Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[C:8]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:37])[CH:35]=[CH2:36])[CH:30]=[CH:31][CH:32]=2)=[N:9][C:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[C:16]([OH:26])[CH:15]=2)=[N:11][CH:12]=1.[P:38](Cl)(=[O:47])([O:43][CH:44]([CH3:46])[CH3:45])[O:39][CH:40]([CH3:42])[CH3:41]>C1COCC1>[P:38]([O:43][CH:44]([CH3:46])[CH3:45])([O:39][CH:40]([CH3:42])[CH3:41])([O:26][C:16]1[CH:15]=[C:14]([NH:13][C:10]2[N:9]=[C:8]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=[O:37])[CH:35]=[CH2:36])[CH:28]=3)[C:7]([Cl:6])=[CH:12][N:11]=2)[CH:19]=[CH:18][C:17]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:47]
Reactant: CC(C)OP(=O)(Cl)OC(C)C
Reactant: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCOCC4)c(O)c3)ncc2Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCOCC4)c(OP(=O)(OC(C)C)OC(C)C)c3)ncc2Cl)c1
Reaction time: 0.08 h
Yield: 35.3 %

Procedure:
n-Butyl lithium (0.14 mL, 2.5 M solution in hexane) was diluted 10-fold in THF (1.4 mL), and the resulting mixture added dropwise to a rapidly stirring solution of N-(3-(5-chloro-2-((3-hydroxy-4-morpholinophenyl)amino)pyrimidin-4-yl)phenyl)acrylamide (100 mg, 0.221 mmol) in THF (5 ml) that was under argon gas and the reaction vessel was immersed in a salt-ice bath (bath temperature about −10° C. to −5° C.). The resulting white suspension was stirred for 5 min, followed by addition of diisopropyl phosphorochloridate (178 mg, 0.885 mmol) to the reaction mixture in a single portion. The suspension became a clear solution within about 5 min, and then reaction mixture was stirred at ambient temperature for about 18 h. Then reaction mixture was evaporated to dryness on a rotary evaporator. The resulting crude residue was purified by silica gel flash chromatography using a mixture of 3% methanol and DCM as eluting solvent to provide the title compound (50 mg, 0.078 mmol, 35.2% yield) as a syrup. 1HNMR (400 MHz, CDCl3): δ 8.52 (bs, 1H), 8.49 (d, 1H, J=8.0 Hz), 8.37 (s, 1H), 7.98 (s, 1H), 7.78 (d, 1H, J=8.0 Hz), 7.41 (d, 1H, J=8.4 Hz), 7.38 (s, 1H), 6.96 (d, 1H, J=8.4 Hz), 6.77 (d, 1H, J=8.0 Hz), 6.45 (m, 2H), 5.68 (t, 1H, J=6.0 Hz), 4.74 (m, 2H), 3.81 (m, 4H), 2.96 (m, 4H). Mass: 616.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH2:30])[CH:10]=1.[CH2:31]([S:33](Cl)(=[O:35])=[O:34])[CH3:32]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:30][S:33]([CH2:31][CH3:32])(=[O:35])=[O:34])[CH:10]=1
Reactant: Cn1cc(-c2ccc3c(c2)ncn3-c2cc(N)cc(-c3cc(F)ccc3F)c2)cn1
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)Nc1cc(-c2cc(F)ccc2F)cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)c1
Yield: 16.2 %

