Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Se:8][C:9]1[C:17]2[O:18][CH2:19][O:20][C:16]=2[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[NH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>ClCCl>[CH2:1]([Se:8][C:9]1[C:17]2[O:18][CH2:19][O:20][C:16]=2[CH:15]=[CH:14][C:10]=1[C:11]([NH:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccc2c(c1[Se]Cc1ccccc1)OCO2
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)c1ccc2c(c1[Se]Cc1ccccc1)OCO2

Procedure:
To a solution of 1.6 g (0.0048 mol) 2-benzylseleno-3,4-methylenedioxybenzoic acid and 0.48 g triethylamine in 50 ml dichloromethane at 0° C. is added in one portion 1.22 g (0.0048 mol) solid bis[2-oxo-3-oxazolidinyl]phosphoryl chloride. After stirring for 30 min 0.44 g (0.44 ml) aniline in 5 ml dichloromethane are added at 0° C. dropwise with stirring followed after 1 hour by a solution of 0.48 g (0.66 ml) triethylamine in 10 ml dichloromethane. After 90 minutes at room temperature the reaction mixture is extracted successively with 50 ml 1N HCl and 50 ml water. The organic phase is dried over sodium sulfate and the solvent removed in vacuum. The crude product is purified by recrystallization from 2-propanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[CH2:5][N:6]=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)(=O)C.[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[CH2:5][NH2:6]
Reactant: COc1cc(Cl)cc(CN=[N+]=[N-])c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(Cl)cc(CN)c1
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
A solution of 3-chloro-5-methoxybenzylazide (5 mmol, 0.988 g) in THF (20 ml) was cooled to −78° C. and LiAlH4 (1 M, 7.5 mmol, 7.5 ml) was added dropwise with stirring. After 30 min the reaction was allowed to reach 0° C. and the mixture was stirred for another 1 h. To the resulting sharp yellow solution was added ethyl acetate (0.3 ml), followed by water (0.3 ml), NaOH (15% w/w in water) and water (0.9 ml). The resulting mixture was filtered and the solids washed with acetonitrile (15 ml). The solvents were evaporated off to provide the title compound (0.792 g, 92%) as a clear, colorless liquid. The product was used in the next step without further purification. An analytical pure sample was obtained by means of flash chromatography (silica, DCM/MeOH/NH3 (30%) 97/3/0.3 v/v/v). 1H NMR (CDCl3, 500 MHz) δ 1.46 (br, 2H), 3.77 (s, 3H), 3.79 (s, 2H), 6.74 (s, 1H), 6.75 (S, 1H) and 6.87 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)OC1>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:29][N:28]1[C:24]([C:2]2[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=2)=[CH:25][CH:26]=[N:27]1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Reactant: COC(=O)c1cc(Br)cs1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)cs1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-bromo-2-thiophenecarboxylate (1 g, 4.52 mmol) in dioxane/H2O (5:1, 16 mL) was added K2CO3 (2.7 g, 19 mmol), bis(tri-t-butylphosphine)palladium(0) (116 mg, 0.226 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (1.2 g, 5.88 mmol). The reaction mixture was heated to 80° C. in a sealed tube. After 1 h, the reaction was partitioned between H2O-DCM and the aqueous phase was extracted several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and used directly: LCMS (ES) m/z 223 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:41]=[C:40]([CH:42]2[CH2:47][CH2:46][N:45]([CH2:48][CH:49]([CH3:51])[CH3:50])[CH2:44][CH2:43]2)[CH:39]=[CH:38][C:37]=1[NH2:52].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:52][C:37]3[CH:38]=[CH:39][C:40]([CH:42]4[CH2:43][CH2:44][N:45]([CH2:48][CH:49]([CH3:51])[CH3:50])[CH2:46][CH2:47]4)=[CH:41][C:36]=3[O:35][CH3:34])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: COc1cc(C2CCN(CC(C)C)CC2)ccc1N
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(C2CCN(CC(C)C)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 120 °C
Yield: 55.3 %

