Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](=O)[CH2:13][C:14]([O:16]CC)=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:20]([C:23]1[CH:33]=[CH:32][C:26]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=1)=[N+:21]=[N-:22].[O-]CC.[Na+].O>C(O)C>[CH2:30]([NH:29][C:27]([C:26]1[CH:32]=[CH:33][C:23]([N:20]2[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:13]([C:14]([OH:16])=[O:15])[N:22]=[N:21]2)=[CH:24][CH:25]=1)=[O:28])[CH3:31]
Reactant: CCOC(=O)CC(=O)CCCCCc1ccccc1
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCCCCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 14 h
Yield: 99.4 %

Procedure:
Ethyl 8-phenyl-3-oxooctanoate (1.01 g, 3.84 mmol, 1.23 eq.) obtained in Example 101a) and 4-azido-N-ethylbenzamide (purity 95%, 0.624 g, 3.12 mmol) were dissolved in ethanol (20 ml), sodium ethoxide (290 mg, 3.84 mmol, 1.23 eq.) was added, and the mixture was stirred at room temperature for 30 min and at 60° C. for 14 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, acidified (pH<3) with 6N hydrochloric acid and stood still at 0° C. The precipitate was collected by filtration, washed with ice-cold water and dried to give the title compound as a pale-yellow powder (1.26 g, 3.10 mmol, 99.5%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH2:19][C:20]([OH:22])=[O:21])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].I[CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH:25]1([CH2:24][CH:19]([C:13]2[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:11]([O:10][CH3:9])[CH:12]=2)[C:20]([OH:22])=[O:21])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COc1ccc(C(CC2CCCC2)C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (58.5 mL of a 0.91M stock solution, 53.2 mmol) cooled to −78° C. was treated with (3,4-dimethoxy-phenyl)-acetic acid (4.97 g, 25.3 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (25.3 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min and at 25° C. for 15 min. At this time, the reaction was cooled to 0° C. and was treated with a solution of iodomethylcyclopentane (5.87 g, 27.8 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL). The reaction mixture was stirred at 0° C. for 30 min. The reaction was then warmed to 25° C. and was stirred at 25° C. for 18 h. The reaction mixture was then quenched by the dropwise addition of saturated aqueous ammonium chloride solution (10 mL). The resulting mixture was concentrated in vacuo. The residue was diluted with water (100 mL) and acidified to pH=1 with a 1N aqueous hydrochloric acid solution. This solution was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with a saturated aqueous lithium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dimethoxy-phenyl)-propionic acid (4.5 g, 63.8%) as a yellow solid: mp 111-112° C.; EI-HRMS m/e calcd for C16H22O4(M+) 278.1518 found 278.1517.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:30][C@H:31]([C:36]2[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=2Br)[C:32]([F:35])([F:34])[F:33])[N:3]=1.[C:44]1(B(O)O)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:44]1([C:37]2[CH:38]=[CH:39][C:40]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:41][C:36]=2[C@@H:31]([O:30][C:4]2[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([N:8]3[CH2:29][CH2:28][C:11]4([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]4)[CH2:10][CH2:9]3)[CH:5]=2)[C:32]([F:33])([F:34])[F:35])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4cc(Br)ccc4Br)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OC(C)(C)C
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4cc(-c5ccccc5)ccc4-c4ccccc4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OC(C)(C)C
Temperature: 90 °C

