Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-])=O)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:17]>C(O)C.[Pd]>[CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:17]
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2n1CCN(C)C
Agent: [Pd]
Solvent: CCO
Product: Cc1cc2cc(N)ccc2n1CCN(C)C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
A solution of compound 23 (0.35 g, 1.415 mmol) in dry ethanol (3 mL) was treated with Pd—C (˜0.05 g) and flushed with hydrogen gas. The reaction was stirred under hydrogen atm. for overnight. The reaction was filtered through celite bed, washed with methanol (3×10 mL) and dried to obtain crude compound 24 (0.29 g, 94%) as a syrup. 1H NMR (DMSO-d6) δ 2.18 (s, 6H), 2.32 (s, 3H), 2.42 (t, 2H, J=7.2 Hz), 4.03 (t, 2H, J=7.2 Hz), 4.37 (s, 2H), 5.88 (s, 1H), 6.42 (dd, 1H, J=2.1, 8.4 Hz), 6.56 (d, 1H, J=2.1 Hz), 7.00 (d, 1H, J=8.7 Hz); ESI-MS (m/z, %) 218 (MH+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([N+:10]([O-])=O)[CH:4]=1.O.NN>COCCOC.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([CH:4]=1)[NH2:10]
Reactant: COc1ccc(C)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: NN
Solvent: COCCOC
Solvent: O
Product: COc1ccc(C)c(N)c1
Temperature: 25 °C

Procedure:
To a solution of 4-methoxy-1-methyl-2-nitrobenzene (18.0 g, 108 mmol) in 160 mL of DME was added Pd/C (10%, 0.9 g) under nitrogen. Then hydrazine hydrate (16.17 g, 323 mmol) was added dropwise. The mixture was heated and stirred under reflux for 4 h. Then another 3 mL of hydrazine hydrate was added and stirred under reflux for 2d. Then the reaction mixture was cooled to RT, filtered through celite and evaporated to dryness to give 5-methoxy-2-methylaniline as yellow oil that solidified upon drying under vacuum to give 14.8 g (100%). 1H NMR (300 MHz, CDCl3): δ 6.94 (d, J=7.53 Hz, 1H), 6.28 (d, J=7.53 Hz, 1H), 6.26 (s, 1H), 3.78 (s, 3H), 3.5 (br, 1H), 2.10 (s, 3H), 1.6 (br, 1H).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.CCOCC.[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)C.[CH:34]1[C:39]([CH:40]=O)=[CH:38][C:37]2[O:42][CH2:43][O:44][C:36]=2[CH:35]=1>CCCCCC>[O:44]1[C:36]2[CH:35]=[CH:34][C:39]([CH:40]=[C:2]([CH3:3])[CH3:1])=[CH:38][C:37]=2[O:42][CH2:43]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: [Li]CCCC
Agent: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)=Cc1ccc2c(c1)OCO2
Reaction time: 4 h

