Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([N+:16]([O-])=O)[CH:10]=2)=[N:7][CH:8]=1>CO.CC(=O)OCC.[Pd]>[CH3:1][O:2][C:3]1[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[N:5][C:6]([C:9]2[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=2)=[N:7][CH:8]=1
Reactant: COc1cnc(-c2ccc(N)c([N+](=O)[O-])c2)nc1N1CCOCC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cnc(-c2ccc(N)c(N)c2)nc1N1CCOCC1
Reaction time: 5 h

Procedure:
A mixture of 4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-2-nitro-phenylamine (0.69 g, 1.0 eq.) and Pd/C (Cat.) in MeOH/EA (10 ml/10 ml) was prepared. The mixture was sharked and H2 gas was injected to the mixture for 4-6 hrs at room temperature. The mixture was filtered with Celite 454 and dried in vacuo to give a black sold (0.65 g, 99.9%) as a product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([NH2:23])=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([N:33]=[C:34]=[S:35])(=O)C1C=CC=CC=1>CC(C)=O>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([NH:23][C:34]([NH2:33])=[S:35])=[CH:11][N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(N)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: COc1cc2c(NC(N)=S)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
(4-Amino-6,7-dimethoxy-isoquinolin-1-ylmethyl)carbamic acid tert-butyl ester (277 mg, 0.831 mmol) was dissolved in dry acetone, and benzoylisothiocyanate (149 mg, 0.914 mmol) was added dropwise. The reaction was stirred at room temperature for 2 h, and was concentrated to yield a yellow solid. This solid was triturated with 50% aqueous EtOH, filtered, and suspended in 10% NaOH (5.0 mL). The reaction mixture was placed in an oil bath that was pre-heated to 98° C. for 1 h, (the solid was dissolved in 10 min). The mixture was cooled and filtered. The yellow solid was washed with water, and dried in vacuo to give (6,7-dimethoxy-4-thioureido-isoquinolin-1-ylmethyl)carbamic acid tert-butyl ester (165 mg; 51%). 1H-NMR (CDCl3): δ, 8.31 (s, 1H), 7.66 (s, 1H), 7.38 (s, 1H), 4.81 (s, 2H), 4.05 (s, 3H), 4.00 (s, 3H), 2.81 (s, 2H), 1.46 (s, 9H); MS: calculated for C18H24N4O4S+H 393.0; found: 392.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:6]([CH:7]=O)=[C:5]([OH:13])[CH:4]=1.[C:14]([NH:18][OH:19])([CH3:17])([CH3:16])[CH3:15]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:6]([CH:7]=[N+:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[O-:19])=[C:5]([OH:13])[CH:4]=1
Reactant: CC(C)(C)NO
Reactant: COc1cc(O)c(C=O)c(OC)c1
Product: COc1cc(O)c(C=[N+]([O-])C(C)(C)C)c(OC)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 4,6-dimethoxy-2-hydroxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 60.7% yield as a yellow crystalline solid, m.p. 97.3° C. (Rf=0.38 on a silica gel plate using 7:3 hexanes/EtOAc as an eluant).
Reaction SMILES: [NH2:1][C:2]1[C:17]([Br:18])=[CH:16][C:5]2[C:6]([C:12](=[O:15])[NH:13][CH3:14])=[C:7](B(O)O)[O:8][C:4]=2[CH:3]=1.Br[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[C:17]([Br:18])=[CH:16][C:5]2[C:6]([C:12]([NH:13][CH3:14])=[O:15])=[C:7]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)[O:8][C:4]=2[CH:3]=1
Reactant: CNC(=O)c1c(B(O)O)oc2cc(N)c(Br)cc12
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(C#N)cc2)oc2cc(N)c(Br)cc12
Yield: 25.4 %

Procedure:
A solution of (6-amino-5-bromo-3-(methylcarbamoyl)benzofuran-2-yl)boronic acid (1 g, 3.19 mmol), 4-bromobenzonitrile (1.17 g, 6.39 mmol), K3PO4.3H2O (1.7 g, 6.39 mmol) and Pd(dppf)Cl2 (40 mg) in dioxane/H2O (10 mL/2 mL) was stirred at 80° C. for 4 h. The mixture was filtered to remove the solid and then the mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried with Na2SO4 and concentrated. The residue was purified by column chromatography (PE:EA=5:1) to give 6-amino-5-bromo-2-(4-cyanophenyl)-N-methylbenzofuran-3-carboxamide (300 mg, yield: 26%). 1H-NMR (CDCl3, 400 MHz) δ 8.09 (d, J=8.0 Hz, 2H), 7.72 (s, 1H), 7.65 (d, J=8.4 Hz, 2H), 6.84 (s, 1H), 5.84 (s, 1H), 4.28 (s, 2H), 3.00 (d, J=4.4 Hz, 3H). MS (M+H)+: 370/372.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:10]=[O:11].[CH3:26][Mg]Cl.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:10]([OH:11])[CH3:26])[CH:12]=[CH:13][C:14]=1[O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:18])[CH3:19]
Reactant: COCCCOc1cc(C=O)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCCOc1cc(C(C)O)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 0 °C
Yield: 99.9 %