Procedure:
To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-1-(2,5-dibromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (660 mg, 0.95 mmol) in dioxane (12 mL) was added phenyl boronic acid (290 mg, 2.4 mmol), Pd2(dppf)Cl2 (70 mg, 0.095 mmol), and Na2CO3 (6.0 mL, 2.0 M, aq). The reaction mixture was heated to 90° C. for 2 h, then cooled to RT, concentrated in vacuo, and extracted with CH2Cl2. The combined organic layers were washed with brine, and dried over Na2SO4. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-tert-butyl 3-ethyl 8-(6-((R)-1-([1,1′:4′,1″-terphenyl]-2′-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH2:36]([N:40]([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:41][CH2:42][CH2:43][NH2:44])[CH2:37][CH2:38][CH3:39]>C1COCC1>[CH2:36]([N:40]([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:41][CH2:42][CH2:43][NH:44][C:16]1[N:17]=[C:18]([C:19]2[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]2[CH2:12][NH:11][C:10](=[O:35])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1)[CH2:37][CH2:38][CH3:39]
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CCCCN(CCCC)CCCN
Solvent: C1CCOC1
Product: CCCCN(CCCC)CCCNc1nc(-c2cc(C(=O)NC(C)C)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 96.5 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (20 mg, 0.04 mmol) in THF (3 mL) were added N,N-dibutyl-1,3-propanediamine (0.041 mL, 0.182 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (24 mg, 96%). LC-MS m/z 622 (M+H)+; 1H-NMR (MeOD) δ 0.98 (t, 6H), 1.30 (m, 10H), 1.46 (m, 4H), 1.52 (m, 2H), 2.30 (s, 3H), 2.41 (m, 6H), 3.07 (m, 2H), 4.11 (s, 2H), 4.23 (m, 1H), 7.15 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([NH2:11])=[O:10])[C:7]([NH2:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].O=[CH:15][C:16]([Cl:19])([Cl:18])[Cl:17]>>[N+:1]([C:4]1[CH:12]=[C:8]2[C:7](=[CH:6][CH:5]=1)[NH:13][CH:15]([C:16]([Cl:19])([Cl:18])[Cl:17])[NH:11][C:9]2=[O:10])([O-:3])=[O:2]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: NC(=O)c1cc([N+](=O)[O-])ccc1N
Product: O=C1NC(C(Cl)(Cl)Cl)Nc2ccc([N+](=O)[O-])cc21

Procedure:
5-Nitroanthranilamide (6.5 g.) and anhydrous chloral (65 ml.) were stirred together at ambient temperature, until thin layer chromatography indicated that all the 5-nitroanthranilamide had disappeared (6 days). The excess of chloral was distilled off, and the resulting syrup was heated with concentrated sulphuric acid (125 ml.) on a steam bath for 10 minutes. The reaction mixture was cooled and poured into ice/water (1 kg.), and the solid product which was precipitated was filtered off, washed with water (3×200 ml.) and crystallised from ethanol (450 ml.) to give 1,2-dihydro-6-nitro-2-trichloromethylquinazolin-4-one, m.p. 278°-280° C.
Reaction SMILES: [C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](O)=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].O=S(Cl)[Cl:15]>>[C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8]([Cl:15])=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Reactant: O=S(Cl)Cl
Product: CC(=O)N1CCC(C(=O)Cl)CC1
Yield: 97 %

