Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:35][CH3:36])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=[O:21])[CH2:16][CH2:15]2)=[CH:10][N:9]=1.[OH-].[Na+:52]>C(O)C>[Na+:52].[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:46])([F:48])[F:47])[CH:44]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:35][CH3:36])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][CH:17]([C:20]([O-:22])=[O:21])[CH2:18][CH2:19]2)=[CH:10][N:9]=1
Reactant: CCOC(=O)N(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCC(C(=O)O)CC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)N(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCC(C(=O)[O-])CC2)cn1

Procedure:
1-(2-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(ethoxycarbonyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yl)-ethyl piperidine-4-carboxylate (70 mg) is dissolved in ethanol (4 ml), and thereto is added 1N-aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 2 hours. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give 1-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(ethoxycarbonyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yl)-piperidine-4-carboxylic acid (44 mg). The resulting 1-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(ethoxycarbonyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yl)-piperidine-4-carboxylic acid (44 mg) is dissolved in ethanol (1 ml), and thereto is added 1N-aqueous sodium hydroxide solution (44 μl), and then the mixture is concentrated under reduced pressure to give 1-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(ethoxycarbonyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yl)-piperidine-4-carboxylic acid sodium salt (45 mg). MS (m/z): 720 [M−Na]−
Reaction SMILES: [CH2:1]([C:3]1([CH2:15][CH3:16])[CH2:14][CH2:13][C:6]2=[C:7]([C:10]([OH:12])=[O:11])[S:8][CH:9]=[C:5]2[CH2:4]1)[CH3:2].[Li][CH2:18][CH2:19]CC.C(I)C>CC#N>[CH2:18]([C:9]1[S:8][C:7]([C:10]([OH:12])=[O:11])=[C:6]2[CH2:13][CH2:14][C:3]([CH2:1][CH3:2])([CH2:15][CH3:16])[CH2:4][C:5]=12)[CH3:19]
Reactant: CCC1(CC)CCc2c(csc2C(=O)O)C1
Reactant: [Li]CCCC
Solvent: CCI
Solvent: CC#N
Product: CCc1sc(C(=O)O)c2c1CC(CC)(CC)CC2

Procedure:
3,5,5-Triethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid is prepared from 5,5-diethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid by treatment with tert.-BuLi followed by ethyliodide in analogy to Example C; LC-MS: tR=1.07 min, [M+1+CH3CN]=308.14.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[C:12]([NH:16][C:17]1[N:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[C:23]=2[Cl:30])[N:20]=[CH:19][CH:18]=1)(=[O:15])[CH2:13][CH3:14]>C(O)(=O)C>[N+:8]([C:18]1[CH:19]=[N:20][N:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[C:23]=2[Cl:30])[C:17]=1[NH:16][C:12](=[O:15])[CH2:13][CH3:14])([O-:11])=[O:9]
Reactant: CCC(=O)Nc1ccnn1-c1ccc(Cl)c(Cl)c1Cl
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCC(=O)Nc1c([N+](=O)[O-])cnn1-c1ccc(Cl)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
2 ml (2.17 g/0.021 mol) of acetic anhydride and then 0.9 ml (1.3 g/0.02 mol) of 98% strength nitric acid are added in succession to 6.4 g (0.02 mol) of 5-propionamido-1-(2,3,4-trichlorophenyl)-pyrazole in 20 ml of glacial acetic acid at 10° C. When the addition is complete, the mixture is stirred for 16 hours at 25° C. To work up the mixture, it is evaporated down in vacuo, the residue is taken up in 20 ml of diethyl ether, the solution is washed three times with a total of 50 to 100 ml of concentrated sodium bicarbonate solution and twice with 50 ml of saturated sodium chloride solution, the solvent is removed in a vacuum from a water pump, and the solid residue is washed with a small amount of water and dried in a high vacuum at 30° C. to 40° C. 5.5 g (76% of theory) of 4-nitro-5-propionamido-1-(2,3,4-trichlorophenyl)-pyrazole of melting point 79°-81° C. are obtained.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][OH:23]>>[CH2:1]([N:5]1[C:9]2=[C:10]([O:23][CH2:22][C:18]3[S:17][CH:21]=[CH:20][CH:19]=3)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Reactant: OCc1cccs1
Product: CC=CCn1c(C)c(C)c2cnnc(OCc3cccs3)c21
Yield: 20.6 %

