Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:5]=[C:6]([Br:8])[CH:7]=1.CO[B:16]1[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]1>O1CCCC1>[Br:8][C:6]1[CH:5]=[C:4]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:3]=[C:2]([B:16]2[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]2)[CH:7]=1
Reactant: CC(C)(C#N)c1cc(Br)cc(Br)c1
Reactant: COB1OC(C)(C)C(C)(C)O1
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cc(Br)cc(B2OC(C)(C)C(C)(C)O2)c1
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 95.4 %

Procedure:
A solution of isopropylmagnesium chloride lithium chloride complex (1.71 ml, 1.65 mmol) in tetrahydrofuran (10 ml) was cooled down to −20° C. 2-(3,5-dibromophenyl)-2-methylpropanenitrile (500 mg, 1.65 mmol, preparation as described in Example 2 step 1) was added in one portion and the reaction stirred for 1.5 hours at −15 to −5° C. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (260.7 mg, 269.9 μL, 1.65 mmol) was added and the reaction was allowed to warm up to room temperature. The reaction mixture was stirred at room temperature for 18 hours. The mixture was partitioned between a diluted solution of ammonium chloride and ethyl acetate. The organic phase was dried over magnesium sulfate and the solvent removed under reduced pressure to afford the title compound as a light yellow solid (551 mg, 95% yield).
Reaction SMILES: [NH2:1][CH:2]([C:22]1[CH:31]=[CH:30][C:29]2[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=2[CH:23]=1)[C:3]([NH:5][C:6]1[CH:21]=[CH:20][C:9]([C:10]([O:12]CC2C=CC=CC=2)=[O:11])=[CH:8][CH:7]=1)=[O:4].[OH-].[Na+]>C1COCC1>[NH2:1][CH:2]([C:22]1[CH:31]=[CH:30][C:29]2[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=2[CH:23]=1)[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:20][CH:21]=1)=[O:4]
Reactant: CC1(C)CCC(C)(C)c2cc(C(N)C(=O)Nc3ccc(C(=O)OCc4ccccc4)cc3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(C(N)C(=O)Nc3ccc(C(=O)O)cc3)ccc21

Procedure:
2.9 g (6.1 mmol) of the ester prepared in (e), 50 ml of THF and 150 ml of a methanolic sodium hydroxide solution (2N) were introduced into a round-bottomed flask and the mixture was heated at reflux for 2 hours. The reaction medium was evaporated to dryness, the residue taken up in water, and acidified to pH 5 with hydrochloric acid. The solids which had precipitated were filtered, washed with water and dried over P2 O5. 1.9 g (83%) of 4-[α-amino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido]benzoic acid of melting point 203°-204° C. were recovered.
Reaction SMILES: [CH:1]([N:4]1[CH2:11][CH:10]2[CH2:12][CH:6]([CH2:7][NH:8][CH2:9]2)[CH2:5]1)([CH3:3])[CH3:2].[OH-].[Na+].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21].O>C(Cl)Cl>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:20]([N:8]1[CH2:9][CH:10]2[CH2:12][CH:6]([CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:11]2)[CH2:7]1)=[O:21]
Reactant: CC(C)N1CC2CNCC(C2)C1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)N2CC3CC(C2)CN(C(C)C)C3)cc1OC
Reaction time: 3 h
Yield: 73.3 %

