Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:7]([CH3:13])[CH2:8][NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:15]([CH:19]([CH3:21])[CH3:20])[C:16](O)=[O:17]>>[CH:19]([C@@H:15]1[S:11][C:10]([NH:9][CH2:8][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:13])=[N:12][C:16]1=[O:17])([CH3:21])[CH3:20]
Reactant: CC(C)C(Br)C(=O)O
Reactant: C[C@@H](CNC(N)=S)c1ccccc1
Product: CC(C)[C@@H]1SC(NC[C@H](C)c2ccccc2)=NC1=O

Procedure:
Synthesis was performed from N-[(2R)-2-phenylpropyl]thiourea and 2-bromo-3-methylbutyric acid according to Method D3.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[C:8]2=[O:14])=[CH:4][CH:3]=1.[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C=O.[C:32](O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:12]=[CH:11][C:10]([CH2:32][N:20]3[CH2:21][CH2:22][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:19]3)=[C:9]([OH:13])[C:8]2=[O:14])=[CH:15][CH:16]=1
Reactant: O=c1c(O)cccn1Cc1ccc(Cl)cc1
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: C=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccn(Cc3ccc(Cl)cc3)c(=O)c2O)CC1
Temperature: 50 °C
Yield: 83.9 %

Procedure:
to a nitrogen purged 2-L round bottom flask equipped with a mechanical stirrer, upright condenser, and thermometer was charged 1-(4-chlorobenzyl)-3-hydroxypyridin-2(1H)-one (1) (50.0 g, 0.21 mol, 1 equiv.), tert-butyl piperazine-1-carboxylate, (2) (79.0 g, 0.42 mol, 2 equiv.) [CAS No. 57260-71-6] and ethanol (750 mL, 15 parts v/w). The solution was stirred and 37% aqueous formaldehyde (34.7 mL, 0.47 mol, 2.2 equiv.) and acetic acid (36.4 mL, 0.64 mol, 3 equiv.) were added and the solution stirred for 1 hour after which the reaction solution was heated to 50° C. for 18 hours. The reaction mixture was then cooled below room temperature and filtered under vacuum. The resulting solid was rinsed with ethanol (250 mL) and dried under a stream of nitrogen to afford 77.2 g (83.9%) of the desired product. 1H NMR (DMSO-d6) δ ppm 7.4 (d, 2H), 7.3 (d, 2H), 7.2 (d, 1H), 6.2 (d, 1H), 5.1 (s, 2H), 3.4-3.2 (m partly under brs water peak, 6H), 2.3 (m, 4H), 1.4 (s, 9H).13C NMR (DMSO-d6) [observed] δ ppm 157.24, 153.77, 144.36, 136.33, 132.15, 129.67, 128.48, 126.86, 124.56, 107.01, 78.74, 54.68, 52.49, 50.64, 43.48, and 28.03.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][C@H:10]([NH:12]C(=O)OC(C)(C)C)[CH3:11])[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[NH2:12][C@H:10]([CH3:11])[CH2:9][C:5]1[CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=[CH:7][CH:6]=1
Reactant: C[C@H](Cc1cccc(CO)c1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@@H](N)Cc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of (R)-tert-butyl 1-(3-(hydroxymethyl)phenyl)propan-2-ylcarbamate (Example 276, step d) (0.78 g) in dichloromethane (20 mL) was treated with trifluoroacetic acid (5 mL) and stirred at room temperature for 40 minutes. Toluene was added and the solution was concentrated in vacuo. The residue was partitioned between 1M aqueous NaOH and DCM and the phases separated. The aqueous phase was extracted twice more with DCM, then the combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford (R)-(3-(2-aminopropyl)phenyl)methanol as a colourless oil that slowly crystallised to a white solid on standing (0.442 g). A mixture of (R)-(3-(2-aminopropyl)phenyl)methanol (0.223 g), (R)-8-(benzyloxy)-5-(2-bromo-1-(tert-butyldimethylsilyloxy)ethyl)quinolin-2(1H)-one (0.72 g), sodium iodide (0.219 g) and Hunig's Base (0.77 mL) in acetonitrile (3 mL) was heated at reflux under nitrogen overnight. More (R)-(3-(2-aminopropyl)phenyl)methanol (0.219 g), Hunig's Base (0.51 mL) and acetonitrile (2 mL) were added and the mixture was heated at reflux over a second night. The cooled reaction mixture was diluted with ethyl acetate, washed twice with water, once with brine, then dried (MgSO4) and concentrated onto flash silica in vacuo. The resulting powder was purified by flash chromatography on silica eluting with 5% triethylamine in ethyl acetate to afford the subtitled compound as a pale yellow foam. Yield 0.525 g.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[NH:25]([C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][C:35]=1[O:43][CH3:44])=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[C:26]1([NH:25][C:32](=[O:33])[C:34]2[CH:39]=[CH:38][C:37]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[N:8][C:9]=4[NH2:11])[N:4]([C@H:12]4[CH2:17][CH2:16][C@@H:15]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)[CH2:14][CH2:13]4)[N:3]=3)=[CH:36][C:35]=2[O:43][CH3:44])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1cc(B(O)O)ccc1C(=O)Nc1ccccc1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1C(=O)Nc1ccccc1