Procedure:
62.5 ml of a 1.6 M solution of butyllithium in hexane was added to 500 ml of anhydrous ether. 38.5 g of isopropyltriphenylphosphonium bromide was added thereto in a nitrogen gas stream and the mixture was stirred for 4 h. 18 g of piperonal was added to the reaction mixture and the resulting mixture was stirred for 5.5 h and then filtered. The filtrate was washed with 1 l of ether, concentrated under reduced pressure and purified according to silica gel column chromatography (hexane/ethyl acetate=10:1) to obtain 13.1 g of the intended compound in the form of a colorless oil.
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@@H:7]([OH:14])[CH2:6][CH2:5]1.F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([CH:25]([CH3:27])[CH3:26])=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[CH:25]([C:22]1[N:20]2[CH:21]=[C:16]([O:14][C@@H:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C@@H:4]([NH2:3])[CH2:5][CH2:6]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1)([CH3:27])[CH3:26]
Reactant: N[C@H]1CC[C@H](O)c2ccccc21
Reactant: CC(C)c1nnc2ccc(F)cn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1nnc2ccc(O[C@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 111.5 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 1.07 g, 26.8 mmol) in dry DMF (20 mL) at room temperature under nitrogen, Intermediate 5b (1.89 g, 11.6 mmol) was added portionwise over 2 min, and the resulting brown solution was stirred for 20 min. Intermediate 1f (1.60 g, 8.93 mmol) was added, and the solution stirred at 60° C. for 2 h. The dark brown solution was cooled to room temperature and concentrated under vacuum. The residue was purified by SCX-2, washing with MeOH (200 mL) and eluting with 2M NH3 in MeOH, to leave a dark brown foam (3.21 g). Further purification by FCC, using 2-10% [2M NH3 in MeOH] in DCM, gave a brown foam (2.11 g, 76%). 1H NMR (400 MHz, d6-DMSO): 1.37 (3H, d), 1.39 (3H, d), 1.59 (1H, m), 1.91 (1H, m), 2.11 (1H, m), 2.33 (1H, m), 3.58 (1H, sept), 3.96 (1H, dd), 5.55 (1H, dd), 7.18-7.37 (4H, m), 7.51 (1H, d), 7.68 (1H, d), 8.20 (1H, d).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@H:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:8][C:9](=[O:15])[C@@H:10]1[CH2:14][CH2:13][CH2:12][NH:11]1)([CH3:4])([CH3:3])[CH3:2].[C:24]([S:28][CH2:29][CH:30]([CH3:34])[C:31](O)=[O:32])(=[O:27])[CH2:25][CH3:26].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:1]([O:5][C:6](=[O:23])[C@H:7]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:8][C:9](=[O:15])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:31](=[O:32])[CH:30]([CH3:34])[CH2:29][S:28][C:24](=[O:27])[CH2:25][CH3:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1
Reactant: CCC(=O)SCC(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCC(=O)SCC(C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
L-Prolyl-L-phenylalanine tert-butyl ester (0.54 g) was added to a solution of 3-propanoylthio-2-methylpropanoic acid (0.30 g) and dicyclohexylcarbodiimide (0.35 g) in dichloromethane (10 ml) cooled in an ice bath. The mixture was stirred in the ice bath for one hour and then at room temperature overnight, followed by concentration under reduced pressure. Ethyl acetate was added to the residue. After cooling, the precipitates were filtered off. The filtrate was washed, dried and concentrated as in Example 26. The residue was chromatographed as in Example 26 to give 1-(3-propanoylthio-2-methylpropanoyl)-L-prolyl-L-phenylalanine tert-butyl ester.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.CC1C=CC(S(O[CH2:23][CH2:24][C:25]2[S:26][C:27]3[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:28]=3[CH:29]=2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].[CH3:41][C@@H:42]1[CH2:46][CH2:45][CH2:44][NH:43]1.C(#N)C>>[Br:34][C:31]1[CH:32]=[CH:33][C:27]2[S:26][C:25]([CH2:24][CH2:23][N:43]3[CH2:44][CH2:45][CH2:46][C@H:42]3[CH3:41])=[CH:29][C:28]=2[CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2cc3cc(Br)ccc3s2)cc1
Reactant: C[C@@H]1CCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCc1cc2cc(Br)ccc2s1
Temperature: 55 °C
Yield: 73.3 %

Procedure:
Toluene-4-sulfonic acid, the product from Example 165D (0.45 g), and K2CO3 (0.23 g, 1.5 eq) was treated with a solution of (2R)-2-methylpyrrolidine solution in acetonitrile (11.1 g, 12.6 mg/g of solution, 1.5 eq). The mixture was heated at 55° C. for 24 hours, allowed to cool to room temperature, and concentrated under reduced pressure. The residue was dissolved in 30 mL EtOAc, washed with 2×10 mL water, concentrated, and the residue was purified by column chromatography (silica gel, 10:90 MeOH:CHCl3) to provide the title compound as an oil (0.26 g, 73.3%). 1HNMR (CDCl3, δ) 1.10 (d, 3H), 1.4-2.0 (m, 4H), 2.20 (q, 1H), 2.30-2.50 (m, 2H), 3.00-3.23 (m, 4H), 6.97 (s, 1H), 7.33 (d of d, 1H), 7.60 (d, 1H), 7.78 (d, 1H). MS (m/z): 324, 326 (M+H)+.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:7][C:8]2[O:12][C:11]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][CH:17]=3)([CH3:13])[CH2:10][C:9]=2[C:24]=1[C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:3])[CH3:2].[C:33]([NH:36][NH2:37])([NH2:35])=[NH:34].Cl>C(O)C.N1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:7][C:8]2[O:12][C:11]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]=[N:37][NH:36][C:33]([NH2:35])=[NH:34])=[CH:18][CH:17]=3)([CH3:13])[CH2:10][C:9]=2[C:24]=1[C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:3])[CH3:2]
Reactant: N=C(N)NN
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(COc1ccc(C=O)cc1)O2
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(COc1ccc(C=NNC(=N)N)cc1)O2
Yield: 96.7 %