Procedure:
A 25-mL, three-necked, round-bottomed flask was equipped with a magnetic stirrer, a standard condenser with a N2 inlet, a 10-mL addition funnel, and two glass stoppers. To a mixture of the amine (31, 0.60 g, 3.57 mmol) in CH2Cl2 (5 mL) and 10% NaOH (3.58 g, 8.93 mmol) was added dropwise a solution of 3,4-dimethoxybenzoyl chloride (0.80 g, 3.92 mmol) in CH2Cl2 (10 mL) over 15 min. Stirring of the mixture was continued for an additional 3 h under N2. An aqueous mixture, formed upon addition of H2O (30 mL), was extracted (CH2Cl2, 4×25 mL). Combined extracts were dried (Na2SO4, 2 h), filtered and concentrated to give a viscous yellow oil. Chromatography of the oil was performed on neutral alumina (74 g, 1.7 cm×32 cm) using 60:40 ethyl acetate/hexanes as eluant. Fractions (Rf = 0.31) were saved and concentrated (rotary evaporator then vacuum pump, overnight, RT/0.2 mm Hg) to give 0.87 g (73.1%) of off-white solid (34); mp 67.5°-69.5° C. IR (KBr) cm-1 3055 (Ar C--H), 2950, 2915, 2845, 2820, 2770, 2750, 2710 (C--H), 1625 (C=O); 1H NMR (DCCl3) δ0.96 (d, 3 H, CH3, J=6.4 Hz), 1.06 (d, 3 H, CH3, J=6.5 Hz), 1.62-1.75 [m, 3 H, H(5) and H(9)], 1.96 [bs, 1 H, H(1)], 2.43 [bd, 1 H, H(4)ax, J=9.7 Hz], 2.51 [bd, 1 H, H(6)ax, J=10.5 Hz], 2.62 [heptet, 1 H, CH(CH3)2, J=6.4 Hz], 2.74 [bd, 1 H, H(6)eq, J=9.9 Hz], 3.00-3.09 [m, 2 H, H(4)eq and H(2)ax ], 3.32 [bd, 1 H, H(8)ax, J=13.2 Hz], 3.83-3.94 [m, 7 H, H(8)eq and OCH3 ], 4.77 [bd, 1 H, H(2)eq, J=13.3 Hz], 6.84-6.94 (m, 3 H, Ar--H); 13C NMR (DCCl3) ppm 16.46, 19.15 (CH3), 29.13 [C(1)], 29.86 [C(5)], 32.36 [C(9)], 46.71 [C(2)], 52.25 [C(4)], 52.65 [C(8)], 54.35 [CH(CH3)2 ], 54.68 [C(6)], 55.88, 55.93 (OCH3), 110.50, 119.64, 130.23, 148.78, 149.39 (Ar--C), 169.90 (C=O). Anal. Calcd. for C19H28N2O3 : C, 68.65; H, 8.49. Found: C, 68.58; H, 8.47.
Reaction SMILES: [OH-].[K+].C(OC([C:8]1[O:9][C:10]2[C:17]([C:18]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[O:19])=[CH:16][C:15]([C:25]([CH3:28])([CH3:27])[CH3:26])=[C:14]([OH:29])[C:11]=2[C:12]=1[CH3:13])=O)C.Cl>O.CO>[CH3:13][C:12]1[C:11]2[C:14]([OH:29])=[C:15]([C:25]([CH3:27])([CH3:26])[CH3:28])[CH:16]=[C:17]([C:18]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[O:19])[C:10]=2[O:9][CH:8]=1
Reactant: CCOC(=O)c1oc2c(C(=O)c3cccs3)cc(C(C)(C)C)c(O)c2c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1coc2c(C(=O)c3cccs3)cc(C(C)(C)C)c(O)c12

Procedure:
To a solution of KOH (0.18 g, 3.21 mmol) in 8.0 mL water and 3.0 mL methanol was added ethyl-3-methyl-4-hydroxy-5-tert-butyl-7-(2-thienoyl)-benzofuran-2-carboxylate, compound 13 (0.412 g, 1.07 mmol). The reaction mixture was heated to reflux for 0.5 hours. The resulting solution was cooled in an ice bath and acidified by the dropwise addition of 2N HCl. The acid was collected by filtration, washed with water and pulled dry over night on the filter funnel to give desired product sufficiently pure for further use. mp 145° C. with decarboxylation; 1H NMR (DMSO-d6) d 1.44 (9H, s), 2.76 (3H, s), 7.17 (1H, dd, J=4 Hz), 7.73 (2H, d, J=4 Hz), 7.90 (1H, s).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Br:9][C:10]1[C:11]([CH3:21])=[CH:12][C:13]2[O:17][CH2:16][C:15]([CH3:19])([CH3:18])[C:14]=2[CH:20]=1.O>ClCCl>[Br:9][C:10]1[C:11]([CH3:21])=[C:12]([C:5](=[O:7])[CH3:6])[C:13]2[O:17][CH2:16][C:15]([CH3:18])([CH3:19])[C:14]=2[CH:20]=1
Reactant: Cc1cc2c(cc1Br)C(C)(C)CO2
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1c(C)c(Br)cc2c1OCC2(C)C
Temperature: 25 °C
Yield: 61.6 %

