Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH2:6][CH2:5]1.Cl[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>C(Cl)(Cl)Cl>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[NH:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH2:8][CH2:9]1
Reactant: COc1ccccc1N1CCN(CCN)CC1
Reactant: Clc1ccccn1
Solvent: ClC(Cl)Cl
Product: COc1ccccc1N1CCN(CCNc2ccccn2)CC1
Temperature: 25 °C

Procedure:
23.5 g of 1-(2-aminoethyl)-4-(2-methoxyphenyl)piperazine [Hexachemie-Reuil Malmaison-France] and 4.85 mL of 2-chloropyridine were stirred at 160° C. in a closed reaction vessel for 10.5 hours. The reaction mixture was cooled to room temperature, dissolved in 320 mL of chloroform and washed with 1N sodium hydroxide (3×320 mL), followed by water (2×400 mL). The organic layer was dried (sodium sulfate) and evaporated to dryness under reduced pressure. The crude product was purified by column flash chromatography eluting with an ethyl acetate-3N NH3 in methanol 100:2 mixture affording, after evaporation of the collected fractions, 5 g of the title compound as an oil. A sample was crystallized from ethyl acetate to give a solid melting at 89-94° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)[N:7]=[CH:6][N:5]=1)[CH3:2].[C:18]1([C@@H:24]2[CH2:26][C@H:25]2[N:27]=[C:28]=[O:29])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:17]=[CH:16][C:14]([NH:15][C:28]([NH:27][C@@H:25]3[CH2:26][C@H:24]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:29])=[CH:13][CH:12]=2)[N:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: O=C=N[C@@H]1C[C@H]1c1ccccc1
Reactant: CCNc1cc(Oc2ccc(N)cc2)ncn1
Solvent: C1CCOC1
Product: CCNc1cc(Oc2ccc(NC(=O)N[C@@H]3C[C@H]3c3ccccc3)cc2)ncn1
Reaction time: 8 h

Procedure:
To a solution of 4-(4-ethylaminopyrimidin-6-yl-oxy)-aniline (Stage 89.1; 271 mg, 1.177 mmol) In THF (5 ml) under N2-atmosphere, trans-2-phenyl-cyclopropyl-isocyanate (188 mg, 1.18 mmol; Aldrich) Is added. Then the solution is stirred for 8 h, whereas a precipitate is formed. Filtration and washing with THF and ether yields the title compound: m.p.: 205-206° C.; 1H-NMR (DMSO-d6): 8.50 (s, HN), 8.11 (s, 1H), 7.42 (d, 2H), 7.27 (m, 3H), 7.15 (m, 3H), 7.01 (d, 2H), 6.67 (s, HN), 5.67 (s, 1H), 3.25 (m, 2H), 2.74 (m, 1H), 1.98 (m, 1H), 1.17 (m, 2H), 1.09 (t, 3H); Anal.: CHN.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7](=O)[C:8]3[C:9](=[CH:11][S:12][CH:13]=3)[NH:10][C:4]=2[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:18]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7](=[S:18])[C:8]3[C:9](=[CH:11][S:12][CH:13]=3)[NH:10][C:4]=2[CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1Nc2ccc(Cl)cc2Nc2cscc21
Solvent: c1ccncc1
Product: S=C1Nc2ccc(Cl)cc2Nc2cscc21
Reaction time: 18 h

Procedure:
A mixture of 0.88 g. of 6-chloro-4,9-dihydro-10H-thieno[3,4-b] [1,5] benzodiazepin-10-one and 1.0 g. of phosphorus pentasulfide in 10 ml. of dry pyridine is stirred and heated under reflux for 4 hours. The reaction mixture is concentrated to dryness and the residue is stirred with 20 ml. of 1N sodium carbonate solution (pH 7-7.2) for 18 hours. The precipitate is collected, washed with water and recrystallized from methanol to give an organic solid, m.p. 235°-237°C. (dec.).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4](OC)=[N:5][S:6](=[O:8])[N:7]=1.[N:11]1([CH2:17][C:18]2[CH:19]=[N:20][N:21]([O:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH:22]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>CO>[CH3:1][NH:2][C:3]1[C:4]([NH:27][CH2:26][CH2:25][CH2:24][O:23][N:21]2[CH:22]=[C:18]([CH2:17][N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH:19]=[N:20]2)=[N:5][S:6](=[O:8])[N:7]=1
Reactant: NCCCOn1cc(CN2CCCCC2)cn1
Reactant: CNC1=NS(=O)N=C1OC
Solvent: CO
Product: CNC1=NS(=O)N=C1NCCCOn1cc(CN2CCCCC2)cn1
Reaction time: 12 h
Yield: 74.1 %

