Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12]P(=O)(OC)OC)[N:8]2[CH3:11])=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[Li+].CC([N-]C(C)C)C.[C:33]([N:40]1[CH2:43][C:42](=O)[CH2:41]1)([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=[C:42]3[CH2:41][N:40]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:43]3)[N:8]2[CH3:11])=[C:4]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: COP(=O)(Cc1nc2c(N3CCOCC3)nc(Cl)nc2n1C)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(C=C2CN(C(=O)OC(C)(C)C)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a cold (−78° C.) suspension of dimethyl (2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methylphosphonate (1.1 g, 2.9 mmol) in THF (26 mL) was added a 2.0M solution of LDA in THF (1.6 mL) The resulting solution was allowed to warm to room temperature before the addition of a solution of 1-Boc-3-azetidinone (0.58 g, 3 4 mmol) in THF (12 mL). The reaction mixture was stirred at room temperature for 2 hours and partitioned between brine and DCM. The organic layer was isolated, washed with brine, dried over MgSO4 and concentrated. The crude residue was then purified by flash chromatography (0-100% EtOAc in heptane) to give the title compound (1.15 g, 93%). LCMS m/z: 421.3 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][CH:9]=[C:10]([C:16](OCC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=[N:4]1)[CH3:2].P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:16]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:8]=[C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C(=CNc1ccnn1CC)C(=O)OCC
Product: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Temperature: 115 °C
Reaction time: 4 h

Procedure:
A mixture of diethyl {[(1-ethyl-1H-pyrazol-5-yl)amino]methylidene}propanedioate (15 gm, 0.0533 mole) (example 2) and phosphorous oxy chloride (76.64 ml, 0.7998 mole) was heated at 110-120° C. under stirring for about 4 hours under argon atmosphere. The reaction mixture was cooled and then poured drop wise into ice water. A pale yellow solid separated which was filtered. The solid was first washed twice with ice cold water and then finally with hexane and dried over vacuum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:19][O:20][C:21](=[O:34])[C@H:22]([CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)[NH2:23]>CO.C(Cl)(Cl)Cl>[CH3:19][O:20][C:21](=[O:34])[C@H:22]([CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)[NH:23][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-tryptophan methyl ester hydrochloride (Sigma), the title compound was prepared as a solid (mp=191-193° C.). The reaction was monitored by tlc (Rf=0.4 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 5% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitrile.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:25])[NH:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][C:19]3[O:22][CH2:23][O:24][C:18]=3[CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])C.CO.[OH-].[K+].Cl>O>[CH2:23]1[O:22][C:19]2[CH:20]=[CH:21][C:16]([C:15]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7](=[O:25])[C:6]=3[C:4]([OH:5])=[O:3])=[CH:17][C:18]=2[O:24]1
Reactant: CCOC(=O)c1c(-c2ccc3c(c2)OCO3)c2ccccc2[nH]c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1c(-c2ccc3c(c2)OCO3)c2ccccc2[nH]c1=O
Yield: 95.4 %

Procedure:
A mixture of 1,2-dihydro-4-(3,4-methylenedioxyphenyl)-2-oxo-3-quinoline carboxylic acid ethyl ester (40 g, 118.6 mmol), methanol (200 ml), water (300 ml) and potassium hydroxide (33.3 g, 593.5 mmol) was refluxed with heat for 40 hours. To the reaction mixture was added 110 ml of 6N-HCl to acidify the mixture to obtain a precipitated crystal by filtration. The crystal obtained was washed with diethylether to give 35 g (yield: 95.4%) of the title compound.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[F:8][C:9]([F:20])([F:19])[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1.[CH2:21]([O:23][C:24](=[O:32])[CH:25](Cl)[C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH3:22]>O>[CH2:21]([O:23][C:24]([CH:25]([O:15][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][C:10]([C:9]([F:19])([F:20])[F:8])=[CH:11][CH:12]=1)[C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[O:32])[CH3:22]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(Cl)C(=O)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(OC(=O)c1ccc(C(F)(F)F)cc1)C(=O)C(C)C
Temperature: 90 °C

