Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:9]=2[CH3:18])[C:5]2[CH:19]=[C:20]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:21]=[C:22]([CH2:23][OH:24])[C:4]=2[N:3]=1.[H-].[Na+].[CH3:33]I.O>CN(C)C=O>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[C:9]=2[CH3:18])[C:5]2[CH:19]=[C:20]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[CH:21]=[C:22]([CH2:23][O:24][CH3:33])[C:4]=2[N:3]=1
Reactant: CI
Reactant: Cc1c(Cn2c(C)nc3c(CO)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1cc(N2CCOCC2)cc2c1nc(C)n2Cc1cccc(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the mixture of [2-methyl-1-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-1H-benzimidazol-4-yl]methanol, prepared as described in Example 43 (160 mg, 0.381 mmol) in N,N-Dimethylformamide (DMF) (15 mL), sodium hydride (30.5 mg, 0.763 mmol) was added in and followed by the addition of methyl iodide (0.048 mL, 0.763 mmol). The reaction was stirred at rt for 3 hours. More sodium hydride (30.5 mg, 0.763 mmol) and methyl iodide (0.048 mL, 0.763 mmol) was added in. The reaction was stirred at rt for another 2 hours then Water (70 mL) was added in. The mixture was extracted with EtOAc (100 mL). The organic phase was washed with Brine (100 mL), dried (MgSO4) and concentrated. The crude was subjected to ISCO purification (0˜2% MeOH/DCM) to give the product. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3 H) 2.54 (s, 3 H) 3.00-3.07 (m, 4 H) 3.37 (s, 3 H) 3.68-3.75 (m, 4 H) 4.76 (s, 2 H) 5.52 (s, 2 H) 6.32 (d, J=7.83 Hz, 1 H) 6.88 (m, 2 H) 7.25 (s, 1 H) 7.60 (d, 1 H). MS(ES+) m/e 434.4 [M+H]+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:10]=2)O1.Cl[C:39]1[N:44]=[C:43]([NH:45][C@H:46]2[CH2:51][CH2:50][CH2:49][C@@H:48]([NH:52][C:53]([C:55]3[N:56]=[CH:57][N:58]([CH3:60])[CH:59]=3)=[O:54])[CH2:47]2)[C:42]([F:61])=[CH:41][N:40]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>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].O>[F:61][C:42]1[C:43]([NH:45][C@H:46]2[CH2:51][CH2:50][CH2:49][C@@H:48]([NH:52][C:53]([C:55]3[N:56]=[CH:57][N:58]([CH3:60])[CH:59]=3)=[O:54])[CH2:47]2)=[N:44][C:39]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:10]=2)=[N:40][CH:41]=1
Reactant: CC1(C)OB(c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncccc23)OC1(C)C
Reactant: Cn1cnc(C(=O)N[C@@H]2CCC[C@H](Nc3nc(Cl)ncc3F)C2)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: Cn1cnc(C(=O)N[C@@H]2CCC[C@H](Nc3nc(-c4nn(C(c5ccccc5)(c5ccccc5)c5ccccc5)c5ncccc45)ncc3F)C2)c1
Temperature: 80 °C

Procedure:
To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-pyrazolo[5,4-b]pyridine, 45, (0.259 g, 0.532 mmol) and N-[(1R,3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexyl]-1-methyl-imidazole-4-carboxamide, 24, (0.150 g, 0.425 mmol) in 2-Me-THF (7.1 mL) and water (1.4 mL) was added K3PO4 (0.316 g, 1.488 mmol). The solution was degassed for 10 minutes under flow of nitrogen. Pd2(dba)3 (0.027 g, 0.030 mmol) and dicyclohexyl-[2-(2,4,6-triisopropylphenyl)-phenyl]phosphane (0.030 g, 0.064 mmol) were added and solution was again degassed under flow of nitrogen. The reaction tube was sealed and heated to 80° C. for 2 hours. The mixture was cooled to room temperature and diluted with water (10 mL). The organic phase was extracted with ethyl acetate, washed with brine (10 mL). The crude was dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-7% MeOH [2N NH3] in ethyl acetate) to give the desired compound: LC/MS Gradient 10-90%, 0.1% formic 5 min, C18/ACN, RT=2.78 min (M+H)=678.73.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1.F[C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1.CC(C)([O-])C.[Na+]>C1COCC1>[CH3:1][C:2]1([CH3:23])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([O:22][C:25]5[CH:30]=[N:29][CH:28]=[CH:27][N:26]=5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(O)cc43)sc2C(=O)N1
Reactant: Fc1cnccn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)Cc2nc(N3CCOc4ccc(Oc5cnccn5)cc43)sc2C(=O)N1
Temperature: 150 °C
Yield: 40.5 %

