Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[C:2]#[CH:3].[CH2:6]([O:13][N:14]1[C:20](=[O:21])[N:19]2[CH2:22][C@H:15]1[CH2:16][CH2:17][C@H:18]2/[C:23](/Cl)=[N:24]/[OH:25])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl.CCOC(C)=O>[CH2:6]([O:13][N:14]1[C:20](=[O:21])[N:19]2[CH2:22][C@H:15]1[CH2:16][CH2:17][C@H:18]2[C:23]1[CH:3]=[C:2]([C:1]([NH2:5])=[O:4])[O:25][N:24]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C#CC(N)=O
Reactant: O=C1N2C[C@@H](CC[C@H]2/C(Cl)=N/O)N1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)c1cc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
Propiolamide (0.30 g, 4.37 mmol) was added to a solution of (2S,5R,Z)-6-(benzyloxy)-N-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbimidoyl chloride (3.64 mmol) in dry DCM (10 mL), followed by the addition of TEA (0.56 mL, 4.0 mmol) in DCM (2 mL) over a 30 minute period. The reaction mixture was stirred at rt overnight. Then the mixture was diluted with EtOAc, washed with water and saturated sodium chloride. The combined organic layer was dried over Na2SO4, concentrated and purified by silica gel column chromatography (gradient elution 5:1 to 1:2, petroleum ether/EtOAc containing 1% TEA) to afford 3-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)isoxazole-5-carboxamide (0.4 g, 32%) as a yellow solid. ESI-MS (EI+, m/z): 343 [M+H]+.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[C:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[CH:19]=2)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].O.O.O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:42].[Mg+2]>C(Cl)Cl.CO>[CH:1]([NH:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[C:25][C:26]3[CH:27]=[CH:28][N+:29]([O-:42])=[CH:30][CH:31]=3)[CH:19]=2)[CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(-c2cccc(C#Cc3ccncc3)c2)c2ncccc2c1=O
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC(C)NC(=O)c1cn(-c2cccc(C#Cc3cc[n+]([O-])cc3)c2)c2ncccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-Isopropyl-1-[3-(4-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from EXAMPLE 3 in methylene chloride (36 mL/mmol) and methanol (3 mL/mmol) was added magnesium monoperoxyphthalate hexahydrate (MMPP, 3.6 eq) and the mixture was stirred at room temperature overnight. A further amount of MMPP (2 eq) was added and stirring was continued for 24 hours. The resulting mixture was filtered through a bed of celite, the filtrate was diluted with methylene chloride and washed with aqueous sodium bicarbonate and water. After drying, the organic phase was evaporated and the crude product was purified by chromatography on silica gel eluting with 10% methanol in methylene chloride to afford the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[NH2:25])[O:5][CH2:6][C@H:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1N=CN([C:31](N2C=NC=C2)=[O:32])C=1.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[O:32]=[C:31]1[NH:25][C:24]2[CH:23]=[CH:22][C:4]([O:5][CH2:6][C@H:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:3][C:2]=2[NH:1]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1ccc(N)c(N)c1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](COc1ccc2[nH]c(=O)[nH]c2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl [(1R)-2-(3,4-diaminophenoxy)-1-phenylethyl]carbamate (Intermediate 6) (318 mg, 0.93 mmol) was placed in a 50-mL RBF under a nitrogen atmosphere and dissolved in DMF (5 mL). CDI (135 mg, 0.83 mmol) was added, and the reaction was stirred at room temperature for four hours. The reaction was added to a separatory funnel containing ethyl acetate (125 mL) and dilute aqueous NaHCO3 (75 mL); the phases were separated, and the organic layer was washed with brine (75 mL), dried over anhydrous Na2SO4 and then concentrated in vacuo. The crude product mixture was then purified by silica gel chromatography to afford tert-butyl {(1R)-2-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)oxy]-1-phenylethyl}carbamate as a white solid. 1H NMR (500 MHz, C2D6SO) δ 10.49 (s, 1H), 10.37 (s, 1H), 7.54 (d, 1H), 7.34 (m, 4H), 7.25 (t, 1H), 6.77 (d, 1H), 6.48 (s, 2H), 4.86 (q, 1H), 3.98 (m, 2H), 1.37 (s, 9H). LRMS (ESI) calc'd for (C16H16N3O4) [M−C4H8+H]+, 314.1; found 314.1.
