Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[O:6][CH2:7][C@H:8]([N:10]1[C:15]2=[N:16][C:17](Cl)=[N:18][CH:19]=[C:14]2[C@H:13]([CH3:21])[N:12]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:11]1=[O:30])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[NH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([Si:5]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[O:6][CH2:7][C@H:8]([N:10]1[C:15]2=[N:16][C:17]([NH:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[N:18][CH:19]=[C:14]2[C@H:13]([CH3:21])[N:12]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:11]1=[O:30])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccccc1
Reactant: COc1ccc(N2C(=O)N([C@H](C)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c3nc(Cl)ncc3[C@@H]2C)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(N2C(=O)N([C@H](C)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c3nc(Nc4ccccc4)ncc3[C@@H]2C)cc1

Procedure:
A solution of 1-[2-(tert-butyl-diphenyl-silanyloxy)-1-(R)-methyl-ethyl]-7-chloro-3-(4-methoxy-phenyl)-4-(S)-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.28 g; 0.45 mmol) (from Example 15a supra) and aniline (0.10 mL; 1.21 mmol) (Aldrich) in toluene (0.25 mL, dried over molecular sieves) was heated in an oil bath at 110° C. for 2 hours. The reaction was diluted with ethyl acetate and washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The crude material was purified by flash chromatography (Biotage 40L; 40:60 ethyl acetate-hexanes) to give 1-[2-(tert-butyl-diphenyl-silanyloxy)-1-(R)-methyl-ethyl]-3-(4-methoxy-phenyl)-4-(S)-methyl-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 0.23 g; 73.0%). This material showed an e.e. of ˜95%.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:20](OC1C=CC=CC=1)=[O:21].C(N(CC)CC)C.[CH3:36][C@@H:37]1[CH2:42][N:41]([C:43]2[C:48]([C:49]([F:52])([F:51])[F:50])=[CH:47][CH:46]=[CH:45][N:44]=2)[CH2:40][CH2:39][NH:38]1>C(Cl)Cl>[CH3:36][C@@H:37]1[CH2:42][N:41]([C:43]2[C:48]([C:49]([F:52])([F:50])[F:51])=[CH:47][CH:46]=[CH:45][N:44]=2)[CH2:40][CH2:39][N:38]1[C:20]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[CH3:12])=[CH:4][CH:3]=1)=[O:21]
Reactant: CN1CCCc2ccc(N)cc21
Reactant: C[C@@H]1CN(c2ncccc2C(F)(F)F)CCN1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H]1CN(c2ncccc2C(F)(F)F)CCN1C(=O)Nc1ccc2c(c1)N(C)CCC2
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 7-amino-1-methyl-1,2,3,4-tetrahydroquinoline (D3) (300 mg, 1.85 mmol) in DCM (5 ml) was added pyridine (164 ul, 2 mmol) followed by phenyl chloroformate (255 ul, 2 mmol) and the solution stirred at ambient temperature for 50 mins. Triethylamine (516 μl 3.7 mmol) was then added followed by a solution of (R)-2-methyl-4-(3-trifluoromethyl-2-pyridyl)piperazine (D22) (454 mg, 1.85 mmol) in DCM (5 ml) and the reaction stirred at ambient temperature until complete by tlc. The reaction mixture was washed (1M HCl, brine), dried over MgSO4 and concentrated in vacuo to give the crude product which was purified by flash chromatography, eluting with an EtOAc/40-60° C. petroleum ether gradient, to give the title compound as a white solid. 1H NMR (250 MHz, CDCl3) δ (ppm): 8.47 (dd, 1H), 7.90 (dd, 1H), 7.05 (dd, 1H), 6.84 (d, 1H), 6.78 (d, 1H), 6.49 (dd, 1H), 6.25 (br, 1H), 4.34 (m, 1H), 3.86 (m, 1H), 3.17-3.62 (m, 6H), 3.05 (m, 1H), 2.89 (s, 3H), 2.70.(t, 2H), 1.96 (m, 2H), 1.36 (d, 3H). MS (ES): MH+ 434.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:37](O)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([O:10][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)[C@@H]1[C@@H](O)CCN1C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1[C@H](OC(=O)c2ccccc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a solution of 7A (13.5 g, 55 mmol) in anhydrous THF (500 mL) was added triphenylphosphine (26 g, 99 mmol), followed by benzoic acid (10.1 g, 82.7 mmol) and DEAD (9.5 mL, 60 mmol). The reaction mixture was stirred at RT for 2 hours, then partitioned between water and CH2Cl2. The organic phase was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was chromatographed (silica gel) eluting with 15% EtOAc/hexane to give 18.1 g of the title compound as a colorless oil.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:23]3[C:18](=[C:19](Cl)[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:25][S:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(OCC)(=O)C.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>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:23]3[C:18](=[C:19]([C:30]4[CH:31]=[CH:32][C:27]([S:26][CH3:25])=[CH:28][CH:29]=4)[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(Oc2ccnc3c(Cl)cccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CSc1ccc(-c2cccc3c(OC4CCN(C(=O)OC(C)C)CC4)ccnc23)cc1

