Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[CH2:35]([CH:37]1[O:39][CH2:38]1)Br>CN(C)C=O>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH2:35][CH:37]1[CH2:38][O:39]1)[N:19]=[CH:18][CH:17]=[C:16]2[O:15][C:4]1[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
4-(5,6-Dimethyl-[2,2′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-ol (compound 338) (97 mg) was dissolved in N,N-dimethylformamide (4 ml), potassium carbonate (107 mg) and epibromohydrin (0.07 ml) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (99 mg, yield 89%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]/[O:12]C)/[CH2:6][CH2:5]2.CC(=CCC)C.Cl([O-])=[O:21].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([C:11]([OH:12])=[O:21])[CH2:6][CH2:5]2
Reactant: [O-][Cl+][O-]
Reactant: CO/C=C1\CCc2cc(Br)ccc21
Agent: CCC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)C1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 56 %

Procedure:
To a solution of the product from Example 70, Part B (300 mg, 1.3 mmol) and 2-methyl-2-pentene (8 ml) in tert-butanol (32 ml) was added a solution of sodium chlorite (1.36 g, 0.12 mmol) in H2O (12 ml) containing sodium dihydrogen phosphate (1.07 g, 8.9 mmol) and the mixture was stirred vigorously for 20 min at room temperature. Solvents were concentrated in vacuo and the residue was diluted with H2O, extracted with EtOAc (3×), extracts combined, dried (Na2SO4), and concentrated in vacuo to give the title compound (180 mg, 56%).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1.[CH3:19][C:20]([CH3:25])=[CH:21][C:22](Cl)=[O:23].Cl>CN(C)C1C=CN=CC=1.O.C(Cl)Cl.C(N(CC)CC)C>[CH2:13]([N:12]([CH2:16][CH:17]=[CH2:18])[C:4]1[N:3]=[C:2]([NH:1][C:22](=[O:23])[CH:21]=[C:20]([CH3:25])[CH3:19])[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=1)[CH:14]=[CH2:15]
Reactant: CC(C)=CC(=O)Cl
Reactant: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CCN(CC=C)c1nc(NC(=O)C=C(C)C)n2oc(=O)nc2n1
Temperature: 5 °C

Procedure:
15 g. of 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one are suspended in 300 ml. of methylene chloride, 30 ml. of triethylamine and 0.9 g. of 4-dimethylaminopyridine. 10.66 g. of 3,3-dimethylacrylyl chloride in 100 ml. of methylene chloride are added dropwise while stirring and cooling to about 5° C. The mixture is then stirred at 0° C. for 1 hour, treated with water and adjusted to pH 4 with 3-N hydrochloric acid. The two phases are separated and the aqueous phase is extracted with methylene chloride. The combined organic extracts are dried over magnesium sulfate and evaporated under reduced pressure. The residue is recrystallized from methylene chloride/diethyl ether, there being obtained pure N-{5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-7-yl}3-methylcrotonamide having a melting point of 165°-166° C.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[CH2:31]([O:33][CH2:34][CH:35]1[CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]1)[CH3:32]>>[CH2:31]([O:33][CH2:34][CH:35]1[CH2:40][CH2:39][CH:38]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH3:29])[N:17]=3)[CH2:11]2)[CH2:37][CH2:36]1)[CH3:32]
Reactant: CCOCC1CCC(=O)CC1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: CCOCC1CCC(N2CC(NC(=O)CNc3nn(C)c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-ethoxymethyl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: C1COCC1.Br[C:7]1[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:9][O:10][CH:11]=1.[CH:18](/B(O)O)=[CH:19]\[CH2:20][CH2:21][CH2:22][CH3:23].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[CH:18]([C:7]1[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:9][O:10][CH:11]=1)=[CH:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: Brc1conc1-c1cccnc1
Reactant: CCCC/C=C/B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCC=Cc1conc1-c1cccnc1
Temperature: 65 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
To anhydrous THF (30 ml) containing compound 64 (0.64 g, 2.84 mmol), were added 1.5 eq of (E)-hexene-1-ylboronic acid (0.55 g). The resulting mixture was stirred for 2 hours under N2. Successively were added 2 eq of K3PO4 (1.2 g), 2 mol % of Pd(OAc)2 (13 mg) and 4 mol % of S-Phos (47 mg). After the addition, the resulting solution was warmed at 65° C. for 18 hours under N2. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether/PE 1/1) to afford 3-(4-hex-1-enyl-isoxazol-3-yl)-pyridine (compound 67A) as an oil (0.47 g, 69%). 1H-NMR (400 MHz, CDCl3): δ 8.9 (d, J=2 Hz, 1H), 8.72 (dd, J=5 Hz, 2 Hz, 1H), 8.49 (s, 1H), 8.0 (dt, J=8 Hz, 2 Hz, 1H), 7.45-7.41 (m, 1H), 6.11-5.99 (m, 2H), 2.22-2.14 (m, 2H), 1.46-1.29 (m, 4H), 0.91 (t, J=7 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:15]([CH:16]=O)=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:18])[O:7]1)=[O:5])[CH3:2].[CH3:19][O:20][C:21](=[O:31])[C@@H:22]([NH2:30])[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:1]([O:3][C:4]([CH:6]1[C:15]([CH2:16][NH:30][C@H:22]([C:21]([O:20][CH3:19])=[O:31])[CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:18])[O:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Oc2cccc(Cl)c2C=C1C=O
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCOC(=O)C1Oc2cccc(Cl)c2C=C1CN[C@@H](CC1CCCCC1)C(=O)OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 36.8 %