Procedure:
The compound was prepared from 2′,5′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-amine (70 mg, 0.175 mmol) using the procedure of Example 2(b) and ethanesulfonyl chloride (26 mg, 0.21 mmol, 1.2 eq.) to give the pure product in 16.2% yield (14 mg). NMR (400 MHz, DMSO-D6): δ10.35 (s, 1H), 8.80 (s, 1H), 8.23 (s, 1H), 8.00 (s, 1H), 7.96 (s, 1H), 7.70 (d, 1H), 7.65-7.60 (m, 4H), 7.51 (s, 2H), 7.49-7.39 (m, 1H), 3.88 (s, 3H), 3.30 (q, 2H), 1.26 (t, 3H), LC-MS (ESI): Calculated mass: 493.53; Observed mass: 494.2 [M+H]+ (rt: 0.1.33 min).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:14])[C:12]#[N:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[ClH:15].C([O:18]CC)C.CO>>[ClH:15].[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:14])[C:12]([NH2:13])=[O:18])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCOCC
Reactant: CC(C)Cc1ccc(C(C)C#N)cc1
Agent: Cl
Solvent: CO
Product: CC(C)Cc1ccc(C(C)C(N)=O)cc1
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A solution of 2-(4-isobutylphenyl)propionitrile (0.2 g; 1.07 mmol) in a (1:1) diethyl ether/methyl alcohol mixture (20 mL) is cooled at T=0-5° C. and gaseous HCl is bubbled into the solution for 1 h. Then the temperature is left to arise to r.t. and the mixture stirred overnight. After solvent evaporation under reduced pressure, the crude is dissolved in methyl alcohol (10 mL) and cooled at T=0-5° C. Ammonia is bubbled into for 1 h and the resulting mixture is left stirring overnight at r.t. After solvent evaporation under reduced pressure, the crude is suspended in diethyl ether (15 mL) and left stirring at r.t. for 2 h. The 2-(4-isobutylphenyl)propionamide hydrochloride (I) is isolated by filtration in vacuo as white solid (0.193 g; 0.80 mmol). Yield 75%. 1H-NMR (DMSO-d6): δ 8.80-8.50 (bs, NH3+Cl−); 7.40 (d, 2H, J=7 Hz); 7.15 (d, 2H, J=7 Hz); 3.98 (q, 1H, J=8 Hz); 2.42 (d, 2H, J=8 Hz); 1.90 (m, 1H); 1.57 (d, 3H, J=8 Hz); 0.88 (d, 6H, J=8 Hz).
Reaction SMILES: [C:1]12([C:11]([O:13][CH:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]([C:18]([O:20]CC)=[O:19])([F:17])[F:16])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O1CCOCC1.[OH-].[Na+:36]>O>[C:1]12([C:11]([O:13][CH:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]([F:16])([F:17])[C:18]([O-:20])=[O:19])=[O:12])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2.[Na+:36]
Reactant: CCOC(=O)C(F)(F)C(OC(=O)C12CC3CC(CC(C3)C1)C2)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(OC(c1ccccc1)C(F)(F)C(=O)[O-])C12CC3CC(CC(C3)C1)C2
Reaction time: 2 h

Procedure:
A mixture of 6.6 g of 2-ethoxycarbonyl-2,2-difluoro-1-phenylethyl 1-adamantanecarboxylate, prepared in Synthesis Example 1-5, 20 g of 1,4-dioxane, and 2.5 g of 25 wt % sodium hydroxide was stirred for 2 hours. Water, 30 g, was added to the reaction solution, which was washed with n-hexane, obtaining an aqueous solution of sodium 3-(adamantane-1-carbonyloxy)-2,2-difluoro-3-phenylpropionate. To this solution, 95 g of an aqueous solution of 4-tert-butylphenyldiphenylsulfonium methylsulfate and 100 g of methylene chloride were added. After stirring for 30 minutes, the organic layer was taken out, washed with water, and concentrated under reduced pressure. Methyl isobutyl ketone was added to the concentrate, which was concentrated again. Diisopropyl ether was added to the concentrate for crystallization. The resulting solid was dried in vacuum, obtaining 5.4 g of the target compound, 4-tert-butylphenyldiphenylsulfonium 3-(adamantane-1-carbonyloxy)-2,2-difluoro-3-phenylpropionate as white crystals (yield 52%).
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[C:21]#[N:22])=[CH2:17])=[CH:12][CH:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]>O=[Pt]=O.C(OCC)(=O)C>[C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH:16]([C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[C:21]#[N:22])[CH3:17])=[CH:14][CH:15]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: C=C(c1ccc(COc2ccc(C(C)=O)c(O)c2CCC)cc1)c1cccc(C#N)c1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCCc1c(OCc2ccc(C(C)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O