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=1)[CH2:3][C:4]#[CH:5].[N:12]([CH2:15][C:16]1[NH:20][C:19]2[CH:21]=[C:22]([CH3:26])[C:23]([CH3:25])=[CH:24][C:18]=2[N:17]=1)=[N+:13]=[N-:14]>>[ClH:1].[ClH:1].[CH3:25][C:23]1[C:22]([CH3:26])=[CH:21][C:19]2[NH:20][C:16]([CH2:15][N:12]3[CH:5]=[C:4]([CH2:3][CH2:2][C:6]4[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=4)[N:14]=[N:13]3)=[N:17][C:18]=2[CH:24]=1
Reactant: Cc1cc2nc(CN=[N+]=[N-])[nH]c2cc1C
Reactant: C#CCCc1c[nH]c(N)n1
Agent: Cl
Product: Cc1cc2nc(Cn3cc(CCc4c[nH]c(N)n4)nn3)[nH]c2cc1C
Yield: 117.6 %

Procedure:
4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.0734 g, 0.432 mmol) was reacted with 2-azidomethyl-5,6-dimethyl-1H-benzimidazole (0.104 g, 0.518 mmol) following the general procedure for click reactions outlined above to produce 4-{2-[1-(5,6-Dimethyl-1Hbenzoimidazol-2-ylmethyl)-1H-[1,2,3]triazol-4-yl]-ethyl}-1H-imidazol-2-ylamine dihydrochloride (0.104 g, 59%) of a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.70 (s, 1H), δ 7.19 (s, 2H), δ 6.23 (s, 1H), δ 5.66 (s, 2H), δ 2.85 (t, 2H), δ 2.68 (t, 2H), □ 2.21 (s, 6H) ppm; 13C (75 MHz, CD3OD) δ 148.2, 147.0, 146.9, 132.3, 128.9, 122.8, 120.0, 115.1, 109.7, 100.4, 25.1, 24.4, 19.2 ppm; HRMS (ESI) calcd for C17H20N8 (M+) 337.1883. Found 337.1886.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([CH:31]=2)[C:28](O)=[O:29])[N:19]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=[N:25][CH:26]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCCc1csc(-c2ccc(F)cc2)n1
Product: O=C(NCCc1csc(-c2ccc(F)cc2)n1)c1cncc(-c2noc(C(F)(F)F)n2)c1
Yield: 17 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)thiazol-4-yl)ethanamine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (30 mg, yield 17%). 1H NMR (400 MHz, DMSO-d6) δ 9.45 (br s, 1H), 9.26 (br s, 1H), 8.82 (t, J=2.0 Hz, 1H), 7.96-7.92 (m, 3H), 7.14-7.08 (m, 3H), 3.94-3.89 (m, 2H), 3.19-3.16 (m, 2H). MS (ESI) m/z: Calculated for C20H13F4N5O2S: 463.07. found: 464.0 (M+H)+.
