Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[O:15][C:14]([SH:16])=[N:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][C:20]=1[C:27]([F:30])([F:29])[F:28]>>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][S:16][C:14]2[O:15][C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)=[N:12][N:13]=2)=[CH:21][C:20]=1[C:27]([F:28])([F:30])[F:29]
Reactant: Sc1nnc(-c2ccc3ncccc3c2)o1
Reactant: COc1ccc(CBr)cc1C(F)(F)F
Product: COc1ccc(CSc2nnc(-c3ccc4ncccc4c3)o2)cc1C(F)(F)F
Yield: 74 %

Procedure:
In the same manner as in Example 7 and using 5-(6-quinolyl)-1,3,4-oxadiazole-2-thiol instead of 5-(1H-indazol-5-yl)-1,3,4-oxadiazole-2-thiol and 4-methoxy-3-(trifluoromethyl)benzyl bromide instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 74%) was obtained as colorless crystals.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[CH:6][C:5]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])=[N:4]1.[F:15][C:16]([F:25])([F:24])[CH2:17][CH2:18][CH:19]([C:22]#[N:23])[C:20]#[N:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:13][C:8]([F:14])([C:5]1[CH:6]=[CH:7][N:3]([CH2:2][C:19]([CH2:18][CH2:17][C:16]([F:15])([F:24])[F:25])([C:20]#[N:21])[C:22]#[N:23])[N:4]=1)[C:9]([F:12])([F:11])[F:10]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: FC(F)(F)C(F)(F)c1ccn(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1ccc(C(F)(F)C(F)(F)F)n1
Yield: 42.4 %

Procedure:
2.01 g of 1-(chloromethyl)-3-(pentafluoroethyl)-1H-pyrazole and 1.39 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 25 ml of N,N-dimethylformamide. 2.38 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.31 g of {[3-(pentafluoroethyl)-1H-pyrazole-1-yl]methyl}(3,3, 3-trifluoropropyl)malononitrile (referred as the compound of the present invention (36), hereinafter) shown by below formula.
Reaction SMILES: [C:1]1([CH2:7][C:8]2([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]3[CH2:13][NH:14][CH2:15][CH2:16][N:11]3[C:10](=[O:17])[O:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:40])[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>O1CCCC1>[C:19]1([CH2:18][C:8]2([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:12]3[CH2:13][N:14]([C:32]([O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:40])[CH2:15][CH2:16][N:11]3[C:10](=[O:17])[O:9]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1OC(Cc2ccccc2)(Cc2ccccc2)C2CNCCN12
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1)N1CCN2C(=O)OC(Cc3ccccc3)(Cc3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
To a solution of 1,1-bis(phenylmethyl)-hexahydro-3H-oxazolo[3,4-a]pyrazin-3-one (0.16 g, 0.50 mmol) in tetrahydrofuran (10 mL) were sequentially added triethylamine (0.14 mL) and phenyl chlorocarbonate (0.12 g, 0.75 mmol), and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The extract was washed with a 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=10:1 to ethyl acetate). The fractions were concentrated, and to the obtained crystals was added diisopropyl ether, collected by filtration and washed with diisopropyl ether to obtain the title compound (0.19 g, yield 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH:12]1([CH:18]=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.N1CCCC1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:18][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: O=CC1CCCCC1
Solvent: C1CCNC1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1Nc2ccc(Cl)cc2C1=CC1CCCCC1
Yield: 67.3 %

Procedure:
A solution of 10 g of 5-chloro-1,3-dihydroindol-2-one, 6.18 g of cyclohexanecarboxaldehyde and 4.93 ml of pyrrolidine in 250 ml of toluene is refluxed for 1 hour, the water formed being removed by means of a Dean-Stark apparatus. The reaction mixture is concentrated to about 90 ml and left to crystallize. The crystalline product formed is filtered off and washed with toluene and then with iso ether to give 9.7 g of the expected product after recrystallization from toluene. M.p.=203°-204° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[CH3:13][C@H:14](N)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@H:14]([CH3:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Cl)ccc2C1
Reactant: C[C@H](N)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](C1=Cc2ccc(Cl)cc2CC1)c1ccccc1