Procedure:
A stirred, cooled (ice-bath) suspension of aluminum chloride (6.85 g, 51.4 mmol) in 50 mL of anhydrous dichloromethane was treated with acetyl chloride (3.7 mL, 51.4 mmol) under argon. A solution of 5-bromo-3,3,3-trimethyl-2,3-dihydro-benzofuran (Compound 47, 5.2 5 g, 25.7 mmol)in 10 mL of anhydrous dichloromethane was cannulated into the clear solution, and the resulting deep red solution was allowed to warm to ambient temperature over 1 hour. The reaction mixture was poured onto iced water and extracted with dichloromethane. The combined organic extract was dried over anhydrous sodium sulfate, filtered and evaporated to a dirty white solid. Flash column chromatography on silica gel using 6% ethyl acetate in hexane as the eluent afforded the title compound (4.5 g, 61.6%). 1H NMR (300 MHz, CDCl3): δ 7.30 (s, 1H), 4.28 (s, 2H), 2.56 (s, 3H), 2.34 (s, 3H), 1.33 (s, 6H).
Reaction SMILES: C[O-].[K+].CO.CO.[NH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13].[CH2:14](Cl)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>COCCOCCOC>[CH2:14]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCl
Reactant: O=C1CCCN1
Agent: C[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: CO
Product: CCCCCCCCN1CCCC1=O
Reaction time: 6 h

Procedure:
230 g of a 31.98 wt. % strength potassium methoxide-methanol solution (1.05 mol) is added dropwise at about 155° C., while distilling methanol to a solution of 85.2 g of 2-pyrrolidone (butyrolactam, 1.0 mol) in 500 ml of diethylene glycol dimethyl ether. For complete removal of all the methanol, the clear solution is evacuated for a short period until reaching 500 mbar. 156 g of n-octyl chloride (1.05 mol) is then metered in likewise at 155° C. over a period of 20 minutes, and the reaction is brought to completion over a period of another 6 hours.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][S:29]C(=O)C)[CH2:12][C@@H:11]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:42][CH2:43][C:44]([CH3:47])([OH:46])[CH3:45].CO.[OH-].[K+]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][S:29][CH2:42][CH2:43][C:44]([OH:46])([CH3:47])[CH3:45])[CH2:12][C@@H:11]([O:33][Si:34]([C:37]([CH3:40])([CH3:38])[CH3:39])([CH3:35])[CH3:36])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)SC[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(O)CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(O)CCSC[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(acetylthiomethyl)androsta-5,7-diene (135 mg, 0.223 mmol) and 4-bromo-2-methylbutan-2-ol (186 mg, 1.12 mmol) in tetrahydrofuran (1.5 ml), was added a 1M potassium hydroxide methanol solution (1.5 ml), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, followed by the addition of a saturated aqueous ammonium chloride solution and the extraction with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove the solvent. The thus obtained residue was purified by preparative thin layer chromatography (4 sheets (each 0.5 mm thickness), dichloromethane:ethyl acetate=9:1, developed once) to give the titled compound (131 mg, 90%) as a colorless oil.
Reaction SMILES: [CH:1]([Si:4]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[O:15][CH3:16])([CH3:3])[CH3:2].[H][H]>CCO.[Pd]>[CH3:16][O:15][C:7]1[CH:8]=[C:9]([NH2:12])[CH:10]=[CH:11][C:6]=1[O:5][Si:4]([CH:17]([CH3:19])[CH3:18])([CH:20]([CH3:22])[CH3:21])[CH:1]([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: COc1cc([N+](=O)[O-])ccc1O[Si](C(C)C)(C(C)C)C(C)C
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Yield: 77.6 %