Procedure:
Add 3-{1-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-vinyl}-benzonitrile (0.105 g, 0.255 mmol), ethyl acetate (50 ml) and PtO2 (0.010 g) to a Parr pressure vessel. Purge the reaction vessel with nitrogen, pressurize the reaction mixture with hydrogen (400 KPa), seal the vessel and agitate the reaction at ambient temperature. Continue the reaction for 2.5 hours. Vent the excess hydrogen from the vessel and purge the vessel with nitrogen. Filter the reaction mixture to remove the platinum catalyst. Add the filtrate and PtO2 (0.019 g) to a Parr pressure vessel. Purge the reaction vessel with nitrogen, pressurize the reaction mixture with hydrogen (400 KPa), seal the vessel and agitate the reaction at ambient temperature. Continue the reaction for 6 hours. Vent the excess hydrogen from the vessel and purge the vessel with nitrogen. Filter the reaction mixture to remove the platinum catalyst and remove the solvent under vacuum. Add the concentrate, ethyl acetate (50 ml) and PtO2 (0.022 g) to a Parr pressure vessel. Purge the reaction vessel with nitrogen, pressurize the reaction mixture with hydrogen (400 KPa), seal the vessel and agitate the reaction at ambient temperature. Continue the reaction for 18 hours. Vent the excess hydrogen from the vessel and purge the vessel with nitrogen. Filter the reaction mixture to remove the platinum catalyst and remove the solvent under vacuum. Add the concentrate, ethyl acetate (150 ml), Pt catalyst from previous filtrations and PtO2 (0.105 g) to a Parr pressure vessel. Purge the reaction vessel with nitrogen, pressurize the reaction mixture with hydrogen (400 KPa), seal the vessel and agitate the reaction at ambient temperature. Continue the reaction for 22.5 hours. Vent the excess hydrogen from the vessel and purge the vessel with nitrogen. Filter the reaction mixture to remove the platinum catalyst. The mixture is filtered and concentrated to give 25 mg, 25%, as a film. LCMS M−1 412.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=O)([CH3:3])[CH3:2].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:5]1[N:4]([CH:1]([CH3:3])[CH3:2])[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:7]=2[N:6]=1
Reactant: CC(C)n1c(=O)[nH]c2ccncc21
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: CC(C)n1c(Cl)nc2ccncc21
Temperature: 0 °C

Procedure:
A mixture of 3-isopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one (0.5 g, 2.82 mmol.) in POCl3 (5 mL) was refluxed for 16 hrs. Then the reaction mixture was poured into ice water and basified with NH4OH to pH=7˜8. The mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated to afford crude 2-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine which was used directly for the next step (150 mg, 27%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[CH3:25])[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[S:26]1(=[O:32])(=[O:31])[CH2:30][CH2:29][CH2:28][NH:27]1>>[CH3:25][C:19]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=1[N:15]1[CH2:16][CH2:17][N:12]([C:10]([C:5]2[CH:4]=[CH:3][C:2]([N:27]3[CH2:28][CH2:29][CH2:30][S:26]3(=[O:32])=[O:31])=[CH:9][C:6]=2[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Reactant: O=S1(=O)CCCN1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C#N)CC2)c(C)c1
Yield: 91.8 %

Procedure:
Using 5-bromo-2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]benzonitrile (797 mg) described in Preparation Example 188 and isothiazolidine 1,1-dioxide (315 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (806 mg) was obtained.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([C:9]1[N:13]=[C:12]([NH:14][C:15]3[C:20]([O:21][C:22]4[C:23]([CH3:28])=[N:24][CH:25]=[CH:26][CH:27]=4)=[CH:19][C:18]([C:29]([F:32])([F:31])[F:30])=[CH:17][N:16]=3)[S:11][N:10]=1)[CH2:2]2.C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41].[ClH:47]>C(Cl)Cl>[ClH:47].[CH3:28][C:23]1[C:22]([O:21][C:20]2[C:15]([NH:14][C:12]3[S:11][N:10]=[C:9]([CH:3]4[CH2:2][CH:1]5[N:8]([C:40](=[O:42])[CH3:41])[CH:5]([CH2:6][CH2:7]5)[CH2:4]4)[N:13]=3)=[N:16][CH:17]=[C:18]([C:29]([F:30])([F:31])[F:32])[CH:19]=2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ncccc1Oc1cc(C(F)(F)F)cnc1Nc1nc(C2CC3CCC(C2)N3)ns1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1C2CCC1CC(c1nsc(Nc3ncc(C(F)(F)F)cc3Oc3cccnc3C)n1)C2
Yield: 47.5 %