Procedure:
2.4 g of 4-methylamino-3-methoxy-1,2,5-thiadiazole 1-oxide and 3.5 g of 3-(4-piperidinomethylpyrazol-1-yloxy)propylamine are dissolved in 50 ml of methanol, and the solution is left to stand at room temperature for 12 hours. The solution is then evaporated down and the residue is chromatographed over neutral Al2O3 (activity level III), using methylene chloride/3% strength methanol as the mobile phase. 4 g of the title compound are obtained, the product being crystallized from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[Cl:22])[NH2:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]([NH:18][C:17]2[CH:19]=[CH:20][C:21]([Cl:22])=[C:15]([Cl:14])[CH:16]=2)=[O:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)NS(=O)(=O)c1ccc(Cl)cc1
Yield: 91.7 %

Procedure:
Following the procedure of Example 1, 5.04 g of 4-chlorobenzenesulfonyl isocyanate and 3.85 g of 3,4-dichloroaniline were allowed to react providing 8.06 g of the desired title product, m.p. 195°-196° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[CH2:29][C@:28]3([CH3:42])[C@@H:30]([CH3:41])[CH2:31][CH2:32][C@H:33]4[C:34]([CH3:40])([CH3:39])[C:35](=O)[CH2:36][CH2:37][C@@:27]34[O:26][C:11]=2[C:12]2[CH2:13][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:15](=[O:18])[C:16]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:62]=[N+:63]=[N-:64].C1C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[N:62]([C@@H:35]1[C:34]([CH3:39])([CH3:40])[C@H:33]2[C@@:27]3([O:26][C:11]4[C:12]5[CH2:13][N:14]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[C:15](=[O:18])[C:16]=5[CH:17]=[C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[C:10]=4[CH2:29][C@:28]3([CH3:42])[C@@H:30]([CH3:41])[CH2:31][CH2:32]2)[CH2:37][CH2:36]1)=[N+:63]=[N-:64]
Reactant: C[C@H]1CC[C@H]2C(C)(C)C(=O)CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Reactant: [N-]=[N+]=N
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: C[C@H]1CC[C@H]2C(C)(C)[C@@H](N=[N+]=[N-])CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Temperature: 25 °C
Yield: 65.8 %

Procedure:
To a solution of Compound (38a) (Step-3 in Example 42) (690 mg, 1.20 mmol) in 35 ml of dry benzene were added dropwise 480 mg (1.83 mmol) of triphenylphosphine and 1.0 ml (1.88 mmol) of 1.9M hydrazoic acid/benzene solution at room temperature with stirring, followed by the addition of 290 μl (1.84 mmol) of diethyl azodicarboxylate and stirring at 80° C. for 20 min. After cooling to room temperature, the solvent was evaporated under reduced pressure. The residue was purified by a column chromatography (Merck, Lobar column, size C; toluene:ethyl acetate=9:1) to give 474 mg (66%) of Compound (44).
Reaction SMILES: [CH2:1]([C@H:3]1[N:8](CC2C=CC=CC=2)[CH2:7][C@@H:6]([CH2:16][OH:17])[O:5][CH2:4]1)[CH3:2]>CO.[Pd]>[CH2:1]([C@H:3]1[NH:8][CH2:7][C@@H:6]([CH2:16][OH:17])[O:5][CH2:4]1)[CH3:2]
Reactant: CC[C@@H]1CO[C@H](CO)CN1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC[C@@H]1CO[C@H](CO)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
[(2S,5R)-5-Ethyl-4-(phenylmethyl)-2-morpholinyl]methanol (0.5 g, 2.125 mmol) was dissolved in CH3OH (20 mL) and placed under a nitrogen atmosphere. Palladium on carbon (10 wt %, 0.023 g, 0.212 mmol) was added and the flask was flushed with nitrogen and evacuated (3×). Then the reaction was placed under an atmosphere of hydrogen (balloon), and stirred at room temperature overnight. The reaction mixture was filtered through celite and concentrated to afford the title compound (0.309 g) as a colorless oil. LC-MS (ES) m/z=146 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[CH3:11]I>>[CH3:9][C:5]1[C:6]([C:7]#[N:8])=[C:2]([NH:1][CH3:11])[S:3][C:4]=1[CH3:10]
Reactant: CI
Reactant: Cc1sc(N)c(C#N)c1C
Product: CNc1sc(C)c(C)c1C#N

