Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1.N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].CCCCCC.C(OCC)(=O)C>CN(C)C=O.O>[Si:17]([O:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:7]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)C1CCC(O)CC1
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Reaction time: 5 h
Yield: 100 %

Procedure:
To a solution of methyl 4-hydroxycyclohexane-carboxylate (a cis/trans mixture, 5.00 g, 31.6 mmol) and imidazole (4.30 g, 63.2 mmol) in dimethylformamide (20 ml) was added t-butyldimethylsilyl chloride (5.72 g, 37.9 mmol) at room temperature, and stirred at the same temperature for 5 hours. After completion of the reaction, an ethyl acetate/toluene (1/1) solution and water were added thereto, and the organic layer was collected, dried over sodium sulfate and distilled under reduced pressure to remove the solvent, whereby methyl 4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexane-carboxylate (8.66 g, 100%) was obtained.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][C:7]([C:13]([OH:15])=[O:14])=[CH:6]2.[C:16](C1(C(O)=O)C2C(=CC=C(O)C=2)CCN1)(OC(C)(C)C)=[O:17]>>[CH3:16][O:17][C:12]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]([OH:15])=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc2cnc(C(=O)O)cc2c1
Reactant: CC(C)(C)OC(=O)C1(C(=O)O)NCCc2ccc(O)cc21
Product: COc1ccc2cc(C(=O)O)ncc2c1
Yield: 17 %

Procedure:
0.25 g (17% in 4 steps) 7-methoxy-isoquinoline-3-carboxylic acid was prepared according to procedure described for the synthesis of 6-methoxy-isoquinoline-3-carboxylic acid (in Example 294) starting from 2.0 g (6.8 mmol) of boc-7-hydroxy-tetrahydroisoquinoline carboxylic acid using 179 mg (0.824 mmol). LCMS: 204 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[N:21]>CN(C=O)C>[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[N:21])=[CH:6][CH:7]=1)#[N:21]
Reactant: OCCCc1ccc(O)cc1
Reactant: N#CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCCCCCOCCCc1ccc(OCCCCCC#N)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A solution of 3-(4-hydroxyphenyl)-1-propanol (2.0 g, 13.1 mmole) in DMF (5 mL) was added to a solution of DMF (35 mL) containing NaH (1.31 g, 60% in mineral oil) at 0° C. under nitrogen atmosphere. The reaction mixture was slowly warmed to 80° C. After stirring for 1 h at 80° C., the reaction mixture was cooled to 0° C., and 6-bromohexanenitrile (5.78 g, 32.83 mmole) was added. The final mixture was re-heated to 80° C., and stirred for 24 h. The reaction mixture was quenched with saturated NaCl solution (200 mL), and the product was extracted with EtOAc (300 mL). The organic layer was washed with brine solution, dried with Na2SO4, and evaporated to dryness, yielding a pale yellow solid. Purification of the crude product by flash silica column chromatography: 4/1 to 1/1 hexane/EtOAc provided 6-{3-[4-(5-cyanopentyloxy)phenyl]propoxy}hexanenitrile in 30% yield (1.33 g). Rf=0.63 in 111 EtOAc/hexane. 1H-NMR (CDCl3, 299.96 MHz): δ (ppm) 7.09-7.07 (d, 2H), 6.81-6.78 (d, 2H), 3.96-3.92 (t, 2H), 3.42-3.37 (m, 4H), 2.64-2.58 (t, 2H), 2.39-2.32 (m, 4H), 1.87-1.52 (m, 14H).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1.Cl.Cl[CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1
Reactant: CC(C)(C)CNc1nc(C#N)nc2ccc(O)cc12
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)CNc1nc(C#N)nc2ccc(OCc3ccncc3)cc12