Procedure:
cis-3-Iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (148 mg, 0.335 mmol), 4-(anilinocarbonyl)-3-methoxyphenylboronic acid (100 mg, 0.369 mmol), palladium tetrakistriphenyphosphine (23 mg, 0.020 mmol) and sodium carbonate (85 mg, 0.845 mmol) were mixed with ethylene glycol dimethyl ether (4 mL) and water (2 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (95:5) as mobile phase to give cis-N1-Phenyl-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxybenzamide (125 mg, 69%). 1H NMR (CDCl3) δ 1.69 (m, 2H), 1.86 (m, 2H), 2.17 (m, 2H), 2.31 (s, 3H), 2.44 (m, 11H), 4.15 (s, 3H), 4.96 (m, 1H), 5.69 (bs, 2H), 7.14 (m, 1H), 7.37 (m, 2H), 7.45 (m, 2H), 7.68 (m, 2H), 8.41 (m, 2H), 9.77 (s, 1H). LC/MS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min.(B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.5 mL/min.): MH+=541.2, Rt=2.58 min.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[CH:21]=3)[NH:16][CH:15]=2)[C:7]=1[F:29].[OH-].[K+].O.Cl>O1CCCC1>[F:29][C:7]1[C:8]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[CH:21]=3)[NH:16][CH:15]=2)=[C:9]([F:12])[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]([OH:30])=[O:2]
Reactant: COC(=O)COc1ccc(F)c(Cc2c[nH]c3ncc(-c4cccnc4)cc23)c1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1ccc(F)c(Cc2c[nH]c3ncc(-c4cccnc4)cc23)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To [2,4-Difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenoxy]-acetic acid methyl ester (P-1465, 20.0 mg, 0.049 mmol) in tetrahydrofuran (8.0 mL) were added potassium hydroxide (100.0 mg, 1.8 mmol) and water (3.0 mL). The reaction was stirred at room temperature overnight and then poured into water, acidified to pH=5 with 1 N HCl, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% methanol in methylene chloride to give the compound as light yellow solid (P-1468, 9.1 mg, 47%). MS (ESI) [M+H+]+=396.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CC[CH2:17][C:16]1=O.O.ICC>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[O:14])[CH:12]([CH2:16][CH3:17])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCI
Solvent: c1ccccc1
Product: CCC1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 100 °C

Procedure:
A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (5 g, 25.1 mmol), pyrollidone (5 mL) and p-toluenesulfonic acid (25 mg) in benzene (100 mL) was heated at reflux for 16 h with azeotropic distillation of water. The resulting enamine solution was cooled to rt and concentrated. The crude enamine was dissolved in acetonitrile (50 mL); iodoethane (4.67 g, 30.1 mmol.) was added and the mixture was heated at 100° C. for 0.5 h, cooled to rt and concentrated. The mixture was dissolved in ethyl acetate (200 mL), washed with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate, and brine. The extract was dried over magnesium sulfate, filtered and concentrated. The crude compound was purified by silica gel chromatography (80% hexanes/20% ethyl acetate) to afford 3-ethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (680 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[C:10]([NH:15][C:16](OC(C)(C)C)=[O:17])([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:14][CH:13]2[C:10]([NH:15][CH:16]=[O:17])([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC12CCC1CN(Cc1ccccc1)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=CNC12CCC1CN(Cc1ccccc1)C2
Reaction time: 3 h
Yield: 59.9 %