Procedure:
To a stirred solution of 6-chloro-2-tetralone (1.0 equiv., 100.0 mmol., 18.06 g) in toluene (300 ml) was added (S)-(-)-α-methylbenzylamine (1.0 equiv., 100.0 mmol., 12.9 ml). The mixture was heated at reflux for 3 hrs with the azeotropic removal of water (Dean-Stark). The cooled reaction mixture was concentrated in vacuo to give the enamine, (S)-6-chloro-2-(α-methylbenzyl)-3,4-dihydronaphthalene, as a purple oil. The oil was taken up in chloroform (150 ml) and saturated aqueous sodium bicarbonate was added (150 ml). The vigorously stirred mixture was treated with acryloyl chloride (1.05 equiv., 105.0 mmol., 8.5 ml) dropwise over 5 min. The reaction mixture was allowed to stir at ambient temperature for 20 min., then diluted with chloroform and the layers separated. The aqueous layer was extracted with chloroform (1x). The combined organics were washed with brine (1x), dried (Na2SO4), and concentrated in vacuo to give 37.9 g of a black oil. The crude oil was subjected to HPLC on silica gel (gradient elution with hexanes increasing to 25% ethyl acetate/hexanes) to give 19.03 g of a purple oil which was further purified by flash chromatography on silica gel (elution with 20% ethyl acetate/hexanes) to give 17.96 g, 53% yield of the title compound as a brown glass which was homogeneous by HPLC analysis (reverse phase, C18, mobile phase:60% acetonitrile/0.5% aqueous ammonium acetate buffer),thin layer chromatography (Silica gel, Rf =~0.5, developed with 40% ethyl acetate/hexanes), and 300 MHz 1H NMR analysis. FDMS:m/e=337. α[D]589 =-24.75 (c=1.0, CHCl3).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:44])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH:35]([CH2:41][CH:42]=C)[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[C:11]([F:45])[CH:10]=1)#[N:2].I([O-])(=O)(=O)=[O:47].[Na+].CC(C)=O.C(#N)C>[Os](=O)(=O)(=O)=O.O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:44])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH:35]([CH2:41][CH2:42][OH:47])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[C:11]([F:45])[CH:10]=1)#[N:2]
Reactant: C=CCC(O[C@H]1CC[C@H](n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3F)c(CCC)n3ncnc32)CC1)C(=O)OCC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CC#N
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(CCO)C(=O)OCC)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of ethyl 2-[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]pent-4-enoate (0.81 g), sodium periodate (1.4 g), acetone (20 mL), acetonitrile (20 mL), water (20 mL) and osmium tetraoxide (0.24 g, 7% immobilized catalyst) was stirred at room temperature for 14 hr. The precipitate was filtered off, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL) and methanol (10 mL). Sodium tetrahydroborate (0.084 g) was added at 0° C., and the mixture was stirred at 0° C. for 3 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture. After evaporation of the solvent under reduced pressure, the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.29 g, 36%).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:29])[N:6]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]([C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])=[N:8]2)#[N:2].C1C[O:33]CC1.O>>[C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:29])[N:6]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:7]([C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])[CH3:14])=[N:8]2)(=[O:33])[NH2:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(C#N)c2c(=O)n1-c1ccccc1
Reactant: C1CCOC1
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(C(N)=O)c2c(=O)n1-c1ccccc1
Temperature: 80 °C

Procedure:
To a solution of (S)-tert-butyl (1-(5-cyano-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate (105 mg, 0.269 mmol) in THF/H2O (1 mL each) was added Ghaffar's catalyst. The mixture was heated to 80° C. overnight. Purification by flash chromatography (25 g silica, 0-100% EtOAc/DCM) provided (S)-tert-butyl (1-(5-carbamoyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate as a white solid. ES/MS 409.1 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:26][CH:27]=[CH2:28].[CH2:29]1[CH2:33]OC[CH2:30]1>>[CH2:26]([C:7]1([CH2:33][CH:29]=[CH2:30])[CH2:6][CH2:5][CH2:4][N:3]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:2]1=[O:1])[CH:27]=[CH2:28]
Reactant: C1CCOC1
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: C=CCC1(CC=C)CCCN(C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 35 %