Procedure:
4-(2,2-Dimethyl-propylamino)-6-hydroxy-quinazoline-2-carbonitrile (0.23 mmol), 4-chloromethyl-pyridine hydrochloride (0.35 mmol) and cesium carbonate (2.3 mmol) are stirred in DMF (3 ml) at RT for 20 hours. Water is added until a clear solution is formed. Then more water is added until the solution gets turbide. The precipitate formed is filtered off, washed with water and dried (vacuum). A powder with mp. 203-205° C., Rf=0.2 (CH2Cl2/MeOH=15:1) is obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CN(C)P(N(C)C)(N(C)C)=O.[CH3:24][CH2:25][O:26][C:27]([CH2:29][N:30]=[C:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:28].Br[CH2:45][C:46]1[S:47][C:48]([N+:51]([O-:53])=[O:52])=[CH:49][CH:50]=1>O1CCCC1>[C:32]1([C:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[N:30][CH:29]([C:27]([O:26][CH2:25][CH3:24])=[O:28])[CH2:45][C:46]2[S:47][C:48]([N+:51]([O-:53])=[O:52])=[CH:49][CH:50]=2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=[N+]([O-])c1ccc(CBr)s1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(Cc1ccc([N+](=O)[O-])s1)N=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
To a stirred solution of diisopropylamine (8.81 g, 87.0 mmol) in tetrahydrofuran (300 ml) at 0° C. was added 1.6M n-butyllithium in hexanes (54 ml, 86.4 mmol) over a 10 minute period. The resulting yellow mixture was stirred for 30 minutes, cooled to -78° C. and hexamethylphosphoramide (15.5 g, 86.2 mmol) was added. To this mixture was added ethyl N-(diphenylmethylene) glycinate (23.0 g, 86.0 mmol) in tetrahydrofuran (100 ml) over a 20 minute period. The dark orange mixture was stirred for 1 hour and then a solution of 2-bromomethyl-5-nitrothiophene (19.0 g, 85.6 mmol) in tetrahydrofuran (100 ml) was added over a 20 minute period. The mixture was stirred for 1 hour and then warmed to 0° C. After quenching with approximately 150 ml of ice-cold water, the mixture was concentrated at reduced pressure. The remaining aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulphate. The solvent was removed at reduced pressure and the resulting dark brown oil was filtered through silica gel eluting with 25% ethyl acetate/hexane to remove excess diisopropylamine . The filtrate was concentrated at reduced pressure and the resulting dark brown oil was placed in vacuo overnight. Ethyl N-diphenylmethylene-3-(5-nitro-2-thienyl)-DL-alaninate (35.3 g) was obtained as a viscous dark brown oil. The product was used without further purification.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]1[C:37]([OH:39])=O.C(N(CC)CC)C.Cl.[NH2:48][C:49]1([C:55]#[C:56][C:57]2[CH:66]=[CH:65][C:60]([C:61]([O:63][CH3:64])=[O:62])=[CH:59][CH:58]=2)[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1>CN(C=O)C.C(OCC)(=O)C>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]1[C:37]([NH:48][C:49]1([C:55]#[C:56][C:57]2[CH:58]=[CH:59][C:60]([C:61]([O:63][CH3:64])=[O:62])=[CH:65][CH:66]=2)[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1)=[O:39]
Reactant: COC(=O)c1ccc(C#CC2(N)CCCCC2)cc1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C#CC2(NC(=O)c3cc4ccccc4[nH]3)CCCCC2)cc1
Reaction time: 0.33 h