Procedure:
To a solution of Example 57 (70 mg, 0.211 mmol) in THF (4 mL) was added 2-fluoropyrazine (41 mg, 0.423 mmol) and sodium tert-butoxide (81 mg, 0.846 mmol). The reaction was heated to 150° C. under microwave irradiation for 50 minutes then cooled to r.t. The resulting precipitate was collected, washed with water (4×10 mL), Et2O (3×10 mL) and dried in vacuo to yield the title compound (35 mg, 41%) as an off-white solid. δH (CDCl3) 8.44 (1H, d, J 1.3 Hz), 8.26 (1H, d, J 2.6 Hz), 8.12 (1H, dd, J 2.8 and 1.5 Hz), 8.02 (1H, d, J 2.6 Hz), 7.01 (1H, d, J 8.9 Hz), 6.86 (1H, dd, J 8.9 and 2.6 Hz), 5.26 (1H, s), 4.42-4.30 (2H, m), 4.15-4.10 (2H, m), 2.86 (2H, s), 1.38 (6H, s). LCMS (ES+) 410.0 (M+H)+, RT 3.04 minutes (Method 2).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[C:21]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:20]=[CH:19][C:3]=1[C:4]([C:6]1[C:14]([Cl:15])=[C:13]([Cl:16])[C:12]([Cl:17])=[C:11]([Cl:18])[C:7]=1[C:8]([OH:10])=[O:9])=O.[CH2:28]([N:30]([CH2:42][CH3:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])[CH:32]=1)[CH3:29]>C(OC(=O)C)(=O)C>[CH2:38]([N:37]([CH2:40][CH3:41])[C:33]1[CH:32]=[C:31]([N:30]([CH2:28][CH3:29])[CH2:42][CH3:43])[CH:36]=[CH:35][C:34]=1[C:4]1([C:3]2[CH:19]=[CH:20][C:21]([N:23]([CH2:24][CH3:25])[CH2:26][CH3:27])=[CH:22][C:2]=2[CH3:1])[C:6]2[C:7](=[C:11]([Cl:18])[C:12]([Cl:17])=[C:13]([Cl:16])[C:14]=2[Cl:15])[C:8](=[O:9])[O:10]1)[CH3:39]
Reactant: CCN(CC)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c(C)c1
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(C2(c3ccc(N(CC)CC)cc3N(CC)CC)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c(C)c1
Yield: 52.4 %

Procedure:
A mixture of 2-(2-methyl-4-(diethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (44.9 g.), N,N,N',N'-tetraethyl-m-phenylenediamine (29.7 g.) and acetic anhydride (50 ml.) was heated (at 85°-90° C.) during three hours. The resulting crystalline product was washed with methanol, slurried in hot ethanol and washed again with methanol, affording 3-(2,4-bis(diethylamino)phenyl)-3-(2-methyl-4-(diethylamino)phenyl)-4,5,6,7-tetrachlorophthalide (I: X=Y4 =(CH3CH2)2N, Y2 =CH3, Z4 =Z5 =Z6 =Z7 =Cl) (34.1 g., m.p. 162°-164° C.).
Reaction SMILES: O[C:2]([C:4]([F:7])(F)F)=O.[CH3:8][C:9]1[N:14]2[CH:15]=[C:16]([CH2:18][CH2:19][C:20]3[NH:21][CH:22]=[C:23]([C:25]4[S:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)[N:17]=[C:13]2[N:12]=[C:11]([CH3:30])[CH:10]=1.[H-].[Na+].BrCCF.CO>CN(C=O)C>[F:7][CH2:4][CH2:2][N:21]1[CH:22]=[C:23]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[C:20]1[CH2:19][CH2:18][C:16]1[N:17]=[C:13]2[N:12]=[C:11]([CH3:30])[CH:10]=[C:9]([CH3:8])[N:14]2[CH:15]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(C)n2cc(CCc3nc(-c4cccs4)c[nH]3)nc2n1
Agent: FCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc(C)n2cc(CCc3nc(-c4cccs4)cn3CCF)nc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 39 %