Procedure:
Sodium Hydride, 60% mineral oil (1.9 g, 46.3 mmol) and dimethylformamide (50 mL) are stirred at room temperature and 4-(trifluoromethyl)benzoic acid (8.0 g, 42.1 mmol) is added. To the resulting slurry is added 2-chloro-4-methyl-3-oxo-pentanoic acid ethyl ester (8.5 g, 44.2 mmol) and the resulting mixture is heated to 90° C. for 3 hr. The reaction mixture is cooled, diluted with water (100 mL), and product is extracted with ethyl acetate (100 mL). The organic layer is washed with water (three 100 mL portions) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to constant weight to give 4-trifluoromethyl-benzoic acid 1-ethoxycarbonyl-3-methyl-2-oxo-butyl ester as a colorless oil, 14.6 g, 100%. The resulting oil is stirred in a mixture of acetic acid (100 mL) and ammonium acetate (9.75 g, 126.5 mmol) at reflux 1 hr, then 20 hr at room temperature. The solvent is removed in vacuo and the residue is partitioned between aqueous saturated sodium hydrogen carbonate (100 mL) and ethyl acetate (100 mL. The layers are separated, the aqueous layer is washed with ethyl acetate (100 mL). The organic extracts are combined, washed with water and brine (100 mL each) dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue is purified over silica eluting with 9:1 hexanes:ethyl acetate to afford 4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carboxylic acid ethyl ester as a white solid, 8.1 g, 60%. MS (M++1) 328.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][OH:28])[CH:22]=2)=[N:17][C:16]([Cl:29])=[CH:15][N:14]=1)(=[O:11])=[O:10]>O1CCCC1.ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[O:28])[CH:22]=2)=[N:17][C:16]([Cl:29])=[CH:15][N:14]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Nc1ncc(Cl)nc1OCc1cccc(CO)c1)c1cccc(Cl)c1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=Cc1cccc(COc2nc(Cl)cnc2NS(=O)(=O)c2cccc(Cl)c2Cl)c1

Procedure:
2,3-Dichloro-N-[5-chloro-3-(3-hydroxymethylphenylmethoxy)-2-pyrazinyl]benzenesulphonamide (Example 106) (0.6 g) and manganese dioxide (1.0 g) in tetrahydrofuran (5 mL) was stirred at room temperature for 16 h. The mixture was diluted with dichloromethane and filtered through celite. The solution was evaporated to dryness and the product crystallised from diethyl ether (0.4 g). Used directly.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1>CN(C=O)C.O>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31][N:10]3[C:11]4[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=4[N:8]=[CH:9]3)=[CH:29][CH:28]=2)=[O:26])=[CH:35][CH:36]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(F)cc3)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.2 %

Procedure:
To a solution of theophylline (1.80 g) in DMF (20 ml) were added potassium carbonate (1.66 g) and 4-(4-fluorobenzoyl)benzyl bromide (2.93 g) and the mixture was stirred at room temperature for 24 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was washed with ether to provide the title compound as white powder (2.79 g, 74%). 1H-NMR (CDCl3) δ: 3.41(3H,s), 3.60(3H,s), 5.59(2H,s), 7.08-7.86(9H,m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([CH3:32])([CH2:12][CH2:13][C:14]1[N:15]([CH3:31])[C:16]([C:19](=[O:30])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:17][CH:18]=1)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.CCOCC>ClCCl>[C:1]([O:5][C:6]([NH:8][C@:9]([CH3:32])([CH2:12][CH2:13][C:14]1[N:15]([CH3:31])[C:16]([C:19](=[O:30])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:18]=1)[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(CC[C@](C)(CO)NC(=O)OC(C)(C)C)ccc1C(=O)CCCCc1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1c(CC[C@](C)(C=O)NC(=O)OC(C)(C)C)ccc1C(=O)CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.3 %