Procedure:
To a solution of 5-chloro-3-formyl-2H-chromene-2-carboxylic acid ethyl ester (1.0 g, 3.74 mmol) in methanol (20 mL) containing molecular sieves (0.7 g) was added commercially available (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (0.83 g, 3.74 mmol) and N,N′-diisopropylethylamine (1.30 mL, 7.49 mmol). The mixture was stirred at 25° C. for 10 h. At this time, sodium cyanoborohydride (0.47 g, 7.49 mmol) and acetic acid (0.47 mL, 7.49 mmol) were added simultaneously to the reaction mixture, and the reaction mixture was stirred for additional 16 hours at 25° C. The reaction mixture was then filtered through celite and washed with methanol. The filtrate was concentrated in vacuo. Flash column chromatography (eluant-ethyl acetate:petroleum ether 1:19, Rf=0.6) over neutral alumina afforded 5-chloro-3-[((S)-2-cyclohexyl-1-methoxycarbonyl-ethylamino)-methyl]-2H-chromene-2-carboxylic acid ethyl ester (0.6 g, 35.7%) as an oil.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[N+:17]([O-:19])=[O:18])[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+]>Cl>[F:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]2)=[C:11]([N+:17]([O-:19])=[O:18])[CH:12]=1
Reactant: CC(=O)N1CCN(c2ccc(F)cc2[N+](=O)[O-])CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cc(F)ccc1N1CCNCC1
Yield: 66.5 %

Procedure:
To 1-acetyl-4-(4-fluoro-2-nitrophenyl)piperazine (10 g) was added 1.2N hydrochloric acid (190 ml) and the mixture was refluxed under heating for 17 hr. The reaction mixture was made alkaline (pH 12) with an aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give a red oil. The oil was crystallized from ethyl acetate-isopropyl ether-hexane to give the title compound (5.6 g) as a red solid.
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:25]=[CH:24][C:17]([O:18][CH:19]([CH3:23])[C:20](O)=[O:21])=[CH:16][CH:15]=1)[C:3]1[CH:12]=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:13])[CH:9]=2)[N:4]=1.S(Cl)([Cl:28])=O>>[CH3:1][N:2]([C:14]1[CH:25]=[CH:24][C:17]([O:18][CH:19]([CH3:23])[C:20]([Cl:28])=[O:21])=[CH:16][CH:15]=1)[C:3]1[CH:12]=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:13])[CH:9]=2)[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: CC(Oc1ccc(N(C)c2cnc3cc(Cl)ccc3n2)cc1)C(=O)O
Product: CC(Oc1ccc(N(C)c2cnc3cc(Cl)ccc3n2)cc1)C(=O)Cl

