Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1B1OC(C)(C)C(C)(C)O1)[C:17]([O:19][CH3:20])=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:23]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[CH3:13])=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11])=[CH2:9]
Reactant: C=Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: C=Cc1ccc(-c2ccc(C(=O)OC)cc2C)cc1[N+](=O)[O-]

Procedure:
4-Chloro-1-ethenyl-2-nitrobenzene (1.1406 g, 6.21 mmol), methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.059 g, 7.46 mmol), 1,1bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.422 g, 0.621 mmol), cesium carbonate (4.25 g, 13.05 mmol) and THF (30 mL) were heated in an 80° C. oil bath overnight. Volatiles were removed under reduced pressure. The pot residue was taken up by dichloromethane and filtered. The filtrate was concentrated in vacuo to afford a dark solid. The resulting solid was purified by flash chromatography (SiO2, Biotage SNAP cartridge, silica gel, 100 g cartridge). The column was eluted by an EtOAc/hexanes mixture (0% to 40%). Related fractions were pooled and evaporated a light orange solid as the titled compound. LCMS calc.=297.10. found=298.10 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2[CH:17]=[N:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH3:21][NH:22][CH3:23]>C(O)C>[CH3:21][N:22]([CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2[CH:17]=[N:18][CH:19]=[N:20][C:6]1=2)=[O:4])[CH3:23]
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2ncncc21
Reactant: CNC
Solvent: CCO
Product: CN(C)CC(=O)N1c2ccccc2NC(=O)c2cncnc21
Reaction time: 0.25 h

Procedure:
5.0 g (0.0174 mol) of 11-chloroacetyl-5,6-dihydropyrimido[4,5-b][1,5]benzodiazepin-5-one are added at 10° C. to 150 ml of a saturated solution of dimethylamine in absolute ethanol, the mixture is stirred for a further 15 minutes at the same temperature and the volatile constituents are then removed on a rotary evaporator. 50 ml of saturated sodium bicarbonate solution are added to the residue, the mixture is extracted several times with chloroform and the organic phase is dried and concentrated. The residue is recrystallized from 6:4 ethyl acetate/methylene chloride; yield: 2.2 g, m.p. 208° to 210° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[C:28](=[O:29])[O:27][C:26]([CH3:31])([CH3:30])[O:25][C:24]=2[CH:32]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][NH:19][C:20]3[CH:21]=[CH:22][C:23]4[C:28](=[O:29])[O:27][C:26]([CH3:30])([CH3:31])[O:25][C:24]=4[CH:32]=3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: CC1(C)OC(=O)c2ccc(N)cc2O1
Reactant: COc1ccc(C#Cc2ccc(C=O)cc2)cc1
Product: COc1ccc(C#Cc2ccc(CNc3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1

Procedure:
The title compound was prepared following the procedure A using 4-[(4-methoxyphenyl)-ethynyl]benzaldehyde (intermediate which may be obtained according to methods disclosed in EP03103780.7) and 7-amino-2,2-dimethyl-4H-1,3-benzodioxin-4-one as a brown powder (%). 1H NMR (CDCl3) δ 7.70 (d, J=8.7 Hz, 1H), 7.48 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.9 Hz, 2H), 7.28 (d, J=8.1 Hz, 2H), 6.86 (d, J=8.9 Hz, 2H), 6.30 (m, 1H), 6.01 (s, 1H), 4.37 (s, 2H), 3.81 (s, 3H), 1.67 (s, 6H). M+ (ESI): 414.1, M− (ESI): 412.1. HPLC, Rt: 4.90 min (purity: 92.8%).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([CH:7]([CH2:10][CH2:11][N:12]([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:8]#[N:9])=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[NH2-].[Na+].Cl[CH2:35][CH2:36][N:37]([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39]>O>[C:1]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=[CH:5][C:4]([C:7]([CH2:35][CH2:36][N:37]([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])([CH2:10][CH2:11][N:12]([CH:13]([CH3:14])[CH3:15])[CH:16]([CH3:18])[CH3:17])[C:8]#[N:9])=[CH:3][CH:2]=1
Reactant: CC(C)N(CCC(C#N)c1ccc(-c2ccccc2)cc1)C(C)C
Reactant: CC(C)N(CCCl)C(C)C
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)N(CCC(C#N)(CCN(C(C)C)C(C)C)c1ccc(-c2ccccc2)cc1)C(C)C
Temperature: 100 °C