Procedure:
3-(8-azabicyclo[3.2.1]octan-3-yl)-N-(3-(2-methylpyridin-3-yloxy)-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-amine (45 mg, 0.0973 mmol) was dissolved in CH2Cl2 (2 mL) and triethylamine (67.8 μL, 0.486 mmol) and acetic anhydride (13.8 μL, 0.146 mmol) were added. After 10 minutes the reaction was partitioned between saturated aqueous NaHCO3 and CH2Cl2, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (10% methanol in EtOAc) to afford 1-(3-(5-(3-(2-methylpyridin-3-yloxy)-5-(trifluoromethyl)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octan-8-yl)ethanone hydrochloride (25 mg, 0.0462 mmol, 47.5% yield) as a solid after HCl salt formation. Mass spectrum (apci) m/z=505.2 (M+H—HCl).
Reaction SMILES: [CH3:1][N:2]([C:15]1[CH:20]=[CH:19][C:18]([N:21]=[N:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[C:32](Cl)(=[O:36])[C:33]([CH3:35])=[CH2:34]>>[N+:29]([C:26]1[CH:27]=[CH:28][C:23]([N:22]=[N:21][C:18]2[CH:19]=[CH:20][C:15]([N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:32](=[O:36])[C:33]([CH3:35])=[CH2:34])=[CH:16][CH:17]=2)=[CH:24][CH:25]=1)([O-:31])=[O:30]
Reactant: C=C(C)C(=O)Cl
Reactant: CN(CCCCCCCCCCCO)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1
Product: C=C(C)C(=O)OCCCCCCCCCCCN(C)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
The 4'-[N-methyl-N-(11-hydroxyundecyl)-amino]-4-nitroazobenzene obtained in process step 1 was reacted with methacryloyl chloride according to the method stated in Example 2, Section 2, to give 4-nitro-4'-[N-methyl-N-(11-methacryloyloxyundec-1-yl)-amino]-azobenzene [methacrylate (A)]. The resulting product had the following physicochemical properties: IR spectrum (KBr pellet): bands at 2,900, 2,850, 1,705, 1,585, 1,490, 1,325, 1,120, 1,150, 1,095, 850 and 810 cm-1 ; 1H nuclear magnetic resonance spectrum (400 MHz, CDCl3, tetramethylsilane as internal standard, chemical shift δ (in ppm): 1.3 to 1.65 (multiplet, 18H), 1.9 (singlet, 3H), 3.1 (singlet, 3H), 3.4 (triplet, 2H), 4.3 (triplet, 2H), 5.6 (singlet, 1H), 6.1 (singlet, 1H), 6.7 (doublet, 2H), 7.9 (doublet, 4H), 8.3 (doublet, 2H); elemental analysis: calculated: 67.3% C, 8.03% H, 13.13% N, 11.25% 0; found: 66.1% C, 7.7% H, 13.8% N, 12.1% 0.
Reaction SMILES: C[O-].[Na+].[Na].[NH:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=O)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.[N:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[N+:17]=[N-:18]>O.CO>[N:16](/[C:19](=[CH:14]\[C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[NH:5][CH:6]=[CH:7]2)/[C:20]([O:22][CH3:23])=[O:21])=[N+:17]=[N-:18]
Reactant: COC(=O)CN=[N+]=[N-]
Reactant: O=Cc1ccc2[nH]ccc2c1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)/C(=C/c1ccc2[nH]ccc2c1)N=[N+]=[N-]
Reaction time: 5 h
Yield: 76.7 %

Procedure:
Under nitrogen, to a sodium methoxide solution (prepared from 15 ml of methanol and 0.66 g (29 mmol) of sodium) a mixture of 1.02 g (7 mmol) of indole-5-carbaldehyde [Helv. Chim. Acta, 1616. (1968)], 3.34 g (29 mmol) of methyl azido-acetate and 7 ml of methanol is added dropwise at 0° C. and the so obtained mixture is stirred at this temperature for 5 h. Then the reaction mixture is diluted with 50 ml of water, and extracted three times with: 50 ml of chloroform. The combined organic layers are washed with 20 ml of water, filtered through a phase separating filter-paper and concentrated to yield 1.3 g (77%) of the title compound. Mp.: 130-133° C. (chloroform).
Reaction SMILES: Cl[CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4].[CH2:8]([NH2:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>C1(C)C=CC=CC=1>[CH2:8]([NH:14][CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: COCC(Cl)C=O
Reactant: CCCCCCN
Solvent: Cc1ccccc1
Product: CCCCCCNC(C=O)COC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The dimethyl acetal of 2-chloro-3-methoxypropionaldehyde (0.1 mole) and toluene (75 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Hexylamine (0.22 mole) is added to the reaction mixture with stirring at room temperature. Stirring is continued fo a period of about 15 minutes. After this time the reaction mixture is heated at reflux for a period of about 1 hour. The reaction mixture is then cooled to room temperature and filtered. The filtrate is stripped of toluene and unreacted starting material under reduced pressure to yield the desired product the dimethyl acetal of 2-hexylamino-3-methoxypropionaldehyde as the residue.
Reaction SMILES: [CH:1]1([OH:14])[CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[OH:13].[CH3:15][CH2:16][CH2:17][CH2:18][CH:19]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[Cl-].[Na+].O>[CH2:16]([CH:15]1[O:13][CH:2]2[CH:1]([CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3]2)[O:14]1)[CH2:17][CH2:18][CH3:19]
Reactant: OC1CCC=CCCC=CCCC1O
Reactant: CCCCC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCCCC1OC2CCC=CCCC=CCCC2O1
Yield: 90 %