Procedure:
N-acetylisonipecotic acid (0.67 g, 3.9 mmol) was added to SOCl2 (4.1 mL). The acid chloride precipitated from solution and petrol (60 mL) was added. The mixture was filtered and the residue was washed several times with petrol to afford the title compound as a white solid (0.716 g, 97%). m.p. 133-138° C. 1H NMR (DMSO): 1.2-1.5 (m, 2H), 1.65-2.0 (m, 2H), 1.94 (s, 3H), 2.3-2.5 (m, 1H), 2.639 (t, J=11.4Hz, 1H), 3.036 (t, J=11.4Hz, 1H), 3.692 (d, J=13.2Hz, 1H), 4.144 (d, J=13.2Hz, 1H). IR (KBr): 1789, 1745, 1660 (cm−1). MS (m/z): 189, 126, 146, 84.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[CH:33]([C@H:36]1[CH2:40][O:39][C:38](=[O:41])[NH:37]1)([CH3:35])[CH3:34].C([Li])CCC>O1CCCC1>[CH:1]1([CH2:6][C@@H:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([N:37]2[C@@H:36]([CH:33]([CH3:35])[CH3:34])[CH2:40][O:39][C:38]2=[O:41])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)[C@H]1COC(=O)N1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 32.6 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionic acid (prepared in Example 12, 5.00 g, 17.4 mmol) in tetrahydrofuran (150 ML) cooled to −78° C. was treated with triethylamine (2.77 mL, 19.9 mmol) followed by trimethylacetyl chloride (2.24 mL, 18.2 mmol). The resulting white slurry was stirred at −78° C. for 15 min and then at 0° C. for 45 min. In a separate flask, a solution of (S)-4-isopropyl-2-oxazolidinone (2.14 g, 16.57 mmol) in tetrahydrofuran (80 mL) cooled to −78° C. was treated with a 2.0M solution of n-butyllithium in hexanes (8.7 mL, 17.4 mmol). This solution was stirred at −78° C. for 10 min. It was then warmed 25° C. and stirred for an additional 10 min. At this time, the first reaction mixture was re-cooled to −78° C. The second reaction mixture was added to the first reaction mixture over a period of 5 min via cannula. The combined reaction was then stirred at −78° C. for 15 min. It was then warmed to 25° C. and was stirred for an additional 1.5 h. At this time, the reaction was quenched by the addition of a saturated aqueous sodium bisulfite solution (50 mL) and extracted with ethyl acetate (3×40 mL). The organic layers were combined, washed with a saturated aqueous sodium bicarbonate solution (1×20 mL), a saturated aqueous sodium chloride solution (1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 85/15 hexanes/ethyl acetate) afforded (1) 3-[3-cyclopentyl-2(S)-(3,4-dichloro-phenyl)-propionyl]-4(S)-isopropyl-oxazolidin-2-one (2.15 g, 33%) as a clear oil: [α]23589=+87.5° (c=0.160, chloroform); EI-HRMS m/e calcd for C20H25Cl2NO3(M+) 397.1211, found 397.1215 and (2) 3-[3-cyclopentyl-2(R)-(dichloro-phenyl)-propionyl]-4(S)-isopropyl-oxazolidin-2-one (1.88 g, 28%) as a white solid: mp 71.9-74.6° C.; [α]23589=−27.6° (c=0.188, chloroform); EI-HRMS m/e calcd for C20H25Cl2NO3(M+) 397.1211, found 397.1212.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[C:22]1([C:28]([CH2:35][CH2:36][CH3:37])([CH2:32][CH2:33][CH3:34])[C:29](Cl)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[C:22]1([C:28]([CH2:35][CH2:36][CH3:37])([CH2:32][CH2:33][CH3:34])[C:29]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCC(CCC)(C(=O)Cl)c1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCC(CCC)(C(=O)C(C(=O)OCC)C(=O)OCC)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
A solution of diethyl malonate (3.03 g, 18.77 mmol) and anhydrous magnesium chloride in acetonitrile (36 mL) at 0° C. was treated with triethylamine (5.2 mL, 37.55 mmol), stirred at 0° C. for 30 min, stirred at 25° C. for 3 hours, cooled to 0° C. and treated dropwise with a solution of the product of Example 1D (18.77 mmol) in acetonitrile (15 mL) over 10 min and stirred at 50° C. for 18 hours. The solution was cooled to 25° C. and concentrated in vacuo. The solids were suspended in ethyl acetate and cooled to 0° C., treated with 4N HCl solution until all solids had dissolved. The organic layer was extracted with water (2×) and with saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (4.51 g, 66%). 1H NMR (300 MHz, CDCl3): δ 7.32 (m, 5 H), 4.50 (s, 1 H), 4.04 (q, J=7.35 Hz, 4 H), 1.97 (m, 4 H), 1.28 (m, 3 H), 0.98 (m, 10 H).
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([CH:9]=[CH:10][C:11]([O:13][CH3:14])=[O:12])[CH2:3]1.C(N(CC)CC)C.[F:22][CH:23]([F:27])[C:24](F)=[O:25]>C1(C)C=CC=CC=1>[F:22][CH:23]([F:27])[C:24](=[O:25])[C:10](=[CH:9][N:4]1[CH2:3][CH:2]([CH3:1])[O:7][CH:6]([CH3:8])[CH2:5]1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C(F)C(F)F
Reactant: COC(=O)C=CN1CC(C)OC(C)C1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)C(=CN1CC(C)OC(C)C1)C(=O)C(F)F
Temperature: -30 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
Methyl 3-(2,6-dimethylmorpholin-4-yl)acrylate (93.5%, 17.5 g, 82 mmol) and triethylamine (8.8 g, 87 mmol) were initially charged in toluene (150 ml) and cooled to −30° C. At this temperature, difluoroacetyl fluoride (10.0 g, 100 mmol) was introduced. The reaction mixture was stirred at −30° C. for 3 h and then, over a period of 1 hour, warmed to room temperature. The reaction mixture was washed with deionized water (100 ml). After separation of the phases, the aqueous phase was extracted once with toluene (100 ml). The toluene phases were combined and washed with an aqueous saturated NaCl solution (100 ml), and the solvent was then removed under reduced pressure. The residue obtained was 21.4 g of an orange solid which, according to GC analysis, consisted to 90.8% of methyl 4,4-difluoro-3-oxo-2-(2,6-dimethylmorpholin-4-ylmethylidene)butyrate (yield: 85.3%). 1H-NMR (CDCl3): δ=1.2 (s, 3H), 1.25 (s, 3H), 2.95 (m, 1H), 3.25 (m, 1H), 3.5 (m, 1H), 3.75 (m, 2H), 3.8 (s, 3H), 6.6 (t, 1H), 7.85 ppm (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[OH-].[Na+].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>O.C(O)C>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N:5][N:6]=1
Reactant: CCCCCCBr
Reactant: Nc1nnc(S)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCSc1nnc(N)s1
Reaction time: 3 h
Yield: 78.7 %