Procedure:
A mixture of 2-{4-[N-methyl-N-(6-chloroquinoxalin-2-yl)amino]phenoxy}propionic acid (2.0 g; compound no 27, Example 9) and thionyl chloride (25 ml) was heated under reflux for a period of 2 hours. The excess thionyl chloride was removed by distillation under reduced pressure to give 2-{4-[N-methyl-N-(6-chloroquinoxalin-2-yl)amino]phenoxy}propionyl chloride. A mixture of n-propanol (10 ml) and triethylamine (10 ml) was added and the mixture was stirred at room temperature for a period of 1 hour. The mixture was poured into water (200 ml) and the aqueous mixture was extracted with dichloromethane. The organic extract was washed several times with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and the residue was chromatographed over alumina (eluent dichloromethane) to give n-propyl 2-{4-[N-methyl-N-(6-chloroquinoxalin-2-yl)amino]phenoxy}propionate as an oil.
Reaction SMILES: [H-].[Na+].O1CCCC1.[Br:8][C:9]1[S:10][C:11]([C:15]2[NH:16][CH:17]=[CH:18][N:19]=2)=[C:12]([Br:14])[N:13]=1.[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25]Cl>>[Br:8][C:9]1[S:10][C:11]([C:15]2[N:19]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:28])([CH3:27])[CH3:20])[CH:18]=[CH:17][N:16]=2)=[C:12]([Br:14])[N:13]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1nc(Br)c(-c2ncc[nH]2)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccnc1-c1sc(Br)nc1Br
Yield: 50.9 %

Procedure:
To a mixture of sodium hydride (2.89 g, 72.2 mmol) in tetrahydrofuran (431 mL, 5310 mmol) was added 2,4-dibromo-5-(1H-imidazol-2-yl)thiazole (18.81 g, 60.88 mmol) in tetrahydrofuran (60 mL, 700 mmol) at 0° C. The mixture was stirred for 30 min before [β-(Trimethylsilyl)ethoxy]methyl chloride (11.85 mL, 66.96 mmol) in tetrahydrofuran (24 mL, 3.0E2 mmol) was added slowly at 0° C. The reaction was quenched with MeOH. The solvent was evaporated and the residue was purified by column chromatography on silica gel to afford 2,4-dibromo-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)thiazole (13.6 g, 81.7%). LCMS (AA) ES+ 440, 442.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.C(B(CC)[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)C>>[CH3:18][C:17]([C:15]1[CH:14]=[CH:13][N:12]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[N:7]=3)=[CH:9][N:10]=[C:11]2[N:16]=1)([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:27]
Reactant: CCB(CC)c1cccnc1
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(Cl)n3)cnc2n1
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(-c4cccnc4)n3)cnc2n1

Procedure:
3-(2-Chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine was reacted with diethyl(3-pyridyl)borane by the method of Example 35 to afford 7-(1-methyl-1-triethylsilanyloxyethyl)-3-[2-(pyridin-3-yl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidine as a white solid: δH (400 MHz, CDCl3) 0.73 (6H, q, J 8.1), 1.01 (9H, t, J 8.0), 1.72 (6H, s), 7.46-7.53 (2H, m), 7.61 (1H, d, J 5.5), 7.67 (1H, d, J 7.0), 8.52 (1H, s), 8.72-8.79 (2H, m), 9.71 (1H, m), 10.24 (1H, d, J 7.0); m/z (ES+) 447 (M++H).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]([C:10]1[O:11][C:12]2[C:18]([N:19]3[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]3=[O:31])=[C:17]([F:32])[CH:16]=[C:15]([Cl:33])[C:13]=2[N:14]=1)([CH3:9])[CH3:8].O>C(Cl)Cl>[OH:6][C:7]([C:10]1[O:11][C:12]2[C:18]([N:19]3[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]3=[O:31])=[C:17]([F:32])[CH:16]=[C:15]([Cl:33])[C:13]=2[N:14]=1)([CH3:9])[CH3:8]
Reactant: COC(C)(C)c1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3nc(C(C)(C)O)oc23)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.4 %