Procedure:
In a 25 mL round-bottomed flask equipped with a reflux condenser and N2 inlet septum was placed a stir bar, 4-(8-chloro-quinolin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (198 mg, 0.57 mmol), 4-methylthiophenylboronic acid (287 mg, 1.7 mmol), tetrakis(triphenylphosphine)palladium (98 mg, 0.085 mmol), 2M sodium carbonate (0.6 mL) and toluene (4 mL). The mixture was refluxed 36 h under N2. The resulting mixture was diluted with ethyl acetate and extracted with H2O. The organic extract was dried and concentrated to give the crude product. The crude product was purified by column chromatography to using 50% EtOAc/Hexane and preparative HPLC to give the desired product. 1H NMR (CDCl3, 400MHz) δ 1.27 (d, 6H), 2.04 (m, 2H), 2.17 (m, 2H), 2.55 (s, 3H), 3.59 (m, 2H), 3.83 (m, 2H), 4.97 (m, 1H), 5.09 (m, 1H), 7.14 (s, 1H), 7.41 (m, 4H), 7.81 (t, 1H), 7.90 (d, 1H), 8.38 (d, 1H), 9.11 (s, 1H). Exact mass calculated for C25H28N2O3S 436.18, found 437.2 (MH+).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][N:8]=2)[N:3]=1.C(O[C:19](=[O:30])[NH:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][OH:29])[CH2:23][CH2:22]1)(C)(C)C.[Cl:31][C:32]1[C:42](C(O)=O)=[CH:41][C:35]2[NH:36][C:37](=[O:40])[CH2:38][S:39][C:34]=2[CH:33]=1>>[CH3:13][O:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([O:29][CH2:28][CH2:27][N:24]3[CH2:23][CH2:22][CH:21]([NH:20][C:19]([C:42]4[C:32]([Cl:31])=[CH:33][C:34]5[S:39][CH2:38][C:37](=[O:40])[NH:36][C:35]=5[CH:41]=4)=[O:30])[CH2:26][CH2:25]3)=[N:3]2)=[N:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Reactant: O=C1CSc2cc(Cl)c(C(=O)O)cc2N1
Reactant: COc1cnc2ccc(Cl)nc2c1
Product: COc1cnc2ccc(OCCN3CCC(NC(=O)c4cc5c(cc4Cl)SCC(=O)N5)CC3)nc2c1

Procedure:
The title compound is prepared as an off-white lyophilizated powder following Scheme 1 and in analogy to Example 1 using 2-chloro-7-methoxy-[1,5]naphthyridine, [1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and 7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: [C:1](S(O[Li])=O)([C:4](C(C(C([C:16]([C:19]([C:22]([F:25])([F:24])[F:23])(F)[F:20])([F:18])[F:17])(F)F)(F)F)(F)F)([F:6])[F:5])([F:3])[F:2]>O>[F:23][C:22]([F:25])([F:24])[C:19]([F:20])=[C:16]([F:18])[F:17].[F:2][C:1]([F:3])=[C:4]([F:6])[F:5]
Reactant: [Li]OS(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: O
Product: FC(F)=C(F)C(F)(F)F
Product: FC(F)=C(F)F
Reaction time: 3.5 h
Yield: 6075.9 %

