Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:31])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]2[N:23]=[C:22]([NH2:24])[N:21]=[C:20]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:19]=2)=[CH:12][CH:11]=1>CO.[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:31])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]2[N:23]=[C:22]([NH2:24])[N:21]=[C:20]([N:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)[N:19]=2)=[CH:12][CH:11]=1
Reactant: Nc1nc(C=Cc2ccc(C(=O)Nc3ccccc3N)cc2)nc(N2CCCCC2)n1
Agent: [Pd]
Solvent: CO
Product: Nc1nc(CCc2ccc(C(=O)Nc3ccccc3N)cc2)nc(N2CCCCC2)n1
Reaction time: 16 h
Yield: 55.8 %

Procedure:
To a solution of 223 (18 mg, 0.043 mmol) in MeOH (5 mL) was added 10% Pd/C (10 mg, 0.021 mmol). The reaction mixture was shaked under a pressure of H2 (40 psi) at room temperature for 16 h using an hydrogenation apparatus. Then, the reaction mixture was purged with N2, filtered through celite, and concentrated. The crude residue was then purified by flash chromatography on silica gel (MeOH/CH2Cl2: 2/98→4/96) to afford the title compound 224 (10 mg, 0.024 mmol, 56% yield). 1H NMR (300 MHz, CDCl3—CD3OD) δ (ppm): 7.82 (d, J=8.1 Hz, 2H), 7.35 (d, J=8.1 Hz, 2H), 7.08 (t, J=7.0 Hz, 1H), 6.89-6.79 (m, 2H), 7.80-6.90 (m, 1H), 3.76 (s, 4H), 3.13 (t, J=8.1 Hz, 2H), 2.88 (t, J=8.1 Hz, 2H),1.90-1.40 (m, 10H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:18]([NH2:20])[CH3:19])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.Cl[C:22]1[C:27]([C:28]#[N:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.C([N:34](CC)C(C)C)(C)C.N>C1COCC1.O1CCOCC1>[NH2:34][C:22]1[C:27]([C:28]#[N:29])=[C:26]([NH:20][C@H:18]([C:7]2[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9][C:10]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH3:19])[N:25]=[CH:24][N:23]=1
Reactant: C[C@H](N)c1cc2ccc(F)cc2nc1-c1ccccn1
Reactant: CCN(C(C)C)C(C)C
Reactant: N#Cc1c(Cl)ncnc1Cl
Agent: N
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc(N)c1C#N)c1cc2ccc(F)cc2nc1-c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.4 %

Procedure:
A mixture of (S)-1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethanamine (85 mg, 0.32 mmol), 4,6-dichloro-5-cyanopyrimidine (55 mg, 0.32 mmol, 1.0 eq) and N,N-diisopropylethylamine (68 μl, 0.38 mmol, 1.2 eq) in THF (3 mL) was stirred at rt for 30 min before heating to 50° C. After 4 h, the mixture was concentrated and purified by column chromatography (EtOAc/1/1) to give a white solid, which was treated with saturated NH3 in dioxane (3 mL) in sealed tube at 110° C. overnight. The reaction mixture was concentrated and purified by reverse phase HPLC (MeCN/H2O/0.1% TFA) and lyophilized to give a white powder 4-amino-6-((S)-1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethylamino)pyrimidine-5-carbonitrile (19 mg, 15%). 1H NMR (500 MHz, CD3OD) δ ppm 1.78 (d, J=6.85 Hz, 3H) 5.82 (q, J=6.85 Hz, 1H) 7.71 (td, J=8.80, 2.45 Hz, 1H) 7.89 (dd, J=9.66, 2.32 Hz, 1H) 8.10 (ddd, J=7.83, 5.62, 0.98 Hz, 1H) 8.19 (s, 1H) 8.27 (dd, J=9.05, 5.87 Hz, 1H) 8.45 (d, J=7.83 Hz, 1H) 8.63 (td, J=7.95, 1.47 Hz, 1H) 8.94 (s, 1H) 9.03-9.09 (m, 1H). Mass Spectrum (ESI) m/e=386 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C@@H:8]([CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)[CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=2)[CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[BH3-]C#N.[Na+].CC(O)=O>CO.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C@@H:8]([CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)[CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]2[CH:18]=[CH:19][C:20]([CH2:23][NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:21][CH:22]=2)[CH:16]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](COc1cncc(-c2ccc(C=O)cc2)c1)Cc1c[nH]c2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](COc1cncc(-c2ccc(CNc3ccccc3)cc2)c1)Cc1c[nH]c2ccccc12
Temperature: 25 °C