Procedure:
3-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (100 mg, 0.22 mmol), 2-(methyloxy)-4-[1-(2-methylpropyl)-4-piperidinyl]aniline (Example 160, step C) (51 mg, 0.19 mmol), and p-toluenesulfonic acid (98 mg, 0.52 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 120° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 3 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (72 mg, 0.105 mmol, 54%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 9.41 (d, J=6.23 Hz, 1H), 8.52 (s, 1H), 8.33 (s, 1H), 8.24 (d, J=5.13 Hz, 1H), 8.04 (d, J=7.87 Hz, 1H), 7.80 (d, J=7.69 Hz, 1H), 7.72 (d, J=8.97 Hz, 1H), 7.57-7.65 (m, 2H), 7.43-7.49 (m, 1H), 7.35-7.43 (m, 1H), 7.16-7.22 (m, 2H), 6.99 (t, J=6.87 Hz, 1H), 6.95 (d, J=1.28 Hz, 1H), 6.78 (dd, J=8.24, 1.28 Hz, 1H), 6.48-6.54 (m, 1H), 3.82 (s, 3H), 2.90 (d, J=10.62 Hz, 2H), 2.40-2.46 (m, 1H), 1.97-2.05 (m, 2H), 1.91 (t, J=10.62 Hz, 2H), 1.65-1.76 (m, 5H), 0.84 (d, J=6.59 Hz, 6H). MS (ESI): 688 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]2[O:19][CH2:18]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([NH:27][CH:28]([CH3:44])[CH2:29][O:30][C:31]1[CH:32]=[CH:33][C:34]2[O:39][C:38]([CH3:41])([CH3:40])[NH:37][C:36](=[O:42])[C:35]=2[CH:43]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)(C)C>[CH3:41][C:38]1([CH3:40])[NH:37][C:36](=[O:42])[C:35]2[CH:43]=[C:31]([O:30][CH2:29][CH:28]([N:27]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:18][CH:17]([OH:19])[CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:14][CH:13]=3)[CH3:44])[CH:32]=[CH:33][C:34]=2[O:39]1
Reactant: CC(COc1ccc2c(c1)C(=O)NC(C)(C)O2)NCc1ccccc1
Reactant: c1ccc(COc2ccc(OCC3CO3)cc2)cc1
Solvent: CC(C)O
Product: CC(COc1ccc2c(c1)C(=O)NC(C)(C)O2)N(Cc1ccccc1)CC(O)COc1ccc(OCc2ccccc2)cc1

Procedure:
A solution of 15.4 g of benzyl [4-(2,3-epoxypropoxy)-phenyl]ether and 17.0 g of 6-(2-benzylaminopropoxy)-2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-one in 100 ml of isopropanol is refluxed for 24 hours, filtered and concentrated by evaporation. Trituration of the residue with approximately 200 ml of ether results in crystallisation of 1-[N-[2-(2,3-dihydro-2,2-dimethyl-4-oxo-4H-1,3-benzoxazin-6-yloxy)-1-methylethyl]benzylamino]-3-(4-benzyloxyphenoxy)propan-2-ol having a melting point of 149°-160° (in which the enantiomer pair A is present in greater amount).
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[OH:18])[N:14]=[CH:13][CH:12]=[C:11]2[O:19][C:20]1[C:21]([CH3:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2.Br[CH2:32][C:33]([NH2:35])=[O:34].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:32][C:33]([NH2:35])=[O:34])[N:14]=[CH:13][CH:12]=[C:11]2[O:19][C:20]1[C:21]([CH3:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2
Reactant: NC(=O)CBr
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCC(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
N,N-Dimethylformamide (1.5 ml) was added to 6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (50 mg), bromoacetamide (62 mg), and potassium carbonate (62 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (49 mg, yield 83%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].Cl[C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[N:13]=1>>[CH3:18][C:16]1[CH:17]=[C:12]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:13]=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[N:15]=1
Reactant: Oc1ccccc1
Reactant: Cc1ccc(-c2nc(C)cc(Cl)n2)cc1
Agent: C[O-]
Agent: [Na+]
Product: Cc1ccc(-c2nc(C)cc(Oc3ccccc3)n2)cc1
Temperature: 160 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
A mixture of 250 g of phenol and 29.7 g of sodium methylate is heated to an interval temperature of 160° C. while simultaneously distilling off methanol. The melt obtained is cooled to 120° C., then 109 g of 4-chloro-6-methyl-2-p-tolylpyrimidine are added and the mixture is stirred for 3 hours at 120° C. After cooling, excess phenol is removed with steam, and the residue is filtered with suction, washed with water and dried. Recrystallisation from methanol yields 119.4 g (86.5% of theory) of 4-methyl-6-phenoxy-2-p-tolylpyrimidine with a melting point of 90°-91° C.
Reaction SMILES: [F:1][C:2](=[CH2:6])[C:3](Cl)=[O:4].[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([Cl:17])[C:15]=1[OH:16])[C:11]#[N:12].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2](=[CH2:6])[C:3]([O:16][C:15]1[C:14]([Cl:17])=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[Cl:7])=[O:4]
Reactant: C=C(F)C(=O)Cl
Reactant: N#Cc1cc(Cl)c(O)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(F)C(=O)Oc1c(Cl)cc(C#N)cc1Cl
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
10 g (0.092 mol) of α-fluoroacryloyl chloride (obtained in accordance with example 1c) were added dropwise, at a temperature of 5° C., with stirring and in the course of 20 minutes, to a solution of 16.7 g (0.089 mol) of 3,5-dichloro-4-hydroxybenzonitrile and 9 g (0.089 mol) of triethylamine in 200 ml of anhydrous methylene dichloride, and the reaction mixture was then stirred for a further 30 minutes at the same temperature. The solid formed was filtered off and washed with 20 ml of anhydrous methylene dichloride. After 0.005 g of hydroquinone monomethyl ether had been added, the volatile constituents in the mixture of filtrate and wash solution were removed by distillation, and the residue was recrystallized from boiling n-heptane. 18.7 g (81% of theory) of 2,6-dichloro-4-cyanophenyl α-fluoroacrylate were obtained, melting point 95° to 99° C.
Reaction SMILES: C1COCC1.II.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[S:25])[CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]2)=[CH:11][CH:10]=1>O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]=[C:16]2[CH2:17][CH2:18][CH:19]3[CH:24]([CH:23]=[CH:22][CH2:21][CH2:20]3)[S:25]2)=[CH:13][CH:14]=1
Reactant: S=C(CCC1C=CCCC1)Nc1ccc(Cl)cc1
Agent: II
Solvent: C1CCOC1
Solvent: O
Product: Clc1ccc(N=C2CCC3CCC=CC3S2)cc1
Temperature: 25 °C

Procedure:
10 ml of THF solution including 2.4 g of iodine was added to 40 ml of THF solution including 2.2 g of N-(4-chlorophenyl)-3-(2-cyclohexene-1-yl) thiopropionamide at 0° C. The temperature was raised to room temperature and the resulting solution was stirred for one night. Then the temperature was cooled to 0° C., and 5 ml of THF solution including 4.1 g of 1,4 diazabicyclo[5,4,0]undec-7-ene(DBU) was dropped into the resulting solution. The solution was stirred at room temperature for one night, and added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.84 of the title compound.
Reaction SMILES: N1C=NC(CC(OCC)=O)=N1.[C:12]1([C:18]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:19]2[CH:23]=[N:22][C:21]([C:24]([O:26]C)=[O:25])=[N:20]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:34]1([C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:19]2[CH:23]=[N:22][C:21]([C:24]([OH:26])=[O:25])=[N:20]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CCOC(=O)Cc1nc[nH]n1
Product: O=C(O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
By a method similar to that in Reference Example 15 and using, instead of ethyl 1H-1,2,4-triazol-3-ylacetate, methyl 1-(triphenylmethyl)-1H-1,2,4-triazole-3-carboxylate obtained in Reference Example 34, the title compound was obtained as a white powder (2.82 g, 98%).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)=[CH2:5].[F-].[Cs+].[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:34])[CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][C:28]2[O:31][CH2:32][O:33][C:27]=2[CH:26]=1>CS(C)=O>[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:34])[CH2:23][CH:24]([C:25]1[CH:30]=[CH:29][C:28]2[O:31][CH2:32][O:33][C:27]=2[CH:26]=1)[CH2:3][C:4]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)=[O:5]
Reactant: C=C(O[Si](C)(C)C)c1ccsc1
Reactant: O=C(C=Cc1ccc2c(c1)OCO2)c1ccccc1O
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(CC(CC(=O)c1ccccc1O)c1ccc2c(c1)OCO2)c1ccsc1
Temperature: 70 °C

Procedure:
1-Trimethylsilyloxy-1-(thiophen-3-yl)ethylene (7.0 mmol; prepared according to J. Chem. Soc.,Perkin Trans. I 1989, 1585) and CsF (0.27 g, 1.76 mmol) were added to a suspension 1-(2-hydroxyphenyl)-3-(3,4-methylenedioxyphenyl)-2-propen-1-one on Wang resin (2.0 g, 1.76 mmol) in dimethyl sulfoxide (30 mL). The reaction mixture was heated to 70° C. for 3 h and the reaction was quenched with 10% AcOH/CH2Cl2. The resin was filtered, washed with DMF (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight to give 1-(2-hydroxyphenyl)-3-(3,4-methylenedioxyphenyl)-5-(thiophen-3-yl)-1,5-pentanedione on Wang resin.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.Cl.[NH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].[OH-].[K+]>C(O)C>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[N:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CN(C)CCCOc1ccccc1C=O
Reactant: CCOC(=O)CN
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CN=Cc1ccccc1OCCCN(C)C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
A stirred solution of 15 g of 2-(3-dimethylaminopropoxy)benzaldehyde and 10.2 g of glycine, ethyl ester, hydrochloride in 300 ml of ethanol is treated with 4.8 g of 85% potassium hydroxide and stirring continued for 3 hours at room temperature. Potassium chloride is filtered off, washed with ethanol, and the solvent is removed on a rotary evaporator (water bath temperature, 30°-35° C.). The residue is dissolved in ether, filtered, and the evaporation repeated to give 20.9 g of an oil. The material is stored in the cold.
Reaction SMILES: [CH2:1]([N:3]1[N:7]=[N:6][C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[S:17][C:13]=3[C:12](=[O:25])[N:11]([CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)[C:10]2=[O:39])=[N:4]1)[CH3:2].[ClH:40]>O1CCOCC1>[ClH:40].[CH2:1]([N:3]1[N:7]=[N:6][C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[S:17][C:13]=3[C:12](=[O:25])[N:11]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:10]2=[O:39])=[N:4]1)[CH3:2]
Reactant: CCn1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4F)cc32)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4F)cc32)n1

Procedure:
Tert-butyl 4-{1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-(2-fluorophenyl)-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (364 mg, compound B59) and a solution of hydrogen chloride in 1,4-dioxane (1.6 ml, 4.0 M) in 1,4 dioxane (10 ml) are reacted according to the procedure described in example B78 to afford the title compound.
Reaction SMILES: [C:1]([NH:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:21](#[N:25])[CH2:22][C:23]#[N:24]>C1(C)C=CC=CC=1>[C:23]([CH:22]([C:21]#[N:25])[C@@H:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:2][C:1]([NH:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=[O:10])#[N:24]
Reactant: N#CCC#N
Reactant: O=C(/C=C/c1ccccc1)NC(=O)c1ccccc1F
Solvent: Cc1ccccc1
Product: N#CC(C#N)[C@H](CC(=O)NC(=O)c1ccccc1F)c1ccccc1

Procedure:
(E)-N-Cinnamoyl-2-fluorobenzamide (26.9 mg, 0.1 mmol), malononitrile (13.2 mg, 0.2 mmol) and the compound (10 mol %) shown in the following Table 2 as an asymmetric catalyst were stirred in toluene (1.0 mL) at room temperature for 27 hr. The reaction mixture was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to give the title compound as a white solid.
Reaction SMILES: C(OC(=O)[N:6]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([Cl:30])[CH:24]=3)[N:15]=2)[CH:9]=1)C=C.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:31]([NH:6][CH2:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([Cl:30])[CH:24]=3)[N:15]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: C=CCOC(=O)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NCc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
tert-Butyl-(3-{2-[2-(3-chloro-4-hydroxy-phenyl)-ethylamino]pyrimidin-4-yl}-benzyl)-carbamic acid allyl ester (Intermediate 120, 168 mg) was dissolved in methylene chloride (5 mL), followed by addition of diisopropylethylamine (0.11 mL), 1,3-dimthylbarbituric acid (78 mg) then Pd(PPh3)4 (50 mg). The mixture was stirred at room temperature overnight. The mixture was washed with saturated NaHCO3, brine, dried over Na2SO4, filtered and chromatographed on silica gel with methyl chloride:methanol (95:5) to afford 120 mg of product in 86% yield. LC-MS showed the product had the expected M+H+ of 411. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.31 ppm) δ 8.3 (d, 1H) 8.1 (s, 1H) 8.0 (d, 1H) 7.5 (m, 2H) 7.2 (d, 1H) 7.1 (d, 1H) 7.0 (m, 1H) 6.8 (d, 1H) 3.9 (s, 2H) 3.7 (m, 2H) 2.8 (m, 2H) 1.3 (s, 9H).
Reaction SMILES: [CH:1]1([CH:7]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:10][OH:11].N1C=CC=CC=1>C(O)C>[CH:1]1([CH:7]=[N:10][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=CC1CCCCC1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=CC1CCCCC1