Procedure:
A 400 ml autoclave was loaded with 100 ml water and 1.0 g of C8F17SO2Li. The autoclave was cooled, evacuated, and loaded with 75 g of hexafluoropropylene and 50 g of tetrafluoroethylene. A solution of 0.5 g of sodium bromate in 50 ml of water was injected over about 3 to 4 hours at 20° to 25° C. The autoclave was vented, the polymeric emulsion recovered, and the emulsion broken by freezing. Filtering, washing 10 times with 200 ml of 1:1 methanol/water, and drying under vacuum gave 31 g of hexafluoropropylene/tetrafluoroethylene copolymer too high in molecular weight to extrude in a melt index apparatus at 372° C. with a 15 kg weight.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:14])[C:3]=1[C:15]1[NH:16][C:17]2[CH:23]=[C:22]([C:24]([NH:26][NH:27][C:28](=O)[C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[O:25])[CH:21]=[CH:20][C:18]=2[N:19]=1.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C1COCC1.O.CCCCCCC>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:28]2[O:25][C:24]([C:22]3[CH:21]=[CH:20][C:18]4[N:19]=[C:15]([C:3]5[C:2]([CH3:1])=[CH:7][C:6]([N:8]6[CH2:13][CH2:12][O:11][CH2:10][CH2:9]6)=[CH:5][C:4]=5[CH3:14])[NH:16][C:17]=4[CH:23]=3)=[N:26][N:27]=2)=[CH:34][CH:33]=1
Reactant: Cc1cc(N2CCOCC2)cc(C)c1-c1nc2ccc(C(=O)NNC(=O)c3ccc(Cl)cc3)cc2[nH]1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: O
Product: Cc1cc(N2CCOCC2)cc(C)c1-c1nc2ccc(-c3nnc(-c4ccc(Cl)cc4)o3)cc2[nH]1

Procedure:
252 mg of 4-Chloro-benzoic acid N′-[2-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-3H-benzoimidazole-5-carbonyl]-hydrazide was placed in a microwave tube and dissolved in 4 ml of THF. 300 mg of (methoxycarbonylsulfamoyl)triethylammonium hydroxide (Burgess Reagent) was added and the tube was sealed and microwaved at 150° C. for 30 minutes. The reaction was then diluted with water and heptane. The precipitates were collected by filtration and purified by column chromatography (heptane:ethyl acetate=1:1 to 1:2) to provide the title compound. LCMS ret T=1.44 min, m/z=486.1, method 10. 1H NMR (400 MHz, MeOD) □ ppm 2.29 (br. s., 6H) 3.36 (br. s., 5H) 3.99 (br. s., 4H) 6.95 (br. s., 2H) 7.81 (s, 2H) 7.95 (br.s., 1H) 8.25 (br. s., 1H) 8.32 (br. s., 2H) 8.56 (br. s., 1H).
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH3:7])[C:4]([OH:6])=O.C[N:9]1CCOCC1.ClC(OCC(C)C)=O.Cl[C:24]1[CH:29]=[C:28]([O:30][C:31]2[C:36]([F:37])=[CH:35][C:34]([NH:38][C:39]([C:41]3([C:44]([NH:46][C:47]4[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=4)=[O:45])[CH2:43][CH2:42]3)=[O:40])=[C:33]([F:54])[CH:32]=2)[CH:27]=[CH:26][N:25]=1>C(Cl)Cl>[F:54][C:33]1[CH:32]=[C:31]([O:30][C:28]2[CH:27]=[CH:26][N:25]=[C:24]([NH:9][C:4](=[O:6])[C@H:3]([O:2][CH3:1])[CH3:7])[CH:29]=2)[C:36]([F:37])=[CH:35][C:34]=1[NH:38][C:39]([C:41]1([C:44]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=2)=[O:45])[CH2:43][CH2:42]1)=[O:40]
Reactant: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2cc(F)c(Oc3ccnc(Cl)c3)cc2F)CC1
Reactant: CO[C@H](C)C(=O)O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Product: CO[C@H](C)C(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 20.9 %