Procedure:
A solution of Example 116A (0.03 g, 0.06 mmol) in 2 mL of MeOH was cooled to 0° C. then treated with aniline (0.018 g 0.2 mmol), NaBH3CN (0.004 g, 0.06 mmol) and AcOH (1 ml). The mixture was allowed to warm to room temperature overnight. The mixture was diluted with ethyl acetate (20 ml), washed with water (10 ml) and brine (10 ml). The ethyl acetate was evaporated off and the residue was used without further purification.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][O:20][CH2:21][CH3:22])[CH:15]=[CH:14][C:13]=1[OH:23])[CH3:8].CI>CN(C)C=O>[CH2:7]([O:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][O:20][CH2:21][CH3:22])[CH:15]=[CH:14][C:13]=1[O:23][CH3:1])[CH3:8]
Reactant: CCOCOc1ccc(O)c(OCOCC)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOCOc1ccc(OC)c(OCOCC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.9 %

Procedure:
Potassium carbonate (14.3 g, 103 mmol) was added to 3a (2.50 g, 10.3 mmol) in N,N-dimethylformamide (103 mL). After 10 minutes, methyl iodide (6.43 mL, 103 mmol) was added and the solution was heated to reflux for 12 hours. Upon cooling to room temperature, the solution was extracted with EtOAc (3×50 mL); combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), and concentrated. The residue was purified by column chromatography (SiO2, 4:1 Hexane:EtOAc) to afford 4a as a yellow oil (2.40 g, 91%): 1H NMR (CDCl3, 500 MHz) δ 6.87 (d, J=2.8 Hz, 1H), 6.72 (d, J=8.9 Hz, 1H), 6.60 (dd, J=13.3, 1.7 Hz, 1H), 5.18 (s, 2H), 5.07 (s, 2H), 3.76 (s, 3H), 3.72-3.69 (m, 2H), 3.68-3.63 (m, 2H), 1.17-1.13 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ 150.7, 146.2, 143.9, 111.2, 107.9, 105.8, 93.2, 93.0, 63.3, 63.0, 55.4, 14.1, 14.0; IR (film) νmax 2976, 2932, 2899, 2835, 1595, 1508, 1393, 1227, 1153, 1103, 1080, 1009, 847 cm−1; HRMS (ESI+) m/z: [M+Na]+ calcd for C13H20O5, 279.1208. found, 279.1181.
Reaction SMILES: C([Li])CCC.C1(NC(C)C)CCCCC1.[C:16](Cl)(=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].Cl.[C:35]([O:38][CH2:39][CH3:40])(=[O:37])[CH3:36]>CCCCCC.O1CCCC1.C(OCC)C>[O:32]=[C:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:36][C:35]([O:38][CH2:39][CH3:40])=[O:37]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCOC(C)=O
Agent: CC(C)NC1CCCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCC(=O)CC(=O)OCC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
502 ml of a 15.12% by weight solution of butyllithium in hexane was added dropwise at -78° C. over a period of 30 minutes to a solution of 128 ml of cyclohexylisopropylamine in 800 ml of tetrahydrofuran. After the addition was complete, the reaction mixture was allowed to warm up to 0° C. over a period of 30 minutes. It was then again cooled to -78° C., after which 38 ml of ethyl acetate were added over a period of 5 minutes. The mixture was then stirred at the same temperature for 10 minutes, after which 75.0 g of palmitoyl chloride were added dropwise to it over a period of 5 minutes. The mixture was then stirred at -78° C. for 10 minutes, after which 250 ml of 20% v/v aqueous hydrochloric acid was added dropwise to the reaction mixture. The reaction mixture was then allowed to warm to room temperature, and 1 liter of diethyl ether was added. The resulting two layers were separated, and the aqueous layer was extracted with diethyl ether. The organic layer was combined with the extract, and this was washed, in turn, with a saturated aqueous solution of sodium bicarbonate and with an aqueous solution of sodium chloride. It was then dried and concentrated by evaporation under reduced pressure. The residue was allowed to stand to produce crystals, which were collected by filtration, to give 55.61 g of the title compound. Recrystallization of the product from cold ethanol gave white prisms melting at 38°-39° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([C:19](O)=[O:20])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][N:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH2:24]>>[CH:1]1([C:7]2[CH:8]=[C:9]([C:19]([NH:24][N:23]([CH3:22])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:20])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:17])([F:16])[F:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Reactant: CN(N)c1ccccc1
Product: CN(NC(=O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1)c1ccccc1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid (example 12c) and 1-methyl-1-phenyl-hydrazine (CAN 618-40-6) as starting materials; MS (EI) 408.4 (M+H)+.
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][CH2:5][CH2:6][OH:7].Br[C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:12]=2[S:11][C:10]=1[C:25]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)=[O:26].O>O1CCCC1>[OH:7][CH2:6][CH2:5][CH2:4][S:3][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:12]=2[S:11][C:10]=1[C:25]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)=[O:26]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(C(=O)c3cccnc3)sc21
Reactant: OCCCS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCO)c(C(=O)c3cccnc3)sc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.8 %