Procedure:
In a mixed solvent of 40 ml of ethanol and 16 ml of pyridine was dissolved 8.54 g of 5-acetoxy-4,6-di-t-butyl-2-(4-formylphenoxymethyl)-2-methyl-2,3-dihydrobenzofuran and 2.38 g of aminoguanidine hydrochloride was added at room temperature. After heating under reflux for 14 hours and then cooling, ethanol and excess pyridine were distilled off using an evaporator and the concentrate was combined with water and extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography eluting with chloroform containing 5% methanol to give 9.31 g of 1-{4-[(5-acetoxy-4,6-di-t-butyl-2-methyl-2,3-dihydrobenzofuran-2-yl)methoxy]benzylideneamino}guanidine (rotamer mixture) as a pale yellow oil (yield 97%).
Reaction SMILES: Cl[C:2]1[C:3]([CH2:12][C:13](C)=C)=[C:4]([OH:11])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N+:8]([C:5]1[C:4]2[O:11][CH:13]=[CH:12][C:3]=2[CH:2]=[CH:7][CH:6]=1)([O-:10])=[O:9]
Reactant: C=C(C)Cc1c(Cl)ccc([N+](=O)[O-])c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=[N+]([O-])c1cccc2ccoc12

Procedure:
In Schema 1, a 3,5-optionally substituted-2-nitrophenol is reacted with a 2-alkenyl chloride, such as 2-methallyl chloride, to form the corresponding 2-(2-alken-1-yloxy)-4,6-optionally substituted-nitrobenzene (I), for example, 4-chloro-2-(2-methyl-2-propen-1-yloxy)nitrobenzene. This product is rear-ranged by heating to 180° C. to give the corresponding 2-(2-alken-1-yl)-6-nitrophenol (II), for example, 3-chloro-2-(2-methyl-2-propen-1-yl)-6-nitrophenol. This compound is then heated in the presence of p-toluenesulfonic acid to give the corresponding 7-nitrobenzofuran (III), for example 4-chloro-2,3-dihydro-2,2-dimethyl-7-nitrobenzofuran. Compound III is then converted to the corresponding amine(IV) by reduction of the nitro group using powdered iron, acetic acid, and water, after which the amine is heated at reflux with trichloromethyl chloroformate to form the corresponding isocyanate(V). The isocyanate is then treated with a 3-amino-3-fluoroalkylacrylate, for example, ethyl 3-amino-4,4,4-trifluorocrotonate, to give the corresponding 3-(2,3-dihydrobenzofuran-7-yl)-6-haloalkyl uracil, for example, 3-(4-chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-yl)-6-trifluoromethyluracil. This uracil which represents certain compounds of this invention may be isolated, or without isolation, may be alkylated with an alkyl iodide, such as methyl iodide, in the presence of anhydrous potassium carbonate to produce the corresponding 3-(2,3-dihydrobenzofuran-7-yl)-1-alkyl-6-haloalkyluracil (VI), for example 3-(4-chloro-2,3-dihydro-2,2-dimethylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH:9]=[CH:10][N:11]1[C:16]([OH:17])=[C:15]2[CH:18]=[C:19]([NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:20]=[C:14]2[N:13]=[CH:12]1.I[C:29]1[CH:50]=[CH:49][C:32]([C:33]([NH:35][C@H:36]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:34])=[CH:31][CH:30]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]([C:29]1[CH:50]=[CH:49][C:32]([C:33]([NH:35][C@H:36]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:34])=[CH:31][CH:30]=1)=[CH:10][N:11]1[C:16]([OH:17])=[C:15]2[CH:18]=[C:19]([NH:21][C:22](=[O:27])[C:23]([CH3:24])([CH3:26])[CH3:25])[N:20]=[C:14]2[N:13]=[CH:12]1
Reactant: CC(C)(C)C(=O)Nc1cc2c(O)n(C=CCOC3CCCCO3)cnc-2n1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(I)cc1)C(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(C(=Cn2cnc3nc(NC(=O)C(C)(C)C)cc-3c2O)COC2CCCCO2)cc1)C(=O)OCC
Reaction time: 12 h