Procedure:
The title compound (cis/trans=20/80) was prepared as a grayish white powder in 20.6% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=20/80) and 2-thiophenemethanol.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:36]=[CH:35][C:18]([CH2:19][NH:20][O:21][C@H:22]4[C@H:27]([O:28][CH3:29])[C@H:26]([O:30][CH3:31])[C@@H:25]([O:32][CH3:33])[C@H:24]([CH3:34])[O:23]4)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH:39](N(C(C)C)CC)(C)C.CI>O1CCCC1.O>[CH3:39][N:20]([CH2:19][C:18]1[CH:35]=[CH:36][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:37])[F:38])=[CH:5][CH:6]=3)[N:11]=2)=[CH:16][CH:17]=1)[O:21][C@H:22]1[C@H:27]([O:28][CH3:29])[C@H:26]([O:30][CH3:31])[C@@H:25]([O:32][CH3:33])[C@H:24]([CH3:34])[O:23]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](ONCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)[C@@H]1OC
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](ON(C)Cc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)[C@@H]1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of N-{4-[1-(4-trifluoromethoxyphenyl)-1 H-[1 ,2,4]triazol-3-yl]-benzyl}O-((2S ,3R,4R,5S ,6S)-3 ,4 ,5-trimethoxy-6-methyl-tetrahydropyran-2-yl)-hydroxylamine. (3; 205 mg, 0.38 mmol) in tetrahydrofuran (THF; 10 mL) was added diisopropylethylamine (DIEA; 300 μL, 1.7 mmol) followed by methyl iodide (250 μL, 4.0 mmol). This solution was heated to reflux. After 1 h, due to apparent precipitation of quaternized DIEA, anhydrous potassium carbonate (K2CO3) was added to the mixture along with methyl iodide (200 μL, 3.2 mmol), and the suspension was allowed to stir at reflux an additional 21 h. The mixture was then cooled to room temperature, diluted with H2O and extracted with EtOAc (2×). The organic fractions were combined, washed with brine, dried with anhydrous Na2SO4 and evaporated at room temperature under vacuum. The resulting crude material was purified by silica gel chromatography (eluting with 60% EtOAc in Hexane). The title product (131 mg, 63%) was isolated as a pale yellow solid: mp 93-100° C.; 1H NMR (400 MHz, CDCl3) δ 8.63 (d, J=4.1 Hz, 1H), 8.16 (d, J=8.3 Hz, 2H), 7.88-7.75 (m, 2H), 7.52 (t, J=10.7 Hz, 2H), 7.39 (t, J=9.5 Hz, 2H), 4.37 (d, J=13.2 Hz, 2H), 3.98-2.89 (m, 15H), 1.25 (dd, J=24.7, 6.2 Hz, 3H); ESIMS m/z 553 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:19]=[C:18]([CH2:20][S:21][CH3:22])[CH:17]=[CH:16][C:12]=1[C:13](O)=O>>[CH3:9][O:10][C:11]1[CH:19]=[C:18]([CH2:20][S:21][CH3:22])[CH:17]=[CH:16][C:12]=1[C:13]1[NH:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[CH:5][CH:6]=2
Reactant: Nc1cccnc1N
Reactant: COc1cc(CSC)ccc1C(=O)O
Product: COc1cc(CSC)ccc1-c1nc2ncccc2[nH]1

Procedure:
Prepared analogously to Example 14 from 2,3-diaminopyridine and 2-methoxy-4-methylthiomethyl-benzoic acid.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C1COCC1.[C:14]1(=[O:20])[CH2:19][CH2:18][CH2:17][CH:16]=[CH:15]1.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][C:14]1([OH:20])[CH2:19][CH2:18][CH2:17][CH:16]=[CH:15]1)[CH3:8]
Reactant: O=C1C=CCCC1
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(O)C=CCCC1
Yield: 95 %