Procedure:
To a solution of 5,7-Dimethyl-2-[2-(4-thiophen-2-yl-1H-imidazol-2-yl)-ethyl]-imidazo[1,2-a]pyrimidine TFA salt (10.9 mg, 0.025 mmol) in DMF (6 mL) was added sodium hydride (60% in mineral oil, 7.0 mg, 0.175 mmol), the reaction vessel was capped and stirred at RT for 5 minutes. 1-Bromo-2-fluoroethane (4.76 mg, 0.0375 mmol) was added and the reaction was shaken under an atmosphere of argon for 30 minutes at RT then 30 minutes at 70° C. To the cooled reaction methanol (100 μL) was added and the solution subjected to preparative LC-MS purification to yield the title compound. 39% yield, LC-MS: m/z=370.2 (MH+), tR=0.43 minutes, method A.
Reaction SMILES: [CH3:1][C:2](=[CH2:10])[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].CC(C)=CCC(OCC)=O.CC(C)C=CC(OCC)=O>>[CH3:1][CH:2]([CH3:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: C=C(C)CCC(=O)OCC
Agent: CCOC(=O)C=CC(C)C
Agent: CCOC(=O)CC=C(C)C
Product: CCOC(=O)/C=C/C(C)C
Yield: 90 %

Procedure:
On the other hand, the isomerization of ethyl 4-methyl-4-pentenoate to ethyl tratis-4-methyl-2-pentenoate is not favored thermodynamically. In fact the equilibrium distribution of isomers at 25° C. is as follows: ethyl 4-methyl-3-pentenoate (90%) and ethyl 4-methyl-2-pentenoate (10%). Despite this adverse equilibrium, ethyl 4- methyl-trans-2-pentenoate is obtained in 90% yield using the process of the present invention. The isomerization of ethyl 4-methyl-4-pentenoate also shows that this method accommodates the isomerization of olefin-esters that contain a tertiary carbon.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.[OH:34][C:35]([CH3:40])([CH3:39])[C:36](O)=[O:37]>CN(C=O)C>[OH:34][C:35]([CH3:40])([CH3:39])[C:36]([N:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1)=[O:37]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Reactant: CC(C)(O)C(=O)O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)C(C)(C)O)C3)ccc1-2
Yield: 21 %

Procedure:
Following the procedure for 318, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 and 2-hydroxyisobutyric acid were reacted in DMF. Purification by trituration with ether then reverse phase preparative HPLC (Gemini C18 column, gradient 40-98% MeOH in H2O+0.1% HCO2H) gave 444 as a white solid (39 mg, 21%). LCMS: RT=11.04 min, [M+H]+=454. 1H NMR δ (ppm) (CDCl3): 8.36 (1 H, d, J=8.19 Hz), 7.90 (1 H, s), 7.11 (1 H, dd, J=8.22, 1.90 Hz), 7.00-6.96 (1 H, m), 5.92-5.83 (1 H, m), 4.74 (1 H, d, J=9.42 Hz), 4.46 (1 H, t, J=9.76 Hz), 4.39 (3 H, t, J=5.47 Hz), 4.14 (1 H, s), 3.87-3.78 (1 H, m), 3.65 (1 H, s), 3.40 (2 H, t, J=5.00 Hz), 1.60 (6 H, d, J=6.63 Hz), 1.43 (6 H, s)
Reaction SMILES: [BH4-].[Na+].[Cl-].[Ca+2].[Cl-].[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[C:26](=[O:27])[N:25]([C:28]3[CH:45]=[CH:44][C:31]([O:32][CH:33]4[CH2:38][CH2:37][CH:36]([C:39](OCC)=[O:40])[CH2:35][CH2:34]4)=[CH:30][CH:29]=3)[C:24]([CH2:46][CH3:47])=[N:23][C:22]=2[CH2:48][CH2:49][CH3:50])=[CH:16][CH:15]=1)#[N:7]>C(O)C.O1CCCC1.C(OCC)(=O)C.Cl>[CH2:46]([C:24]1[N:25]([C:28]2[CH:45]=[CH:44][C:31]([O:32][CH:33]3[CH2:34][CH2:35][CH:36]([CH2:39][OH:40])[CH2:37][CH2:38]3)=[CH:30][CH:29]=2)[C:26](=[O:27])[C:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:9]3[C:8]([C:6]#[N:7])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:19][CH:18]=2)=[C:22]([CH2:48][CH2:49][CH3:50])[N:23]=1)[CH3:47]
Reactant: CCCc1nc(CC)n(-c2ccc(OC3CCC(C(=O)OCC)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1nc(CC)n(-c2ccc(OC3CCC(CO)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.25 h
Yield: 69.5 %