Procedure:
In 24 ml of water and 24 ml of ethanol, 11.6 g of 2-amino-5-mercapto-1,3,4-thiadiazole and 3.8 g of sodium hydroxide were dissolved, 14.0 g of 1-bromohexane was added to this solution, and the mixture was heated to 70°-80° C. and stirred for 3 hours. After cooling, water was added and the mixture was filtered. The residue was washed with water, dried under reduced pressure, and recrystallized from an ethanol/n-hexane (1:1) mixture. Thus 14.5 g of 2-amino-5-hexylthio-1,3,4-thiadiazole was obtained. m.p. 113°-115° C. Yield 77%.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2-].[Na+].[CH2:26]([C:33]1[CH:37]=[CH:36][S:35][C:34]=1[C:38](=O)[C:39]([O:41][CH3:42])=[O:40])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>C1COCC1>[CH2:26]([C:33]1[CH:37]=[CH:36][S:35][C:34]=1/[C:38](=[CH:2]\[O:3][CH3:4])/[C:39]([O:41][CH3:42])=[O:40])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(=O)c1sccc1Cc1ccccc1
Agent: [Cl-]
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO/C=C(/C(=O)OC)c1sccc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (methoxymethyl)triphenylphosphonium chloride and sodamide (0.4 g of a 1:1 molar mixture) in dry THF was added a solution of methyl 2-(3-benzyl-2-thienyl)-2-oxoacetate (220 mg, 0.8 mmol) in dry THF (5 ml). The reaction mixture was stirred at room temperature for 30 minutes. More (methoxymethyl)triphenylphosphonium chloride and sodamide (0.2 g of a 1:1 molar mixture) were added and stirring was continued for a further one hour. The reaction mixture was poured into water and then extracted with ether. The combined ether layers were washed with water and brine and then dried. Filtration through a pad of silica gel to remove triphenylphosphine oxide, followed by HPLC (eluent dichloromethane) afforded (Z)-methyl 2-(3-benzyl-2-thienyl)-3-methoxypropenoate, an oil (100 mg), 1H nmr: delta 3.64 (3H, s), 3.78 (6H, s), 6.75 (1H, d), 7.0-7.4 (6H, m), 7.60 (1H, s) ppm; and (E)-methyl 2-(3-benzyl- 2-thienyl)-3-methoxypropenoate, an oil (30 mg), 1H nmr: delta 3.64 (3H, s), 3.80 (3H, s), 3.82 (3H, s), 6.56 (1H, s), 6.75 (1H, d), 7.0-7.3 (6H, m) ppm.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[NH:11][CH:12]=[C:13]([CH:15]=[O:16])[N:14]=1>CC#N>[Br:1][C:12]1[N:11]=[C:10]([CH3:9])[NH:14][C:13]=1[CH:15]=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(C=O)c[nH]1
Solvent: CC#N
Product: Cc1nc(Br)c(C=O)[nH]1
Reaction time: 72 h
Yield: 35.3 %