Procedure:
6.8 g of 3-benzyl-1-(t-butoxycarbonylamino)-3-azabicyclo[3.2.0]heptane was dissolved in 20 ml of methylene chloride, and 50 ml of trifluoroacetic acid was added thereto, followed by stirring for 3 hours. The reaction mixture was concentrated, mixed with an aqueous solution of sodium hydroxide under cooling with ice, and extracted with chloroform. After the extract was dried over anhydrous magnesium sulfate, the chloroform was distilled off. The resulting crude product was dissolved in 47 ml of formic acid, and 17 g of acetic anhydride was added dropwise thereto, under cooling with ice, over a period of 90 minutes. After the addition of ice water, the resulting mixture was neutralized by the addition of an aqueous solution of sodium hydroxide under cooling with ice, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (using a 30:1 mixture of chloroform and methanol as the eluent) to obtain 3.1 g of 3-benzyl-1-formylamino-3-azabicyclo[3.2.0]heptane.
Reaction SMILES: CC(C)=O.[O-]S([O-])(=O)=O.[Mg+2].[CH2:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O[C:25]([CH3:29])([CH3:28])[C:26]#[N:27]>CN(C)C(=O)C>[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(O)C#N
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C#N)N1CCN(Cc2ccccc2)CC1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
4.5 ml of acetone, 20 g of dry MgSO4, 10 g of N,N-dimethylacetamide, 10 g of 1-benzylpiperazine and 9.5 ml of 2-hydroxyisobutyronitrile are mixed together and heated at 45° C. for 48 hours with vigorous stirring. The reaction mixture is poured onto ice and left stirring for 30 minutes. The mixture is extracted with ether, the organic phase is washed several times with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. 13 g of the expected product are obtained.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH2:10][NH:11][C:12](=O)[CH2:13]2.O>C1COCC1.ClCCl>[CH3:7][N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH2:10][NH:11][CH2:12][CH2:13]2
Reactant: CN1C2CCC1CC(=O)NC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1C2CCNCC1CC2
Temperature: 0 °C
Yield: 69 %

Procedure:
To a suspension of LiAlH4 (0.61 g) in anhydrous THF (30 ml), cooled at 0° C., and kept under an argon inert atmosphere, a solution in THF of 9-methyl-3,9-diazabicyclo[4.2.1]nonan-4-one obtained in example 1 is dropwise added (1.00: of compound in 10 ml of THF). The obtained mixture is heated at reflux for 48 hours and then cooled at 0° C. Then water (3 ml) is slowly added to the mixture. After water addition, the mixture is kept under stirring for 1:0 minutes. A precipitate is formed, that at the end is filtered under vacuum and washed with dichloromethane. The obtained filtrate is evaporated obtaining an oil which is dissolved in dichloromethane. The obtained solution is then anhydrified on sodium sulphate and the solvent evaporated. The residual oil is distilled (45-50° C./0.1 mmHg) to give 0.63 g of 9-methyl-3,9-diazabicyclo[4.2.1]nonane (2a) as a colourless oil.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:56])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:52]([CH3:55])[CH2:53][CH3:54])[C@H:33]([O:50][CH3:51])[CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C@H:42]([O:48][CH3:49])[C@H:43]([C:45](O)=[O:46])[CH3:44])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:57][C@H:58]1[NH:62][C:61](=[O:63])[NH:60][C@H:59]1[CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][C:69]([NH:71][CH2:72][CH2:73][NH:74][C:75](=[O:85])[C@H:76]([CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1)[NH2:77])=[O:70].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:20])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:52]([CH3:55])[CH2:53][CH3:54])[C@H:33]([O:50][CH3:51])[CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C@@H:42]([C@@H:43]([CH3:44])[C:45](=[O:46])[NH:77][C@@H:76]([CH2:78][C:79]3[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=3)[C:75](=[O:85])[NH:74][CH2:73][CH2:72][NH:71][C:69](=[O:70])[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64][C@H:59]3[C@@H:58]([CH3:57])[NH:62][C:61](=[O:63])[NH:60]3)[O:48][CH3:49])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:56])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: C[C@H]1NC(=O)N[C@H]1CCCCCC(=O)NCCNC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)NCCNC(=O)CCCCC[C@@H]1NC(=O)N[C@@H]1C)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Yield: 27.4 %