Procedure:
To a solution of 16 parts of α-(4-biphenylyl)-α-[2-(diisopropylamino)ethyl]acetonitrile in 150 parts by volume of toluene is added 2.7 parts of sodium amide and the solution is heated over a period of 15 minutes at about 100° C. Then 13 parts of 2-chloro-N,N-diisopropylethylamine in 40 parts by volume of toluene is added slowly over a period of 20 minutes. This mixture is heated at 100°-105° C. for about 90 minutes and then cooled to room temperature when 150 parts by volume of water is added. The organic layer is separated, dried over calcium sulfate, filtered and the solvent evaporated to afford α-(4-biphenylyl)-α,α-bis[2-(diisopropylamino)ethyl]acetonitrile, as a low melting solid. This compound is identical with the compound of Example 2, Method A.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][C:3](=O)[CH2:2]2.O1CCOCC1>O>[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2
Reactant: O=C1CN2CCC(CC2)N1
Solvent: O
Solvent: C1COCCO1
Product: C1CN2CCC(CC2)N1
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
To the solution of 1,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAlH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90° C. (0.1 mbar) to yield 1,4-diazabicyclo[3.2.2]nonane (11.1 g; 78%) as colourless hygroscopic material.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]([N:12]2[C:16]([C:17](O)=[O:18])=[CH:15][N:14]=[CH:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:20])[O:3]1.C(Cl)(=O)C(Cl)=O.O[NH:29][C:30](=[NH:32])[CH3:31]>ClCCl.C(Cl)(Cl)Cl>[CH3:21][C:2]1([CH3:1])[CH:11]([N:12]2[C:16]([C:17]3[O:18][N:32]=[C:30]([CH3:31])[N:29]=3)=[CH:15][N:14]=[CH:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:20])[O:3]1
Reactant: CC(=N)NO
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1noc(-c2cncn2C2c3ccccc3C(=O)OC2(C)C)n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
3-(3,3-Dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carboxylic acid (0.538 g, 1.88 mmol) (Example 23) is dissolved in dichloromethane (4 mL) and cooled to 0° C. Oxalyl chloride (0.41 mL, 4.702 mmol) is added and the cooling bath is removed. The mixture is stirred at room temperature for 3 h. The reaction mixture is concentrated in vacuo. The residue obtained is redissolved in chloroform and N-hydroxyacetamidine (0.181 g, 2.44 mmol) is added. The reaction mixture is stirred at reflux for 72 h. The mixture is cooled to room temperature, washed with saturated solution of sodium bicarbonate and is extracted with dichloromethane. The organic phase is dried over Na2SO4 and concentrated in vacuo. The residue is purified by silica gel chromatography (hexane-ethyl acetate, 3:7) to give dimethyl-4-[5-(3-methyl-[1,2,4]oxadiazol-5-yl)-imidazol-1-yl]-isochroman-1-one as a white solid; MS (ESI) m/z 325.0 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 1.26 (s, 3 H), 1.61 (s, 3 H), 2.55 (s, 3 H), 6.94 (s, 1 H), 7.56 (d, J=7.1 Hz, 1 H), 7.63 (s, 1 H), 7.72 (td, J=7.6, 1.3 Hz, 1 H), 7.80 (td, J=7.6, 1.3 Hz, 1 H), 8.01 (s, 1 H), 8.30 (dd, J=7.8, 1.3 Hz, 1 H).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH:25][C:26]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)=[NH:27])[CH:23]=3)[NH:18][CH:17]=2)[CH2:11]1)C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O.[NH4+].[OH-]>ClCCl>[CH3:1][NH:2][CH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH:25][C:26]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)=[NH:27])[CH:23]=3)[NH:18][CH:17]=2)[CH2:11]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)C1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC1CCCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 982 %