Procedure:
3-(3-methoxypropoxy)-4-[(triisopropylsilyl)oxy]benzaldehyde (12 g, 32.7 mmol) was dissolved in tetrahydrofuran (300 mL) and the solution was cooled to 0° C. Methyl magnesium chloride (109 mL, 327 mmol) was added dropwise. The temperature was then allowed to rise to room temperature and the mixture was stirred an hour. At 0° C., saturated aqueous ammonium chloride was added to hydrolyze the reaction mixture. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 12.5 g (quantitative yield) of the desired product as a yellow oil.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[CH3:12][NH2:13]>C(O)C>[CH3:12][NH:13][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: CN
Reactant: COc1ccncc1[N+](=O)[O-]
Solvent: CCO
Product: CNc1ccncc1[N+](=O)[O-]

Procedure:
2.36 g 4-methoxy-3-nitro-pyridine and 2.33 ml methylamine (40% in water) are refluxed in 25 ml of ethanol for 3 h. Then the reaction mixture is evaporated to dryness. 2.3 g product are obtained in the form of a solid.
Reaction SMILES: Br[C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=2[CH:5]=[N:6][CH:7]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:3]3[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=3[CH:5]=[N:6][CH:7]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCC(=O)NC1CCc2c(Br)cncc21
Product: CCC(=O)NC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Yield: 87 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (rac)-N-(4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)propionamide (intermediate A-4) was reacted with 4-(trifluoromethyl)phenylboronic acid to give the title compound as grey solid in 87% yield. MS: 335.1 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[CH2:22][CH2:21][C:20]3[N:19]4[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]4)=[CH:13][C:12]=3[C:11]2=[O:23])[N:5]=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:50]=[C:44]3[CH2:45][N:46]([CH3:49])[CH2:47][CH2:48][N:43]3[N:42]=2)[C:26]1=[O:51].CC([O-])=O.[Na+].C(#N)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH:8]([C:7]1[C:6]([N:10]2[CH2:22][CH2:21][C:20]3[N:19]4[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]4)=[CH:13][C:12]=3[C:11]2=[O:23])=[N:5][CH:4]=[CH:3][C:2]=1[C:29]1[CH:28]=[C:27]([NH:40][C:41]2[CH:50]=[C:44]3[CH2:45][N:46]([CH3:49])[CH2:47][CH2:48][N:43]3[N:42]=2)[C:26](=[O:51])[N:25]([CH3:24])[CH:30]=1)=[O:9]
Reactant: CN1CCn2nc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)cc2C1
Reactant: O=Cc1c(Cl)ccnc1N1CCc2c(cc3n2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CN1CCn2nc(Nc3cc(-c4ccnc(N5CCc6c(cc7n6CCCC7)C5=O)c4C=O)cn(C)c3=O)cc2C1
Temperature: 100 °C
Yield: 60.3 %