Procedure:
A solution of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP, 249 mg, 0.51 mmol) and indole-2-carboxylic acid (83 mg, 0.51 mmol) in DMF (5 ml) was treated with triethylamine (0.21 ml, 1.5 mmol). After 20 min, methyl 4-(1-amino-cyclohex-1-yl-ethynyl)-benzoate hydrochloride (150 mg, 0.51 mmol) was added and the reaction mixture was stirred for additional 16 h. The reaction mixture was diluted with ethyl acetate (50 ml) and the organic layer was washed with water (25 ml), 1M aqueous HCl (25 ml), saturated sodium bicarbonate (25 ml), and brine, dried over sodium sulfate, and concentrated in vacuo to provide crude methyl 4-[1-(1H-indol-2-yl-carbonylamino)-cyclohex-1-yl-ethynyl]-benzoate which was used without further purification.
Reaction SMILES: [Si]([O:8][CH:9]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:10][CH2:11][C@@H:12]1[C@@H:24]2[C@@H:15]([O:16][C:17](=[O:25])[CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH2:23]2)[CH2:14][C@H:13]1[O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)(C(C)(C)C)(C)C>O1CCCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[OH:8][CH:9]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:10][CH2:11][C@@H:12]1[C@@H:24]2[C@@H:15]([O:16][C:17](=[O:25])[CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH2:23]2)[CH2:14][C@H:13]1[O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1
Reactant: CCCCCCCC(CC[C@@H]1[C@H]2CC=CCCCC(=O)O[C@H]2C[C@H]1OC1CCCCO1)O[Si](C)(C)C(C)(C)C
Agent: CCCCCCCC(CC[C@@H]1[C@H]2C/C=C\CCCC(=O)O[C@H]2C[C@H]1OC1CCCCO1)O[Si](C)(C)C(C)(C)C
Agent: CCCCCCCC(O)CC[C@@H]1[C@H]2C/C=C\CCCC(=O)O[C@H]2C[C@H]1OC1CCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCCCCCC(O)CC[C@@H]1[C@H]2CC=CCCCC(=O)O[C@H]2C[C@H]1OC1CCCCO1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A solution of (8aR,9R,10R,11aS,Z)-9-[3-(tert-butyldimethylsilyloxy)decyl)-10-(tetrahydro-2H-pyran-2-yloxy)-4,5,8,8a,9,10,11,11a-octahydrocyclo-penta[b]oxecin-2(3H)-one (25 g, 44 mmol) in 350 ml tetrahydrofuran and 49 ml TBAF (1M in tetrahydrofuran) were added into 1-liter round-bottom flask. The reaction mixture was stirred at 50° C. for 3 hours and quenched by 200 ml saturated NaHCO3 aqueous solution. Then, the mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous MgSO4. The solid was filtered off and organic solvent was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. Yield of the titled compound was 15 g (75%).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[CH2:3][N:4]([CH3:30])[C:5]1[C:10]([C:11]#[N:12])=[C:9]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[NH:24][CH:23]=[N:22][N:21]=3)[CH:17]=[CH:16][C:15]=2[CH3:25])[N:8]=[C:7](S(C)(=O)=O)[N:6]=1.C(OC([N:40]1[CH2:44][CH2:43][C@@H:42]([NH2:45])[CH2:41]1)=O)(C)(C)C>C(#N)C>[CH3:1][C:2]([CH3:32])([CH3:31])[CH2:3][N:4]([CH3:30])[C:5]1[C:10]([C:11]#[N:12])=[C:9]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[NH:24][CH:23]=[N:22][N:21]=3)[CH:17]=[CH:16][C:15]=2[CH3:25])[N:8]=[C:7]([NH:45][C@@H:42]2[CH2:43][CH2:44][NH:40][CH2:41]2)[N:6]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: Cc1ccc(-c2nnc[nH]2)cc1Nc1nc(S(C)(=O)=O)nc(N(C)CC(C)(C)C)c1C#N
Solvent: CC#N
Product: Cc1ccc(-c2nnc[nH]2)cc1Nc1nc(N[C@@H]2CCNC2)nc(N(C)CC(C)(C)C)c1C#N
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A solution of 4-[(2,2-dimethyl-propyl)-methyl-amino]-2-methanesulfonyl-6-[2-methyl-5-(4H-[1,2,4]triazol-3-yl)-phenylamino]-pyrimidine-5-carbonitrile (10 mg, 0.022 mmol) and 1-tert-butoxycarbony-3(R)-amino-pyrrolidine (0.08 g, 0.4 mmol) in 2 mL of acetonitrile was heated with stirring at 80° C. for 18 h. Volatiles were the removed in vacuo and the product was purified by flash chromatography.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1.[N:23]12[CH2:30][CH2:29][CH:26]([CH2:27][CH2:28]1)[C:25](=[O:31])[CH2:24]2.Cl>C1COCC1.CCCCCC.C(O)C>[Cl:16][C:17]1[C:22]([C:25]2([OH:31])[CH:26]3[CH2:29][CH2:30][N:23]([CH2:28][CH2:27]3)[CH2:24]2)=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: O=C1CN2CCC1CC2
Reactant: Clc1cnccn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCO
Product: OC1(c2nccnc2Cl)CN2CCC1CC2
Temperature: -77 °C
Reaction time: 0.33 h
Yield: 84.8 %