Procedure:
Under nitrogen atmosphere, 20 mL of toluene was added to 3.05 g (5 mmol, 1.0 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.48 g (5 mmol) of 2-cyclohexen-1-one in 5 mL of toluene was added dropwise while stirring at 0˜5° C. The mixture was stirred at 0˜5° C. for 3 hours. 10 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL (×2) of an aqueous saturated sodium chloride solution, 10 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 10 mL of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 0.87 g of the desired product (yield 95%).
Reaction SMILES: C([O:5][C:6]([N:8]([CH2:42][CH3:43])[C:9]1[C:10]([CH2:37]OC(=O)C)=[N:11][CH:12]=[C:13]([C:15]2[CH:24]=[CH:23][C:22]3[N:21]=[CH:20][C:19]4[N:25]([CH3:36])[C:26](=[O:35])[N:27]([C:28]5[C:29]([CH3:34])=[N:30][N:31]([CH3:33])[CH:32]=5)[C:18]=4[C:17]=3[CH:16]=2)[CH:14]=1)=[O:7])(C)(C)C.[C-]#N.[K+]>CCO.CCOC(C)=O>[CH3:33][N:31]1[CH:32]=[C:28]([N:27]2[C:18]3[C:17]4[CH:16]=[C:15]([C:13]5[CH:12]=[N:11][C:10]6[CH2:37][O:7][C:6](=[O:5])[N:8]([CH2:42][CH3:43])[C:9]=6[CH:14]=5)[CH:24]=[CH:23][C:22]=4[N:21]=[CH:20][C:19]=3[N:25]([CH3:36])[C:26]2=[O:35])[C:29]([CH3:34])=[N:30]1
Reactant: CCN(C(=O)OC(C)(C)C)c1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cnc1COC(C)=O
Agent: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCN1C(=O)OCc2ncc(-c3ccc4ncc5c(c4c3)n(-c3cn(C)nc3C)c(=O)n5C)cc21
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A mixture of acetic acid 3-(tert-butoxycarbonyl-ethyl-amino)-5-[1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-2-ylmethyl ester (stage 155.1.1, 0.107 mmol) and KCN (0.16 mmol) in EtOH (0.6 ml) was stirred for 17 h at 80° C. The RM was diluted with EtOAc and washed with water, with brine, dried over Na2SO4, filtered and evaporated. The residue The residue was absorbed on silica gel and purified by flash chromatography (CH2Cl2/MeOH 0% to 8%). The fractions containing product were evaporated together to give the title compound as an off-white solid. (HPLC: tR 2.42 min (Method A); M+H=470 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.00 (s, 1H), 8.35-8.32 (m, 1H), 8.17-8.13 (m, 1H), 8.11 (s, 1H), 8.04-8.00 (m, 1H), 7.62-7.59 (m, 1H), 7.49-7.47 (m, 1H), 5.40-5.31 (m, 2H), 4.04-3.85 (m, 2H), 3.87 (s, 3H), 3.59 (s, 3H), 1.97 (s, 3H), 1.24 (t, 3H))
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:20](=[O:35])[N:21]([CH3:34])[C@@H:22]([C:30](=[O:33])[NH:31][CH3:32])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:34][N:21]([C@@H:22]([C:30](=[O:33])[NH:31][CH3:32])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:20](=[O:35])[C@H:8]([NH:7][CH3:6])[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC
Yield: 87.5 %

Procedure:
N-Methyl-N-{(1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl}carbamic acid tert-butyl ester (600 mg, 1.19 mmol) was stirred in trifluoroacetic acid/methylene chloride (1:1, 5 mL) for 10 min and the volatiles were removed in vacuo. The residue was stripped with diethylether (2×5 mL) and dissolved in methanol (2 mL) and mixed with sodium hydrogen carbonate (10 mL) and ethylacetate (15 mL). The organic phase was separated and dried (magnesium sulfate) to afford 420 mg of (2R)-N-methyl-2-methylamino-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]([CH3:22])=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.[CH:27](=O)[CH3:28].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]([CH3:22])=[C:6]([N:8]([CH2:27][CH3:28])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1
Reactant: COC(=O)c1cc(Cl)cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CC(=O)O
Product: CCN(c1cc(Cl)cc(C(=O)OC)c1C)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.08 h
Yield: 96.6 %