Procedure:
Dissolve triisopropyl-(2-methoxy-4-nitro-phenoxy)-silane (95.7 g, 294.0 mmol) in EtOH (1800 mL) and add 5% Pd/C (10.0 g). Hydrogenate the slurry at room temperature under 50 psi hydrogen for 8 h. Filter the slurry through a pad of Celite® and rinse with EtOH. Concentrate the filtrate in vacuo to give a brown oil. Purify by flash chromatography, using a gradient from 100% hexanes to 20% EtOAc/hexanes, to give the title compound as a brown solid (67.4 g, 77.6% yield). MS (ES+) 296.2 (M+1)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](OS(C2C=CC(C)=CC=2)(=O)=O)=[C:6]([O:21][CH3:22])[CH:5]=1)(=[O:3])[CH3:2].[CH:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CCCCCCC.C(Cl)Cl>[C:23]([C:7]1[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][C:6]=1[O:21][CH3:22])#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: COc1cc(C(C)=O)ccc1OS(=O)(=O)c1ccc(C)cc1
Reactant: C#CCCCCC
Solvent: ClCCl
Solvent: CCCCCCC
Product: CCCCCC#Cc1ccc(C(C)=O)cc1OC

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-acetyl-2-methoxy-phenyl ester and 1-heptyne following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/DCM 1:1; yield (110 mg, 90%); 1H NMR δ (CDCl3): 7.50-7.41 (m, 3H), 3.91 (s, 3H), 2.59 (s, 3H), 2.47 (t, J=7.14 Hz, 2H), 1.63 (p, J=7.22 Hz, 2H), 1.5-1.29 (m, 4H), 0.91 (t, J=7.13 Hz, 3H); LCMS m/z: 244.
Reaction SMILES: C(C[N:10]1[CH:14]=[C:13](C2C=CC=CC=2)[N:12]=[CH:11]1)(=O)C1C=CC=CC=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:12]1[C:13]2[N:10]=[CH:14][CH:13]=[N:12][C:14]=2[NH:10][CH2:11]1
Reactant: O=C(Cn1cnc(-c2ccccc2)c1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cnc2c(n1)NCN2
Temperature: 20 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
A solution of 2-[1(S)-{1,1-dimethylethoxy)carbonylamino}-2-(3-indolyl)ethyl]-1-(benzoylmethyl)-4-phenyl-1H-imidazole (prepared as described previously) (100 mg) in a mixture of 10% TFA in DCM (1.3 mL) was stirred for about 3 hours at about 20° C. and concentrated under reduced pressure to yield the expected dihydro-imidazo-pyrazine (yield=95%). LC/MS: calculated MW: 402.19, m/z=403.2 (M+H).
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]([OH:14])=O)=[CH:3]1.[CH2:15]([C@H:22]1[CH2:26][NH:25][C@H:24]([C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:32][CH:31]=2)=[O:28])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]([N:25]2[CH2:26][C@H:22]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][C@H:24]2[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:32][CH:31]=2)=[O:28])=[O:14])=[CH:3]1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)Cc1c[nH]c2ccccc12
Yield: 39.3 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-indol-3-yl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 98, (2S,4R)-1-(2-(1H-indol-3-yl)acetyl)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (12.9 mg, 39.3%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.91 (s, 1H), 9.99 (s, 1H), 7.56 (m, 3H), 7.35-7.07 (m, 10H), 7.01-6.94 (m, 5H), 4.50 (m, 1H), 3.75 (m, 2H), 3.69 (s, 2H), 2.61 (m, 3H), 1.90 (m, 2H). MS (EI) for C34H30FN3O3. found 548.6 (MH+).
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([CH2:6][C:7]3([C:13]42[N:19]=[C:18]([NH2:20])[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[F:29]>>[Cl:22][C:23]1[CH:24]=[C:25]([C:2]2[CH:15]=[C:14]3[C:5]([CH2:6][C:7]4([C:13]53[N:19]=[C:18]([NH2:20])[C:17]([CH3:21])=[N:16]5)[CH2:8][CH2:9][O:10][CH2:11][CH2:12]4)=[CH:4][CH:3]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCOCC1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: CC1=NC2(N=C1N)c1cc(-c3ccc(F)c(Cl)c3)ccc1CC21CCOCC1
Yield: 42 %