Procedure:
N-bromosuccinimide (0.900 g, 5.0 mmol) was added to a stirred solution of 2-methyl-1H-imidazole-4-carbaldehyde (0.500 g, 5.0 mmol) in CH3CN (50 mL). The reaction mixture was stirred for 3 days in the dark and then concentrated in the presence of silica gel. The absorbed crude material was purified by column chromatography (5-70% EtOAc/hexanes) to afford the title compound (0.334 g, 35%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 13.34 (br. s., 1H), 9.48 (s, 1H), 2.31 (s, 3H). ES-LCMS: m/z 189.2, 191.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+]([NH:26][C:27](N)=[O:28])([O-])=O.O>C(O)C>[NH2:26][C:27]([N:12]1[CH2:11][CH2:10][C:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:22][CH:21]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:14][CH2:13]1)=[O:28]
Reactant: NC(=O)N[N+](=O)[O-]
Reactant: O=[N+]([O-])c1ccc(OC2(c3ccccc3)CCNCC2)cc1
Solvent: CCO
Solvent: O
Product: NC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)(c2ccccc2)CC1
Yield: 88.3 %

Procedure:
To a stirred solution of 4.0 g of 4-(4-nitrophenoxy)-4-phenylpiperidine in 50 ml of 95% ethanol was added 1.68 g of nitrourea in 50 ml of 95% ethanol. The reaction mixture was refluxed for two hours and then poured into 200 ml of water. The aqueous suspension was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting solid was purified by high pressure liquid chromatography (silica gel; elution with 5% methanol/dichloromethane) to yield 4.04 g (91.20%) of 1-aminocarbonyl-4-(4-nitrophenoxy)-4-phenylpiperidine, m.p. 203°-206° C.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]([CH2:17][CH2:18][CH3:19])[C:6](=[O:16])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]([CH2:17][CH2:18][CH3:19])[C:6](=[O:16])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([O:26][CH3:25])=[O:36])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: CCCN(Cc1ccc(F)cc1F)C(=O)CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN(Cc1ccc(F)cc1F)C(=O)CCc1ccc(OCc2ccccc2C(=O)OC)cc1
Yield: 43.9 %

Procedure:
N-(2,4-Difluorobenzyl)-3-(4-hydroxyphenyl)-N-propylpropanamide (290 mg, 0.87 mmol) was dissolved in acetonitrile (10 ml). 2-Bromomethyl-benzoic acid methyl ester (209 mg, 0.913 mmol) was added followed by potassium carbonate, anhydrous (180 mg, 1.305 mmol). The mixture was heated to reflux overnight and then evaporated to dry. Water and ethyl acetate were added and two phases were separated. The organic phase was dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE®SI, 20 g/70 ml) using DCM and then MeOH/DCM (1:99) as eluant gave 184 mg the desired product, yield 44%.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[F:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[F:28])[NH2:24].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:20][C:21]1[CH:22]=[C:23]([NH:24][C:16](=[O:18])[CH2:15][C:3]2[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[N:4]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: Nc1ccc(F)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(CC(=O)Nc2ccc(F)c(F)c2)nc(N2CCOCC2)cc1=O
Yield: 54.4 %

Procedure:
The product is prepared according to the procedure described in example 5, using 250 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 68, 169 mg of 3,4-difluoroaniline, and 285 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 2 ml of pyridine and 2 ml of N,N-dimethylformamide. 180 mg of N-(3,4-difluorophenyl)-2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=2.[C:13]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:12][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([CH3:13])[CH:3]=[N:4]2)=[CH:9][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc2cc(Br)cnc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cnc2cc(F)ccc2c1
Temperature: 90 °C
Yield: 74 %

Procedure:
3-bromo-7-fluoro-quinoline (Intermediate 30) (100 mg, 0.442 mmol) was combined with K2CO3 (153 mg, 1.10 mmol), anhydrous 1,4-dioxane (3 mL), and trimethylboroxine (0.092 mL, 0.663 mmol). Nitrogen was bubbled in to degas the reaction and Pd(PPh3)4 (50.9 mg, 0.044 mmol) was added. This was degassed again and then heated to 90° C. for 5 h. The reaction was cooled and partitioned between ethyl acetate and sat. aq. NaHCO3. The separated aqueous layer was extracted with ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave 7-fluoro-3-methyl-quinoline (52.7 mg) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J=1.8 Hz, 1 H) 7.93 (s, 1 H) 7.65-7.79 (m, 2 H) 7.32 (td, J=8.6, 2.5 Hz, 1 H) 2.52 (s, 3 H); MS (M+1): 162.1.