Procedure:
To a suspension of sodium hydride (0.068 g) in dry tetrahydrofuran (25 ml) was added dropwise a solution of 3-mercaptopropanol (0.14 g) in dry tetrahydrofuran (5 ml). After 15 minutes, a solution of 5-bromo-3-methyl-1-(2-methylpropyl)-6-[(pyridin-3-yl)carbonyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.60 g, Example 39 step c) in dry tetrahydrofuran (20 ml) was added dropwise and the reaction was stirred for 3 hours at room temperature. The solution was poured into water and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by normal-phase HPLC eluting with a gradient of 0-5% ethanol in dichloromethane to give the title compound as a cream solid (0.35 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][N:6]1[C:11](=[O:12])[CH:10]=[CH:9][C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7]1.[C:22](Cl)(=O)[O:23]C1C=CC([N+]([O-])=O)=CC=1.N1C=CC=CC=1.[O:41]1[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][CH2:49][NH2:50])[CH2:43][CH2:42]1>C(Cl)Cl.CCOC(C)=O>[O:41]1[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][CH2:49][NH:50][C:22]([NH:1][C:2]2[CH:21]=[CH:20][CH:19]=[C:4]([CH2:5][N:6]3[C:11](=[O:12])[CH:10]=[CH:9][C:8]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[N:7]3)[CH:3]=2)=[O:23])[CH2:43][CH2:42]1
Reactant: NCCCN1CCOCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1cccc(Cn2nc(-c3ccccc3)ccc2=O)c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(NCCCN1CCOCC1)Nc1cccc(Cn2nc(-c3ccccc3)ccc2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3-aminobenzyl)-6-phenylpyridazin-3(2H)-one (280 mg, 1010 μmol) and 4-nitrophenyl carbonochloridate (215 mg, 1067 μmol) in CH2Cl2 (5 mL) was added pyridine (82 μl, 1010 μmol). The resulting mixture was stirred at rt overnight. A solution of 3-morpholinopropan-1-amine (170 mg, 1179 μmol) in CH2Cl2 (3 mL) was added to the mixture, resulting in a yellow solution. After 1 h, the solution was diluted with EtOAc (30 mL) and was washed with NaOH (1 N, 10 mL, 3×). The organic layer was further washed with H2O (10 mL), NaHCO3 (satd., 10 mL), dried over Na2SO4 and concentrated. The yellow film was triturated with hexane-EtOAc (2:1). The oil was washed with ether, acetone in ether (10%), and pumped to a yellow foam (>110 mg). LCMS (ESI pos. ion): calc'd for C25H29N5O3: 447.5; found: 448.3 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.63-1.71 (m, 2 H) 2.32-2.43 (m, 6 H) 3.26-3.36 (m, 2 H) 3.52-3.59 (m, 4 H) 5.36 (s, 2 H) 5.51 (br. s., 1 H) 6.71 (br. s., 1 H) 7.01 (d, J=10.04 Hz, 1 H) 7.19 (d, J=7.53 Hz, 1 H) 7.24-7.31 (m, 1 H) 7.32 (s, 1 H) 7.36 (d, J=8.03 Hz, 1 H) 7.40-7.50 (m, 3 H) 7.67 (d, J=9.54 Hz, 1 H) 7.78 (d, J=7.53 Hz, 2 H).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=1[CH:16]([OH:18])[CH3:17]>C(Cl)Cl.CCOCC.[O-2].[O-2].[O-2].[Cr+6]>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([F:7])=[C:9]([C:16](=[O:18])[CH3:17])[CH:10]=1)#[N:13]
Reactant: CC(O)c1cc(C#N)ccc1F
Agent: [Cr+6]
Agent: [O-2]
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1cc(C#N)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of pyridine (3.52 mL, 43.6 mmol) in CH2Cl2 (10 mL) was added dry chromium trioxide (2.18 g, 21.80 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 30 min. 4-fluoro-3-(1-hydroxyethyl)benzonitrile (600 mg, 3.63 mmol) dissolved in CH2Cl2 (10 mL) was added via canula. The reaction mixture was stirred for 10 min. and was diluted with ether and celite and stirred for an additional 20 min. The reaction mixture was filtered through a pad of celite and washed with ethyl acetate. The organic was washed then with 5% HCl and sat'd NaHCO3, brine, dried over MgSO4, and concentrated in vacuo to provide product:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([CH2:14][NH:15][C:16]([C:18]2[S:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[O:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[O:13])[C@H:10]([CH2:14][NH:15][C:16]([C:18]2[S:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[O:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)c2ccc(Cl)s2)[C@H](O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(=O)[C@H](CNC(=O)c2ccc(Cl)s2)C1
Reaction time: 3 h
Yield: 72.9 %