Procedure:
Under a nitrogen atmosphere a stirred solution of 3.8 mL (3.8 mmole) of 1M boron tribromide (in methylene chloride) in 50 mL of methylene chloride was cooled to about -40° C., and a solution of 0.6 gram (2.6 mmole) of 3-[2-(1-methoxy-1-methylethyl)-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione in 50 mL of methylene chloride was added dropwise at such a rate as to maintain the reaction mixture temperature below -30° C. Upon completion of the addition the reaction mixture was allowed to warm to ambient temperature, where it stirred for about 18 hours. At the conclusion of this period the reaction mixture was poured into water and thoroughly extracted with methylene chloride. The combined extracts were washed with an aqueous saturated sodium chloride solution, dried with sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to a brown oil, which was subjected to column chromatography on silica gel. Elution was with 1:4 ethyl acetate to heptane. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.3 gram of 3-[2-(1-hydroxy-1-methylethyl)-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]1([C:19]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:23][NH:22][C:21](=[O:31])[CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O[CH2:33][CH2:34][C:35]1[CH:36]=[C:37]([CH:44]=[CH:45][CH:46]=1)[O:38][CH2:39][C:40]([O:42][CH3:43])=[O:41].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[O:31]=[C:21]1[N:22]([CH2:33][CH2:34][C:35]2[CH:36]=[C:37]([CH:44]=[CH:45][CH:46]=2)[O:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])[N:23]=[C:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:20]1
Reactant: COC(=O)COc1cccc(CCO)c1
Reactant: O=c1cc(-c2ccccc2)c(-c2ccccc2)n[nH]1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)COc1cccc(CCn2nc(-c3ccccc3)c(-c3ccccc3)cc2=O)c1
Temperature: 0 °C
Reaction time: 1.75 h
Yield: 96.9 %

Procedure:
Diethyl azodicarboxylate (2.73 g, 2.50 mL, 16 mmol) was added to a stirred solution of 5,6-diphenyl-3(2H)-pyridazinone (3.00 g, 12 mmol), methyl [3-(2-hydroxyethyl)-phenoxy]acetate (2.80 g, 13 mmol) and triphenylphosphine (4.12 g, 16 mmol) in dry THF (75 mL) maintained at 0° C. The ice bath was removed and the mixture stirred at room temperature for 1.75 hours before removal of the solvent. The residue was chromatographed twice on columns of silica gel using mixtures of diethyl ether and hexanes (7:3) and then (3:2) as eluent to give methyl [3-[2-(1,6-dihydro-6-oxo-3,4-diphenyl-1-pyridazinyl)ethyl]phenoxyacetate] (5.12 g, 98%), contaminated with 0.6 equivalents of 1,2-dicarbethoxy hydrazine, as a white foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH2:15])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:16]1[CH:17]=[C:18]([C:25](O)=[O:26])[N:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=12>>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH:15][C:25]([C:18]2[N:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]3=[N:16][CH:17]=2)=[O:26])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1cnc2ccccn12
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2C[C@@H]21
Product: CC(C)(C)OC(=O)N1[C@H](CNC(=O)c2cnc3ccccn23)C[C@@H]2C[C@@H]21