Procedure:
Prepared as in Example 21b from 2-amino-4,5-dimethylthiophene-3-carbonitrile and methyl iodide.
Reaction SMILES: [Na].[NH:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>C(O)C>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1)[CH3:13]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)CBr
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)Cn1ccnc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
118.2 g (5.1 mol) sodium are slowly added to 2.5 liters ethanol. 350.0 g (5.1 mol) imidazole are then added and 570 ml (858.6 g, 5.1 mol) ethyl bromoacetate are added dropwise at an internal temperature of 20-25° C. The mixture is stirred at RT for 24 h. The solid which has precipitated out is filtered off, the ethanol is removed in vacuo and the mixture is filtered again. The residue is purified by column chromatography over silica gel (mobile phase: ethyl acetate).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[C@H:21]([CH:22]=O)[CH2:20][C@H:19]2[C@@H:17]1[CH2:18]2)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(Cl)Cl>[C:9]([O:13][C:14]([N:16]1[C@H:21]([CH2:22][NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:20][C@H:19]2[C@@H:17]1[CH2:18]2)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@H](C=O)C[C@@H]2C[C@@H]21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@H](CNCc2ccccc2)C[C@@H]2C[C@@H]21
Reaction time: 14 h

Procedure:
Benzylamine (17.5 mmol, 1.0 eq) is added to a solution of (1S,3S,5S)-3-formyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (17.5 mmol, 1.0 eq) in DCM (100 mL). The mixture is treated with sodium triacetoxyborohydride (24.5 mmol, 1.4 eq), stirred for additional 14 h, poured into water (200 mL) and stirred vigorously for 10 min. The layers are separated and the aqueous layer is extracted twice with DCM (2×100 mL). The combined organic layers are washed with sat. NaHCO3 solution (100 mL) and water (100 mL), dried over Na2SO4 and concentrated in vacuo to give the desired benzylamine as a brownish oil which is used without further purification. LC-MS (basic): tR=0.96 min; [M+H]+=303.3.
Reaction SMILES: [CH3:1][NH:2][CH:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[S:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])(=[O:19])=[O:18]>>[C:10]1([CH:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:2]([CH3:1])[S:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])(=[O:19])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CNC(c1ccccc1)c1ccccc1
Reactant: COC(=O)CS(=O)(=O)Cl
Product: COC(=O)CS(=O)(=O)N(C)C(c1ccccc1)c1ccccc1
Yield: 37 %

Procedure:
The subtitle compound (3.05 g, 37%) was prepared as a clear brown oil from N-methyl benzhydrylamine (prepared according to the method of Z. Horii, T Sakai and Inoi, Pharm Bull., 1955, 3, 159) (10.7 g, 50.7 mmol) and methyl chlorosulfonylacetate (4.27 g, 24.7 mmol), using the method of Example 1(a).
Reaction SMILES: [OH:1][C:2]1[C:9]([C:10]2([CH3:13])[CH2:12][CH2:11]2)=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br-:14].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.CO>[Br:14][C:7]1[CH:8]=[C:9]([C:10]2([CH3:13])[CH2:11][CH2:12]2)[C:2]([OH:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: CC1(c2cccc(C=O)c2O)CC1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: CC1(c2cc(Br)cc(C=O)c2O)CC1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 92.8 %