Procedure:
5 g of 5,9-cyclododecadien-1,2-diol, 2.4 g of valeric aldehyde, a spatula of p-toluenesulfonic acid and 200 ml of 80/100 petroleum ether were charged into a 250 ml two-neck flask equipped with a water separator and the mixture was taken to reflux for 1 h. The reaction mixture was then poured on ice, neutralized with brine, dried and concentrated. Distillation in a bulb-to-bulb apparatus produced 6.06 g of 14-butyl-13,15-dioxabicyclo[10.3.0]pentadeca-4,8-diene.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][O:11][N:12]1[C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][CH2:14][C:13]1([CH3:21])[CH3:20].[OH-].[Na+].Cl>C1COCC1.CO>[CH3:20][C:13]1([CH3:21])[CH2:14][CH2:15][CH2:16][C:17]([CH3:18])([CH3:19])[N:12]1[O:11][CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:22])=[O:2]
Reactant: COC(=O)c1ccccc1CON1C(C)(C)CCCC1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CCCC(C)(C)N1OCc1ccccc1C(=O)O
Reaction time: 24 h
Yield: 77.2 %

Procedure:
2-(2,2,6,6-Tetramethylpiperidin-1-yloxymethyl)-benzoic acid methyl ester (946 mg, 3.1 mmol) was diluted in THF/methanol (1:1, 10 mL). To the solution was added 25% NaOH (aq) (5 mL) at room temperature. After 24 h, the reaction was acidified with 10% HCl and extracted with CH2Cl2 (×3). The combined extracts were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (Hex/EtOAc=1:1) to give 2-(2,2,6,6-tetramethylpiperidin-1-yloxymethyl)-benzoic acid as a white solid (697 mg, 77%). Rf=0.6 (Hex:EtOAc=1:1); 1H NMR (300 MHz, CDCl3): δ 8.01 (d. J=7.8 Hz, 1H), 7.59 (d, J=7.5 Hz, 1H), 7.53 (t, J=7.2 Hz, 1H), 7.39 (t, J=7.5 Hz, 1H), 5.27 (s, 2H), 1.69-1.46 (br m, 6H), 1.22 (s, 12H): 2-(2,2,6,6-Tetramethylpiperidin-1-yloxymethyl)-benzoic acid (697 mg, 2.39 mmol) and Nhydroxysuccinimid (330 mg, 2.87 mmol) were dissolved in dry CH2Cl2 (10 mL) under argon atmosphere. A solution of N,N′-dicyclohexylcarbodiimide (DCC) (592 mg, 2.87 mmol) was slowly added to the solution at 0° C. After 10 h of stirring, the reaction mixture was filtered through a short pad of silica gel with CH2Cl2 and the filtrate was concentrated to give a crude product. Purification of the crude product by column chromatography on silica gel (Hex:EtOAc=2:1) gave the final product as a white solid (680 mg, 73%). mp=145° C.; Rf=0.5 (Hex:EtOAc=2:1); 1H NMR (500 MHz, CDCl3): δ 8.17 (d, J=7.8 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.68 (t, J=7.8 Hz, 1H), 7.38 (t, J=7.5 Hz, 1H), 5.22 (s, 2H), 2.90 (s, 4H), 1.48 (br s, 4H), 1.36 (br s, 1H), 1.32 (br s. 1H), 1.19 (s, 6H), 1.17 (s, 6H); 13C NMR (125 MHz, CDCl3) 169.48, 161.45, 143.56, 134.61, 131.29, 127.39, 126.78, 121.73, 76.07, 60.14, 39.86, 33.07, 25.86, 20.64, 17.29; IR (neat): 2932 (w), 1767 (m), 1741 (s), 1468 (w), 1375 (w), 1229 (m), 1207 (s), 1132 (w), 1071 (m), 983 (S), 843 (w), 737 (s), 647 (m) cm-1; Anal. Calcd for C21H28N2O5: C. 64.93; H, 7.27; N, 7.21, Found; C. 64.95; H, 7.15; N, 7.10.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][C:6]=2[CH:18]=1.N.[CH3:20][N:21]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N>[O:11]([CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([C:20]#[N:21])=[CH:18][C:6]=2[CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Ic1ccc2oc(COc3ccccc3)cc2c1
Reactant: CN1CCCC1=O
Agent: N
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2oc(COc3ccccc3)cc2c1
Temperature: 130 °C
Reaction time: 3 h
Yield: 15 %