Procedure:
81.1 To a solution of (3R,4S)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (600 mg, prepared according to example 79.5) in 10 ml of CH2Cl2 was added at 5° C. 2.30 ml of NEt3 and 1.59 g of SO3-pyridine complex, the solution was warmed to 22° C. and stirring was continued for 3 h. The mixture was washed with aqueous NH4Cl, the organic layer was dried and evaporated. The residue was chromatographed on silica (heptane/AcOEt, 2:1) to give 435 mg of (R)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester. Pale yellow solid. MS 303.0 ([M-isobutene+H]+)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[I:14]N1C(=O)CCC1=O>C(O)(=O)C>[I:14][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1nccc(-c2ccccc2)n1
Solvent: CC(=O)O
Product: Nc1ncc(I)c(-c2ccccc2)n1
Yield: 16 %

Procedure:
To a stirred solution of 500 mg (2.9 mmol) 2-amino-4-phenylpyrimidine in 38 ml acetic acid was added 689 mg (3.1 mmol) N-iodosuccinimide and stirring continued in the dark at room temperature for 16 h. The reaction mixture was then concentrated in vacuo and the residue partitioned between ether and water. The organic phase was then dried over sodium sulfate and concentrated in vacuo. Trituration in ether/ethyl acetate then afforded 138 mg (16%) 5-iodo-4-phenyl-pyrimidin-2-ylamine as a yellow crystalline solid. EI-MS m/e (%): 297 (M+, 100), 170 ([M—I]+, 38).
Reaction SMILES: C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[C:25]([O:28][C:29]1[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][C:32]([N:38]=[C:39]=[O:40])=[CH:31][C:30]=1[CH:41]([CH3:43])[CH3:42])(=[O:27])[CH3:26].[NH2:44][C:45]1[CH:46]=[N:47][C:48]2[C:53]([C:54]=1[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[Cl:61])=[CH:52][C:51]([CH3:62])=[CH:50][C:49]=2[CH3:63]>C1C=CC=CC=1.C(OCC)(=O)C>[C:25]([O:28][C:29]1[C:30]([CH:41]([CH3:43])[CH3:42])=[CH:31][C:32]([NH:38][C:39](=[O:40])[NH:44][C:45]2[CH:46]=[N:47][C:48]3[C:53]([C:54]=2[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=2[Cl:61])=[CH:52][C:51]([CH3:62])=[CH:50][C:49]=3[CH3:63])=[CH:33][C:34]=1[CH:35]([CH3:37])[CH3:36])(=[O:27])[CH3:26]
Reactant: Cc1cc(C)c2ncc(N)c(-c3ccccc3Cl)c2c1
Reactant: CC(=O)Oc1c(C(C)C)cc(N=C=O)cc1C(C)C
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC(=O)Oc1c(C(C)C)cc(NC(=O)Nc2cnc3c(C)cc(C)cc3c2-c2ccccc2Cl)cc1C(C)C
Reaction time: 0.67 h

Procedure:
Triethylamine (0.15 ml) was dropwise added to a mixture of 4-acetoxy-3,5-didiisopropylbenzoic acid (238 mg), diphenylphosphoryl azide (300 mg) and benzene (10 ml) under stirring. The mixture was further stirred for 30 mins. at room temperature, and for 40 mins. under reflux to prepare a solution of 4-acetoxy-3,5-diisopropylphenylisocyanate. After cooling, to the solution were added a solution of 3-amino-4-(2-chlorophenyl)-6,8-dimethylquinoline (255 mg) in benzene (255 mg) and then triethylamine (0.15 ml). The whole was stirred for 2 hrs. at room temperature, then for 3 hrs. under reflux, and thereto was added ethyl acetate. The organic layer was separated, washed with 2N-hydrochloric acid and water successively, and dried over anhydrous magnesium sulfate and then distilled to remove the solvent. The residue was recrystallized from a mixture of acetone and isopropyl ether to give 3-[3-(4-acetoxy-3,5-diisopropylphenyl)ureido]-4-(2-chlorophenyl)-6,8-dimethylquinoline as colorless needles. Yield 367 mg (74.9%). m.p. 248°-249° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][C@H:4]([NH:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:5]([OH:7])=[O:6].[CH2:16]=O.[H][H]>C(O)C.[Pd]>[CH3:1][CH:2]([CH3:15])[CH2:3][C@H:4]([N:8]([CH3:16])[CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:5]([OH:7])=[O:6]
Reactant: CC(C)C[C@H](NC1CCOCC1)C(=O)O
Reactant: [H][H]
Reactant: C=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)C[C@@H](C(=O)O)N(C)C1CCOCC1
Yield: 92.1 %

Procedure:
A mixture of (S)-4-methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid (9.09 g, 42.3 mmol, Example 18, Step A) and aqueous HCHO (10 mL of 37.2%, 3.72 g, 124 mmol) was agitated in an atmosphere of hydrogen (pressure, 47-52 psi) at 50° C. in absolute ethanol (250 mL) in the presence of Pd/C (20%, 1 g) until the absorption of hydrogen almost ceased. The catalyst was removed by filtration. The filtrate was concentrated in vacuo to dryness. Fifty milliliter of water was added and concentrated to dryness, and this operation was repeated twice to remove most of HCHO. Absolute ethanol (50 mL) was then added and concentrated to dryness to remove residual water. The white solid collected was triturated with acetone. Filtration and drying under vacuum gave 8.93 g (92%) of the desired product as a white solid; mp 185-190° C. (decomposed). APCI-MS m/z 230.2 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:13]2[CH2:18][C@H:17]([C:19](=[O:26])[CH2:20][C:21](OCC)=[O:22])[CH2:16][CH2:15][N:14]2[C:27]([O:29][CH3:30])=[O:28])[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:11])([F:10])[F:9].[OH-].[Na+].[NH2:33]O.Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([C@H:13]2[CH2:18][C@H:17]([C:19]3[O:26][NH:33][C:21](=[O:22])[CH:20]=3)[CH2:16][CH2:15][N:14]2[C:27]([O:29][CH3:30])=[O:28])[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:10])([F:9])[F:11]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2cc(F)c(C(F)(F)F)c(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(F)c(C(F)(F)F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 6.9 %