Procedure:
To a solution of tert-butyl 4-{[5-chloro-3-(methoxycarbonyl)-2-methylphenyl]amino}piperidine-1-carboxylate (125 mg, 0.33 mmol) in 1,2-dichloroethane (1.6 ml) at room temperature under nitrogen was added acetaldehyde (37 μl, 0.65 mmol) followed by acetic acid (0.11 ml, 1.96 mmol). This solution was stirred for 5 minutes before adding sodium triacetoxyborohydride (0.21 g, 0.98 mmol) at room temperature. The reaction was monitored by LCMS and after 4.5 h a further acetaldehyde (73 μl, 1.31 mmol) and sodium triacetoxyborohydride (0.28 g, 1.31 mmol) were added to the reaction mixture. The mixture was stirred for a further 18 hours after which deionized water (10 ml) was added and the mixture was neutralised with solid NaHCO3. The phases were separated and the aqueous layer was extracted with EtOAc (2×10 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (10 g silica, Isolute cartridge, gradient of eluents; 99:1 Heptane:EtOAc to 8:2 Heptane:EtOAc) to give 131 mg (98%) of the title compound as a thick colourless oil. LC-MS 98%, m/z=433.5/435.1 (M+Na), 1H NMR (500 MHz, Chloroform-d) δ ppm 7.57 (1H, d, J=2.21 Hz), 7.22 (1H, d, J=2.05 Hz), 3.97-4.14 (2H, m), 3.90 (3H, s), 3.04 (2H, q, J=6.99 Hz), 2.81-2.91 (1H, m), 2.70 (2H, br. t, J=11.50, 11.50 Hz), 2.45 (3H, s), 1.69-1.80 (2H, m), 1.47-1.56 (2H, m), 1.46 (9H, s), 0.87 (3H, t, J=7.09 Hz).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]C)=O)[CH2:3][CH2:2]1.[NH3:11]>>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:11])=[O:9])[CH2:3][CH2:2]1
Reactant: COC(=O)C1CCOCC1
Reactant: N
Product: NC(=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 43.5 h
Yield: 74.6 %

Procedure:
Concentrated aqueous ammonia (50 mL) was added to methyl tetrahydro-2H-pyran-4-carboxylate (50 g, 347 mmol) and the reaction mixture was stirred for 43.5 hours at room temperature. The reaction mixture was then cooled in an ice water bath, after which the precipitate was filtered out and dried under reduced pressure at 40° C. to afford 33.4 g of the title compound (74.6% yield).
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH:11]1[CH2:14][N:13]([CH2:15][C@H:16]([OH:21])[C:17]([O:19][CH3:20])=[O:18])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]2[N:29]([C:32]3[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:39])[N:30]=[CH:31][C:24]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[Si:3]([O:10][CH:11]1[CH2:14][N:13]([CH2:15][C@H:16]([O:21][C:23]2[N:28]=[CH:27][N:26]=[C:25]3[N:29]([C:32]4[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=4[Cl:39])[N:30]=[CH:31][C:24]=23)[C:17]([O:19][CH3:20])=[O:18])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: COC(=O)[C@@H](O)CN1CC(O[Si](C)(C)C(C)(C)C)C1
Reactant: Clc1cccc(Cl)c1-n1ncc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H](CN1CC(O[Si](C)(C)C(C)(C)C)C1)Oc1ncnc2c1cnn2-c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 30.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil) (127 mg, 3.17 mmol) was added to (S)-methyl 3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxypropanoate (Intermediate AD3) (765 mg, 2.64 mmol) in anhydrous THF (30 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2,6-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate BA3) (871 mg, 2.91 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was neutralised with 1M citric acid and the reaction mixture diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×50 mL). The combined organics were washed with saturated brine (75 mL),dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 50 to 100% EtOAc in isohexane to afford the product (445 mg, 30.5%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I.C(N(CC)CC)C>[CH3:11][S:8]([C:4]1[CH:3]=[C:2]([C:36]#[C:35][Si:32]([CH3:34])([CH3:33])[CH3:31])[CH:7]=[CH:6][CH:5]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1cccc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccc(S(C)(=O)=O)c1
Temperature: 82.5 °C

Procedure:
Into a sealable tube was weighed 2.06 g (8.76 mmol) of 1-bromo-3-methanesulfonyl-benzene, 93 mg of palladium acetate, 122 mg of triphenylphosphine, 79 mg of copper (I) iodide, 10.0 mL of triethylamine, and 2.0 mL of trimethylsilylacetylene. The reaction vessel was sealed and was heated at 80-85° C. for 1 h then was filtered of solids with added ethyl acetate. The filtrate was concentrated in vacuo and was purified by silica gel flash chromatography (Jones Flashmaster, 50 g Silica gel, gradient elution from 100% hexanes to 40% ethyl acetate over 30 minutes). Appropriate fractions were combined and concentrated in vacuo affording (3-methanesulfonyl-phenylethynyl)-trimethylsilane as a faintly yellow oil, yield: 1.60 g (72%). 1H NMR (CDCl3): δ 8.04 (s, 1H), 7.88 (d, J=8 Hz, 1H), 7.71 (d, J=8 Hz, 1H), 3.05 (s, 3H), 0.27 (s, 9H).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1.[C:15]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:20]([O:19][C:17](=[O:18])[C:16]([C:15]([O:23][CH2:24][CH3:25])=[O:22])=[CH:7][C:6]1[CH:9]=[CH:10][C:3]([N:2]([CH3:14])[CH3:1])=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12])[CH3:21]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CN(C)c1ccc(C=O)c([N+](=O)[O-])c1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1ccc(N(C)C)cc1[N+](=O)[O-])C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.2 %

