Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:11]([S-:13])[CH3:12].[Na+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:13][CH2:11][CH3:12])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Cl)ccc1F
Reactant: CC[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSc1ccc(Cl)cc1C#N
Yield: 99.9 %

Procedure:
(Step 1) A mixture of 5-chloro-2-fluorobenzonitrile (5.83 g) and sodium ethanethiolate (3.47 g) was stirred in N,N-dimethylformamide (50 ml) at room temperature for 14 hr. The reaction solution was treated with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 5-chloro-2-(ethylsulfanyl)benzonitrile (7.4 g).
Reaction SMILES: [O:1]1[C:5]2=[N:6][CH:7]=[C:8]([CH:10]=O)[CH:9]=[C:4]2[CH:3]=[CH:2]1.[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13]C(O)=O.C([O-])(=O)C.[NH4+:25]>C(O)C>[CH2:19]([O:18][C:12](=[O:17])[CH2:13][CH:10]([NH2:25])[C:8]1[CH:9]=[C:4]2[CH:3]=[CH:2][O:1][C:5]2=[N:6][CH:7]=1)[CH3:20]
Reactant: [NH4+]
Reactant: O=Cc1cnc2occc2c1
Reactant: CCOC(=O)CC(=O)O
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCOC(=O)CC(N)c1cnc2occc2c1
Temperature: 25 °C

Procedure:
A solution containing aldehyde 23-2 (1.5 g, 10 mmol), ethyl hydrogen malonate (1.6 g, 20 mmol), and ammonium acetate (3.8 g, 50 mmol) in anhydrous ethanol (125 mL) was heated at reflux for 8 h. After cooling to room temperature, the solvent was evaporated and the residue partitioned between sat. sodium bicarbonate and EtOAc, the organic layer removed, dried, and concentrated. Chromatography of the residue afforded the amino ester 23-3 as a waxy solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][C:11]1[O:15][N:14]=[C:13]([C:16](Cl)=[O:17])[CH:12]=1>>[CH3:10][C:11]1[O:15][N:14]=[C:13]([C:16]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([NH2:1])=[CH:3][CH:4]=2)=[O:17])[CH:12]=1
Reactant: NCc1ccc(N)cc1
Reactant: Cc1cc(C(=O)Cl)no1
Product: Cc1cc(C(=O)NCc2ccc(N)cc2)no1

Procedure:
4-Aminobenzylamine (265 mg, 2.17 mmol) and 5-methyl-3-isoxazoyl chloride (316 mg, 2.17 mmol) were converted to the title compound by the procedure of Preparation 1 except that a 2:1 mixture of mono to bis acylated products resulted which were separated by partitioning the mixture in 100 mL of ethyl acetate and 100 mL of 1N aqueous hydrochloric acid. The organic was extracted an additional two times with the acid and the combined acid extracts were made basic (about pH 8) with saturated aqueous sodium bicarbonate. This basic solution was extracted with ethyl acetate and the organic extracts were dried over magnesium sulfate, filtered, and concentrated to yield 94 mg of the monoacylated title compound. (18.7%). MS(FD) m/z 231 (M+). IR(KBr) υ=3334, 1646, 1551, 1519, 1459 cm−1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]([CH2:14][CH3:15])=[C:12]([CH2:16][N:17]3[C@@H:26]([CH2:27][OH:28])[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18]3)[C:11]([CH2:29][CH3:30])=[N:10]2)=[C:4]([CH3:31])[CH:3]=1.[H-].[Na+].[CH2:34](I)[CH3:35]>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]([CH2:14][CH3:15])=[C:12]([CH2:16][N:17]3[C@@H:26]([CH2:27][O:28][CH2:34][CH3:35])[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18]3)[C:11]([CH2:29][CH3:30])=[N:10]2)=[C:4]([CH3:31])[CH:3]=1
Reactant: CCI
Reactant: CCc1nn(-c2c(C)cc(Br)cc2C)c(CC)c1CN1Cc2ccccc2C[C@@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC[C@H]1Cc2ccccc2CN1Cc1c(CC)nn(-c2c(C)cc(Br)cc2C)c1CC
Reaction time: 0.08 h
Yield: 141.1 %