Procedure:
A mixture containing 3.48 g of 3-(3-tetrahydropyr-2-yloxyprop-1-en-1-yl)-4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidine, 3.12g (1.2 equiv.) of diethyl N-(4-iodobenzoyl)glutamate, 546 mg (20%) of tris-(2-methylphenyl)phosphine, 201 mg (10%) of palladium acetate and 85.5 mg (5%) of cuprous iodide in 15 ml of triethylamine and 240 ml of acetonitrile is heated at reflux under nitrogen. After 12 hours., 1.17 g of diethyl N-(4-iodobenzoyl)glutamate are added and the reaction mixture is heated at reflux under nitrogen for an additional 12 hours. The reaction mixture then is concentrated under reduced pressure and the residue chromatographed on silica gel, eluting with 20:1 ethyl acetate:hexane. (Any recovered starting material can be recycled through the foregoing procedure.) The concentrated material is dissolved in 1:5 ethyl acetate:ether and this solution is refrigerated for 15 hours. The solid which forms is collected by filtration, washed with cold ethyl acetate and dried to yield diethyl N-[ 4-(1-(tetrahydropyr-2-yloxy)-3-(4-hydroxy-6 -pivaloylaminopyrrolo[2,3-d]pyrimidin-3-yl)prop-2-en-2yl)benzoyl]glutamate.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:34]=[CH:33][C:8]([CH2:9][NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].Cl.[CH2:36]([O:38][C:39](=[O:42])[CH2:40][NH2:41])[CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][C:19]([F:20])([F:22])[F:21])[N:14]=[C:13]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:28]([NH:41][CH2:40][C:39]([O:38][CH2:36][CH3:37])=[O:42])=[O:29])=[CH:31][CH:32]=3)[N:12]=2)=[CH:33][CH:34]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(CNc2nc(Nc3ccc(C(=O)O)cc3)nc(OCC(F)(F)F)n2)cc1
Reactant: CCOC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOc1ccc(CNc2nc(Nc3ccc(C(=O)NCC(=O)OCC)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a solution of 4-(4-(4-(allyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (100 mg, 0.21 mmol) in DCM (3 mL) was added glycine ethyl ester HCl (44 mg, 0.32 mmol), HATU (120 mg, 0.32 mol) and iPr2NEt (0.11 mL, 0.63 mmol). The mixture was stirred at r.t. for 16 hours before all the solvents were removed under vacuum. All solvents were removed under vacuum and the residue was purified by silica gel column (EtOAC/Hexanes=40% to 60%) to give ethyl 2-(4-(4-(4-(allyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)acetate (100 mg, 81%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH2:8][CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13])=[O:7])=[CH:4][CH:3]=1.[CH-:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.[CH-:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1.[Fe+2:27].[Cl-].[Al+3].[Cl-].[Cl-].O>C(Cl)Cl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C-:17]2[CH:21]=[CH:20][CH:19]=[CH:18]2)=[O:13])=[O:7])=[CH:4][CH:3]=1.[CH-:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1.[Fe+2:27]
Reactant: O=C(Cl)CCCCC(=O)c1ccc(Cl)cc1
Agent: [Fe+2]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C(CCCCC(=O)[c-]1cccc1)c1ccc(Cl)cc1
Reaction time: 1.5 h