Procedure:
To a solution of tert-butyl 2-oxopiperidine-1-carboxylate (8.22 g, 41.3 mmol) in anhydrous THF (80 mL) was added LiHMDS (1.0 M in THF, 103 mL, 103 mmol) dropwise under nitrogen atmosphere at −78° C. and the reaction mixture was stirred for 20 min at the same temperature and then 3-bromoprop-1-ene (10.7 mL, 124 mmol) was added to. The resulting mixture was stirred for 15 min at −78° C. and warmed to rt, quenched with water (15 mL), and concentrated in vacuo. The residue was diluted with water (30 mL) and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL), then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/50) to give the title compound as yellow oil (3.95 g, 35%).
Reaction SMILES: Br[C:2]1[S:26][C:5]2=[N:6][C:7]([CH3:25])=[C:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[C:4]2[CH:3]=1.O(C([N:34]1[CH:38]=[C:37](B(O)O)[CH:36]=[N:35]1)=O)C(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CN(C=O)C.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>[CH3:25][C:7]1[N:6]=[C:5]2[S:26][C:2]([C:37]3[CH:38]=[N:34][NH:35][CH:36]=3)=[CH:3][C:4]2=[C:9]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:8]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CC(C)(C)OC(=O)n1cc(B(O)O)cn1
Reactant: CCOC(=O)c1c(C)nc2sc(Br)cc2c1NS(=O)(=O)c1ccccc1
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: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)nc2sc(-c3cn[nH]c3)cc2c1NS(=O)(=O)c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of ethyl 2-bromo-6-methyl-4-[(phenylsulfonyl)amino]thieno[2,3-b]pyridine-5-carboxylate (Description 67) (6.27 g, 13.77 mmol), 1-tert-butoxylcarbonyl-1H-pyrazole-4-boronic acid, pinacol ester (8.10 g, 27.5 mmol), tetrakis(triphenylphosphine)palladium(0) (0.796 g, 0.688 mmol) and potassium carbonate (5.71 g, 41.3 mmol) in 1,4-dioxane (40 mL), DMF (20 mL) and water (10 mL) was heated at 100° C. for ca. 3.5 h. After cooling to RT, the reaction mixture was filtered through celite and the filtrate was concentrated. The residue was purified via normal phase chromatography eluting with 0-100% ethyl acetate in DCM, to give the title compound (5.81 g). LCMS (A) m/z: 443 [M+1]+, Rt 1.05 min (acidic).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:13])[N:8]([CH2:10][CH2:11][CH3:12])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18]>C(OCC)(=O)C.O>[Cl:22][C:21]([Cl:24])([Cl:23])[CH2:20][O:19][C:17](=[O:18])[NH:13][C:7]1[N:8]([CH2:10][CH2:11][CH3:12])[N:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: CCCn1nc(C(C)(C)C)cc1N
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCn1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 103.1 %