Procedure:
To a solution of (2R)-2-t-butoxycarbonylamino-2-methyl-4-[1-methyl-5-(5-phenylpentanoyl)pyrrol-2-yl]butan-1-ol (0.3520 g, 0.80 mmol) obtained in Example (43a) in dichloromethane (8 ml) were added successively molecular sieves 4A (0.2234 g) and pyridinium dichromate (0.4594 g, 1.22 mmol), and the resulting mixture was stirred at room temperature for 20 hours. After stirring, ether was added to the reaction mixture, and the resulting mixture was filtered. The filtrate was evaporated in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (3:2) as the eluent to afford the title compound (0.2195 g, yield: 63%).
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:33]=[CH:32][C:8]([CH2:9][N:10]([CH2:18][C:19]2[N:20](COCC[Si](C)(C)C)[CH:21]=[CH:22][N:23]=2)[C:11]([C:13]2[NH:14][CH:15]=[CH:16][N:17]=2)=[O:12])=[CH:7][CH:6]=1)C>FC(F)(F)C(O)=O.ClCCl>[CH:4]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH2:18][C:19]2[NH:20][CH:21]=[CH:22][N:23]=2)[C:11]([C:13]2[NH:17][CH:16]=[CH:15][N:14]=2)=[O:12])=[CH:32][CH:33]=1)=[O:3]
Reactant: CCOC(OCC)c1ccc(CN(Cc2nccn2COCC[Si](C)(C)C)C(=O)c2ncc[nH]2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1ccc(CN(Cc2ncc[nH]2)C(=O)c2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the compound 17 (970 mg), a 50% trifluoroacetic acid-dichloromethane solution (10 mL) was added under ice cooling. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and an aqueous 2N sodium hydroxide solution (20 mL) was added to the residue. The aqueous layer was extracted twice with dichloromethane (50 mL). The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated to obtain the title compound having the following physical properties. The obtained compound was used in the following reaction without being purified.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:29][CH2:30][N:31]([CH:34]3[CH2:36][CH2:35]3)[C:32](=[O:33])[C:10]=12)C1C=CC=CC=1.OS(O)(=O)=O>C(O)(=O)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:17]2([CH2:16][C:12]3[N:11]4[CH2:29][CH2:30][N:31]([CH:34]5[CH2:35][CH2:36]5)[C:32](=[O:33])[C:10]4=[C:9]([OH:8])[C:14](=[O:15])[N:13]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:23][CH:24]=1
Reactant: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccc(Cl)cc4)CCCC3)n2CCN1C1CC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C1c2c(O)c(=O)nc(CC3(c4ccc(Cl)cc4)CCCC3)n2CCN1C1CC1
Reaction time: 1 h
Yield: 56.4 %

Procedure:
9-benzyloxy-6-[1-(4-chlorophenyl)-cyclopentylmethyl]-2-cyclopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (327) (30 mg, 0.06 mmol) was taken up in acetic acid (1 mL) and H2SO4 (0.2 mL) was added slowly to the reaction at 0° C. and stirring was continued at room temperature for 1 h. The reaction was quenched with aqueous saturated NaHCO3 and extracted with ethyl acetate (2×15 ml). The combined extracts were dried and concentrated under reduced pressure. The obtained crude product was purified by preparative HPLC to get 6-[1-(4-chlorophenyl)-cyclopentylmethyl]-2-cyclopropyl-9-hydroxy-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (328) as an off-white solid (14 mg, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]([CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:36])[CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:34])[CH2:18][CH2:17]1)[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.[CH3:40][NH:41][CH3:42]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]([C:7]1[CH:8]=[CH:9][C:10]([C:11](=[O:13])[N:41]([CH3:42])[CH3:40])=[CH:14][CH:15]=1)[CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:36])[CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:27]2[C:28]([CH3:34])=[CH:29][CH:30]=[CH:31][C:32]=2[CH3:33])[CH2:18][CH2:17]1
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(Cl)c2)c2ccc(C(=O)O)cc2)CC1
Reactant: CNC
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(Cl)c2)c2ccc(C(=O)N(C)C)cc2)CC1
Yield: 73.9 %

Procedure:
Using general procedure E, 4-((3-chloro-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid (see EXAMPLE 86) (40 mg, 0.074) and dimethylamine (2.0M in THF, 56 μL, 0.11 mmol) afforded COMPOUND 87 as a white solid (31 mg, 71%). 1H NMR (CDCl3) δ 0.89-1.20 (m, 2H), 1.00 (d, 3H, J=6.3 Hz), 1.50-1.54 (m, 1H), 1.70-1.83 (m, 3H), 2.16 (t, 1H, J=11.1 Hz), 2.30 (s, 6H), 2.56 (t, 1H, J=12.0 Hz), 2.74-2.90 (m, 3H), 3.03 (s, 6H), 3.24-3.31 (m, 1H), 3.62-3.69 (m, 1H), 3.81 (s, 2H), 3.84-3.91 (m, 1H), 6.52 (d, 2H, J=8.4 Hz), 6.96 (d, 2H, J=7.5 Hz), 7.02-7.12 (m, 3H), 7.21-7.28 (m, 4H), 8.39 (br s, 1H). 13C NMR (CDCl3) δ 13.81, 19.54, 29.32, 30.67, 31.31, 40.24, 43.98, 48.67, 52.54, 56.18, 60.96, 112.31, 124.37, 124.68, 126.63, 127.30, 127.77, 128.88, 129.70, 130.16, 134.41, 134.83, 138.96, 142.53, 149.98, 170.32, 172.18. ES-MS m/z 575 (M+H). Anal. Calcd. for C34H43N4ClO2.0.5CH2Cl2: C, 67.09; H, 7.18; N, 9.07. Found. C, 66.75; H, 7.12; N, 8.94.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:25])([F:24])[F:23])[CH:16]=[C:15]([F:27])[CH:14]=3)=[CH:11][C:10]([NH2:28])=[N:9]2)=[CH:4][CH:3]=1.[O:29]=[C:30]1[NH:34][CH2:33][C@@H:32]([C:35](O)=[O:36])[CH2:31]1.CCN=C=NCCCN(C)C.Cl.O>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:24])([F:25])[F:23])[CH:16]=[C:15]([F:27])[CH:14]=3)=[CH:11][C:10]([NH:28][C:35]([C@H:32]3[CH2:31][C:30](=[O:29])[NH:34][CH2:33]3)=[O:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1C[C@H](C(=O)O)CN1
Reactant: C[C@@H](OCc1cc(F)cc(-c2cc(N)nn2-c2ccc(Cl)cc2)c1)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: C[C@@H](OCc1cc(F)cc(-c2cc(NC(=O)[C@@H]3CNC(=O)C3)nn2-c2ccc(Cl)cc2)c1)C(F)(F)F
Reaction time: 0.5 h
Yield: 26 %