Procedure:
To a solution of (R)-2-methoxy-propionic acid (300 mg, 2.88 mmol) and N-methylmorpholine (432 mg, 4.32 mmol) in anhydrous CH2Cl2 was added drop wise isobutyl chloroformate (588 mg, 4.32 mmol). The resultant mixture was stirred at RT for 1 h. N-(4-(2-Chloropyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (200 mg, 0.452 mmol) was added and the resulting mixture was stirred at RT for 12 h. The reaction mixture was concentrated under vacuo and purified by HPLC separation to give (R)—N-(2,5-difluoro-4-((2-(2-methoxypropanamido)pyridin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (50 mg, 21%). 1H NMR (400 MHz, CDCl3): δ 9.79 (s, 1H), 9.07 (s, 1H), 8.51 (s, 1H), 8.32-8.27 (m, 1H), 8.16 (d, J=5.6 Hz, 1H), 7.83 (d, J=2 Hz, 1H), 7.48-7.44 (m, 2H), 7.06-6.98 (m, 3H), 6.66-6.64 (m, 1H), 3.82 (q, J=6.8 Hz, 1H), 3.50 (s, 3H), 1.75-1.67 (m. 4H), 1.42 (d, J=6.8 Hz, 3H); MS (ESI): m/z 529.1[M+H]+.
Reaction SMILES: [C:1]([O:4][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=O)[CH3:2].[NH2:20]C(N)=S>CN(C=O)C.ClCCl>[CH3:2][C:1]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:20]=1
Reactant: NC(N)=S
Reactant: CC(=O)OC(C(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 160 °C
Yield: 74 %

Procedure:
2-Oxo-1,2-diphenylethyl acetate 24 (0.20 g, 0.79 mmol) was dissolved in DMF (10 mL). Thiourea was then added and the reaction was refluxed (160° C., oil bath) under nitrogen atmosphere. As the reaction progressed, the color changed from colorless to a light yellow-orange and had an odorous smell. The reaction was monitored by TLC and when complete, the reaction mixture was dissolved in dichloromethane (40 mL) and then washed with water (3×30 mL). The dichloromethane layer was separated and dried over anhydrous sodium sulfate. Removal of the drying agent by filtration and rotary evaporation of the solvent gave a crude oil that was purified by flash chromatography on silica gel (dichloromethane) to provide 25 (74%): Rf: 0.098 (hexane/ethyl acetate, 2:1); FTIR 2920.50; 1220.30; 1502.00, 1588.24 cm−1; 1H NMR (400 MHz, CDCl3) δ: 2.617 (s, 3H); 7.25-7.66 (m, 10H, aromatic); 13C NMR (100 MHz, CDCl3) δ 160.35, 145.41, 134.82, 126.46-132.14, 13.92; HRMS calcd for C16H13NO (M+H)+ 236.1075, Found: 236.1077.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH2:5]([N:12]1[CH:21]=[C:20]([CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:28]3[CH:29]=[C:30]([CH:35]=[CH:36][C:37]=3[CH3:38])[C:31](OC)=[O:32])[CH:18]=2)[C:13]1=[O:39])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([Mg]Cl)(C)C>C1COCC1>[CH2:5]([N:12]1[CH:21]=[C:20]([CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:28]3[CH:29]=[C:30]([CH:35]=[CH:36][C:37]=3[CH3:38])[C:31]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[O:32])[CH:18]=2)[C:13]1=[O:39])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(=O)n(Cc4ccccc4)cc(CCCN(C)C)c3c2)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccccc3)cc(CCCN(C)C)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of cyclopropylamine (0.18 mL) and the product from step ii) (120 mg) in THF (5 mL) was treated with isopropylmagnesium chloride (2N/THF, 1 mL) and stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL), and extracted into ethyl acetate (2×10 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo. Purification by HPLC gave the title compound as a solid (31 mg).
Reaction SMILES: [OH-].[Na+].[N:3]#[C:4][NH2:5].Cl[CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12].C(Cl)Cl>O>[C:4]([N:5]1[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1=[O:12])#[N:3]
Reactant: N#CN
Reactant: O=C(Cl)CCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: N#CN1CCCCC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
59.4 g (1.484 moles) of sodium hydroxide are dissolved in 370 ml of water and the solution is cooled to 0° C. To this solution are added 13.2 g (0.742 mole) of cyanamide in portions. Then 115 g (0.742 mole) of δ-chlorovaleryl chloride are added dropwise, at 0°-8° C., over 1 hour to the clear, colourless cyanamide solution. The ensuing reaction is strongly exothermic, so that intensive cooling is necessary. When the dropwise addition is complete, the mixture is stirred for 1 hour at 0° C. Then 740 ml of methylene chloride are added and the reaction mixture is subsequently warmed for 1 hour to reflux temperature (40° C.). The two phases are separated in a separating funnel. The aqueous phase is extracted once more with 740 ml of methylene chloride. The combined organic phases are dried over sodium sulfate, filtered, and the solvent is removed in a water jet vacuum. Yield: 79.6 g (86.4% of theory). The crude product is a pale yellowish liquid which, according to gas chromatographic analysis, contains 79.95% of N-cyanopiperidone. An isomer is not detected. High vacuum distillation of the crude product yields 44 g (47.8% of theory) of N-cyanopiperidone as a pale yellowish liquid with a boiling point of 125° C./13.3 Pa. Gas chromatographic analysis shows the product to be 99.19% pure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)=[C:11]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:10]=1)[CH3:2].[OH:30][C:31]1[CH:41]=[CH:40][C:34]2[C:35](=[O:39])[CH2:36][CH2:37][O:38][C:33]=2[C:32]=1[CH2:42][CH2:43][CH3:44].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:30][C:31]2[CH:41]=[CH:40][C:34]3[C:35](=[O:39])[CH2:36][CH2:37][O:38][C:33]=3[C:32]=2[CH2:42][CH2:43][CH3:44])=[C:11]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:10]=1)[CH3:2]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: CCOC(=O)CCCCc1ccc(OCCCCCBr)c(CCC(=O)OCC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCCOc2ccc(CCCCC(=O)OCC)cc2CCC(=O)OCC)ccc2c1OCCC2=O
Temperature: 25 °C
Yield: 90.3 %