Procedure:
To a stirred mixture of Intermediate 23a (0.774 g, 4.27 mmol) in ethyl acetate (4 mL) and 1 M aqueous NaOH (7.7 mL, 7.7 mmol) was added 2,2,2-trichloroethyl chloroformate (0.62 mL, 4.50 mmol) and the mixture was stirred at room temperature for 1.5 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with water and saturated aqueous NaCl, then evaporated to give the title compound (1.57 g) as an oil. LCMS (Method 3): Rt 4.28 min, m/z 356/358/360 [MH+]. 1H NMR (300 MHz, CDCl3): 0.90 (3H, t, J 7.5 Hz), 1.28 (9H, s), 1.78-1.87 (2H, m), 3.92 (2H, t, J 7.4 Hz), 4.83 (2H, s), 6.08 (1H, s), 6.46 (1H, s).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:16]=[C:15]2[N:6]([C:7](=[O:17])[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=32)[N:5]=1.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>N1C=CC=CC=1>[CH3:25][C:24]1[CH:26]=[CH:27][C:21]([S:18]([O:1][CH2:2][CH2:3][C:4]2[CH:16]=[C:15]3[N:6]([C:7](=[O:17])[NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=43)[N:5]=2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: O=c1[nH]c2ccccc2c2cc(CCO)nn12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2cc3c4ccccc4[nH]c(=O)n3n2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
12.0 g (0.052 mole) of 2-(2-hydroxyethyl)pyrazolo-[1,5-c]quinazolin-5(6H)-one is taken up in pyridine (120 ml), cooled down to 0° and treated with 11.0 g (0.058 mole or 1.1 equivalent) of 98% tosyl chloride. The mixture is stirred for 4 hours, keeping the temperature below 20° during the reaction period, after which it is poured onto 1.8 l. of ice-water and stirred until solids form. The off-white precipitates are filtered off and dried in vacuo at 100° for 3 hours. Yield: 17.43 g, m.p. 194°-196°; 87.4% crude yield.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[C:15]([O:19][CH3:20])(=[O:18])[CH:16]=[CH2:17]>C(Cl)Cl>[C:1]1([S:7][CH2:17][CH2:16][C:15]([O:19][CH3:20])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC(=O)OC
Reactant: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCSc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Thiophenol (440 mg, 4 mmol) and Et3N (70 μ1, 0.5 mmol) were dissolved in CH2Cl2 (5 ml). Methyl acrylate (412 mg, 4.8 mmol) was added dropwise. The reaction was exothermic. After stirring at room temperature for 30 minutes, the excess methyl acrylate was removed in vacuo. TLC: silica gel, Et2O-hexane 1:2, UV Rf =0.58. The crude title ester was used without further purification.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.Cl[Si](C)(C)C.[CH:20]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1>ClCCl.O>[CH:20]1([C:25]([NH:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCC(N)C(=O)O
Reactant: O=C(Cl)C1CCCC1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(NC(=O)C1CCCC1)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
35 g (339 mmol) 2-aminobutanoic acid and 75.6 g (747 mmol) triethylamine are suspended in 300 ml of dichloromethane and stirred at 0° C. 81 g (747 mmol) chlorotrimethylsilane are added dropwise, then the mixture is stirred for 1 hour at room temperature and for 1 hour at 40° C. After cooling down to −10° C., 45 g (339 mmol) cyclopentanecarbonyl chloride are added slowly. The reaction mixture is stirred for 2 hours at −10° C. and then for 1 hour at room temperature. At 0° C., 50 ml of water are added. The mixture is diluted with water and dichloromethane, filtered and the solid product washed with water/dichloromethane 9:1, toluene and diethylether.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.O.[NH2:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O1CCOCC1>[NH2:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Reactant: Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2cccc(N)c2)cc1
Yield: 82.2 %

Procedure:
The title compound (230 mg, 82%) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (270 mg, 0.803 mmol, prepared in example 1), 3-aminobenzeneboronic acid monohydrate (150 mg, 0.968 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol), 2 M sodium carbonate (290 mg in 1.4 mL water) and 1,4-dioxane (5.5 mL) in a manner analogous to the procedure described in Example 2.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH3:22])[C:14]4=[O:23])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.CC1(C)C(C)(C)OB(/[CH:32]=[CH:33]/[C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)O1.[C:54]([OH:60])([C:56]([F:59])([F:58])[F:57])=[O:55]>C(Cl)Cl>[F:57][C:56]([F:59])([F:58])[C:54]([OH:60])=[O:55].[CH3:22][N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@:13]2([CH2:12][C@H:11]2[C:7]2[CH:6]=[C:5]3[C:10]([C:2](/[CH:32]=[CH:33]/[C:34]4[CH:35]=[CH:36][C:37]([N:40]5[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]5)=[CH:38][CH:39]=4)=[N:3][NH:4]3)=[CH:9][CH:8]=2)[C:14]1=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(/C=C/B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: CN1C(=O)[C@@]2(C[C@H]2c2ccc3c(I)n[nH]c3c2)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)[C@@]2(C[C@H]2c2ccc3c(/C=C/c4ccc(N5CCNCC5)cc4)n[nH]c3c2)c2ccccc21
Reaction time: 2 h
Yield: 4 %