Procedure:
A solution of 7.2 ml 2,2,6,6-tetramethylpiperidine (0.034 mol) in 300 ml of dry THF was cooled to -8° C. as 25 ml of 1.6 M butyllithium (0.04 mol) in hexane was added dropwise. The reaction was stirred 20 min then cooled to -77° C. A solution of 2.9 ml of 2-chloropyrazine (0.031 mol) in 5 ml of THF was added to the reaction dropwise. After 15 min, 4.4 g of 3-quinuclidinone (0.0352 mol) in 5 ml of THF was added dropwise and the reaction stirred another 1.5 h. A solution of 8 ml of concentrated HCl and 4 ml of ethanol was added and the cooling was removed. When the temperature reached -5° C., 20 ml of 5 N NaOH was added and the volatile organics were evaporated. The residue was suspended in 50 ml of ice-water and the mixture filtered. The aqueous filtrate was extracted 3× with 50 ml of CHCl3. The extracts were combined with the solid collected from the filtration and the volume of the mixture adjusted to 450 ml with additional CHCl3. The mixture was heated on a steam bath until most of the solid had dissolved. The mixture was dried, filtered, and the solvent evaporated to give a dark brown solid that was recrystallized from isopropanol to give 6.3 g of (7), mp 215°-216° C. NMR ppm (CDCl3) 1.25(1H, m), 1.5 (2H, m), 2.2 (1H, m), 2.65-3.1 (6H, m), 3.6 (1H, bs), 4.05 (1H, d), 8.3 (1H, d), 8.5 (1H, d). Anal. C11H14ClN3O requires C: 55.12; H: 5.89; N: 17.53%. Found C: 55.21; H: 5.99; N: 17.30%.
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].[N:7]#[N:8].[CH3:9][C:10]([CH3:35])([O:12][C:13]([NH:15][C@H:16]([C:32]([OH:34])=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[O:14])[CH3:11].O.CO.CI>C(OCC)(=O)C>[N:7]#[N:8].[CH3:11][C:10]([CH3:35])([O:12][C:13]([NH:15][C@H:16]([C:32]([O:34][CH3:1])=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])=[O:14])[CH3:9]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: N#N
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Cesium carbonate (4.28 g., 13.1 mmoles) was added to a mixture of N2 -[(1,1-dimethylethoxy)carbonyl]-N6 -[(Phenylmethoxy)carbonyl]-L-lysine (10 g., 26.3 mmoles) and 20% water-methanol (60 ml.). The solution became homogeneous within 5 minutes so the solvent was stripped and the residual water removed azeotropically with acetonitrile (3×). The resulting oil was dried in vacuo, dissolved in dry dimethyl-formamide and treated with methyl iodide (3.2 ml., 2.0 eq.). The reaction mixture was stirred at room temperature for 1.5 hours under argon, diluted with ethyl acetate (200 ml.) and washed successively with water (2×25 ml.), saturated sodium bicarbonate (25 ml.) and brine (25 ml.). The organic phase was dried (anhydrous magnesium sulfate), filtered, evaporated to dryness and dried in vacuo to give 10.11 g., of product as a light yellow syrup; Rf =0.30 (ethyl acetate:hexanes, 1:2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][N:8]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ncc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ncc3cc(Br)cnc32)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5-Bromo-1H-pyrazolo[3,4-b]pyridine (1.39 g) in DMF (6 ml) was cooled in an ice-bath under nitrogen and treated portionwise with sodium hydride (0.308 g) (60% dispersion in oil) over a period of about 15 min. The reaction was left to stir in the ice-bath for 40 min, then treated with tosyl chloride (1.469 g) in DMF (2 ml). The reaction was left to stir in the ice-bath under nitrogen and the ice left to melt overnight. The reaction was stirred for a total of 20 h. The reaction was treated cautiously with water (6 ml) and stirred for 5 min. The reaction was poured onto water (60 ml), filtered and the residue treated with DCM (20 ml). The mixture was stirred, and then pushed through a frit into a cartridge with a hydrophobic frit. The solution was allowed to drip through, and then this procedure was repeated with further DCM (2×15 ml). The combined filtrates were evaporated to dryness to give the title compound as a brown solid, 1.802 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[N:5]=[C:4]([CH3:17])[N:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH3:16])=[C:8]([C:6]2[N:5]=[C:4]([CH3:17])[N:3]=[C:2]([NH:23][C:22]3[CH:24]=[CH:25][C:19]([Cl:18])=[CH:20][CH:21]=3)[CH:7]=2)[CH:13]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COc1ccc(Cl)cc1-c1cc(Cl)nc(C)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)cc1-c1cc(Nc2ccc(Cl)cc2)nc(C)n1
Temperature: 80 °C
Reaction time: 6 h
Yield: 50.9 %

Procedure:
To an argon saturated solution of 4-chloro-6-(5-chloro-2-methoxy-phenyl)-2-methyl-pyrimidine (50 mg, 0.18 mmol), 4-chloroaniline (23 mg, 0.18 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (66 mg, 0.1 mmol) and sodium tert-butoxide (26 mg, 0.27 mmol) in toluene (10 ml) was added tris(dibenzylideneacetone)-dipalladium (92 mg, 0.1 mmol). After stirring at 80° C. under an argon atmosphere for 6 hours, the mixture was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:5 followed by 1:3) to provide the title compound (33 mg, 51% yield) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:41][C:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]([NH2:52])=[CH:44][CH:43]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[Br:41][C:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]([NH:52][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:10]=[C:2]([F:1])[CH:3]=2)=[CH:44][CH:43]=1
Reactant: Nc1ccc(Br)c2ccccc12
Reactant: O=C(O)c1cc(F)cc(N2CCOCC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Br)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.8 %