Procedure:
A mixture of 89 g (0.5 mol) of 4-dimethylamino-2-nitrobenzaldehyde [H. Baumann, et al German Pat. 2,363,458], 237 g (1.4 mol) of diethyl malonate, 3.44 g (40.4 mmol) of piperidine and 2.43 g (40.4 mmol) of acetic acid in 400 mL of toluene was refluxed for 16 hours under argon, with a Dean Stark trap attached. The solution was cooled to room temperature and washed with 200 mL of 5% aqueous KOH. The organic phase was separated, dried over sodium sulfate (Na2SO4), filtered, and the solvent evaporated. The dark red solid residue was dissolved in 40 mL of CH2Cl2 and 100 mL of hexane added. After standing for 1 hour, the solution was filtered to yield 10.4 g of orange crystals. Recrystallization from CH2Cl2 - hexane produced an analytical sample, m.p. 101°-102° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]([NH:7][CH2:8][C:9]1[N:10]=[C:11]2[CH:17]=[C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]([CH3:29])[CH:19]=3)[N:15]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[N:13][CH:14]=1)=[O:6].N1C(C)=CC=CC=1C.[Si:46](OS(C(F)(F)F)(=O)=O)([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47]>C(Cl)Cl>[Si:46]([O:1][CH2:2][CH2:3][CH2:4][C:5]([NH:7][CH2:8][C:9]1[N:10]=[C:11]2[CH:17]=[C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]([CH3:29])[CH:19]=3)[N:15]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:35])[CH3:36])[C:12]2=[N:13][CH:14]=1)=[O:6])([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: COc1ccc2c(c1)c(-c1cc3nc(CNC(=O)CCCO)cnc3n1COCC[Si](C)(C)C)cn2C
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COc1ccc2c(c1)c(-c1cc3nc(CNC(=O)CCCO[Si](C)(C)C(C)(C)C)cnc3n1COCC[Si](C)(C)C)cn2C
Temperature: -5 °C
Reaction time: 0.03 h
Yield: 74 %

Procedure:
A flask was charged with 4-hydroxy-N-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)butanamide (0.130 g, 0.248 mmol) and DCM (5 mL). The mixture was cooled to about −5° C. To the mixture was added 2,6-lutidine (0.064 mL, 0.54 mmol). After about 2 min, TBDMSOTf (0.063 mL, 0.273 mmol) was added. The mixture was stirred at about −5 to 0° C. for about 2 h. The mixture was concentrated under reduced pressure and the residue was purified using silica gel chromatography with an elution gradient of 0 to 80% EtOAc/heptane to give 4-(tert-butyldimethylsilyloxy)-N-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)butanamide (0.117 g, 74%): LC/MS (Table 2, Method a) Rt=3.40 min; MS m/z 638 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[C:31]1([O:37][C:38](Cl)=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1(C)C=CC=CC=1>CCCCCC>[O:37]([C:38]([N:8]1[CH2:9][CH2:10][C:11]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: FC(F)(F)c1ccc(OC2(c3ccccc3)CCN(Cc3ccccc3)CC2)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C(Oc1ccccc1)N1CCC(Oc2ccc(C(F)(F)F)cc2)(c2ccccc2)CC1

Procedure:
A solution of 10.0 g of 1-benzyl-4-phenyl-4-(p-trifluoromethylphenoxy)piperidine and 4.1 g of phenylchloroformate in 100 ml. of toluene was refluxed for 17 hours. The toluene was removed under reduced pressure to give a colorless oil which when rubbed with a glass rod in the presence of hexane gave a white solid of 1-phenoxycarbonyl-4-phenyl-4-(p-trifluoromethylphenoxy)piperidine.