Procedure:
To an ambient temperature solution of (R)-{2-[1-(4-bromo-2,6-dimethylphenyl)-3,5-diethyl-1H-pyrazol-4-ylmethyl]-1,2,3,4-tetrahydro-isoquinolin-3-yl }-methanol (0.45 g, 0.93 mmol) in anhydrous tetrahydrofuran (12 ml) was added sodium hydride (224 mg of 60% sodium hydride mineral oil dispersion; 5.6 mmol of sodium hydride was added. After stirring for 5 minutes, ethyl iodide (0.37 ml, 4.7 mmol) was added all at once. The reaction mixture was then stirred for 21 hours. The solvent was removed in vacuo, and the remaining residue was extracted with ethyl acetate/water (10 ml of each). The aqueous phase was separated, and then extracted twice with equal volumes of fresh ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to afford a yellow oil (0.67 g). Flash chromatography (silica gel, 40 micron mesh; elution with ethyl acetate/hexane =1:6 in volume) afforded the title compound as a light yellow oil (332 mg).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:18]=[CH:17][NH:16][N:15]=3)[N:11]3[CH:19]=[CH:20][N:21]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.[CH:22]1([CH:25]=[CH:26][C:27]#[N:28])[CH2:24][CH2:23]1.C(#N)C.C1CCN2C(=NCCC2)CC1>>[CH:22]1([CH:25]([N:16]2[CH:17]=[CH:18][C:14]([C:12]3[N:11]4[CH:19]=[CH:20][N:21]=[C:10]4[CH:9]=[C:8]([C:6]4[CH:5]=[N:4][N:3]([CH3:2])[CH:7]=4)[N:13]=3)=[N:15]2)[CH2:26][C:27]#[N:28])[CH2:24][CH2:23]1
Reactant: N#CC=CC1CC1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cc[nH]n3)n2)cn1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cn1cc(-c2cc3nccn3c(-c3ccn(C(CC#N)C4CC4)n3)n2)cn1
Temperature: 45 °C
Yield: 17.5 %

Procedure:
7-(1-Methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-3-yl)imidazo[1,2-c]pyrimidine hydrochloride (Example 129, Step C, 50.2 mg, 0.148 mmol) and 3-cyclopropylacrylonitrile (Preparation B; 69.1 mg, 0.742 mmol) were suspended in acetonitrile (742 μL, 0.148 mmol). DBU (88.8 μL, 0.594 mmol) was added to the reaction mixture and heated at 45° C. for 15 hours. The reaction mixture was purified by reverse phase HPLC using a 0-100% acetonitrile/water gradient. The resultant solid was diluted in Et2O, sonicated, filtered and washed with Et2O to afford the title compound as a light yellow solid (9.3 mg, 17% yield). MS (apci) m/z=359.2 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8](S(C)=O)[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][S:16](=[O:19])[CH2:15][CH2:14]2)[C:5]=1[N+:20]([O-:22])=[O:21])[CH3:2].[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.O>C(O)C>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][S:16](=[O:19])[CH2:15][CH2:14]2)[C:5]=1[N+:20]([O-:22])=[O:21])[CH3:2]
Reactant: C1CNCCN1
Reactant: CCOc1nc(S(C)=O)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]
Solvent: CCO
Solvent: O
Product: CCOc1nc(N2CCNCC2)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]