Procedure:
tert-Butyl methyl(3-(5-(thiophene-2-carboximidamido)-1H-indol-3-yl)cyclohexyl)carbamate (0.60 g, 0.13 mmol) was treated with 20% TFA solution (31 mL) in dichloromethane at 0° C. and the mixture left to stir for 2 hours at 0° C. The solution then was neutralized with 10% NH4OH, the organic layer separated and evaporated. The crude product was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 1:4) to give the final product as a yellow solid (0.45 g, quantitative). 1H-NMR (DMSO-d6) δ 1.51-1.60 (m, 3H), 1.69-1.77 (m, 3H), 1.83-1.91 (m, 1H), 1.96-2.07 (m, 1H), 2.40 (s, 3H), 3.24-3.51 (m, 3H), 6.20 (brs, 2H, NH), 6.63 (d, 1H, J=10.2 Hz), 7.02 (d, 2H, J=10.4 Hz), 7.09 (dd, 1H, J=3.6, 4.8 Hz), 7.58 (d, 1H, J=5.1 Hz), 7.71 (d, 1H, J=3.3 Hz), 10.59 (s, 1H, NH); ESI-MS (m/z, %) 353 (MH+, 80), 322 (100), ESI-HRMS (MH+) calc. for C20H25N4S (MH+), calculated: 353.1794. found: 353.1812.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:21]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]5[NH:28][CH:29]=[CH:30][C:23]=45)=[CH:20][N:19]([CH2:31][C:32](O)=[O:33])[N:18]=3)=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N=C=NCCCN(C)C)C.[CH3:46][O:47][C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([NH2:54])[CH:49]=1>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:46][O:47][C:48]1[CH:49]=[C:50]([NH:54][C:32](=[O:33])[CH2:31][N:19]2[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[NH:28][CH:29]=[CH:30][C:23]=34)[C:17]([C:14]3[CH:15]=[CH:16][C:11]([NH:10][C:8]([NH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:9])=[CH:12][CH:13]=3)=[N:18]2)[CH:51]=[CH:52][CH:53]=1
Reactant: COc1cccc(N)c1
Reactant: O=C(O)Cn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COc1cccc(NC(=O)Cn2cc(-c3ccnc4[nH]ccc34)c(-c3ccc(NC(=O)Nc4ccccc4)cc3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
To a solution of [3-(4-{[(phenylamino)carbonyl]amino}phenyl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]acetic acid (0.166 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.249 mmol), 4-dimethylaminopyridine (0.249 mmol) and N,N-dimethylformamide (3.2 mL) at room temperature was added m-anisidine (0.415 mmol). The reaction mixture was stirred overnight at room temperature, concentrated in vacuo, taken up in ethyl acetate (10 mL) and washed with saturated aqueous sodium bicarbonate (10 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. Purification by Gilson reverse phase HPLC afforded the title compound as a white solid (26%). ESMS [M+H]+: 558.4
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH2:26]([C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](O)=[O:31])[CH3:27]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:30]([C:29]4[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=4[CH2:26][CH3:27])=[O:31])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CCc1ccccc1C(=O)O
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: CCc1ccccc1C(=O)N1CCC(N2N=C(c3ccc(OC)c(OC)c3)C(C)(C)C2=O)CC1