Procedure:
Following general procedure D using #105 (36.6 mg, 0.047 mmol, 1.0 eq.), #255 (19 mg, 0.047 mmol, 1.0 eq.), HATU (22.4 mg, 0.056 mmol, 1.2 eq.) and Hunig's base (0.025 mL, 0.141 mmol) in 1.5 mL of DMF following by purification (Method J) yielded #256 (15 mg, 27%) as a white solid. LC-MS (Protocol Q1): m/z 1164.8 [M+H+], retention time=0.99 minutes.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[C:3]#C.[CH2:6]([Li])CCC.CCCCCC.[C:17]([O:22][CH2:23][CH3:24])(=[O:21])[C:18]([CH3:20])=[O:19]>C1COCC1>[OH:19][C:18]([CH3:6])([C:20]#[C:1][CH:2]([CH3:5])[CH3:3])[C:17]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: [Li]CCCC
Reactant: CCOC(=O)C(C)=O
Reactant: C#CC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(O)C#CC(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
To a solution of 3-methylbut-1-yne (0.5 g, 0.73 mmol), in dry THF (12 mL) was added dropwise at 0° C. a solution of n-butyllithium in hexane (1.6 N solution, 4.57 mL, 0.73 mmol). After being stirred for 0.25 h at 0° C., the solution was cooled at −78° C. and transferred dropwise by cannulation into a solution of ethyl pyruvate (0.80 mL, 0.73 mmol) in dry THF (12 mL) at −78° C. The resulting solution was stirred at −78° C. for 0.5 hr and quenched by the addition of saturated aqueous NH4Cl (10 mL). The mixture was extracted twice with Et2O (100 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and filtered. The filtrate solvent was removed on a rotary evaporator to give ethyl 2-hydroxy-2,5-dimethyl-3-hexynoate as a clear oil (0.85 g, 63%). LC-MS M+H=185. 1H NMR, 400 MHz, CDCl3, 4.26-4.32 ppm (m, 2H); 3.38 ppm (s, 1H); 2.53-2.58 ppm (m, 1H); 1.63 ppm (s, 3H); 1.32 ppm (t, J=7.14 Hz, 3H); and 1.15 ppm (d, J=6.96 Hz 6H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[C:11]3/[C:12](=[O:20])[NH:13][C:14]4[C:19]/3=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:8]=2)[CH:3]=[N:2]1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[N:33]=[CH:32][C:31](C3C4C(=CC(C=O)=CC=4)NN=3)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1>>[CH3:21][N:22]1[CH2:23][CH2:24][N:25]([C:28]2[N:33]=[CH:32][C:31]([C:3]3[C:4]4[C:9](=[CH:8][C:7]([CH:10]=[C:11]5[C:19]6[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=6)[NH:13][C:12]5=[O:20])=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[CH:30][CH:29]=2)[CH2:26][CH2:27]1
Reactant: O=C1Nc2ccccc2/C1=C\c1ccc2cn[nH]c2c1
Reactant: CN1CCN(c2ccc(-c3n[nH]c4cc(C=O)ccc34)cn2)CC1
Product: CN1CCN(c2ccc(-c3n[nH]c4cc(C=C5C(=O)Nc6ccccc65)ccc34)cn2)CC1