Procedure:
A round-bottomed flask was charged with 4-chloro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-2(1H)-yl)nicotinaldehyde 147a (100 mg, 0.30 mmol), 1-methyl-3-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 135a (116 mg, 0.30 mmol), PdCl2(dppf) (25 mg, 0.03 mmol), K3PO4.3H2O (160 mg, 0.60 mmol), NaOAc (59 mg, 0.60 mmol), acetonitrile (10 mL), and H2O (5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified on flash column chromatography eluting with 1:3 petroleum/ethyl acetate to afford 147b as a yellow solid (100 mg, 60%). LCMS: [M+H]+ 553
Reaction SMILES: CC(C)([O-])C.[K+].Cl[CH2:8][C:9]([O:11][C@@H:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@@H:13]1[N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:10].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]=[O:35])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[CH2:22]([N:21]([CH2:24][CH3:25])[C@H:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][C@H:12]1[O:11][C:9]([C@H:8]1[C@H:34]([C:31]2[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)[O:35]1)=[O:10])[CH3:23]
Reactant: COc1ccc(C=O)cc1
Reactant: CCN(CC)[C@H]1c2ccccc2C[C@H]1OC(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCN(CC)[C@H]1c2ccccc2C[C@H]1OC(=O)[C@@H]1O[C@H]1c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
In 5-10 min., 0.95 grams (8.5 mmol) of potassium tert-butoxide was added, in small portions, to a solution of 2.05 grams (7.3 mmol) of (1S,2R)-1-(diethylamino)-2-indanyl chloroacetate and 1.0 gram (7.3 mmol) of p-anisic aldehyde in 40 ml of toluene at 20° C. The temperature increased to 25° C. After 30 minutes' stirring the reaction was quenched using a diluted NaHCO3 solution in water. The organic layer was separated and washed with water, dried using Na2SO4 and evaporated. Yield: 2.75 grams (90%) of a yellow oil. This oil is a mixture of (2R,3S)-3-(4-methoxyphenyl)oxirane-2-carboxylic (1S,2R)-1-(diethylamino)-2-indanyl ester (diastereomeric ratio 89:11) and (2R,3S)-3-(4-methoxyphenyl)oxirane-2-carboxylic tert-butyl ester (enantiomeric excess 80%). 1H NMR (200 MHz, CDCl3): 1.02 (2*t, 6H), 2.48-2.78 (m,4H), 2.95-3.27 (m, 2H), 3.44 (d, J=2.0 Hz) and 3.48 (d, J=2.0 Hz, together 1H for major and minor diastereomers, resp.), 3.80 (s, 3H), 4.02 (d, J=2.0 Hz) and 4.07 (d, J=2.0 Hz, together 1H for minor and major diastereomers, resp.), 4.60 (d, 1H), 5.62-5.75 (m, 1H), 6.85 (d, 2H) and 7.15-7.38 (d+m, 6H). 13C NMR (50.31 MHz, CDCl3): 14.71 (q), 37.58 (t), 45.35 (t), 55.30 (q), 56.85 (d), 57.97 (d), 66.51 (d), 77.02 (d), 113.49 (d), 114.10 (d), 124.93 (d), 125.32 (d), 126.81 (d), 127.12 (d), 127.27 (d), 127.74 (s), 139.16 (s), 160.18 (s) and 168.16 (s). (2R,3S)-3-(4-Methoxyphenyl)oxirane-2-carboxylic tert-butyl ester: 1H NMR (200 MHz, CDCl3): 1.43 (s, 9H), 3.33 (d, 1H), 3.73 (s, 3H), 3.89 (d, 3H), 6.81 (d, 2H) and 7.14 (d, 2H).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:9]=[C:10]([S:15]([N:18]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]2)(=[O:17])=[O:16])[CH:11]=[CH:12][C:13]=1[F:14].O.CC1C=CC(S(O)(=O)=O)=CC=1.ClCCl>O>[Br:7][C:8]1[CH:9]=[C:10]([S:15]([N:18]2[CH2:19][CH2:20][CH:21]([O:24][CH:6]3[CH2:5][CH2:4][CH2:3][CH2:2][O:1]3)[CH2:22][CH2:23]2)(=[O:17])=[O:16])[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: O=S(=O)(c1ccc(F)c(Br)c1)N1CCC(O)CC1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1ccc(F)c(Br)c1)N1CCC(OC2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.3 %

Procedure:
3,4-Dihydro-2H-pyran (0.28 mL, 3.1 mmol) was added dropwise to a 0° C. solution of Example 354a (0.51 g, 1.5 mmol), 4-methylbenzenesulfonic acid hydrate (0.59 g, 3.1 mmol), and dichloromethane (28 mL). The reaction mixture was stirred at ambient temperature for 5 hours. Water was added and the mixture was extracted with dichloromethane. The organic layer was washed with water, saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, dichloromethane/gradient with methanol) to afford the title compound (420 mg, 65.9% yield).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)=[CH:16][C:14]=3[CH:15]=2)[CH2:4][CH2:3]1.[O:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[CH:18]=[CH:19][C:13]3[O:12][CH2:11][CH2:10][C:9]([CH2:8][N:5]4[CH2:4][CH2:3][CH:2]([NH:1][CH:30]5[CH2:31][CH2:32][O:27][CH2:28][CH2:29]5)[CH2:7][CH2:6]4)=[CH:15][C:14]=3[CH:16]=2)=[CH:21][CH:22]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(CN2CCC(N)CC2)CCO3)cc1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(CN2CCC(NC4CCOCC4)CC2)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.2 %