Procedure:
1 gm (2.9 mols) of 6-ethoxy-2-methylsulfinyl-5-nitro-4-(1-oxido-thiomorpholino)-pyrimidine [m.p. 164°-165°C, prepared from 6 ethoxy-2-methylthio-5-nitro-4-(1-oxido-thiomorpholino)-pyrimidine and 30% hydrogen peroxide in dilute acetic acid] was refluxed together with 5 gm (58 millimols) of piperazine in 50 ml of ethanol for 10 minutes. The reaction mixture was then poured into water, and the aqueous mixture was extracted with chloroform. The chloroform phase was dried, evaporated to dryness, and the residue was recrystallized from ethanol. Yield: 0.9 gm (84.7% of theory); m.p. 220°-222°C.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH:16](I)([CH3:18])[CH3:17].C(=O)(O)[O-].[Na+]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]2)=[O:7])=[CH:14][CH:15]=1
Reactant: CC(C)I
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)N1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 77.5 %

Procedure:
A mixture of 34.16 g (0.165 mol) of the 4-(4-fluorobenzoyl)piperidine, 33.80 g (0.199 mol) of isopropyl iodide and excessive sodium bicarbonate in 600 mL of acetonitrile was heated at reflux for 14 h. The solvent was removed in vacuo, and the residue was partitioned between CH2Cl2 and dilute NaOH. The CH2Cl2 solution was dried (Na2SO4), and the solvent was removed in vacuo to give a solid. This was recrystallized from CH2Cl2 /hexane to give 31.89 g (77.6%) of crystalline solid, mp 120°-121° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][CH:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[NH:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[CH2:5][C:4]([CH3:27])([CH3:26])[NH:3]1.[C:29](Cl)(=[O:33])[O:30][CH2:31][CH3:32].[OH-:35].[Na+]>C1(C)C=CC=CC=1>[CH2:31]([O:30][C:29]([N:8]([CH:6]1[CH2:7][C:2]([CH3:28])([CH3:1])[NH:3][C:4]([CH3:27])([CH3:26])[CH2:5]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([C:29]([O:30][CH2:31][CH3:32])=[O:35])[CH:16]1[CH2:17][C:18]([CH3:25])([CH3:24])[NH:19][C:20]([CH3:23])([CH3:22])[CH2:21]1)=[O:33])[CH3:32]
Reactant: CC1(C)CC(NCCCCCCNC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: [OH-]
Reactant: CCOC(=O)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)N(CCCCCCN(C(=O)OCC)C1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1

Procedure:
The N,N'-bis-(ethoxycarbonyl)-N,N'-bis-(2,2,6,6-tetramethyl-piperidin-4-yl)-hexamethylenediamine was prepared by reacting N,N'-bis-(2,2,6,6-tetramethyl-piperidin-4-yl)-hexamethylenediamine with ethyl chlorocarbonate in toluene in the presence of aqueous NaOH and was crystallised from octane.
Reaction SMILES: [F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Cl:17][C:18]1[CH:19]=[C:20]([N:24]=[C:25]=[O:26])[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:24][C:25]([NH:16][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]3[N:4]([CH3:7])[N:5]=[CH:6][C:2]=3[F:1])[CH:9]=2)=[O:26])[CH:21]=[CH:22][CH:23]=1
Reactant: COc1ccc(N)cc1-c1c(F)cnn1C
Reactant: O=C=Nc1cccc(Cl)c1
Product: COc1ccc(NC(=O)Nc2cccc(Cl)c2)cc1-c1c(F)cnn1C
Yield: 27 %