Procedure:
The title compound is prepared analogously as described for GP3 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2-ethylbenzoic acid as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](=[O:16])[CH2:13][CH2:14][Cl:15])[NH:8][C:7](=[O:17])[CH2:6][CH2:5]2.N1C=CC=CC=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].[Cl-].[Na+]>CN(C)C=O>[CH3:24][S:25]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](=[O:16])[CH2:13][CH2:14][Cl:15])[NH:8][C:7](=[O:17])[CH2:6][CH2:5]2)(=[O:27])=[O:26]
Reactant: O=C1CCc2cc(O)c(C(=O)CCCl)cc2N1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)Oc1cc2c(cc1C(=O)CCCl)NC(=O)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.06 Grams of 6-hydroxy-7-(3-chloropropionyl)-3,4-dihydrocarbostyril and 1.8 g of anhydrous pyridine were mixed with 50 ml of dimethylformamide. Then the mixture was cooled with ice and 2.5 g of methanesulfonyl chloride was added to the mixture and stirred at a room temperature for 3 hours. The reaction mixture was poured into 100 ml of a saturated sodium chloride solution and extracted with chloroform. The chloroform layer was washed with water, dried and chloroform was removed by distillation under a reduced pressure to obtain a residue. The residue was crystallized by adding 80 ml of hexane to obtain crude crystals. The crude materials were collected by filtration and were recrystallized from ethanol to obtain 4.5 g of 6-methylsulfonyloxy-7-(3-chloropropionyl)-3,4-dihydrocarbostyril in white crystals.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([OH:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C)=[CH:13][C:12]=2[O:29][CH3:30])=[C:5]([CH3:31])[N:4]=1>CO>[ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([OH:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:13][C:12]=2[O:29][CH3:30])=[C:5]([CH3:31])[N:4]=1
Reactant: COc1cc(OCCCO[Si](C)(C)C(C)(C)C)ccc1Cc1c(C)nc(N)nc1O
Agent: Cl
Solvent: CO
Product: COc1cc(OCCCO)ccc1Cc1c(C)nc(N)nc1O
Reaction time: 14 h

Procedure:
Concentrated hydrogen chloride (2.5 mL) was added dropwise to a solution of the product from step (v) (4.33 g) in methanol (43 mL) at RT and stirred for 14 h. The mixture was concentrated and diluted with methanol. The precipitate was collected by filtration, washed with methanol and dried to give 2.87 g of the sub-title compound as a white solid, which was used without further purification; 1H NMR (300 MHz, d6-DMSO) δ=12.59 (2H, brs), 8.05 (2H, s), 6.89 (1H, d), 6.51 (1H, d), 6.36 (1H, dd), 3.97 (2H, t), 3.52 (2H, t), 3.46 (2H, s), 2.13 (3H, s), 1.78-1.86 (2H, m); LC-MS: m/z 320.
Reaction SMILES: [C:1]1([C:7]2[C:14]3[S:13][C:12]([NH2:15])=[N:11][C:10]=3[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[S:18][C:19]([C:23](Cl)=[O:24])=[C:20]([CH3:22])[N:21]=1.C1(C)C=CC=CC=1.C(O)C(N)(CO)CO>CN(C1C=CN=CC=1)C.C1COCC1>[C:1]1([C:7]2[C:14]3[S:13][C:12]([NH:15][C:23]([C:19]4[S:18][C:17]([Cl:16])=[N:21][C:20]=4[CH3:22])=[O:24])=[N:11][C:10]=3[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1nc2[nH]nc(-c3ccccc3)c2s1
Reactant: Cc1nc(Cl)sc1C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: NC(CO)(CO)CO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1nc(Cl)sc1C(=O)Nc1nc2[nH]nc(-c3ccccc3)c2s1
Temperature: 70 °C
Reaction time: 18 h
Yield: 21 %

Procedure:
To a vial charged with 3-phenyl-1H-pyrazolo[3,4-d]thiazol-5-ylamine (30 mg, 0.139 mmol), PS-DMAP (Argonaut resin, 558 mg, 6 equiv.), and a stirring bar was added THF (2 mL) and 2-chloro-4-methyl-thiazole-5-carbonyl chloride solution in toluene (0.52 M, 1.3 mL, ca. 5 equiv.). The reaction mixture was stirred at 70° C. for 18 hours, then cooled to room temperature and treated with PS-trisamine (Argonaut resin, 674 mg, 20 equiv.) for 2 hours. The resin was filtered, washed with THF and the solvent was evaporated. The resulting crude mixture was treated with MeOH (1 mL) and a 4 N aqueous solution of NaOH (0.25 mL). The reaction mixture was further stirred at room temperature for 2 hours, then a 1 N aqueous solution of HCl was added to adjust the pH to 7, and the mixture was extracted with EtOAc (3×). Purification on silica gel with 0-10% MeOH in CH2Cl2 as eluent provided 11 mg (21% yield) of 2-chloro-4-methyl-thiazole-5-carboxylic acid (3-phenyl-1H-pyrazolo[3,4-d]thiazol-5-yl)-amide as an off-white solid. 1H-NMR (d6-DMSO) δ: 7.75 (d, 2H), 7.54 (t, 2H), 7.39 (t, 1H), 2.65 (s, 3H); HPLC/MS m/z: 376.0 [MH]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH2:14])=[N-]>CCOCC>[C:1]1([CH2:7][CH2:8][C:9]([O:11][CH3:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)CCc1ccccc1
Temperature: 0 °C
Yield: 83.1 %