Procedure:
To 4-amino-1-(7-(4-methylphenyl)-2,3-dihydro-1-benzooxepin-4-yl)methylpiperidine (0.4 g) and tetrahydro-4H-pyran-4-one (0.12 g) dissolved in 1,2-dichloroethane (10 ml) was added under ice cooling sodium triacetoxyborohydride (0.34 g), and the resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was evaporated to remove the solvent, was neutralized with a 1 N aqueous solution of sodium hydroxide and was then extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, was then dried with anhydrous magnesium sulfate, and was evaporated under reduced pressure to remove the solvent. The residue was subjected to purification using a silica gel column (methanol/triethylamine/ethyl acetate) to obtain crude crystals. The crude crystals were recrystallized from ethyl acetate/hexane to obtain 1-(7-(4-methylphenyl)-2,3-dihydro-1-benzooxepin-4-yl)methyl-4-((tetrahydropyran-4-yl)amino)piperidine (compound 80) (0.17 g) as colorless crystals.
Reaction SMILES: [C@@H:1]1([N:14]2[C:23]3[N:22]=[CH:21][N:20]=[C:18]([OH:19])[C:17]=3[N:16]=[CH:15]2)[O:13][C@H:6]([CH2:7][O:8]P(O)(O)=O)[C@@H:4]([OH:5])[C@H:2]1[OH:3].C1N(CCS(O)(=O)=O)CCOC1.[OH-].[Na+]>Cl>[C@@H:1]1([N:14]2[C:23]3[N:22]=[CH:21][N:20]=[C:18]([OH:19])[C:17]=3[N:16]=[CH:15]2)[O:13][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: O=P(O)(O)OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Agent: Cl
Agent: O=S(=O)(O)CCN1CCOCC1
Agent: [Na+]
Product: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O

Procedure:
The phosphomonoesterase activity was measured under the following condition using 5′-inosinic acid as a substrate. The reaction was performed at 30° C. for 10 minutes in a reaction solution (1 ml) containing 10 μmol/ml of 5′-inosinic acid, 100 μmol/ml of MES/NaOH buffer (pH 6.0), and an enzyme. The reaction was stopped by adding 200 μl of 2 N hydrochloric acid. After that, precipitates were removed by centrifugation. Then, inosine produced by the hydrolytic reaction was quantitatively measured. An amount of enzyme to produce 1 μmol of inosine per 1 minute under this standard reaction condition was defined as 1 unit.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:27])=[C:7]([C:9]2[NH:10][C:11](=[O:26])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]#[C:21][CH:22]4[CH2:24][CH2:23]4)=[CH:16][C:15]=3[F:25])[N:13]=2)[CH:8]=1.[C:28](Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[Cl:27][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:7]=1[C:9]1[NH:10][C:11](=[O:26])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][CH:22]3[CH2:24][CH2:23]3)=[CH:16][C:15]=2[F:25])[N:13]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C#CC4CC4)cc3F)c(=O)[nH]2)c1
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C#CC4CC4)cc3F)c(=O)[nH]2)c1
Yield: 32.2 %

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chlorophenyl)-2-(4-(2-cyclopropylethynyl)-2-fluorophenyl)-2H-1,2,4-triazol-3(4H)-one (0.100 g, 0.266 mmol), pivaloyl chloride (0.040 g, 0.319 mmol), THF (10.0 mL) and TEA (2 mL) to afford 0.040 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 0.78 (m, 2H), 0.919 (m, 2H), 1.11 (br s, 9H), 1.56 (m, 1H), 4.28 (br d, 2H), 7.32-7.41 (m, 3H), 7.56 (br s, 3H), 8.16 (s, 1H), 12.46 (s, 1H); MS (m/z): 467.22 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.C(O[CH:12]=[C:13]([CH3:16])[CH:14]=O)C>C(O)(=O)C>[CH3:16][C:13]1[CH:12]=[N:1][C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=2[CH:14]=1
Reactant: NC1=CC(=O)CCC1
Reactant: CCOC=C(C)C=O
Solvent: CC(=O)O
Product: Cc1cnc2c(c1)C(=O)CCC2
Temperature: 0 °C

Procedure:
A mixture of 3-aminocyclohex-2-enone (24.1g, 0.22m) and 3-ethoxy-2-methylacrolein (27.7g, 0.24m) in glacial acetic acid (55 ml.) was heated at reflux for 24 hours, cooled to 0° C and filtered. The solid (5g.) was recrystallised from ethanol as colourless needles m.p. 253° and identified di(2-methylprop-2-enalyl)amine.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:17]1[NH:21][CH:20]=[C:19]([C:22]([O:24]CC)=[O:23])[CH:18]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(O)C>[CH2:3]([C:17]1[NH:21][CH:20]=[C:19]([C:22]([OH:24])=[O:23])[CH:18]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCc1cc(C(=O)OCC)c[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCCc1cc(C(=O)O)c[nH]1
Yield: 64.8 %