Procedure:
To a 1-methyl-2-pyrrolidinone (10 mL) solution of 5-iodo-2-phenoxymethyl-benzofuran (250 mg, 0.714 mmol) described in Production Example 75-1-1 were added zinc cyanide (168 mg, 1.43 mmol) and tetraquis(triphenylphosphine) palladium (0) (165 mg, 0.143 mmol). This mixture was stirred at 130° C. for 3 hours. After adding ice water and concentrated aqueous ammonia to the reaction mixture and stirring, the reaction mixture was extracted with ethyl acetate. The organic layer was separated followed by washing with sat. NaCl, drying over anhydrous magnesium sulfate and concentrating under a reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain the title compound (27 mg, 15%).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:1][C:2]1[N:7]=[C:6]([O:8][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(=O)[nH]1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(Oc2ccc(C=O)cc2)n1
Temperature: 130 °C
Yield: 82.9 %

Procedure:
To a solution of 6-methyl-2(1H)-pyridinone (2 g, 18.33 mmol) and 4-fluorobenzaldehyde (2 ml, 18.64 mmol) in DMF (60 mL), was added K2CO3 (3.80 g, 27.5 mmol). The mixture was heated at 130° C. overnight. After cooling, the reaction mixture was diluted in water, extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4, concentrated to afford the title compound (3.24 g, 15.19 mmol, 83% yield) as a brown oil. LCMS: rt=2.77 min, [M+H+]=214
Reaction SMILES: [C:1]([C:5]1[C:9]([Cl:10])=[C:8]([C:11]([O:13]CC)=[O:12])[N:7]([CH3:16])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([C:5]1[C:9]([Cl:10])=[C:8]([C:11]([OH:13])=[O:12])[N:7]([CH3:16])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1c(Cl)c(C(C)(C)C)nn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 12-L, four neck round bottom flask equipped with overhead air stirrer, positive pressure nitrogen inlet, thermocouple, and addition funnel was charged with ethyl 3-tert-butyl-4-chloro-1-methyl-1H-pyrazole-5-carboxylate (282 g, 1.15 mol) and EtOH (4.3 L). 3M NaOH (960 mL, 2.87 mol) was added in one portion and the resulting slurry began to clarify immediately. The resulting mixture was stirred at room temperature for 2 h and yielded a turbid solution. The turbid solution was evaporated and the resulting aqueous slurry was diluted with H2O (2 L). The basic solution was acidified to pH˜2 using concentrated HCl. The aqueous layer was extracted with dichloromethane (2×800 mL), dried over MgSO4, filtered, and evaporated to yield 3-tert-butyl-4-chloro-1-methyl-1H-pyrazole-5-carboxylic acid as an off-white solid. 1H NMR (CHLOROFORM-d) δ: 4.11 (s, 3H), 1.41 (s, 9H)
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:11]=[C:10]([NH2:12])[CH:9]=[CH:8][N:7]=1.[CH3:13][C:14](O)=[O:15]>C(OC(=O)C)(=O)C>[C:14]([O:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:11]=[C:10]([NH2:12])[CH:9]=[CH:8][N:7]=1)(=[O:15])[CH3:13]
Reactant: Nc1ccnc(CSCCO)n1
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCCSCc1nccc(N)n1
Reaction time: 16 h

Procedure:
A mixture of 2-(2-hydroxyethylthiomethyl)-4-aminopyrimidine (1.5 g.) in HOAc (5 ml.) and acetic anhydride (5 ml.) was stirred at 25° for 16 hours. The solvent was evaporated in vacuo to give 2-(2-acetoxyethylthiomethyl)-4-aminopyrimidine as a gum which was used without further purification.