Procedure:
The title compound was synthesized as described for Example 26a in 42% yield, starting from 6′-bromo-5-methyl-2″,3″,5″,6″-tetrahydro-3′H-dispiro[imidazole-2,1′-indene-2′,4″-pyran]-4-amine (Example 25, 75 mg, 0.22 mmol) and 3-chloro-4-fluorobenzeneboronic acid (45.1 mg, 0.26 mmol); 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.72 (dd, 1 H), 7.52 (m, 2 H), 7.42 (m, 2 H), 6.80 (d, 1 H), 6.60 (br. s, 1 H), 3.66 (m, 2 H), 3.48 (t, 1 H), 3.40 (m, 1 H), 3.20 (m, 1 H), 3.07 (m, 1 H), 2.19 (s, 3 H), 1.71 (td, 1 H), 1.23 (m, 3 H), MS (ES+) m/z 398 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([NH:25][CH2:26][C@@H:27]3[C@H:32]([CH3:33])[CH2:31][CH2:30][CH2:29][NH:28]3)=[N:22][C:21]=2[CH:34]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([NH:25][CH2:26][C@@H:27]3[C@H:32]([CH3:33])[CH2:31][CH2:30][CH2:29][N:28]3[C:7]([C:6]3[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[N:11]3[CH:15]=[N:14][CH:13]=[N:12]3)=[O:9])=[N:22][C:21]=2[CH:34]=1
Reactant: Cc1ccc(-n2cncn2)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1nc2cc(Cl)ccc2o1
Product: Cc1ccc(-n2cncn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(1H-1,2,4-triazol-1-yl)benzoic acid and 5-chloro-N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 465 [M+1]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[C:13]3[N:14]([C:17]4[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=4)[N:15]=[CH:16][C:12]=3[CH2:11][CH2:10][C:8]=2[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CN(C=O)C>[N:33]1([C:21]([C:20]2[CH:19]=[CH:18][C:17]([N:14]3[C:13]4[C:7]5[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=5[CH2:10][CH2:11][C:12]=4[CH:16]=[N:15]3)=[CH:25][CH:24]=2)=[O:23])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: C1COCCN1
Reactant: CC(=O)Nc1nc2c(s1)-c1c(cnn1-c1ccc(C(=O)O)cc1)CC2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2c(s1)-c1c(cnn1-c1ccc(C(=O)N3CCOCC3)cc1)CC2
Reaction time: 0.25 h