Procedure:
5-(4-Chlorobenzoyl)pentanoyl chloride (5.2g; 0.02 mole) in methylene chloride (100 ml) and ferrocene (3.75g; 0.02 mole) were stirred at 0.5° and aluminium chloride (2.7g; 0.02 mole) was added slowly over 0.5 hr. The mixture was stirred at 0.5° for 1.5 hr then water was added. The organic layer was separated. The aqueous layer was extracted with methylene chloride and the combined organic fractions were washed with water, dried (magnesium sulphate) and evaporated to yield a brown solid. This was recrystallized from petroleum ether (60°-80°) to yield pure 5-(4-chlorobenzoyl)pentanoyl ferrocene; 3.23g (40%); mp 103°-6°.
Reaction SMILES: [CH2:1]([O:8][CH:9]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[F:32][C:33]([F:42])([F:41])[C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH2:37]>ClCCl.CN(C)C1C=CN=CC=1.O>[CH2:14]([O:13][CH:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:10]([NH:37][C:36]1[CH:38]=[CH:39][CH:40]=[C:34]([C:33]([F:32])([F:41])[F:42])[CH:35]=1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(O)C(OCc1ccccc1)OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)C(OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
A stirred solution of dibenzyloxyacetic acid (4.0 g) in dichloromethane (40 ml) was cooled to 0° C. and treated dropwise with, successively, DMF (100 mg) and oxalyl chloride (2.0 g). After 30 min pyrridine (3.52 g), 3-trifluoromethyl aniline (2.64 g) and 4-dimethylaminopyridine (100 mg) were added. The mixture was stirred at 0° C. for a further 30 min then allowed to warm to room temperature. After 3 hours the mixture was poured into water, extracted with ethyl acetate and the extracts washed successively with dilute hydrochloric acid, water, aqueous sodium bicarbonate solution and brine. After drying (MgSO4) the extracts were evaporated under reduced pressure to give the sub-title compound (5.62 g) as an orange gum, sufficiently pure to be used in step d).
Reaction SMILES: [C:1]([O:11]C)(=O)[C:2]1[NH:9][C:7](=[O:8])[NH:6][C:4](=[O:5])[CH:3]=1.C(O)(=O)C1NC(=O)NC(=O)C=1.S(Cl)([Cl:26])=O>N1C=CC=CC=1>[C:1]([Cl:26])(=[O:11])[C:2]1[NH:9][C:7](=[O:8])[NH:6][C:4](=[O:5])[CH:3]=1
Reactant: COC(=O)c1cc(=O)[nH]c(=O)[nH]1
Reactant: O=S(Cl)Cl
Agent: O=C(O)c1cc(=O)[nH]c(=O)[nH]1
Solvent: c1ccncc1
Product: O=C(Cl)c1cc(=O)[nH]c(=O)[nH]1

Procedure:
Org. Chem, 27, 3507 (1962) describes that methyl orotate can be synthesized by reacting orotic acid with thionyl chloride in the presence of a catalytic amount of pyridine to give orotyl chloride, which is then heated in methanol.
Reaction SMILES: [O:1]([CH2:19][CH:20]([CH3:30])[CH2:21][CH2:22][CH2:23][C:24]1(OCC[O:26]1)[CH3:25])[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.C(=O)(O)[O-].[Na+]>CC(C)=O>[O:1]([CH2:19][CH:20]([CH3:30])[CH2:21][CH2:22][CH2:23][C:24](=[O:26])[CH3:25])[Si:2]([C:15]([CH3:16])([CH3:17])[CH3:18])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(CCCC1(C)OCCO1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)CCCC(C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C