Procedure:
To a solution 128 (0.34 g, 1.9 mmol) in DCM-MeOH (3:2, 20 mL) was added tetrabutylammonium tribromide (0.98 g, 2.0 mmol) and the resulting mixture was stirred at RT for 75 min. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and water. The EtOAc layer was washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with EtOAc/hexane to afford 0.45 g (91%) of 5-bromo-2-hydroxy-3-(1-methylcyclopropyl)benzaldehyde (130) as a light yellow solid.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[N:6][C:5]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])=[N:4]1.[CH2:15]([CH:18]([C:21]#[N:22])[C:19]#[N:20])[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:15]([C:18]([CH2:2][N:3]1[CH:7]=[N:6][C:5]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])=[N:4]1)([C:21]#[N:22])[C:19]#[N:20])[CH:16]=[CH2:17]
Reactant: FC(F)(F)C(F)(F)c1ncn(CCl)n1
Reactant: C=CCC(C#N)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCC(C#N)(C#N)Cn1cnc(C(F)(F)C(F)(F)F)n1

Procedure:
1-(chloromethyl)-3-(pentafluoroethyl)-1H-1,2,4-triazole and 1.02 g of allyl malononitrile were dissolved in 28 ml of N,N-dimethylformamide. 2.76 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and then subjected to preparative high performance liquid chromatography to obtain 0.54 g of allyl {[3-(pentafluoroethyl)-1H-1,2,4-triazole 1-yl]methyl}malononitrile (referred as the compound of the present invention (35), hereinafter) shown by below formula.
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1.C([O-])(=O)C.[Na+].C(O)(=O)C>CCOCC>[Br:1][C:6]1[C:7]([O:10][CH3:11])=[N:8][CH:9]=[C:4]([Br:3])[CH:5]=1
Reactant: BrBr
Reactant: COc1ccc(Br)cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1ncc(Br)cc1Br
Temperature: 80 °C
Reaction time: 4 h
Yield: 62.2 %

Procedure:
Bromine (17.8 g, 111 mmol) was added to a solution of 5-bromo-2-methoxypyridine (12.0 g, 63.8 mmol), sodium acetate (5.23 g, 63.8 mmol), and acetic acid (65 mL). The mixture was stirred at 80° C. for 4 h and then at room temperature for 12 h. The mixture was diluted with ether and washed with water, sodium bicarbonate and hypo solution. The organic layer was dried over sodium sulphate, filtered and concentrated. Purification by chromatography using 1-5% ethyl acetate in pet ether provided 10.6 g of the desired compound: 1H NMR (300 MHz, DMSO-d6) 8.20-8.40 (m, 2H), 3.92 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][C:5](OC)=[C:4](OCC2CCN(C)CC2)[CH:3]=1.C(O)(=O)C.[CH:28](N)=[NH:29]>COCCO>[N:1]1[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8](=[O:10])[NH:29][CH:28]=1
Reactant: N=CN
Reactant: CCOC(=O)c1cc(OC)c(OCC2CCN(C)CC2)cc1N
Solvent: COCCO
Solvent: CC(=O)O
Product: O=c1[nH]cnc2ccccc12
Temperature: 115 °C
Reaction time: 0.5 h
Yield: 173.8 %

Procedure:
A solution of ethyl 6-amino-3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (16.1 g, 50 mmol) in 2-methoxyethanol (160 ml) containing formamidine acetate (5.2 g, 50 mmol) was heated at 115° C. for 2 hours. Formamidine acetate (10.4 g, 100 mmol) was added in portions every 30 minutes during 4 hours. Heating was prolonged for 30 minutes after the last addition. After cooling, the volatiles were removed under vacuum. The solid was dissolved in ethanol (100 ml) and methylene chloride (50 ml). The precipitate was removed by filtration and the filtrate was concentrated to a final volume of 100 ml. The suspension was cooled to 5° C. and the solid was collected by filtration, washed with cold ethanol followed by ether and dried under vacuum overnight at 60° C. to give 6-methoxy-74(1-methylpiperidin-4-yl)methoxy)-3,4-dihydroquinazolin-4-one (12.7 g, 70%).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[C-]#N.[Na+].[CH:17](=[CH:24][C:25](=[O:27])[CH3:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[O:8]=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:24][C:25](=[O:27])[CH3:26]
Reactant: O=Cc1ccccc1
Reactant: CC(=O)C=Cc1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)CC(C(=O)c1ccccc1)c1ccccc1
Yield: 66.6 %