Procedure:
The title compound was synthesized according to the method of Example A45, except substituting (1R*,2S*)-2-(3-iodo-1H-indazol-6-yl)-1′-methylspiro[cyclopropane-1,3′-indolin]-2′-one (37 mg, 0.090 mmol) and (E)-tert-butyl 4-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)phenyl)piperazine-1-carboxylate (45 mg, 0.109 mmol). The solvent was removed and the Boc-protected amine purified by column chromatography (silica gel, CH2Cl2/MeOH, 95:5) to give an impure product which dissolved into CH2Cl2 (2.0 mL) and TFA (200 uL) was added. The reaction was stirred for 2 h, the solvent removed and the residue purified by prep-HPLC to give the title compound as an off-white powder (2.0 mg, 4.0%); 1H NMR (400 MHz, CD3OD) δ 7.97 (d, J=8.5 Hz, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.46-7.41 (m, 2H), 7.30 (d, J=17 Hz, 1H), 7.15 (t, J=7.2 Hz, 1H), 7.06-6.99 (m, 4H), 6.65 (t, J=8.0 Hz, 1H), 6.02 (d, J=7.7 Hz, 1H), 3.49-3.44 (m, 4H), 3.40-3.31 (m, 8H), 2.28-2.25 (m, 1H), 2.21-2.18 (m, 1H); MS ESI [M+H]+ 476.2, calcd for [C30H29N5O+H]+ 476.25.
Reaction SMILES: C[C:2]([C:11]1[N:12]([CH3:31])[C:13](=[O:30])[C:14]2[C:19]([C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1C)=[CH:18][CH:17]=[C:16](Br)[CH:15]=2)([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].C[Si]([C:36]#[CH:37])(C)C.[CH3:38]CN(C(C)C)C(C)C>C(#N)C.[Cu]I.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>[CH3:8][C:7]([O:6][CH:2]([C:11]1[N:12]([CH3:31])[C:13](=[O:30])[C:14]2[C:19]([C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH3:38])[CH:22]=1)=[CH:18][CH:17]=[C:16]([C:36]#[CH:37])[CH:15]=2)[C:3]([OH:5])=[O:4])([CH3:10])[CH3:9]
Reactant: Cc1ccc(-c2c(C(C)(OC(C)(C)C)C(=O)O)n(C)c(=O)c3cc(Br)ccc23)c(C)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: C#Cc1ccc2c(-c3ccc(C)c(C)c3)c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c2c1

Procedure:
A mixture of methyl [7-bromo-4-(2,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl][(1,1-dimethylethyl)oxy]acetic acid (46.0 mg, 0.095 mmol), trimethylsilylacetylene (0.067 mL, 0.473 mmol), copper(I) iodide (3.60 mg, 0.019 mmol) and Hunig's base (0.066 mL, 0.378 mmol) in acetonitrile (1.5 mL) was treated with Pd(PPh3)4 (10.93 mg, 9.46 μmol) and then irradiated in the microwave at 120° C. for 20 minutes. LCMS indicated only 20% conversion to the desired product. N,N-dimethylformamide (DMF) (1.0 mL), trimethylsilylacetylene (0.067 mL, 0.473 mmol) and Pd(PPh3)4 (10.93 mg, 9.46 μmol) were added and the mixture was irradiated in the microwave at 120° C. for 30 minutes. LCMS indicated near complete conversion to the desired product. The mixture was diluted with ethyl acetate and washed successively with saturated sodium sulfate, water, and then brine. The organic phase was dried over sodium sulfate, filtered and concentrated to give a dark residue. The crude residue in tetrahydrofuran (THF) (1.500 mL) was treated with tetrabutylammoniumfluoride (0.142 mL, 0.142 mmol, 1 M solution in THF) at 0° C. and then stirred at ambient temperature for 5 minutes. The mixture was concentrated and purified by reverse phase chromatography to afford the title compound as a tan solid (26 mg, 64%). LC/MS (m/z) ES+=432 (M+1).