Procedure:
To a solution of 1-(4-chlorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (about 0.110 mol) prepared in the previous step in N,N-dimethylacetamide (0.5 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid (17 mg) prepared in Preparation 14 and WSC.HCl (32 mg) at room temperature, and the mixture was stirred for 0.5 hours. To this reaction mixture was added water, and then the precipitated solid was collected by filtration. The resulting solid was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=9/1) to give the titled compound (18 mg).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:12]=[C:11]([CH3:13])[C:9]([NH2:10])=[C:8]([CH3:14])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[Br:15][CH:16]([CH3:20])[C:17](Br)=[O:18].C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[Br:15][CH:16]([CH3:20])[C:17]([NH:10][C:9]1[C:11]([CH3:13])=[CH:12][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][C:8]=1[CH3:14])=[O:18]
Reactant: CC(Br)C(=O)Br
Reactant: CCCCOc1cc(C)c(N)c(C)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCOc1cc(C)c(NC(=O)C(C)Br)c(C)c1

Procedure:
To a chilled (ca 10°) solution of 50.7 g (0.263 mole) of 4-butoxy-2,6-dimethylaniline [Buchi et al., Helv. Chim. Acta, 34, 278 (1951)] in 224 ml glacial acetic acid was added rapidly 62.4 g (.289 mole) of 2-bromo-propionyl bromide and immediately thereafter a chilled (ca 5°) solution of 87.2 g sodium acetate thihydrate in 362 ml water. This mixture was shaken for one-half hour, filtered, washed with water until the washes were neutral, and dried in vacuo over silica gel and KOH; yield 68.9 g (71.6%); m.p. 132.5° - 133.5°. The product was recrystallized from 95% ethanol; m.p. 135.5° - 136°.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH2:3][CH2:2]1.[NH2:22][C@@H:23]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:24]([NH:26][CH3:27])=[O:25]>>[CH3:30][C:29]([CH3:32])([CH3:31])[CH2:28][C@H:23]([NH:22][C:15]([C:13]1[CH:12]=[CH:11][C:10]([C:18]([F:21])([F:20])[F:19])=[C:9]([O:8][CH2:7][CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[N:14]=1)=[O:17])[C:24](=[O:25])[NH:26][CH3:27]
Reactant: CNC(=O)[C@@H](N)CC(C)(C)C
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCC2CCOCC2)n1
Product: CNC(=O)[C@H](CC(C)(C)C)NC(=O)c1ccc(C(F)(F)F)c(OCC2CCOCC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-((tetrahydro-2H-pyran-4-yl)methoxy)-5-(trifluoromethyl)picolinic acid and (2S)-2-amino-N,4,4-trimethyl-pentanamide (CAN 1160161-70-5) as starting materials, MS (EI): m/e=446.4 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:27])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH2:18][CH2:19][O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:31]([O:33][CH2:34][C:35]([Cl:38])([Cl:37])[Cl:36])=[O:32]>CCOC(C)=O>[Cl:36][C:35]([Cl:38])([Cl:37])[CH2:34][O:33][C:31](=[O:32])[NH:27][C:7]1[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH2:18][CH2:19][O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[CH:11]=2)[N:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(Cl)c(OCCOC3CCCCO3)c2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc(Cl)c(OCCOC3CCCCO3)c2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101 %