Procedure:
A solution of cyclohexanecarboxaldehyde (11.2 g, 100 mmol), hydroxylamine hydrochloride (7.2 g, 104 mmol) and pyridine (8.5 mL) in ethanol (150 mL) was stirred for 18 hours, then concentrated in vacuo. The residue was taken up in 10% aqueous citric acid and extracted with ethyl acetate (3×150 mL). The organics were combined, dried over MgSO4 and concentrated to afford cyclohexanecarboxaldehyde oxime which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[CH2:8][CH2:7]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>C(N(CC)CC)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:32]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=2)=[O:33])[CH2:10][CH2:11]1
Reactant: COc1cccc(N=C=O)c1
Reactant: Nc1ccccc1N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(NC(=O)Nc2ccccc2N2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)c1
Yield: 14.5 %

Procedure:
2-[4-(3,4-dichlorobenzyl)-piperazin-1-yl]-phenylamine (45 mg) was dissolved in a solution of triethylamine in dichloromethane (3 mL, 0.29 M in triethylamine). This solution was added to a test tube containing 3-methoxyphenyl isocyanate (45 mg). After standing at ambient temperature for several days, the reaction was directly passed through a small pad of silica and eluted with 10% ethyl acetate in hexanes, then with 50% ethyl acetate in hexanes. Solvent removal left 26.2 mg of the product, which was subsequently repurified by silica gel chromatography to afford 9.4 mg product: MS m/z 484 (M)+.
Reaction SMILES: C(N)C1C=CC=CC=1.C(O[C:17]([N:19]([CH2:21][C:22]([NH:24][CH2:25][C:26]([NH:28][C@H:29]([C:33]([NH:35][C@H:36]([P:38](=[O:41])([OH:40])[OH:39])[CH3:37])=[O:34])[CH2:30][CH2:31][CH3:32])=[O:27])=[O:23])C)=O)C1C=CC=CC=1>>[NH:19]([CH2:21][C:22]([NH:24][CH2:25][C:26]([NH:28][C@H:29]([C:33]([NH:35][C@H:36]([P:38](=[O:39])([OH:41])[OH:40])[CH3:37])=[O:34])[CH2:30][CH2:31][CH3:32])=[O:27])=[O:23])[CH3:17]
Reactant: CCC[C@H](NC(=O)CNC(=O)CN(C)C(=O)OCc1ccccc1)C(=O)N[C@@H](C)P(=O)(O)O
Solvent: NCc1ccccc1
Product: CCC[C@H](NC(=O)CNC(=O)CNC)C(=O)N[C@@H](C)P(=O)(O)O

Procedure:
In a manner analogous to that described in Example 5(A)(iii), from the monobenzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-sarcosyl-glycyl-L-norvalyl)amino]-ethylphosphonic acid there was obtained (1R)-1-(N-sarcosyl-glycyl-L-norvalylamino)-ethylphosphonic acid of melting point 255°-257° C. (decomposition); [α]D20 =-64.2°; [α]36520 =-235° (c=0.49% in water).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:28])[C:13]1[CH:18]=[C:17]([O:19]CC2C=CC=CC=2)[CH:16]=[CH:15][C:14]=1[OH:27])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO>[OH:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:28])[C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=1[OH:27])[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(N[C@H](CO)Cc1ccccc1)c1cc(OCc2ccccc2)ccc1O
Solvent: CO
Product: O=C(N[C@H](CO)Cc1ccccc1)c1cc(O)ccc1O
Reaction time: 2 h
Yield: 85 %

Procedure:
In a flask equipped with a magnetic stirring bar and a rubber septum is dissolved the N-{(S)-1-hydroxy-3-phenyl-2-propyl}-5-benzyloxy-2-hydroxybenzamide in methanol. Nitrogen is bubbled through the solution and 10% Pd on charcoal is added. After flushing with nitrogen, the suspension is placed under hydrogen atmosphere and stirred for 2 hours. The suspension is flushed with nitrogen and filtered and rinsed over Celite. The filtrate is concentrated under vacuum. In this fashion is obtained N-{(S)-1-hydroxy-3-phenyl-2-propyl }-2,5-dihydroxybenzamide (85%).