Procedure:
To an ice-cooled and stirred solution of 3-phenylpropionic acid (8.0 g, 0.053 mol) in 30 ml of ether was slowly added an excess solution of diazomethane in ether. After concentration of ether, the residue was distilled under reduced pressure to give a colorless transparent oil of methyl 3-phenylpropionate (7.25 g, 0.044 mol, yield 83.1%, b.p. 106°-108° C./10 mmHg), which was assigned the structure by the following data:
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[CH:17]1[C:22]([CH:23]=O)=[CH:21][C:20]2[O:25][CH2:26][O:27][C:19]=2[CH:18]=1>>[CH:1]([N:4]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:23]([C:22]2[CH:17]=[CH:18][C:19]3[O:27][CH2:26][O:25][C:20]=3[CH:21]=2)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(C)N(C(N)=O)c1ccc2c(c1)OCO2
Product: CC(C)N1C(=O)NC(c2ccc3c(c2)OCO3)c2cc3c(cc21)OCO3
Yield: 41 %

Procedure:
The title compound was synthesized from N-isopropyl-N-[3.4-(methylenedioxy)phenyl]urea and piperonal by the procedure described in example 10 in 41% yield, mp: 87-89° C. 1H NMR (CDCl3,): 6.77 (s, 3H), 6.68 (s, 1H), 6.28 (s, 1H), 5.96 (s, 2H), 5.92-5.90 (m, 2H), 5.22 (d, J=1.8, 1H), 4.98 (br s, 1H), 4.44 (m, 2H), 1.58-1.54 (m, 6H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([CH3:9])([CH3:8])[C:5]([OH:7])=[O:6].[CH3:10]CCCCC.C[Si](C=[N+]=[N-])(C)C>C(OCC)C.CO>[CH3:10][O:6][C:5](=[O:7])[C:4]([CH3:9])([CH3:8])[CH2:3][CH2:2][OH:1]
Reactant: CCCCCC
Reactant: CC(C)(CCO)C(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C(C)(C)CCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
Step B To the mixture of 4-hydroxy-2,2-dimethyl-butanoic acid (2.2 g, 16.6 mmol) in ethyl ether (16 mL) and methanol (24 mL) at 0° C. was added a hexane solution (2.0 M) of trimethylsilyldiazomethane (Aldrich) (12.5 mL, 25 mmol). The reaction mixture was stirred at 0° C. for 1 h. The solvents were evaporated. The residue was taken up in ethyl acetate, washed with diluted aqueous HCl solution, saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated to give 4-hydroxy-2,2-dimethyl-butyric acid methyl ester as a colorless oil (1.5 g, 62%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[CH:6]=[O:7])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC#N.O>[CH2:19]([O:11][C:10]1[C:9]([CH3:12])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH2:1][CH3:2])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCc1cc(C=O)cc(C)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCc1cc(C=O)cc(C)c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
To a solution of 3-ethyl-4-hydroxy-5-methyl-benzaldehyde (34.9 g, 0.213 mol) in MeCN (350 mL), K2CO3 (58.7 g, 0.425 mol) and benzylbromide (36.4 g, 0.213 mol) is added. The mixture is stirred at 60° C. for 2 h before it is cooled to rt, diluted with water and extracted twice with EA. The org. extracts are washed with water and concentrated to give crude 4-benzyloxy-3-ethyl-5-methyl-benzaldehyde as an orange oil (45 g). 1H NMR (CDCl3): δ1.29 (t, J=7.5 Hz, 3H), 2.40 (s, 3H), 2.77 (q, J=7.8 Hz, 2H), 4.90 (s, 2H), 7.31-7.52 (m, 5H), 7.62 (d, J=1.5 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H), 9.94 (s, 1H).
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=1[CH:9](O)[C:10]([O:12][CH3:13])=[O:11].[Na+].[Cl-]>>[Br:2][CH:9]([C:8]1[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=1[O:6][CH3:5])[C:10]([O:12][CH3:13])=[O:11]
Reactant: BrP(Br)Br
Reactant: COC(=O)C(O)c1ccccc1OC
Agent: [Cl-]
Agent: [Na+]
Product: COC(=O)C(Br)c1ccccc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
146.6 ml (1.57 moles) of phosphorus tribromide are added dropwise to 109.7 g (0.562 mole) of methyl 2-methoxymandelate, while cooling well. After 3 hours stirring at room temperature, the mixture is poured into 3N NaCl solution, and extracted with methylene chloride. After washing the organic phase with water, it is dried with Na2SO4 and is concentrated. 140.7 g of the title compound are obtained as a yellowish oil which is used further without purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH2:20][CH2:21][O:22][CH3:23])[CH3:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[N:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32][CH:31]=1>>[CH3:23][O:22][CH2:21][CH2:20][N:18]([CH3:19])[CH:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([C:34]4[CH:35]=[N:30][CH:31]=[N:32][CH:33]=4)[N:3]=[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:5]=3[CH:10]=2)[CH2:13][CH2:14]1
Reactant: OB(O)c1cncnc1
Reactant: COCCN(C)C1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: COCCN(C)C1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cncnc4)nc3s2)CC1