Procedure:
prepared by reaction of (1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester with imidazo[1,2-a]pyridine-3-carboxylic acid. LC-MS (acidic): tR=0.74 min; [M+H]+=357.1.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([C:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=3)=[CH:21][NH:22]2)=[CH:18][CH:17]=1.C(O)C>CS(C)=O>[CH3:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([C:25]3[CH2:26][CH2:27][N:28]([CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]4[CH:14]=[CH:13][CH:12]=[C:11]5[C:7]=4[CH:8]=[CH:9][NH:10]5)[CH2:29][CH:30]=3)=[CH:21][NH:22]2)=[CH:18][CH:17]=1
Reactant: Cc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1ccc2c(C3=CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.389 g, 2.05 mmol) and 6-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.400 g, 1.87 mmol) using ethanol as reaction solvent. Yield 0.260 g (35%) as an orange foam. mp 99-103° C. (dec). FDMS m/e=401 (M+ of free base). α[D]589=+5.1 (c=0.98, dimethylsulfoxide).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([NH:15][CH2:16][C:17]([F:20])([CH3:19])[CH3:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1>[Pt].C(#N)C>[Cl:1][C:2]1[C:11]([NH2:12])=[C:10]([NH:15][CH2:16][C:17]([F:20])([CH3:18])[CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)(F)CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Agent: [Pt]
Solvent: CC#N
Product: CC(C)(F)CNc1c(N)c(Cl)nc2ccccc12
Yield: 105.2 %

Procedure:
A Parr vessel was charged sequentially with 2-chloro-N-(2-fluoro-2-methylpropyl)-3-nitroquinolin-4-amine (4.75 g, 15.8 mmol), acetonitrile (50 mL), and 5% platinum on carbon (475 mg) and placed under hydrogen pressure (40 psi, 2.8×105 Pa) overnight. The reaction mixture was filtered through a layer of CELITE filter aid. The filter cake was washed with methanol. The filtrate was concentrated under reduced pressure to provide 4.45 g of 2-chloro-N4-(2-fluoro-2-methylpropyl)quinoline-3,4-diamine as a solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]1)=[CH:11][C:10]([C:29]1[CH:34]=[C:33]([Cl:35])[C:32]([OH:36])=[C:31]([Cl:37])[CH:30]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>>[NH2:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([NH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:29]4[CH:30]=[C:31]([Cl:37])[C:32]([OH:36])=[C:33]([Cl:35])[CH:34]=4)[CH:11]=3)[N:6]=[CH:5][C:4]=2[C:1](=[O:3])[CH3:2])[CH2:16][CH2:17]1
Reactant: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](N)CC1

Procedure:
Following general procedure A-2, tert-butyl trans-4-[3-acetyl-6-(3,5-dichloro-4-hydroxyphenyl)quinolin-4-ylamino]cyclohexylcarbamate (46 mg, 0.085 mmol) was reacted with TFA (2 mL) to afford the desired product (19.4 mg, 51%) as an orange solid: 1H NMR (500 MHz, DMSO-d6+D2O) δ 8.92 (s, 1H), 8.20 (s, 1H), 8.04 (d, J=8.9 Hz, 1H), 7.89 (d, J=8.7 Hz, 1H), 7.63 (s, 2H), 4.09 (s, 1H), 3.20-3.11 (m, 1H), 2.68 (s, 3H), 2.26 (d, J=12.7 Hz, 2H), 2.08 (d, J=10.1 Hz, 2H), 1.69-1.58 (m, 2H), 1.57-1.46 (m, 2H); ESI MS m/z 444 [C23H23Cl2N3O2+H]+; HPLC>99% (AUC), tR=8.70 min.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].N1C=CC=CC=1.[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(Cl)Cl>[S:37]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])([C:34]1[CH:35]=[CH:36][C:31]([CH3:41])=[CH:32][CH:33]=1)(=[O:39])=[O:38]
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CCCCCCCCCCCCCCCCCCCS(=O)(=O)c1ccc(C)cc1
Reaction time: 14 h
Yield: 94 %

Procedure:
ln 90 ml of methylene chloride was dissolved methyl 20-hydroxyeicosanoate (8.0 g, 23.4 mmoles). To the obtained solution were added pyridine (7.93 g, 93.4 mmoles) and then, under ice-cooling, p-toluenesulfonyl chloride (8.90 g, 46.7 mmoles) gradually over a period of 1 hour. The mixture was stirred for 14 hours in a refrigerator. After the completion of the reaction, the reaction mixture was subjected to the same after-treatment steps as in Reference Example 1, to give methyl 20-tosyleicosanoate (10.57 g, 91%) having the following properties.