Procedure:
A mixture of 1.69 g (3.58 mmol) of 4-(5-bromopentyloxy)-3-(3-ethoxy-3-oxopropyl)benzenepentanoic acid ethyl ester from the preceding example, 0.738 g (3.58 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, 2.07 g (14.98 mmol) of anhydrous potassium carbonate, and 37.5 mL of 2-butanone was stirred and refluxed for 18.5 hr. After being cooled to room temperature, the mixture was filtered through anhydrous magnesium sulfate and the solids were washed thoroughly with ethyl acetate. The filtrate and washes were combined and concentrated in vacuo and the crude product was purified by flash chromatography on 250 g of silica gel, eluting with hexane-ethyl acetate (4:1). There was obtained 1.93 g (90.1%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]/[C:9](/[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=2)=[C:10](/[NH:12][C:13](=[O:28])[C:14]([CH3:27])([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)[CH3:15])\[CH3:11])=[CH:4][CH:3]=1.C([O-])([O-])=[O:38].[K+].[K+].OO.CCCCCCC>C(OC(C)C)(=O)C.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]/[C:9](/[C:29]2[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=2)[C:35]([NH2:36])=[O:38])=[C:10](/[NH:12][C:13](=[O:28])[C:14]([CH3:15])([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][N:18]=2)[CH3:27])\[CH3:11])=[CH:4][CH:3]=1
Reactant: C/C(NC(=O)C(C)(C)Oc1ccc(C(F)(F)F)cn1)=C(\Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CCCCCCC
Solvent: CS(C)=O
Solvent: CC(=O)OC(C)C
Product: C/C(NC(=O)C(C)(C)Oc1ccc(C(F)(F)F)cn1)=C(\Cc1ccc(Cl)cc1)c1cccc(C(N)=O)c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 0.02 %