Procedure:
1-t-Butyldiphenylsiloxy-6,6-ethylenedioxy-2-methyl-heptane (75.35 g) in acetone (2 l) is treated with 10% hydrochloric acid (75 ml) and the solution is allowed to stir at room temperature for two and one half hours. The reaction mixture is neutralized with a saturated sodium bicarbonate solution (150 ml) the salt is removed by filtration and the solvent is removed in vacuo. The resulting residue is partitioned between ether and water, the aqueous phase is extracted with ether, and the combined ether extracts are washed with brine and dried (Na2SO4). The solvent is removed in vacuo to give the crude product which is purified via silica gel chromatography (5% EtOAc/hexane) to give 1-t-butyldiphenylsiloxy-2-methyl-6-oxo-heptane (61.95 g, 92%; ir (neat) 5.85μ(C=O); nmr (CDCl3,δ), 0.92 (d, 3H, CH3CH<), 1.05 [s, (CH3)3C], 2.07 (s, 3H, CH3C=O), 3.45 (d, 2H, CHCH2O), 7.2-7.8 (m, 10H, 2φ).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[C:23]([C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1)(=[O:25])[CH3:24]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:35]2[CH2:34][CH2:33][N:32]([C:29]3[CH:28]=[CH:27][C:26]([C:23](=[O:25])[CH3:24])=[CH:31][CH:30]=3)[CH2:37][CH2:36]2)=[O:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Reactant: COc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Product: COc1nc2ccccc2nc1NC(=O)N1CCN(c2ccc(C(C)=O)cc2)CC1
Yield: 71 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate and 1-(4-acetylphenyl)-piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([CH3:6])[C:3](Cl)=[O:4].[CH3:8][N:9]([CH3:12])[CH:10]=[O:11]>C(N(CC)CC)C>[CH3:8][N:9]([CH3:12])[C:10](=[O:11])[C:3](=[O:4])[C:2]([Cl:7])([Cl:1])[CH3:6]
Reactant: CC(Cl)(Cl)C(=O)Cl
Reactant: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)C(=O)C(C)(Cl)Cl

Procedure:
The procedure of Example 1 was followed using 32g (0.2 mole) of 2,2-dichloropropionyl chloride and 44g (0.6 mole) of dimethylformamide and 20g (0.2 mole) of triethylamine. Obtained following distillation was 12g of pure N,N-dimethyl-3,3-dichloro-2-oxobutyramide as a clear, colorless liquid: Bp: 68°-70° (0.2mm); ir (λmax, film) 5.7 (s), 6.1 (s), 7.1 (s), 9.3 (s), 9.9 (s), 12.6 (s) microns.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH2:15])[CH2:13][OH:14])([CH3:4])([CH3:3])[CH3:2].[CH:17](=O)[CH:18]([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:15][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:13][OH:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)CO
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CN[C@H](CO)CCCCNC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 31 %

Procedure:
(S)-(5-Amino-6-hydroxy-hexyl)-carbamic acid tert-butyl ester (3) (6.85 g) was dissolved in 200 mL CH2Cl2. Isobutyraldehyde (2.67 mL) was added and this solution was stirred for 2 hours. Sodium triacetoxyborohydride (1.1 eq) was added and the solution was stirred for 2 hours at RT. The solution was washed with sat. NaHCO3. The milky organic phase was separated and evaporated to dryness. The residue was purified by column chromatography using 99:1 EtOAc (100%) to EtOAc-MeOH(NH3) 99-1. as the eluent. Fractions containing the product were evaporated yielding 2.60 g (31%) of the title compound.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.I[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1>>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([N:17]2[C:9]3=[N:8][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:12][C:11](=[O:13])[N:10]3[CH2:14][CH2:15][C@H:16]2[C:18]([F:20])([F:21])[F:19])=[CH:24][CH:25]=1
Reactant: COc1ccc(I)cc1
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Agent: COc1ccnc2c1ccc1c(OC)ccnc12
Product: COc1ccc(N2c3nc(N4CCOCC4)cc(=O)n3CC[C@H]2C(F)(F)F)cc1

Procedure:
The product is prepared according to the procedure described in Example 12, using 100 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e), 108 mg of 1-iodo-4-methoxybenzene and 79 mg of 4,7-dimethoxy-1,10-phenanthroline. After purification by silica chromatography (eluent: CH2Cl2/MeOH 98/02), 31 mg of (8S)-9-(4-methoxyphenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of a cream foam, the characteristics of which are the following: