@@H:43]([NH2:51])[CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:35][CH:34]=1>CN(C=O)C>[S:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:41][C@H:42]([OH:52])[C@@H:43]([NH:51][C:11](=[O:13])[C@H:6]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:35][CH:34]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-c2nccs2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nccs2)cc1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, 938 mg (4.96 mmol) of N-methoxycarbonyl-(L)-iso-leucine, 1.78 g (9.3 mmol) of EDC and 838 mg (6.2 mmol) of HOBT are dissolved in 13.7 ml of DMF. After 30 min, 2.6 ml (18.6 mmol) of TEA are added and then a solution of 1.45 g (3.1 mmol) of 1-[4-(thiazol-2-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-amino-6-phenyl-2-azahexane (Example 17b) in 28 ml of DMF is added dropwise thereto. After 3 hours the reaction mixture is concentrated by evaporation; the residue is taken up in ethyl acetate and a small amount of THF and washed with water, sat. NaHCO3 solution, water and brine. The aqueous phases are extracted with ethyl acetate; the combined organic phases are dried over Na2SO4 and concentrated by evaporation. Column chromatography (SiO2 ; methylene chloride/THF 5:1) and stirring from ethyl acetate/DIPE yield the title compound: HPLC20-100 : tRet =16.3; FAB MS (M+H)+ =640.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[S:8](N)([NH2:11])(=[O:10])=[O:9]>O1CCOCC1>[CH3:1][C@@H:2]1[NH:3][CH2:4][CH2:5][N:6]([S:8]([NH2:11])(=[O:10])=[O:9])[CH2:7]1
Reactant: C[C@H]1CNCCN1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: C[C@H]1CN(S(N)(=O)=O)CCN1
Yield: 19.4 %

Procedure:
To a solution of (2S)-2-methylpiperazine (0.914 g) in dioxane (10 ml) was added sulfamide (0.746 g) and the reaction mixture was then heated at reflux in dioxane for 3 d. The reaction mixture was partitioned between EtOAc (150 ml) and H2O (150 ml) and the aqueous re-extracted with EtOAc (2×150 ml). Organics were collected dried and reduced in vacuo to yield (3S)-3-methylpiperazine-1-sulfonamide as a white solid (0.27 g). A mixture of (3S)-3-methylpiperazine-1-sulfonamide (0.27 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.628 g) and 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester ((the product of example 5 step i), 0.50 g) in dioxane (20 mL) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 30 mins. The reaction mixture was then reduced in vacuo and the residue was partitioned between EtOAc (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow solid. Yield: 0.940 g
Reaction SMILES: [CH2:1]([N:3]1[CH:7]([CH2:8][CH2:9][O:10][C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)[CH:6]=[N:5][NH:4]1)[CH3:2].[C:18]1([C:24]2[O:28][N:27]=[CH:26][C:25]=2[CH2:29][CH2:30][C:31](O)=[O:32])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:1]([N:3]1[CH:7]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([NH:15][C:31](=[O:32])[CH2:30][CH2:29][C:25]3[CH:26]=[N:27][O:28][C:24]=3[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:17]=2)[CH:6]=[N:5][NH:4]1)[CH3:2]
Reactant: CCN1NN=CC1CCOc1ccc(N)cc1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCN1NN=CC1CCOc1ccc(NC(=O)CCc2cnoc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
A mixture of 4-[2-(3-ethyl-4H-triazol-4-yl)ethoxy]aniline (1.12 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (1.04 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.89 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.11 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-[4-[2-(3-ethyl-4H-triazol-4-yl)ethoxy]phenyl]-3-(5-phenyl-4-isoxazolyl)propionamide (1.58 g, yield 76%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from acetone-hexane. melting point: 167–168° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2].[F:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][C:46]=1[F:47].C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:44]3[CH:43]=[CH:42][C:41]([F:40])=[C:46]([F:47])[CH:45]=3)[CH:25]=[C:26]([O:28][CH2:29][CH3:30])[CH:27]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(OCC)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC)cc(-c3ccc(F)c(F)c3)c2)c1CCC(=O)OCC
Yield: 23.4 %

Procedure:
A similar procedure as described in Example 44, step 3 was used, starting from 4-[3-[6-(3-bromo-5-ethoxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (305 mg, 0.5 mmol), 3,4-difluoro-phenylboronic acid (164 mg, 1.0 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (55 mg, 0.075 mmol), and cesium carbonate (331 mg, 1.0 mmol) to obtain 4-[2-(2-ethoxycarbonyl-ethyl)-3-[6-(3′,4′-difluoro-5-ethoxy-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid ethyl ester (75 mg, 23%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C37H46F2O7 (M+Na)+ 663.3104. found 663.3102.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12](=[O:23])[O:13][C:14]3[C:19]([C:20]=2[CH3:21])=[CH:18][CH:17]=[C:16]([OH:22])[CH:15]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[I-].[N:25]1([C:35](N2C=C[N+](C)=C2)=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12](=[O:23])[O:13][C:14]3[C:19]([C:20]=2[CH3:21])=[CH:18][CH:17]=[C:16]([O:22][C:35]([N:25]2[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:28][CH2:27][CH2:26]2)=[O:36])[CH:15]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C[n+]1ccn(C(=O)N2CCCc3ccccc32)c1
Reactant: COc1ccc(-c2c(C)c3ccc(O)cc3oc2=O)cc1OC
Agent: [I-]
Product: COc1ccc(-c2c(C)c3ccc(OC(=O)N4CCCc5ccccc54)cc3oc2=O)cc1OC
Yield: 21.2 %

Procedure:
The title compound (50 mg, 21% yield, oil) was prepared from 3-(3,4-dimethoxy-phenyl)-7-hydroxy-4-methyl-chromen-2-one (156 mg, 0.50 mmol) and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide (188 mg, 0.51 mmol).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH2:6][C:7](OCC)=[O:8])(=[O:3])[CH3:2].[BH4-].[Na+].CO.[OH-].[Na+]>C1COCC1.O>[F:18][C:14]1[CH:13]=[C:12]([C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][CH2:7][OH:8])[CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C[C@H](NC(C)=O)c1cccc(F)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](CCO)c1cccc(F)c1
Temperature: 50 °C
Yield: 99.5 %

Procedure:
A stirred suspension of ethyl (3S)-3-(acetylamino)-3-(3-fluorophenyl)propanoate (2.5 g, 9.9 mmol) and sodium borohydride (0.76 g, 20 mmol) in THF (20 ml) was heated at 50° C. under a nitrogen atmosphere. Methanol (1.8 ml) was then carefully added dropwise and the reaction mixture heated under reflux for one hour. The reaction was allowed to cool to room temperature then water (10 ml) and aqueous sodium hydroxide solution (1.5 g NaOH in 4 ml water) carefully added dropwise. The solution was extracted with ethyl acetate (3×30 ml) and the combined organic extracts dried (MgSO4) and evaporated to give the title compound as a white solid (2.08 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=O.[Br:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[NH:23][C:22]2=[O:31]>>[Br:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:25][CH2:26][N:27]([C:11](=[O:13])[CH2:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:15])[F:14])[CH2:28][CH2:29]1)[NH:23][C:22]2=[O:31]
Reactant: O=C1NC2(CCNCC2)c2c(Br)cccc21
Reactant: O=C(O)CCc1ccccc1C(F)(F)F
Product: O=C1NC2(CCN(C(=O)CCc3ccccc3C(F)(F)F)CC2)c2c(Br)cccc21

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 28 using 3-(2-(trifluoromethyl)phenyl)propanoic acid and 7-bromospiro[isoindoline-1,4′-piperidin]-3-one. LC-MS Method 2 tR=2.206, min, m/z=481; 1H NMR (CDCl3) 1.43 (d, 2H), 2.68 (t, 2H), 2.80-2.92 (m, 3H), 3.15 (t, 2H), 3.32 (t, 1H), 3.92 (d, 1H), 4.85 (d, 1H), 7.25 (m, 2H), 7.40 (m, 2H), 7.56 (d, 1H), 7.65 (d, 1H), 7.79 (d, 1H), 9.20 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:10]2[C:9]3[CH:11]=[C:12]([S:19]([O-:22])(=[O:21])=[O:20])[CH:13]=[C:14]([S:15]([O-:18])(=[O:17])=[O:16])[C:8]=3[CH:7]=[CH:6][C:5]=2[N+:4]([CH2:23][CH2:24][CH2:25][S:26]([O-:29])(=[O:28])=[O:27])=[C:3]1[CH3:30].[Na+:32].[Na+].[CH2:34]1COS(=O)(=O)CC1>>[CH3:1][C:2]1([CH3:31])[C:10]2[C:9]3[CH:11]=[C:12]([S:19]([O-:22])(=[O:20])=[O:21])[CH:13]=[C:14]([S:15]([O-:18])(=[O:16])=[O:17])[C:8]=3[CH:7]=[CH:6][C:5]=2[N+:4]([CH2:23][CH2:24][CH:25]([S:26]([O-:29])(=[O:28])=[O:27])[CH3:34])=[C:3]1[CH3:30].[Na+:32].[Na+:32]
Reactant: CC1=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C
Reactant: O=S1(=O)CCCCO1
Agent: [Na+]
Product: CC1=[N+](CCC(C)S(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C

Procedure:
Compound 4 was prepared analogously to compound 3 (Example 3), except that 1,4-butanesultone is used as a starting material.
Reaction SMILES: [OH:1][CH:2]([CH3:20])[CH2:3][N:4]1[C:12]2[C:7](=[C:8]([C:15]([F:18])([F:17])[F:16])[C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[CH3:19].O[C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=1>>[C:13]([C:9]1[C:8]([C:15]([F:18])([F:16])[F:17])=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:4]([CH2:3][CH:2]([O:1][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=1)[CH3:20])[C:5]([CH3:19])=[CH:6]2)#[N:14]
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(C)O
Reactant: CC(=O)Nc1ccc(O)cc1
Product: CC(=O)Nc1ccc(OC(C)Cn2c(C)cc3c(C(F)(F)F)c(C#N)ccc32)cc1