Procedure:
3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 3-chlorophenylisocyanate, in a similar manner as described in Example 1.68. An additional purification by flash chromatography (SiO2, Hexanes/EtOAc gradient elution) was necessary, providing a 10 mg (27% yield) of Compound 83: LCMS m/z (%)=377 (M+H37Cl, 25), 375 (M+H35Cl, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.28 (s, 1H), 8.16 (s, 1H), 7.80 (s, 1H), 7.64 (dd, J1=8.8 Hz, J2=2.8 Hz, 1H), 7.48 (d, J=2.8 Hz, 1H), 7.38 (d, JH,F=4.8 Hz, 1H), 7.34 (dd, J1=9.2 Hz, J2=0.8 Hz, 1H), 7.26 (dd, J1=8.2, J2=8.2 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 7.00 (dd, J1=8.8 Hz, J2=0.8 Hz, 1H), 3.83 (s, 3H), 3.65 (s, 3H). 19F NMR (376 MHz, acetone-d6) δ: −177.35 (d, JH,F=4.1 Hz, 1F).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.[OH-].[K+]>C(O)C.O>[CH3:21][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH:4]([CH2:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][O:7]2)[C:3]([OH:22])=[O:2])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: COC(=O)C(CC1CCCCO1)c1ccc(S(C)(=O)=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCCCO2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
A solution of 2-(4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid methyl ester (prepared as in Example 8, 75 mg, 0.23 mmol) in ethanol (5 mL) was treated with a solution of potassium hydroxide (32 mg, 0.58 mmol) in water (1 mL). The reaction was stirred for 3 h at 25° C. The reaction was then concentrated in vacuo to remove the ethanol and then acidified to pH=2 with a 1N aqueous hydrochloric acid solution. This solution was then extracted with methylene chloride 3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, hexanes to 60/40 hexanes/ethyl acetate plus 1% acetic acid) afforded 2-(4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid (60 mg, 85%) as a white solid: FAB-HRMS m/e calcd for C15H20O5S (M+H)+ 313.1109. found 313.1111.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17]C(OC(C)(C)C)=O)[CH2:9][C@:10]([CH2:15][OH:16])([CH3:14])[C:11](O)=[O:12])=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[OH:52][CH2:53][CH2:54][N:55]1[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1.CC#N.Cl.O1CCOCC1>C(Cl)Cl>[N:55]1([CH2:54][CH2:53][O:52][C:11](=[O:12])[C@@:10]([CH2:15][OH:16])([CH3:14])[CH2:9][C@H:8]([NH2:17])[CH2:7][C:4]2[CH:5]=[CH:6][C:1]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:2][CH:3]=2)[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1
Reactant: OCCN1CCCCC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@](C)(CO)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CC#N
Product: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OCCN1CCCCC1
Reaction time: 0.03 h

Procedure:
(2S,4R)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (125 mg, 302 μmol), HOBt (240 mg, 1.8 mmol), and EDCI (320 μL, 1.8 mmol) were dissolved in DCM and stirred for 2 minutes. N-(2-Hydroxyethyl)piperidine (401 μL, 3.0 mmol) was added and the resulting mixture was stirred at room temperature for 3 hours. The mixture was diluted with DCM and washed with saturated aqueous NaHCO3 solution. The organic layer was separated, dried, concentrated, then purified (Interchim reverse phase chromatography column; 5-70% MeCN in water with 0.5% TFA). The purified material was combined with MeCN (3.0 mL, 58 mmol) and 4 M HCl in dioxane (0.3 mL, 1.2 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. The solvent was removed and azeotroped with toluene (2×) to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 2-piperidin-1-yl-ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][N:20]=1>>[Cl:25][C:24]1[C:19]([N:15]2[CH2:16][CH2:17][CH:12]([S:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)(=[O:11])=[O:10])[CH2:13][CH2:14]2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCNCC1
Reactant: Clc1cccnc1Cl
Product: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCN(c2ncccc2Cl)CC1
Yield: 32.6 %

Procedure:
Using the procedure from Example 7A, Step 7E, 4-[(3,4-dichlorophenyl)sulfonyl]piperidine (200 mg, 0.68 mmol) was reacted with 2,3-dichloropyridine (201 mg, 1.36 mmol) to afford the title compound (90 mg), a white solid, in 33% yield.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([C:10]([OH:12])=[O:11])[CH2:2]1.C(N(CC)C(C)C)(C)C.[CH3:22][O:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([S:34](Cl)(=[O:36])=[O:35])=[CH:26][CH:25]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:22][O:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([S:34]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]([C:10]([OH:12])=[O:11])[CH2:2]2)(=[O:36])=[O:35])=[CH:26][CH:25]=1
Reactant: COc1ccc(S(=O)(=O)Cl)c2ccccc12
Reactant: O=C(O)C1CNc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)N2CC(C(=O)O)c3ccccc32)c2ccccc12
Yield: 73.2 %