Reaction SMILES: [NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:9]([OH:11])=O)[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:47][C@H:48]([C:64]([NH:66][C@H:67]([C:77]([C:79]([O:81][CH3:82])=[O:80])=[O:78])[CH2:68][O:69][CH2:70][C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)=[O:65])[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[CH:52][CH:51]=1.FC(C(O)=O)(F)F.CCN(CC)CC>CN(C=O)C>[NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:9]([NH:47][C@H:48]([C:64]([NH:66][C@H:67]([C:77]([C:79]([O:81][CH3:82])=[O:80])=[O:78])[CH2:68][O:69][CH2:70][C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=1)=[O:65])[CH2:49][C:50]1[CH:51]=[CH:52][C:53]([O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[CH:54][CH:55]=1)=[O:11])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1
Reactant: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)C(=O)[C@H](COCc1ccccc1)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of Cbz-His (1.00 g, 3.47 mmol) in DMF (15 mL) at 0° C. was added HOBT (0.64 g, 4.16 mmol) and DCC (0.86 g, 4.16 mmol). Tyr(OBn)-Ser(OBn)-CO2Me.TFA (from Step 2 above, 2.0 g, 3.47 mmol) was added followed by Et3N (0.58 mL, 4.16 mmol). The mixture was allowed to warm to room temperature and stirred overnight. The mixture was filtered and the filtrate was diluted with CHCl3, washed twice with saturated aqueous NaHCO3, brine, dried over MgSO4, and concentrated. Flash chromatography (2-5% MeOH/CHCl3) gave 2.14 g of the title compound as a white solid, mp 175°-176°C.; FAB-MS 734 (m+1);
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:22][C:23]([F:34])([F:33])[O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[F:22][C:23]([F:33])([F:34])[O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: NC(=O)c1cc(-c2ccc(O)cc2)no1
Reactant: FC(F)(F)Oc1ccccc1CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(OCc3ccccc3OC(F)(F)F)cc2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.3 %

Procedure:
3-(4-Hydroxy-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 2; 50 mg, 0.24 mmol), K2CO3 (37 mg, 0.27 mmol) and tetrabutylammonium iodide (9 mg, 0.024 mmol) were taken up in DMF (2.4 mL). 2-(Trifluoromethoxy)benzyl bromide (38 mg, 0.27 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by high-throughput purification to give 3-[4-(2-trifluoromethoxy-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (1.2 mg, 1.3%). HRMS Calcd. for C18H14F3N2O4 (M+H)+, 379.0900. Found: 379.0987.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][Mg]Cl.[Cu](C#N)C#N.Br[C:14]1[N:32]=[CH:31][CH:30]=[CH:29][C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:20]=1)=[O:17].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:25]([C:21]1[CH:20]=[C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:29]=[CH:30][CH:31]=[N:32][C:14]=2[CH2:1][C:2]([CH3:7])([CH3:6])[CH3:3])[CH:24]=[CH:23][CH:22]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)c1cccc(NC(=O)c2cccnc2Br)c1
Reactant: CC(C)(C)C[Mg]Cl
Agent: N#C[Cu]C#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)Cc1ncccc1C(=O)Nc1cccc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
2,2-Dimethylpropylmagnesium chloride (1 M-diethylether, 4.8 mL, 4.8 mmol) was added to a suspension of copper cyanide (215 mg, 2.40 mmol) in THF (6 mL) at −78° C. After stirring at the same temperature for 1 hour, 2-bromo-N-(3-tert-butylphenyl)nicotinamide (200 mg, 0.601 mmol) was added all at once as a solid. The reaction mixture was gradually warmed to room temperature and the reaction was allowed to stir overnight. Saturated ammonium chloride solution and ethyl acetate was added, and the reaction mixture was filtered through celite and rinsed with ethyl acetate. The layers were separated and the product was extracted once more with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the crude material was purified using silica gel column chromatography using a gradient of 20%-50% ethyl acetate in hexanes to yield N-(3-tert-butylphenyl)-2-(2,2-dimethylpropyl)nicotinamide (168 mg, 0.517 mmol, 86%). Rf=0.45 (toluene: ethyl acetate=2:1).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25].O>CN(C=O)C>[C:24]([CH2:23][CH2:22][CH2:21][CH2:20][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])=[C:3]1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)#[N:25]
Reactant: Cc1c(-c2cccnc2)[nH]c2ccccc12
Reactant: N#CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2cccnc2)n(CCCCC#N)c2ccccc12
Reaction time: 0.5 h

Procedure:
A solution of 3-methyl-2-(3-pyridyl)indole (2.09 g) in 12 ml of DMF is added to a suspension of 0.528 g of 50% sodium hydride (dispersion in mineral oil) in 6 ml of DMF at 0°. The mixture is stirred at 0° for 0.5 hour and is treated with a solution of 1.78 g of 5-bromovaleronitrile in 4 ml of DMF. This mixture is stirred at room temperature overnight and is poured into 125 ml of water. This is extracted with 2×50 ml of ether, the extract is washed with 3×20 ml of water and dried over MgSO4 to give 1-(4-cyanobutyl)-3-methyl-2-(3-pyridyl)-indole as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:7][N:6]([S:8]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH3:19])(=[O:10])=[O:9])[CH:5]([CH2:20][C:21]([OH:23])=O)[C:4](=[O:24])[NH:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C@H:59]1([NH2:68])[C:67]2[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=2)[CH2:61][CH2:60]1>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1([CH3:25])[CH2:7][N:6]([S:8]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH3:19])(=[O:9])=[O:10])[CH:5]([CH2:20][C:21]([NH:68][CH:59]2[C:67]3[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=3)[CH2:61][CH2:60]2)=[O:23])[C:4](=[O:24])[NH:3]1
Reactant: Cc1cc(C)c(S(=O)(=O)N2CC(C)(C)NC(=O)C2CC(=O)O)c(C)c1
Reactant: N[C@@H]1CCc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[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: Cc1cc(C)c(S(=O)(=O)N2CC(C)(C)NC(=O)C2CC(=O)NC2CCc3ccccc32)c(C)c1
Reaction time: 0.03 h

Procedure:
[5,5-Dimethyl-3-oxo-1-(2,4,6-trimethyl-benzenesulfonyl)-piperazin-2(R,S)yl]-acetic acid (50 mg, 0.135 mmol) was dissolved in DMF (2.5 mL) and DIEA (0.1 mL) was added to make a solution. HATU (117 mg, 0.31 mmol) was added and after stirring for two min, (R)-(−)-indanamine (0.1 mL) was added and the mixture was stirred overnight. The solution was poured into EtOAc (50 mL), washed with saturated NH4Cl (1×50 mL), 1 N HCl (1×50 mL), saturated NaHCO3 (1×50 mL), and saturated brine (1×50 mL). The organic layer was dried with Na2SO4, filtered, and concentrated in vacuo to provide a crude brown oil (140 mg). This crude oil was purified by SiO2 column chromatography (40 to 100% EtOAc in hexanes) to produce pure title compound. MS (APCI pos) 484 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1.CO[CH2:13][Cl:14].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[CH2:13][Cl:14]
Reactant: COCCl
Reactant: CC(C)c1ccc(Br)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)c1ccc(Br)c(CCl)c1
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 98.5 %

Procedure:
Under an argon atmosphere, 12.5 g (64 mmol) of 1-bromo-4-isopropylbenzene was placed in a 300 mL Schlenk flask, and 40 mL of carbon tetrachloride and 28.9 mL (384 mmol) of chloromethyl methyl ether were added. The mixture was cooled to −30° C., and after adding 17.1 g (128 mmol) of aluminum chloride, heated to 0° C., then stirred for 20 minutes, and thereafter heated to room temperature and then stirred for 5 minutes. The reaction solution was poured into ice water, and 100 mL of 2M hydrochloric acid and 100 mL of dichloromethane were added while stirring well. After separating the organic layer, the aqueous layer was extracted two times with 50 mL of dichloromethane, and then the organic layers were combined. The organic layer was then dried on anhydrous sodium sulfate and then filtered, and by then distilling off the dichloromethane, 15.6 g of 1-bromo-2-chloromethyl-4-isopropylbenzene was obtained as a transparent, pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:5]2[CH2:6][N:7]([CH:11]([CH3:13])[CH3:12])[C:8](=[O:10])[CH2:9][N:4]2[N:3]=1.Br[C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>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>[Br:22][C:20]1[CH:21]=[C:16]([NH:1][C:2]2[CH:14]=[C:5]3[CH2:6][N:7]([CH:11]([CH3:12])[CH3:13])[C:8](=[O:10])[CH2:9][N:4]3[N:3]=2)[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CC(C)N1Cc2cc(N)nn2CC1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)N1Cc2cc(Nc3cc(Br)cn(C)c3=O)nn2CC1=O
Temperature: 100 °C
Yield: 78.9 %

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 151e (200 mg, 1.0 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (268 mg, 1.0 mmol), Pd2(dba)3 (50 mg, 0.050 mmol), xantphos (58 mg, 0.10 mmol), Cs2CO3 (652 mg, 2.0 mmol) and 1,4-dioxane (20 mL). The system was subjected to three cycles of vacuum/argon flush and heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (2×10 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80:1 to 30:1) to afford 151f (300 mg, 79%) as a yellow solid. MS-ESI: [M+H]+ 380.2