Procedure:
Synthesized as described in Example 139C using 1-(2-hydroxypropyl)-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 335) and N-(4-hydroxyphenyl)acetamide: MS (ES) m/z 414 (M−1).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].IC.[C:13](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:13])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(C)c(Br)c(C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.4 %

Procedure:
To a 0° C. solution of 4-bromo-3,5-dimethylphenol (1.00 g, 4.98 mmol) in DMF (10.0 mL) was added iodomethane (1.41 g, 9.96 mmol) and potassium carbonate (1.37 g, 9.96 mmol). The mixture was stirred for 5 h at room temperature. The mixture was poured into water and extracted with ethyl acetate (15 ml*3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica gel chromatography to give 2-bromo-5-methoxy-1,3-dimethylbenzene (1.00 g) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.57 (s, 2H), 3.69 (s, 3H), 2.31 (s, 6H).
Reaction SMILES: CON(C)[C:4](=[O:17])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[CH3:16].[CH2:19]1COCC1>O>[CH3:16][C:7]1[CH:8]=[CH:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]=1[CH2:5][C:4](=[O:17])[CH3:19]
Reactant: CON(C)C(=O)Cc1c(C)ccc2ccccc12
Reactant: C1CCOC1
Solvent: O
Product: CC(=O)Cc1c(C)ccc2ccccc12
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 41 %

Procedure:
N-methoxy-N-methyl-2-(2-methyl-naphthalen-1-yl)-acetamide (1.01 g, 4.16 mmol) was dissolved in freshly distilled THF (17 mL) in an argon-purged, round-bottom flask. The mixture was chilled to 0° C. and methyl magnesium bromide (2.08 mL of 3.0 M soln in Et2O, 6.23 mmol) was added via syringe. The reaction was stirred at 0° C. for 75 minutes. TLC analysis (silica, 20% acetone-hexanes) indicated complete consumption of the starting material. The reaction was carefully quenched with a mixture of AcOH (1 mL) in EtOAc (5 mL). The quenched reaction was diluted with H2O and extracted three times with EtOAc. The organic extracts were combined, washed with brine solution, dried over Na2SO4, filtered through celite, and concentrated. Purification by flash chromatography (SiO2, 20% EtOAc-hexane) gave 1-(2-methyl-naphthalen-1-yl)-propan-2-one (343 mg, 1.73 mmol) in 41% yield. MS (APCI) m/z 199.1 (M+H). 1H NMR (300 MHz) CDCl3 δ 7.85 (m, 2H), 7.72 (d, J=9.4 Hz, 1H), 7.47 (m, 2H), 7.36 (d, J=8.2 Hz, 1H), 4.18 (s, 2H), 2.51 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:13]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([O:6]C(C)C)=[O:5].[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1[C:13]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1c(OC(C)C)cccc1C(=O)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(OC(C)C)cccc1C(=O)O
Temperature: 65 °C
Yield: 122.6 %

Procedure:
To a solution of propan-2-yl 2-methyl-3-(propan-2-yloxy)benzoate (Cpd MM, 3.97 g, 16.8 mmol) in THF (40 mL) was added 2N NaOH (25.2 mL, 50.4 mmol). The reaction mixture turned light yellow and was heated at 65° C. for 3 days. The reaction mixture was cooled to room temperature, then concentrated under vacuum. The residue was acidified with 10% HCl (aq) then extracted with EtOAc. The organic layer was washed with brine, dried with Na2SO4 then concentrated under vacuum to give 2-methyl-3-(propan-2-yloxy)benzoic acid (Cpd NN, 4.0 g, 100%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].[Br:18][C:19]1[C:20]([O:29][CH3:30])=[C:21]([C:25]([O:27][CH3:28])=[O:26])[S:22][C:23]=1Br>C1(C)C=CC=CC=1>[Br:18][C:19]1[C:20]([O:29][CH3:30])=[C:21]([C:25]([O:27][CH3:28])=[O:26])[S:22][C:23]=1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1sc(Br)c(Br)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(-c2ccc(Cl)cc2Cl)c(Br)c1OC
Temperature: 110 °C
Yield: 47.1 %

Procedure:
16.60 g of (2,4-dichlorophenyl)boronic acid and then, dropwise, 87 ml of a 2M solution of Na2CO3 are added to a solution of 28.70 g of the compound of step A) in 110 ml of toluene. Argon is sparged into the reaction mixture for 30 minutes, 5.03 g of tetrakis are then added and the mixture is heated at 110° C. for 18 hours. After cooling to AT, 80 ml of distilled water are added to the reaction mixture, extraction is carried out with 80 ml of EtOAc, drying is carried out over Na2SO4 and the solvent is evaporated off under vacuum. The reaction crude is purified by silica gel chromatography, elution being carried out with heptane and then with a heptane/EtOAc mixture (85/15; v/v). 16.21 g of the expected compound are obtained.