Procedure:
To 2,3-dihydro-1H-indole-3-carboxylic acid (A) (3.59 g, 22.0 mmol) was added aqueous N,N-dimethylformamide (DMF) (3:2 v/v; 75 cm3), and then N,N-diisopropylethylamine (9.0 cm3, 50.7 mmol). The mixture was stirred at room temperature for 5 min, before 4-methoxy-1-naphthyl sulfonyl chloride (B)(5.64 g, 22.0 mmol) was added. After stirring for a further 16 h at room temperature saturated aqueous sodium bicarbonate (60 cm3) was added and the organic material was extracted into ethyl acetate (60 cm3). The organic layer was then washed with a further portion of saturated aqueous sodium bicarbonate (40 cm3) before the aqueous fractions were combined and acidified to pH 5 with 5N hydrochloric acid. The desired material was then extracted from the acidified aqueous mixture into ethyl acetate (2×60 cm3), which was subsequently dried over sodium sulfate and evaporated under reduced pressure to afford the title compound (C) (6.1 g, 16.1 mmol, 73%).
Reaction SMILES: F[C:2](F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13]N=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.[CH3:33][O:34][C:35](Cl)=[O:36]>>[CH3:33][O:34][C:35]([N:30]1[CH2:31][CH2:32][CH:27]([NH:26][C:11]2[CH:2]=[CH:13][C:14]([C:15](=[O:16])[C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])=[C:9]([NH2:8])[N:10]=2)[CH2:28][CH2:29]1)=[O:36]
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: COC(=O)Cl
Reactant: O=C(O)C(F)(F)F
Product: COC(=O)N1CCC(Nc2ccc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The title compound was prepared from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt (Example 22) and methylchloroformate (Aldrich 99%) using the procedure described in Example 24. HRMS, observed: 403.1781, Calcd for (M+H)+: 403.1776.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].C([O-])([O-])=O.[K+].[K+].[Br:16][C:17]1[CH:22]=[CH:21][C:20](F)=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=1>COCCOC.O>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=1
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)C(C(=O)OC)c1ccc(Br)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of dimethyl malonate (7.8 mL, 68.2 mmol) in DME (100 mL) at 0° C. was added K2CO3 (12.6 g, 91.0 mmol). The reaction mixture was stirred for 30 min, and then 4-bromo-1-fluoro-2-nitrobenzene (10.0 g, 45.5 mmol) was added. The reaction mixture stirred at 40° C. overnight. The reaction was cooled, diluted with water (200 mL), and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL), dried (Na2SO4) and concentrated. The residue was triturated with PE:EtOAc=8:1 (30 mL) to 13.0 g (86%) of the title compound as a yellow solid. [M+H] Calc'd for C11H10BrNO6, 332, 334. Found, 332, 334.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[N:9]=[CH:10][C:5]2=[C:4]([N:17]2[CH2:23][CH:22]3[O:24][CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[N:3]=1.C(N(CC)CC)C.Cl[C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34]>ClCCl.C1(C)C=CC=CC=1>[CH:22]12[O:24][CH:19]([CH2:20][CH2:21]1)[CH2:18][N:17]([C:4]1[N:3]=[C:2]([Cl:1])[N:7]=[C:6]3[N:8]([CH:11]4[CH2:12][CH2:13][N:14]([C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[CH2:15][CH2:16]4)[N:9]=[CH:10][C:5]=13)[CH2:23]2
Reactant: CC(C)OC(=O)Cl
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2cnn(C3CCNCC3)c2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(Cl)nc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
650 mg (1.7 mmol) of 3-(6-chloro-1-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane was suspended in 15 mL dichloromethane and triethylamine (0.5 mL) was added followed by addition of a 1N solution of isopropyl chloroformate in toluene. The mixture was stirred at room temperature overnight, diluted with dichloromethane and washed with sat. aqueous NaHCO3. The organic phase was dried over MgSO4, filtered and concentrated to give 696 mg (1.6 mmol) of the title compound. MS: 435.3/437.3 [M+H].
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[CH:11]1[C:23]2[CH:22]([CH2:24][O:25][C:26](Cl)=[O:27])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C>>[NH:1]([C:26]([O:25][CH2:24][CH:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]2[C:23]1=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:27])[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: NC(=O)CC[C@H](N)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C