Procedure:
To a 5 L, 3-necked round bottom flask equipped with overhead stirrer, thermocouple, and nitrogen inlet was added 524 g of the cyano enamide product of Example 14, N-[(1Z)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylprop-1-en-1-yl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide, and 112 g K2CO3. DMSO (2.7 L) was charged and the vessel was submerged in a RT water bath. Hydrogen peroxide solution (165 mol of a 30% aqueous solution) was slowly added to the reactor such that the temperature never rose above 25° C. After the addition was complete, the reaction was aged for 1 hour. The batch was diluted with 1 L of isopropyl acetate and filtered over a bed of SOLKA FLOC. The bed was washed with 4.5 L of isopropyl acetate and the resulting solution was transferred to a 50 L extractor containing 5.5 L of water. The layers were separated and the organic layer was washed twice with 3.1 L of water, concentrated to 5 L, and solvent switched to 5 L toluene at −60° C. Upon completion of the solvent switch, 500 mol of heptane was added and the mixture was cooled to 20° C. The batch was aged for 30 minutes at 20° C., then filtered and washed with 1 L of toluene. The resulting solid was dried overnight under a stream of nitrogen to afford 522 g of the title compound (99.4 LCAP, 98.0 wt %, 0.02% dppb-oxide, 512 g assay).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[NH:4][N:3]=1.[C:14]1([C:23]2[CH:28]=[CH:27][C:26]([C:29]([OH:31])=O)=[CH:25][CH:24]=2)[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1>>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[NH:4][N:3]=[C:2]([NH:1][C:29]([C:26]3[CH:25]=[CH:24][C:23]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([NH:1][C:2]5[CH:6]=[C:5]([C:7]6[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=6)[NH:4][N:3]=5)=[O:22])=[CH:18][CH:19]=4)=[CH:28][CH:27]=3)=[O:31])[CH:6]=2)=[CH:8][CH:9]=1
Reactant: O=C(O)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: Cc1ccc(-c2cc(N)n[nH]2)cc1
Product: Cc1ccc(-c2cc(NC(=O)c3ccc(-c4ccc(C(=O)Nc5cc(-c6ccc(C)cc6)[nH]n5)cc4)cc3)n[nH]2)cc1

Procedure:
Compound 476 was prepared from 3-amino-5-(4-methylphenyl)pyrazole and biphenyl-4,4′-dicarboxylic acid. [M+H]+ calcd for C34H29N6O2: 553.24; found: 553.06.
Reaction SMILES: Br[CH:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[C:3]1=[O:13].Cl.CS(C)=[O:17]>>[OH2:11].[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3](=[O:13])[C:2](=[O:17])[C:10]2=[O:11]
Reactant: O=C1c2ccc(O)cc2C(=O)C1Br
Reactant: CS(C)=O
Agent: Cl
Product: O
Product: O=c1c(=O)c2ccc(O)cc2c1=O
Reaction time: 0.5 h

Procedure:
A solution of 0.01 mol of 2-bromo-5-hydroxyindan-1,3-dione in 10 ml dimethyl sulphoxide was heated to 80° C. for 30 minutes. 50 ml of a 1N hydrochloric acid solution was added, after which heating was continued for 30 minutes. The oily suspension obtained after cooling was extracted with ethyl ether. The organic phase was washed in water and dried over magnesium sulphate.
Reaction SMILES: [I:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([O:15]C)[N:10]=2)=[CH:4][C:3]=1[CH3:17]>Br.C(O)(=O)C.O>[I:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[N:10]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: COc1nccc(-c2cc(C)c(I)c(C)c2)n1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(-c2cc[nH]c(=O)n2)cc(C)c1I
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4-(4-Iodo-3,5-dimethylphenyl)-2-methoxypyrimidine is dissolved in 33% solution of HBr in acetic acid (7.7 mL) and the mixture is stirred for 12 hours at room temperature. Then the mixture is diluted with water. The formed precipitate is filtered off, washed with acetone and dried. Yield: 1 g; LC (method 11): tR=0.92 min; Mass spectrum (ESI+): m/z=327 [M+H]+.