Procedure:
3-Fluoro -5-morpholin-4-yl-benzoic acid (4.45 g, 19.8 mmol) and HBTU (8.19 g, 21.6 mmol) are stirred at room temperature in dry DMF (40 ml) for 1 hour. 4-Bromo-naphthalen-1-ylamine (4.0 g, 18.0 mmol) and diisopropylethylamine (4.8 ml, 27 mmol) are then added and the mixture is stirred at room temperature for 16 hours. The mixture is poured into ethyl acetate (300 ml) and washed with water (250 ml). The organic layer is dried over anhydrous sodium sulfate and evaporated to dryness. The residue is crystallized from ethyl acetate and hexanes to give N-(4-bromo-naphthalen-1-yl)-3-fluoro-5-morpholin-4-yl-benzamide as a pink powder (1.688 g). Mp: 195-6° C. 1H NMR 300 MHz (DMSO-d6) δ 10.5(s, 1H), 8.19(d, 1H, J=6 Hz), 8.04(d, 1H, J=8.4 Hz), 7.94(d, 1H, J=8.4 Hz), 7.71(m, 2H), 7.53(d, 1H, J=8.1 Hz), 7.47(s, 1H), 7.25(d, 1H, J=8.4 Hz), 7.05(d, 1H, J=12.3 Hz), 3.76(s, 4H), 3.26(s, 4H). MS: 429 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:38]4[CH:39]=[CH:40][C:35]([CH2:34][OH:33])=[CH:36][CH:37]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: OCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CO)cc4)cc23)CC1
Temperature: 160 °C
Yield: 30.2 %

Procedure:
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (20.0 mg, 0.048 mmol), K3PO4 (21.0 mg, 0.096 mmol) and [4-(hydroxymethyl)phenyl]boronic acid (30.0 mg, 0.193 mmol) in dioxane/H2O (2 mL/0.7 mL) was bubbled argon for 5 minutes prior to addition of Pd(PPh3)4 (5.0 mg, 0.0048 mmol). The reaction mixture was heated in a microwave reactor (Smith synthesizer) for 20 minutes at 160° C. The solvent was evaporated, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine (10 mL), dried over MgSO4, filtered, concentrated, and purified by reverse phase HPLC method A (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (6.4 mg, 30%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][C@@H:14]([OH:16])[CH2:13][C@H:12]1[C:17]1[NH:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=2)[N:21]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].CC1(C)C(C)(C)OB([C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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]>[CH3:1][O:2][C:3](=[O:29])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][C@@H:14]([OH:16])[CH2:13][C@H:12]1[C:17]1[NH:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:38]3[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=3)=[CH:24][CH:23]=2)[N:21]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](O)C[C@H]1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](O)C[C@H]1c1nc(-c2ccc(-c3ccc(N)cc3)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Yield: 78.5 %

Procedure:
To a solution of ((S)-1-{(2S,4S)-2-[4-(4-bromo-phenyl)-1H-imidazol-2-yl]-4-hydroxy-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (1.8 g, 3.87 mmol) in dioxane (30 mL) and water (10 mL), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (848 mg, 3.87 mmol), sodium carbonate (820 mg, 7.74 mmol) and Pd(dppf)Cl2 (316 mg, 0.39 mmol) were added and the reaction mixture was heated at reflux for 3 h, cooled to RT, filtered and concentrated, extracted with EtOAc (50 mL), and washed with water (50 mL). The organic layer was dried over sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (eluted with 1% to 3% methanol in DCM) to give the title intermediate (1.45 g, 65% yield). 1H NMR (CH3OD, 400) δ (ppm) 7.70 (m, 2H), 7.67 (m, 2H), 7.45 (m, 2H), 7.29 (s, 1H), 6.80 (d, J=6.8 Hz, 1H), 5.82 (d, J=9.2 Hz, 1H), 5.29 (d, J=8.8 Hz, 1H), 4.59 (s, 1H), 4.34 (d, J=8.8 Hz, 1H), 4.16 (d, J=8.0 Hz, 1H), 3.95-4.04 (m, 1H), 3.79-3.83 (m, 1H), 3.76 (s, 3H), 2.55-2.69 (m, 1H), 2.32 (m, 1H), 1.60-2.03 (m, 1H), 1.00 (m, 3H), 0.3-0.85 (m, 3H).