Procedure:
5.48 g (37.5 mmoles) of finely ground glutamine (Chemical Dynamics Corp.) was placed in a 250 mL round bottom flask (oven dried) which was fitted with a heating mantle and condenser (oven dried). A nitrogen gas line was attached at the top of the condenser. The solid was suspended in 87.5 mL of dry N,N-dimethyl-acetamide and stirred vigorously. 19.04 mL (150 mmoles) of Tms-Cl was injected in one portion. The mixture was warmed slightly for 1 hour and cooled in an ice bath. 9-Fluorenylmethyloxycarbonyl chloride (6.47 g, 25 mmoles) and 19.78 mL (175 mmoles) of diisopropylethylamine were added. The solution was stirred in ice for 20 minutes and warmed to room temperature for 1-1.5 hrs. The mixture was concentrated on a rotary evaporator and then distributed between 200 mL diethyl ether and 250 mL 2.5% sodium bicarbonate. The phases were separated and the aqueous layer was extracted with 2×50 mL diethyl ether. The ether layers were backwashed with 2×25 mL H2O. The combined aqueous layers were acidified to pH 2 with 1.0N HCl. The white precipitate was filtered, washed with cold H2O and dried under high vacuum. Appropriate solvents were used to recrystallize the product. The product was found to be homogeneous (Table II).
Reaction SMILES: Br[C:2]1[N:3]=CN[C:6]=1[CH2:7]SCCN.CSC(SC)=C[N+]([O-])=O.[N+:21]([CH:24]=[C:25](SC)[NH:26][CH2:27][CH2:28][S:29][CH2:30][C:31]1[NH:35][CH:34]=[N:33][C:32]=1[Br:36])([O-:23])=[O:22].C(N)C#C>>[N+:21]([CH:24]=[C:25]([NH:3][CH2:2][C:6]#[CH:7])[NH:26][CH2:27][CH2:28][S:29][CH2:30][C:31]1[NH:35][CH:34]=[N:33][C:32]=1[Br:36])([O-:23])=[O:22]
Reactant: NCCSCc1[nH]cnc1Br
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1Br
Agent: C#CCN
Agent: CSC(=C[N+](=O)[O-])SC
Product: C#CCNC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1Br

Procedure:
When 2-[(4-bromo-1H-imidazol-5-yl)methylthio]ethylamine (prepared according to the procedure described in Belgian Patent 779,775) is reacted with 1,1-bis(methylthio)-2-nitroethylene according to the procedure of Example 6, Step A, and the resultant 1-nitro-2-methylthio-2-{2-[(4-bromo-1H-imidazol-5-yl)methylthio]ethylamino}ethylene is treated with propargylamine by the procedure of Example 6, Step B, the title compound is produced.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=[C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:15]#[N:16])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].CO>[C:1]1([CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([CH:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:15]#[N:16])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: N#CC(=C1CCN(Cc2ccccc2)CC1)c1cccs1
Agent: [Pd]
Solvent: CO
Product: N#CC(c1cccs1)C1CCN(Cc2ccccc2)CC1

Procedure:
A mixture of 70 parts of α-[1-(phenylmethyl)-4-piperidinylidene]-2-thiopheneacetonitrile in 800 parts of methanol is hydrogenated at normal pressure and at room temperature with 10 parts of palladiumon charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding 70 parts of 1-(phenylmethyl)-α-(2-thienyl)-4-piperidineacetonitrile as a residue.