Procedure:
To a solution of sodium borohydride (0.85 g) in ethanol (10 mL)-tetrahydrofuran (10 mL) was added calcium chloride (1.3 g) under ice-cooling, and the mixture was stirred for 15 min. A solution of ethyl 4-{4-[5-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethyl-6-oxo-4-propylpyrimidin-1(6H)-yl]phenoxy}cyclohexanecarboxylate (1.7 g) in tetrahydrofuran (10 mL) was added, and the mixture was further stirred for 2 hr. Small pieces of ice were added in the reaction mixture and the mixture was stirred for 15 min and diluted with ethyl acetate and 1 M hydrochloric acid. The organic layer was separated, washed with saturated sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (1.1 g, 71%) as a solid.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:17]([C:19]1[NH:20][C:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C:26]=2[C:27]=1[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=O.N1CCCCC1>C(O)C>[N:1]1([C:7]2[CH:15]=[C:14]3[C:10]([C:11](=[CH:17][C:19]4[NH:20][C:21]5[CH2:22][CH2:23][CH2:24][CH2:25][C:26]=5[C:27]=4[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Reactant: O=C1Cc2ccc(N3CCOCC3)cc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C(O)CCc1c(C=C2C(=O)Nc3cc(N4CCOCC4)ccc32)[nH]c2c1CCCC2
Yield: 36.4 %

Procedure:
A mixture of 4 g of 6-(morpholin-4-yl)-2-oxindole, 3.75 g of 3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)propionic acid, and 1.8 mL of piperidine in ethanol (60 mL) was refluxed for 6 hrs. The reaction mixture was concentrated and acidified with 6 N hydrochloric acid to pH 6. The precipitate was collected by filtration, washed once with water, twice with ethyl acetate and twice with methanol to give 2.6 g of 3-[2-(6-Morpholin-4-yl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]propionic acid as an orange solid (34% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([NH:11][CH:12]2[CH2:15][C:14]([F:17])([F:16])[CH2:13]2)[N:5]=[C:4]([S:18][CH3:19])[N:3]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:20][S:21]([O:10][CH2:9][CH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([S:18][CH3:19])=[N:5][C:6]=1[NH:11][CH:12]1[CH2:13][C:14]([F:16])([F:17])[CH2:15]1)(=[O:23])=[O:22]
Reactant: CSc1nc(Cl)c(CCO)c(NC2CC(F)(F)C2)n1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CSc1nc(Cl)c(CCOS(C)(=O)=O)c(NC2CC(F)(F)C2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 103.2 %

Procedure:
To a solution of 2-{4-chloro-6-[(3,3-difluorocyclobutyl)amino]-2-(methylsulfanyl)pyrimidin-5-yl}ethanol (714 mg, 2.31 mmol) in DCM (38.5 mL) was added TEA (1.12 mL, 8.06 mmol), methanesulfonyl chloride (0.455 mL, 5.76 mmol) and DMAP (17 mg, 0.138 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h and at room temperature for 1 h. The reaction mixture was washed with water (3×), and the organic layer was dried (Na2SO4) and concentrated under reduced pressure to give 925 mg (>99%) of the title compound as a yellow solid. This material was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J=5.7 Hz, 1 H), 4.40-4.29 (m, 1 H), 4.26 (t, J=6.8 Hz, 2 H), 3.14 (s, 3 H), 3.05 (t, J=6.8 Hz, 2 H), 3.02-2.89 (m, 2 H), 2.85-2.68 (m, 2 H), 2.44 (s, 3 H). m/z (APCI+) for C12H16ClF2N3O3S2 388.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=O)=[CH:4][CH:3]=1.[CH3:13][Mg]I>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][CH:3]=1)[CH2:6][CH2:7][CH:8]=[C:9]2[CH3:13]
Reactant: O=C1CCCc2ccc(Cl)cc21
Reactant: C[Mg]I
Product: CC1=CCCc2ccc(Cl)cc21