Procedure:
To a solution of Intermediate 53a (445 mg, 1.13 mmol) in EtOAc (4 mL) and 1N sodium hydroxide solution (2.40 mL, 2.40 mmol) was added 2,2,2-trichloroethyl chloroformate (165 μL, 1.20 mmol), and the mixture stirred vigorously at RT for 1.5 h. The aqueous layer was extracted with EtOAc (2×10 mL), and then the combined organics dried and concentrated in vacuo. The residue was purified by FCC, using 0-30% EtOAc in cyclohexane, to give the title compound (650 mg, 100%). LCMS (Method 3): Rt 4.90 min, m/z 568, 570, 572 [MH+].
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[CH:9][N:8]([C@@H:25]3[CH2:28][C@H:27]([C:29](O)=[O:30])[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.F[B-](F)(F)F.O=[C:38]1C=CC=[CH:40][N:39]1OC(N(C)C)=[N+](C)C.C(N(C(C)C)CC)(C)C.CNC>CN(C)C=O>[CH3:38][N:39]([CH3:40])[C:29]([C@H:27]1[CH2:28][C@@H:25]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:12]=3)=[CH:9]2)[CH2:26]1)=[O:30]
Reactant: CN(C)C(On1ccccc1=O)=[N+](C)C
Reactant: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2[C@H]1C[C@@H](C(=O)O)C1
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 45 mg (0.11 mmol) of cis-3-[4-amino-5-(3benzyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylic acid in 2 ml of N,N-dimethylformamide is added 36 mg (0.12 mmol) of O-(1,2-dihydro-2-oxo-1-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate and 39 μl (0.23 mmol) of diisopropylethylamine. 40 μl of a 5.6 M solution of dimethylamine are added thereto. After stirring the solution for 15 min at RT, working-up is effected by partitioning between water and ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated in vacuo to provide cis-3-[4-amino-5-(3-benzyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylic acid dimethylamide. Analytical HPLC: tR=6.81 min (Grad 2); ES-MS: m/eo=442.0.
Reaction SMILES: [CH3:1][C:2]([CH2:6][NH2:7])([CH2:4][NH2:5])[CH3:3].[NH2:8][C:9](N)=N>>[CH3:1][C:2]1([CH3:3])[CH2:6][NH:7][C:9]([NH2:8])=[N:5][CH2:4]1
Reactant: N=C(N)N
Reactant: CC(C)(CN)CN
Product: CC1(C)CN=C(N)NC1

Procedure:
The process according to claim 1 wherein a mixture of neopentyldiamine and guanidine hydrohalide is initially reacted to form 5,5-dimethyl-2-amino-1,4,5,6-tetrahydropyrimidine hydrohalide and further reacting the latter with the hydrazine reactant.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:29]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:30])[CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([OH:26])=O)=[CH:18][CH:17]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.Cl.[CH2:66]([O:73][NH2:74])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][C:24](=[O:26])[NH:74][O:73][CH2:66][C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=[CH:20][CH:21]=2)=[CH:27][CH:28]=1)[C:29]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: NOCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(CCC(=O)O)cc2)cc1)C(=O)N1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(CCC(=O)NOCc3ccccc3)cc2)cc1)C(=O)N1CCOCC1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 66.3 %

Procedure:
The acid 14 (2.0 g, 4.0 mmol) was dissolved in dry DMF (35 mL) and cooled to 0-5° C. 1-Hydroxybenzotriazole (0.6 g, 4.4 mmol), EDCI (0.77 g, 4.0 mmol), and triethylamine (1.68 mL, 12.0 mmol) were added to the above mixture followed by stirring for 15 min. O-Benzylhydroxylamine hydrochloride (0.7 g, 4.4 mmol) was added and the mixture was allowed to come to room temperature and stirred for 18 h. The solvent was evaporated under reduced pressure and the residual oil was taken up in EtOAc (100 mL). The organic layer was extracted with 2.0 M HCl (1×20 mL), saturated NaHCO3 (1×20 mL), and brine (1×50 mL). The resulting EtOAc layer was dried and concentrated to yield the crude product. Flash chromatography on silica gel (hexanes:ethyl acetate—1:1 containing 1% acetic acid) yielded the desired benzyl hydroxamate 15 (1.6 g, 66%). 1H NMR (400 MHz, DMSO-d6): 10.93 (s, 1H), 7.28-7.35 (m, 5H), 7.19 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.4 Hz, 2H), 4.68 (s, 2H), 4.52 (m, 1H), 3.21-3.49 (m, 8H), 2.72-2.80 (m, 4H), 2.21 (t, J=7.6 Hz, 2H), 1.29 (s, 9H).