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:27][N:28]([CH3:45])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[CH3:27][N:28]([CH2:29][C:30]1[CH:31]=[C:32]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])=[O:15])[C:5]3[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=3[CH:10]=2)[CH:33]=[CH:34][CH:35]=1)[CH3:45]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CN(C)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(CN(C)C)c3)cc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in a similar manner as described for example 12 from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-methyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (100 mg, 0.240 mmol) and dimethyl{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}amine (93 mg, 0.312 mmol). The product obtained from HPLC purification was treated with a saturated solution of NaHCO3, solids that crashed out were filtered, and air-dried for 15 min. The product was then triturated first from EtOAc (containing EtOH) and then hexanes. The solid was then concentrated from MeOH, and triturated with ether, and then dried in vacuum oven overnight. The product was collected as a white solid (56 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (s, 1H) 8.66 (t, J=4.93 Hz, 1H) 8.37 (s, 1H) 8.09 (s, 1H) 7.83 (s, 1H) 7.71-7.76 (m, 2H) 7.46 (t, J=7.96 Hz, 1H) 7.33 (d, J=7.58 Hz, 1H) 5.89 (s, 1H) 5.19 (quin, J=6.63 Hz, 1H) 4.40 (s, 1H) 4.39 (s, 1H) 3.49 (s, 2H) 2.22 (s, 3H) 2.19 (s, 6H) 2.12 (s, 3H) 1.51 (s, 3H) 1.49 (s, 3H); LC-MS (ES) m/z=472.2 [M+H]+
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[Br-].C[O:14][C:15](=[CH:36][C:37]([O:39][CH3:40])=[O:38])[CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[O-].[Na+].S(=O)(=O)(O)O>CO.O1CCOCC1.O>[S:1]1[C:5]([CH:6]=[CH:16][C:15](=[O:14])[CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: O=Cc1cc2ccccc2s1
Reactant: COC(=O)C=C(C[P+](c1ccccc1)(c1ccccc1)c1ccccc1)OC
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Br-]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: COC(=O)CC(=O)C=Cc1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.8 %

Procedure:
In 20 ml of methanol were dissolved 1.6 g of benzo[b]thiophene-2-aldehyde and 5.1 g of [2-methoxy-3-(methoxycarbonyl)allyl]triphenylphosphonium bromide, and to this solution was added dropwise 2.1 g of a 28% by weight solution of sodium methoxide in methanol with stirring at room temperature over 10 minutes. This mixture was further reacted at the same temperature for 20 minutes, and the solvent was then removed by distillation under reduced pressure. To the residue was added 20 ml of water, and the resulting mixture was extracted with 20 ml of chloroform. The extract was dried with anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (Wako Silica Gel C-200; eluent: benzene/n-hexane (3:1 by volume) mixture) to obtain an oily substance. This oily substance was dissolved in 12 ml of dioxane, and to the resulting solution was added 12 ml of 0.1N sulfuric acid. The resulting mixture was subjected to reaction at 100° C. for 1.5 hours. This reaction mixture was then cooled to room temperature and 20 ml of water was added thereto, after which the precipitated crystals were collected by filtration. These crystals were washed with water and then dried to obtain 1.1 g of methyl 5-(2-benzo-[b]thienyl)-3-oxo-4-pentenoate having a melting point of 105°-107° C.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[C:7]([CH2:11][CH2:12][OH:13])[CH:8]=[CH:9][CH:10]=2)[CH2:2]1.N1C=CC=CC=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[O:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[C:7]([CH2:11][CH2:12][O:13][S:26]([C:23]3[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=3)(=[O:28])=[O:27])[CH:8]=[CH:9][CH:10]=2)[CH2:2]1
Reactant: OCCc1cccc(C2COC2)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2cccc(C3COC3)c2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 21.9 %

Procedure:
4.9 g of 2-(3-oxetan-3-yl-phenyl)-ethanol were dissolved in 30 ml of DCM and 9.5 ml of pyridine were added at room temperature. The mixture was cooled to 0° C. and 6.3 g of p-toluenesulfonyl chloride were added at 0° C. Stirring was continued for 6 h at room temperature. Then the volatiles were evaporated, the residue was dissolved in 100 ml of EA and washed with 100 ml of a saturated aqueous solution of sodium hydrogencarbonate. The aqueous layer was extracted two times with 100 ml each of EA. The combined organic layers were dried with magnesium sulfate and evaporated. Silica gel chromatography (EA/HEP 1:1) of the residue yielded 2.0 g of the title compound.