Procedure:
A solution of 3.5 mg (0.01 mmol) 4-(7-acetylamino-4,5-dihydro-pyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-1-yl)-benzoic acid (prepared analogously to Example 1) in 0.5 ml DMF is combined with 4 μL (0.03 mmol) triethylamine and 4 mg (0.01 mmol) O-pentafluorophenyl-1,1,3,3-tetramethyluronium hexafluorophosphate (PFTU) and stirred for 15 minutes. A solution of 1 mg (0.01 mmol) morpholine in 0.5 ml DMF is added to this mixture and it is shaken for 12 hours at ambient temperature. Then 3 mg polyamine resin HL (0.01 mmol, 200-400 mesh) are added and the mixture is shaken for a further 8 hours. The resin is filtered off and the filtrate is evaporated to dryness in vacuo.
Reaction SMILES: [F:1][C:2]([F:15])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:14])=[O:13].[CH3:16][Mg]Br.Cl>C(OCC)C>[F:1][C:2]([F:15])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:16])([OH:13])[CH3:14]
Reactant: C[Mg]Br
Reactant: CC(=O)CCCCCCCCC=C(F)F
Agent: Cl
Solvent: CCOCC
Product: CC(C)(O)CCCCCCCCC=C(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.2 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 2.0 grams (0.009 mole) of methyl 10,10-difluoro-9-decenyl ketone in 25 ml of diethyl ether was cooled to 0° C., and 2.96 ml (0.009 mole) of methylmagnesium bromide (3.1 Molar solution) was added via syringe. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature. Analysis of the reaction mixture by gas chromatography indicated that the reaction had stopped at approximately 50% of completion. An additional 3.0 ml of methylmagnesium bromide was added via syringe, and the reaction mixture was allowed to stir for 18 hours. After this time the reaction mixture was poured into 20 ml of ice containing 5 ml of an aqueous 10% hydrochloride acid solution. The aqueous layer was separated and washed with three 10 ml portions of diethyl ether. The extracts were combined with the organic layer, and the combination was washed with three 10 ml portions of water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished with methylene chloride and then with methanol. The appropriate fractions were combined and concentrated under reduced pressure yielding 1.1 grams of 12,12-difluoro-2-methyl-11-dodecen-2-ol. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([N:12]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[O:11].[CH3:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C(=O)([O-])[O-].[K+].[K+].CO>C(Cl)Cl.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:19]1([N:12]([CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])[C:10](=[O:11])[CH2:9][CH2:8][O:7][CH2:6][CH2:5][C:4]2[CH:25]=[CH:26][CH:27]=[C:2]([C:32]3[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=3)[CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(CN(C(=O)CCOCCc1cccc(Br)c1)C1CCCCC1)OC
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)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: [K+]
Solvent: ClCCl
Solvent: CO
Product: COC(CN(C(=O)CCOCCc1cccc(-c2cnn(C)c2)c1)C1CCCCC1)OC
Temperature: 100 °C
Yield: 108.3 %

Procedure:
To 3-(3-bromophenethoxy)-N-cyclohexyl-N-(2,2-dimethoxyethyl)propanamide (1.4 g), prepared as in Preparation 3 Step iii), within a 35 mL microwave tube with stirrer were added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.92 g), potassium carbonate (0.88 g) and Pd(Ph3P)4 (0.18 g) followed by methanol (8 mL). The vial was sealed and heated within a CEM Discover microwave at 100° C. for 15 min. The mixture was diluted with DCM and washed once with water, once with brine, dried over sodium sulphate and the solvent evaporated to afford crude material as an orange oil. This was purified on silica using ethyl acetate as the eluent to afford the product (1.52 g). MS [M+H-MeOH]+=412 (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 7.92 (s, 1H), 7.78 and 7.77 (2×s, 1H), 7.40-7.32 (m, 2H), 7.23 and 7.22 (2×t, J=7.6 Hz, 1H), 7.07-7.03 (m, 1H), 4.52 and 4.36 (2×t, J=5.3 Hz, 1H), 4.05-3.95 and 3.69-3.60 (2×m, 1H), 3.901 and 3.898 (2×s, 3H), 3.75-3.64 (m, 4H), 3.34 (s, 3H), 3.32 (s, 3H), 3.34 and 3.25 (2×d, J=5.1 Hz, 2H), 2.84 and 2.83 (2×t, J=6.6 Hz, 2H), 2.65 and 2.63 (2×t, J=6.1 Hz, 2H), 1.79-1.04 (m, 10H); a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH3:30])=[O:18].Br[C:32]1[S:33][C:34]([C:37]([N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)=[O:38])=[CH:35][N:36]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:32]2[S:33][C:34]([C:37]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)=[O:38])=[CH:35][N:36]=2)[CH:5]=[CH:4][C:3]=1[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH3:30])=[O:18]
Reactant: O=C(c1cnc(Br)s1)N1CCCC1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(-c2ncc(C(=O)N3CCCC3)s2)cc1F
Yield: 32 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure A using [2-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl[2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-methanone (354 mg, 0.85 mmol) and (2-bromo-thiazol-5-yl)-pyrrolidin-1-yl-methanone (222 mg, 0.85 mmol) to give 130 mg (32% yield). MS (ES+) 471.3 (M+H)+