Procedure:
According to the procedure for the synthesis of (E)-3-((1H-indazol-6-yl)methylene)indolin-2-one, except substituting 3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indazole-6-carbaldehyde (40 mg, 0.12 mol), the title compound was prepared as a yellow solid (4.9 mg, 9%). A mixture of (E)- and (Z)-isomers (79:21 by NMR) was obtained. 1H NMR (400 MHz, DMSO-d6) δ 13.34 (br. s, 1H), 10.64 (br. s, 1H), 8.76 (d, J=2.3 Hz, 1H), 8.14 (dd, J=8.8, 2.5 Hz, 2H), 7.91 (s, 1H), 7.79 (s, 1H), 7.62 (d, J=7.8, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.24 (t, J=7.5 Hz, 1H), 6.99 (d, J=9.0 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.85 (t, J=7.3 Hz, 1H), 3.57 (t, J=4.5 Hz, 4H), 2.42 (t, J=5.0 Hz, 4H), 2.23 (s, 3H); MS ESI 437.2 [M+H]+, calcd for [C26H24N6O+H]+ 437.20.
Reaction SMILES: O.O=[CH:3][C:4]([OH:6])=[O:5].[NH2:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[C:13]([O:15][CH3:16])=[O:14].[CH3:17][O:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>C(#N)C>[CH3:16][O:15][C:13]([C:9]1[S:10][CH:11]=[CH:12][C:8]=1[NH:7][CH:3]([C:22]1[CH:23]=[N:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=1)[C:4]([OH:6])=[O:5])=[O:14]
Reactant: COC(=O)c1sccc1N
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=CC(=O)O
Solvent: O
Solvent: CC#N
Product: COC(=O)c1sccc1NC(C(=O)O)c1ccc(OC)nc1
Yield: 100 %

Procedure:
To a suspension of 2-oxoacetic acid hydrate (156 mg, 1.70 mmol) and methyl 3-aminothiophene-2-carboxylate (267 mg, 1.70 mmol) in acetonitrile (15 ml), was added 6-methoxypyridin-3-ylboronic acid (260 mg, 1.70 mmol). The reaction mixture was refluxed for 2 hours and the solvent was evaporated to obtain 2-(2-(methoxycarbonyl)thiophen-3-ylamino)-2-(6-methoxypyridin-3-yl)acetic acid (548 mg, 100% yield). The product was used in the next step without any further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[H-].[Na+].[C:28]1([S:34]([CH2:37][CH2:38][O:39][C:40](=[O:69])[CH2:41][O:42][C:43]2[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][C:44]=2[O:53][CH2:54][C:55]([O:57][CH2:58][CH2:59][S:60]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)(=[O:62])=[O:61])=[O:56])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>C(Cl)Cl>[C:28]1([S:34]([CH2:37][CH2:38][O:39][C:40](=[O:69])[CH2:41][O:42][C:43]2[CH:48]=[CH:47][C:46]([S:49]([N:21]3[C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=[C:17]3[S:15]([CH2:14][C:3]3[C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[CH:6]=[CH:5][N:4]=3)=[O:16])(=[O:50])=[O:51])=[CH:45][C:44]=2[O:53][CH2:54][C:55]([O:57][CH2:58][CH2:59][S:60]([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)(=[O:62])=[O:61])=[O:56])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: O=C(COc1ccc(S(=O)(=O)Cl)cc1OCC(=O)OCCS(=O)(=O)c1ccccc1)OCCS(=O)(=O)c1ccccc1
Agent: Cc1c(OCC(F)(F)F)ccnc1C[S+]([O-])c1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1ccc(OCC(=O)OCCS(=O)(=O)c2ccccc2)c(OCC(=O)OCCS(=O)(=O)c2ccccc2)c1
Reaction time: 3 h
Yield: 78 %

Procedure:
To a heterogeneous mixture of 2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)pyridin-2-ylmethanesulfinyl]-benzimidazole, (LANSOPRAZOLE) (500 mg, 1.35 mmol) in CH2Cl2 (10 mL) was added NaH (40 mg, 1.63 mmol) at room temperature resulting in a clear solution. To this clear mixture was added [2-(2-benzenesulfonyl-ethoxycarbonylmethoxy)-4-chlorosulfonyl-phenoxy]-acetic acid 2-benzenesulfonyl-ethyl ester (Intermediate 29, 1.0 g, 1.63 mmol, 1.2 eq) in CH2Cl2 (5 mL) at room temperature, and the mixture was stirred for 3 h. Thereafter water was added, the mixture was extracted with CH2Cl2, and the organic layers were dried and concentrated under reduced pressure. The residual oil was purified by column chromatography (CH2Cl2 to 2% MeOH in CH2Cl2) to yield Intermediate 30 (1.05 g, 78%) as an off-white foam.