Procedure:
Trans-methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-4-(3-ethoxy-3-oxopropanoyl)-piperidine-1-carboxylate (110 mg, 0.25 mmol) (from example 70, step 1) was dissolved in MeOH (5 mL) and cooled to −40° C. Sodium hydroxide (0.066 mL, 0.25 mmol) dissolved in water (0.500 mL) was added. After 20 min at −40° C., hydroxylamine (50% by weight in water, 7.71 μL, 0.25 mmol) was added and stirring continued for 4 h. The reaction mixture was then added to a prewarmed 80° C. solution of 6 M hydrogen chloride (1.299 mL, 7.80 mmol) and stirred for 1 h. The solvent was evaporated in vacuo. DCM (50 mL) and water (50 mL) were added, shaken and the phases separated. The organic phase was dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×20 ID mm) using a gradient of 20-65% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer, over 30 minutes with a flow of 19 mL/min. Trans-methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (7.00 mg, 6.85%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 1.61-1.73 (m, 1H), 1.90-2.01 (m, 1H), 2.06 (dt, 1H), 2.56 (d, 1H), 2.76 (t, 1H), 2.89 (t, 1H), 3.78 (s, 3H), 4.13-4.47 (m, 1H), 5.46-5.74 (m, 1H), 5.68 (s, 1H), 6.89 (d, 2H). MS m/z 407 (M+H)+
Reaction SMILES: [CH3:1][C@@:2]12[CH2:9][CH2:8][CH2:7][N:6]1[C@@H:5]([C:10]([Cl:13])([Cl:12])[Cl:11])[O:4][C:3]2=[O:14].[CH:15](NC(C)C)(C)[CH3:16].ClC(Cl)(Cl)[C@H]1OC(=O)[C@H]2N1CCC2.C(Br)C=C>>[CH2:1]([C@@:2]12[CH2:9][CH2:8][CH2:7][N:6]1[C@@H:5]([C:10]([Cl:13])([Cl:12])[Cl:11])[O:4][C:3]2=[O:14])[CH:15]=[CH2:16]
Reactant: C[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Reactant: CC(C)NC(C)C
Agent: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@H]12
Solvent: C=CCBr
Product: C=CC[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Yield: 40 %

Procedure:
(Wang et al. Synlett 1999, 1, 33) The reaction was carried out following a similar procedure to that described for the preparation of oxazolidinone 8 using n-butyllithium (1.31 M, 9.93 cm3, 13.0 mmol), diisopropylamine (1.82 cm3, 13.0 mmol), oxazolidinone 7 (2.10 g, 8.7 mmol) and allyl bromide (2.25 cm3, 26.0 mmol) to afford oxazolidinone 10 (1.48 g, 60%) as a light orange oil for which the NMR data were in agreement with the literature.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22].CN(C)C1C=CC=CC=1.[C:32](Cl)(=[O:36])[C:33](Cl)=[O:34]>C1(C)C=CC=CC=1>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH2:14][N:13]1[C:3]2[C:2](=[CH:12][CH:11]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=2)[NH:1][C:33](=[O:34])[C:32]1=[O:36]
Reactant: CCOC(=O)c1ccc(N)c(NCc2ccc(Cl)cc2Cl)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)c1ccc2[nH]c(=O)c(=O)n(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 4-amino3-(2,4-dichlorobenzylamino)benzoate (1.53 g) and dimethylaniline (0.71 g) in toluene was added oxalyl dichloride (0.51 ml). After stirring at room temperature for 1.5 hr, ice was added to the reaction mixture. The toluene layer was separated and washed with 6N hydrochloric acid. The toluene layer was concentrated, and the residue was washed with methyl t-butyl ether and dried to give the object compound (1.03 g) as white crystals.