Procedure:
A solution of 21.2 g (0.2 mol) of benzaldehyde and 100 ml of absolute dimethylformamide is added dropwise in the course of 1/2 hour to a mixture of 4.9 g (0.1 mol) of NaCN and 100 ml of absolute dimethylformamide in a manner analgous to Example 3. Stirring is then continued for 11/2 hours at 35° C. A solution of 21.9 g (0.15 mol) of benzalacetone and 100 ml of dimethylformamide is then slowly added dropwise in the course of 31/2 hours at 35° C. Stirring is then continued for 31/2 hours at the same temperature. The reaction mixture is treated with twice its quantity of water and the product is worked up in a manner analogous to Example 5. 43.5 g of crude product are obtained from which 25.2 g of 1,4-dioxo-1,2-diphenyl-pentane (67% of theoretical) are obtained by distillation. B.p.: 166° C/0.4 mm Hg; m.p.: 60°-61° C C17H16O2 (253.3) Calculated: C, 80.92; H, 6.39. Found: C, 80.62; H, 6.50.
Reaction SMILES: [N:1]1([C:7](=[O:11])[CH2:8][C:9]#[N:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[ClH:12]>[Pt].CO>[ClH:12].[NH2:10][CH2:9][CH2:8][C:7]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:11]
Reactant: N#CCC(=O)N1CCOCC1
Agent: [Pt]
Agent: Cl
Solvent: CO
Product: NCCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.5 %

Procedure:
A nitrogen inerted reactor is charged with 5% Pt—C (43 g; 58% water-wet) followed by 3-morpholin-4-yl-3-oxo-propionitrile (2.8 mol). A solution of MeOH (3.4 L) and 12N HCl (3.08 mol) is added at such a rate as to maintain an internal temperature of ca. 25° C. The vessel and its contents are degassed via three N2 pressure purges (50 psi). The atmosphere is switched to hydrogen via three H2 pressure purges (50 psi), and the reaction is stirred vigorously at ca. 25° C. under a sustained pressure of hydrogen (50 psi) for ca. 24 hours. The H2 pressure is released and replaced with N2. The reaction is passed through filter agent, which is subsequently washed with MeOH (500 mL). The reaction is concentrated in vacuo to a volume of ca. 1.4 L, and IPA (2.2 L) is added. The reaction mixture is cooled to 0° C. and filtered. The filter cake is washed with MtBE (500 mL) and dried under vacuum at ca. 30° C. to provide 3-amino-1-morpholin-4-yl-propan-1-one, hydrochloride as a white solid (439 g). This material is used in subsequent steps without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:16])=O.CN(C=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([Cl:16])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)COc1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)COc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of 4-chlorophenoxy acetic acid (9.32 g, 0.05 mol) in CH2Cl2 (150 mL) was added oxalyl chloride (32.5 mL, of 2M in CH2Cl2) and DMF (0.2 mL). The resulting mixture was stirred at rt overnight under Ar. The mixture was concentrated in vacuo to give 10.3 g (100%) of 56a as colorless oil. 1H NMR (60 MHz, CDCl3): δ 7.0-6.7 (m, 4H), 4.8 (s, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][CH:28]([C:33]2[CH:38]=[CH:37][C:36](Br)=[CH:35][C:34]=2[F:40])[C:29]([F:32])([F:31])[F:30])[N:3]=1.[CH3:41][O:42][C:43]1[CH:44]=[N:45][CH:46]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:48]=1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][CH:28]([C:33]2[CH:38]=[CH:37][C:36]([C:47]3[CH:46]=[N:45][CH:44]=[C:43]([O:42][CH3:41])[CH:48]=3)=[CH:35][C:34]=2[F:40])[C:29]([F:32])([F:31])[F:30])[N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(OC(c3ccc(Br)cc3F)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cncc(-c2ccc(C(Oc3cc(-c4ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc4)nc(N)n3)C(F)(F)F)c(F)c2)c1
Temperature: 150 °C
Yield: 38.8 %