Procedure:
Using general procedure A (Exp. 1.1), 7-chloro-3,4-dihydro-2H-naphthalen-1-one (Lit. 13) was reacted with MeMgI to give 6-chloro-4-methyl-1,2-dihydro-naphthalene as a yellow oil. MS: 178.0 ([M]+).
Reaction SMILES: [S:1]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][C:23]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:22]2=[O:32])=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].Br[C:34]1[CH:35]=[N:36][C:37]2[C:42]([CH:43]=1)=[CH:41][CH:40]=[CH:39][CH:38]=2.C([O-])(C)(C)C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>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].O1CCOCC1>[N:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:43]=[C:34]([N:29]2[CH2:30][CH2:31][C:23]3([C:22](=[O:32])[N:21]([CH2:20][C:13]4[C:14]5[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=5)[N:11]([S:1]([C:4]5[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=5)(=[O:2])=[O:3])[CH:12]=4)[CH2:26][CH2:25][CH2:24]3)[CH2:27][CH2:28]2)[CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(CN3CCCC4(CCNCC4)C3=O)c3ccccc32)cc1
Reactant: Brc1cnc2ccccc2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(CN3CCCC4(CCN(c5cnc6ccccc6c5)CC4)C3=O)c3ccccc32)cc1
Temperature: 100 °C
Yield: 72.6 %

Procedure:
The mixture of 2-((1-tosyl-1H-indol-3-yl)methyl)-2,9-diazaspiro[5.5]undecan-1-one (100 mg, 0.15 mmol, contains 1.7 moleq TFA), 3-bromoquinoline (49 mg, 0.23 mmol), Pd2dba3 (7 mg, 7.7 μmol), sodium t-butanolate (45 mg, 0.46 mmol), 2-(2-dicyclohexylphosphanylphenyl)-N,N-dimethylaniline (DavePhos, 6.1 mg, 0.015 mmol) and dry dioxane (2 mL) was placed in a microwave tube and flushed with argon. The tube was sealed and the suspension was heated at 100° C. for 1 h under microwave conditions. The reaction mixture was diluted with ethyl acetate and washed with water and brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting brown oil was purified by flash chromatography (EtOAc/heptane 3:1) to yield the title compound (63 mg, 68%). [LCMS RtA=1.31 min, [M+H]+=579.2].
Reaction SMILES: [Br:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][C:8]=2[CH3:12])[C:3]1=[O:15].[BH4-].[Na+]>CO>[Br:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][C:8]=2[CH3:12])[CH:3]1[OH:15]
Reactant: COc1cc(C)c2c(c1)C(=O)C(Br)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)c2c(c1)C(O)C(Br)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the ice-cold solution of 2-bromo-7-methoxy-5-methyl-3,4-dihydro-2H-naphthalen-1-one (10 g, 0.04 mol) obtained in Step 1 in methanol (100 mL) was added sodium borohydride (2.0 g, 0.05 mol) and the mixture was stirred for 2 h at room temperature. The reaction mixture was cooled and quenched with acetone and concentrated. The mixture was diluted with water and extracted in diethyl ether. The organic layer was washed with brine, dried and concentrated to yield the 2-bromo-7-methoxy-5-methyl-1,2,3,4-tetrahydro-naphthalen-1-ol, 8.0 g, which was used as such in Step 3.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.[I-].[K+].Br[CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)[C:16]([O:18][CH3:19])=[O:17]>CO.C1C=CC=CC=1.O>[Cl:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[CH:22][CH:21]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: Oc1cccc(Cl)c1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C(Oc1cccc(Cl)c1)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 1.19 g of sodium methoxide and 3.21 g of m-chlorophenol in 40 ml of methanol is added 50 mg of potassium iodide and 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate in 10 ml of benzene. The mixture is refluxed overnight and poured into 100 ml of water. The mixture is extracted with ether and the ether extracts washed with 5% NaOH, water, saturated NaCl solution and dried (MgSO4). The solvent is removed under vacuum to give an oil. Chromatography over silica gel (solvent-benzene) gives the product as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[C:16]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:17]3[CH:22]=[N:21][N:20]([CH:23]([CH3:25])[CH3:24])[C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:17]3[CH:22]=[N:21][N:20]([CH:23]([CH3:25])[CH3:24])[C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)nc2c1cnn2C(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc(C2CCN(C(=O)OC(C)(C)C)CC2)nc2c1cnn2C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
To a stirred solution of ethyl 6-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (0.45 g, 1.086 mmol) in EtOH (10 mL), 10% Pd/C in catalytic amount was added and stirred it at room temperature under hydrogen pressure (bladder pressure) for 3 hr. On completion of reaction, reaction mass was filtered through celite bed, then filtrate was concentrated under reduce pressure to give the desired compound (0.34 g, 75%).
Reaction SMILES: CCCCN1C=[N+](C)C=C1.[C:11]1([CH3:18])[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[Zn+2]>[CH3:18][C:11]1[CH:16]=[CH:15][C:14]([S:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:27])=[O:26])=[C:13]([CH3:17])[CH:12]=1
Reactant: Cc1cccc(C)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CCCCn1cc[n+](C)c1
Agent: O=S(=O)(NS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Zn+2]
Product: Cc1ccc(S(=O)(=O)c2ccccc2)c(C)c1
Yield: 99 %