Procedure:
1-((2-Chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)-N-(2-methoxyethyl)-N-methylpiperidin-4-amine was reacted with pyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 270. NMR (CDCl3): 1.60-1.68 (m, 2H, CH2), 1.77-1.79 (m, 2H, Ch2), 2.06-2.11 (m, 2H, CH2), 2.34 (s, 3H, CH3), 2.42-2.48 (m, H, CH), 2.67-2.70 (m, 2H, CH2), 3.03-3.06 (m, 2H, CH2), 3.37 (s. 3H, CH3), 3.47-3.50 (m, 2H, CH2), 3.77 (s, 2H, CH2), 3.90-3.92 (m, 4H, 2×CH2), 3.99-4.01 (m, 4H, 2×CH2), 7.16 (s, H, ArH), 9.28 (s, H, ArH), 9.69 (s, 2H, 2×ArH). MS: (ESI+): MH+=484.26
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]([CH3:29])([CH3:28])[CH2:12][C@@H:13]([C@H:22]1[O:26][C:25](=[O:27])[CH2:24][CH2:23]1)[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:40](Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1>[CH2:40]([C@@H:24]1[CH2:23][C@@H:22]([C@@H:13]([NH:14][C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:12][C:11]([CH3:29])([CH3:28])[CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:26][C:25]1=[O:27])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(CCOCc1ccccc1)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CCOCc1ccccc1)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1C[C@@H](Cc2ccccc2)C(=O)O1
Reaction time: 0.5 h

Procedure:
A solution of 1.76 g of 5(S)-[5-benzyloxy-1(S)-tert-butoxycarbonylamino-3,3-dimethylpentyl]-2-oxo-tetrahydrofuran in 30 ml of tetrahydrofuran is added to a mixture of 9.14 ml of a 1M lithiumbis(trimethylsilyl)amide solution in tetrahydrofuran and 30 ml of tetrahydrofuran at -78° C. under argon and the mixture is stirred for 30 min. 0.63 ml of benzyl bromide in 30 ml of tetrahydrofuran are then added dropwise. After the mixture has been stirred at -78° C. for 3.5 h, the reaction is quenched by addition of 1.6 ml of propionic acid and the mixture is diluted with diethyl ether. The organic phase is washed with a 10% aqueous citric acid solution and a 1M sodium bicarbonate solution, dried over sodium sulfate and concentrated. Purification over silica gel (mobile phase D) gives the title compound: Rf (D)=0.23; FAB-MS: (M+H)+ =496.