Procedure:
A microwave vial (2 ml) was charged with (S)-3-(4-{2-amino-6-[1-(4-bromo-2-fluoro-phenyl)-2,2,2-trifluoro-ethoxy]-pyrimidin-4-yl}-phenyl)-2-tert-butoxycarbonylamino-propionic acid (130 mg, 0.2 mmol), 3-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (70 mg, 0.3 mmol) 1 ml of acetonitrile, and 0.7 ml of water. To this mixture was added 0.4 ml of aqueous sodium carbonate (1M), followed by 14 mg (5 mol %) of dichlorobis(triphenylphosphine) palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness, the residue was dissolved in 2.5 ml of methanol and purified with Prep HPLC to give 51 mg of (S)-3-[4-(2-amino-6-{2,2,2-trifluoro-1-[2-fluoro-4-(5-methoxy-pyridin-3-yl)-phenyl]-ethoxy}-pyrimidin-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([OH:9])=O)[C@H:3]([CH2:5][CH3:6])[CH3:4].Cl.[CH2:21]([O:28][P:29]([CH2:38][C@H:39]([OH:49])[CH2:40][NH:41][C:42](=[O:48])[C@@H:43]([NH2:47])[CH:44]([CH3:46])[CH3:45])([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][P:29]([CH2:38][C@H:39]([OH:49])[CH2:40][NH:41][C:42](=[O:48])[C@@H:43]([NH:47][C:7](=[O:9])[C@@H:2]([NH:1][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH:3]([CH3:4])[CH2:5][CH3:6])[CH:44]([CH3:46])[CH3:45])([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:30])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)[C@H](N)C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Agent: Cl
Product: CCC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1)C(C)C

Procedure:
The title compound was prepared substantially in a similar manner as Step 1, Example 10 using N—Z-Ile-OH and [(R)-3-((S)-2-amino-3-methyl-butyrylamino)-2-hydroxy-propyl]-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride as the starting materials. The title compound was purified by SiO2 chromatography using 0-4% MeOH/CH2Cl2 as the eluent. 1H NMR (CD3OD, 300 MHz): δ 7.3 (m, 10H), 5.2-4.95 (m, 4H), 4.17 (d, 1H), 4.12 (m, 1H), 3.95 (d, 1H), 3.20 (m, 2H), 2.12-2.01 (m, 1H), 1.90-1.76 (m, 3H), 1.70-1.61 (m, 6H), 1.55-1.47 (m, 3H), 1.36-1.14 (m, 4H), 1.11-0.95 (m, 14H). 31P NMR (CD3OD, 300 MHz): δ 59.06, 58.33. LCMS m/z: [M+H]+=672.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:20])[CH:7](OC(=O)C)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2][CH2:3][CH3:4].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22]1>>[CH2:1]([O:5][C:6](=[O:20])[CH:7]([NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:21][CH:22]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Reactant: c1ccc2[nH]ccc2c1
Product: CCCCOC(=O)C(NC(=O)OC(C)(C)C)c1c[nH]c2ccccc12

Procedure:
A solution of 20.2 g. (0.070 mol.) of N-t-butoxycarbonyl-2-acetoxyglycine n-butyl ester and 8.8 g. (0.075 mol.) of indole in 300 ml. of toluene was slowly distilled over a 30 minute interval with periodic replacement of the toluene with fresh solvent. After an additional 45 minutes the reaction mixture was cooled and the solvent was evaporated in vacuo. The residue was triturated with hexane to give α-(N-t-butoxycarbonylamino)indole-3-acetic acid n-butyl ester, m.p. 127°-128° (ether-hexane).