Procedure:
An aqueous solution of 1N sodium hydroxide (25 ml) was added to an ethanol solution (120 ml) of 3.53 g (11 mmol) of ethyl 5-tetradecylpyrrole-3-carboxylate, and the whole was heated under reflux for 16 hours. After removal of the ethanol, the residue was acidified with diluted hydrochloric acid and extracted with ethyl acetate. The extract was then washed with water and dried over anhydrous magnesium sulfate. The residue was purified by subjecting it to silica gel column chromatography (eluent: ethyl acetate/hexane=1/4) to obtain 2.19 g (68% yield) of 5-tetradecylpyrrole-3-carboxylic acid, m.p. 83°-85° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](I)[CH:7]=1)[CH3:2].[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)(O)[O-].[Na+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:7]=[C:8]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:14])[C:20]=2[Cl:21])[CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: CCOC(=O)Cc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)Cc1cccc(-c2cccc(Cl)c2Cl)c1

Procedure:
A mixture of 3-iodobenzeneacetic acid ethyl ester (0.87 g, 3 mmol, prepared by the method described in J. Chem. Soc. 1963, 5437), 2,3-dichlorophenylboronic acid (0.85 g, 4.5 mmol), bis(triphenylphosphine)palladium dichloride (0.10 g, 0.15 mmol) and 2 N aqueous sodium bicarbonate solution (3 mL) in p-dioxane (6 mL) was heated at 160° C. in a microwave reactor for 5 min. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluted with ethyl acetate in hexanes to provide the title product (0.48 g).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:13])[C:9]#[C:10][CH2:11][OH:12].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>O1CCOCC1>[OH:12][CH2:11][C:10]#[C:9][CH2:8][O:13][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: OCC#CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)OCC#CCO)cc1
Reaction time: 2 h
Yield: 26.9 %

Procedure:
At 10° C., a solution of triethylamine (17.5 ml, 128.0 mmol) in absolute dioxane (60 ml) is added dropwise to a solution of but-2-yne-1,4-diol (10 g, 116.1 mmol) and 4-toluenesulfonyl chloride (24.4 g, 128.0 mmol) in absolute dioxane (230 ml), and the mixture is stirred for 2 h. The mixture is then stirred at RT overnight. The reaction mixture is filtered off with suction through kieselguhr, and the filter cake is washed with ethyl acetate (20 ml). The organic phase is concentrated under reduced pressure. Further purification is carried out by chromatography [toluene/acetone (8.5:1.5)] on a silica gel column. This gives the title compound (7.5 g) as a light yellow oil. TLC, silica gel (glass plates), [toluene/acetone (8:2)], Rf=0.49.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[CH:9][C:10]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)=[CH:11][C:6]=2[C:5](=[O:23])[N:4]([CH2:24][CH2:25][CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[C:3]1=[O:34].[Li+].CC([N-]C(C)C)C.[F:43][C:44]([F:54])([F:53])[C:45]1[CH:52]=[CH:51][C:48]([CH:49]=[O:50])=[CH:47][CH:46]=1>C1COCC1>[OH:50][CH:49]([C:48]1[CH:47]=[CH:46][C:45]([C:44]([F:43])([F:53])[F:54])=[CH:52][CH:51]=1)[C:11]1[C:6]2[C:5](=[O:23])[N:4]([CH2:24][CH2:25][CH2:26][O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[C:3](=[O:34])[N:2]([CH3:1])[C:7]=2[N:8]=[CH:9][C:10]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(Oc3cccc(C(F)(F)F)c3)cnc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(C(F)(F)F)cc3)c(Oc3cccc(C(F)(F)F)c3)cnc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a solution of 1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-6-(3-(trifluoromethyl) phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (210 mg, 0.438 mmol) in THF (5 mL) at −78° C. was added LDA (1.8 M in THF, 1.2 mL, 2.16 mmol). The reaction was stirred at −78° C. for 30 min then 4-(trifluoromethyl)benzaldehyde (153 mg, 0.879 mmol) was added. The reaction was stirred for 1 h, quenched with aq. NaHCO3 (5 mL) then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep TLC eluted with PE/EA (4:1) to give 5-(hydroxy(4-(trifluoromethyl)phenyl)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-6-(3-(trifluoromethyl)phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (200 mg, 69.9% yield) as a clear oil. LCMS: [MH+-THP] 570 and TR=1.933 min.