Procedure:
Zinc(II) bis-triflimide (0.062 g, 1 mol %) was dissolved in [bmim] [NTf2] (1.0 g) in a round-bottomed flask equipped with a magnetic stirrer and reflux condenser and m-xylene (2.12 g, 20 mmol) and benzene sulfonyl chloride (1.76 g, 10 mmol) were added. The mixture was heated under reflux for 18 hours and was analysed by gas chromatographic analysis as in previous examples. All the benzene sulfonyl chloride had reacted and mostly 2,4-dimethyldiphenylsulfone had formed (yield=99%, 20:1 isomer ratio {by NMR}). The major product is shown below, the structure of the minor isomer is not known but is believed to be the 2,6-dimethyl isomer.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[C:7]([F:22])=[C:8]([N:13]([CH2:20][CH3:21])[CH2:14][C:15]2[NH:16][CH:17]=[N:18][CH:19]=2)[CH:9]=[CH:10][C:11]=1[F:12].Cl>O1CCCC1>[CH2:20]([N:13]([CH2:14][C:15]1[NH:16][CH:17]=[N:18][CH:19]=1)[C:8]1[C:7]([F:22])=[C:6]([C:11]([F:12])=[CH:10][CH:9]=1)[CH:2]=[O:1])[CH3:21]
Reactant: CCN(Cc1cnc[nH]1)c1ccc(F)c(C2OCCO2)c1F
Agent: Cl
Solvent: C1CCOC1
Product: CCN(Cc1cnc[nH]1)c1ccc(F)c(C=O)c1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.8 %

Procedure:
To a stirred solution of (3-[1,3]dioxolan-2-yl-2,4-difluoro-phenyl)-ethyl-(3H-imidazol-4-ylmethyl)-amine (0.22 g, 0.70 mmol) in tetrahydrofuran (5 ml) was added a 3 N aqueous solution of hydrochloric acid (0.93 ml, 2.79 mmol) and the mixture was stirred at room temperature for 48 h. The mixture was then concentrated in vacuo and the residue taken up in ethyl acetate and washed with 1 N aq. sodium hydroxide solution. The layers were separated and the aqueous phase was back extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, then dried over magensium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (column: Isolute® Flash-NH2 (Separtis); eluent: methanol/dichloromethane gradient) to yield a yellow gum (111 mg, 48%); MS (ISP): 266.0 ((M+H)+.).