Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH:9]1[CH2:14][CH:13]2[CH2:15][CH2:16][CH:10]1[CH2:11][C:12]2=[O:17].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:19]1([CH:18]2[CH:11]3[C:12](=[O:17])[CH:13]4[CH2:15][CH2:16][CH:10]3[CH:9]([CH2:14]4)[NH:8]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccccc1
Reactant: NC1CC2CCC1CC2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C2CCC3C(C2)NC(c2ccccc2)C13
Yield: 90.8 %

Procedure:
A three neck 3 L flask, fitted with a well isolated soxhlet (300 mL) filled with molecular sieves (3 Å), was charged with 5-amino-bicyclo[2.2.2]octan-2-one trifluoro-acetic acid salt (Preparation 76, 85.0 g, 336 mmol, 1.0 eq), benzaldehyde (37.5 mL, 369 mmol, 1.1 eq) and DCM (1.25 L). The suspension was heated to reflux. The clear reaction mixture was concentrated to a tan solid. The latter was suspended in a mixture of diethyl ether (600 mL) and EtOH (50 mL). The solids were collected by filtration (P3) and thoroughly washed with ethyl acetate and diethyl ether. The filter cake was dried in vacuo to yield title compound as an off-white solid (104 g, 305 mmol, 91%, 97.3% pure (HPLC)).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[N:42]=[C:41]([C:43]2([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44]2)[CH:40]=[CH:39][CH:38]=1>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:37]3[N:42]=[C:41]([C:43]4([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44]4)[CH:40]=[CH:39][CH:38]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: NC(=O)C1(c2cccc(Br)n2)CC1
Product: C[C@@H](c1ccc(-c2cccc(C3(C(N)=O)CC3)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 68 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 1-(6-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid amide following a procedure analogous to that described in Example 1. Yield: 68% of theory; LC (method 1): tR=1.92 min; Mass spectrum (ESI+): m/z=514 [M+H]+.
Reaction SMILES: [S:1]([OH:27])([O:4][CH2:5][CH:6]1[CH:13]2[CH:9]([O:10]C(C)(C)[O:12]2)[CH:8]([N:16]2[CH:24]=[N:23][C:22]3[C:21](=[O:25])[NH:20][C:19]([NH2:26])=[N:18][C:17]2=3)[O:7]1)(=[O:3])=[O:2]>O>[S:1]([OH:27])([O:4][CH2:5][C@@H:6]1[C@H:13]([OH:12])[C@H:9]([OH:10])[C@H:8]([N:16]2[CH:24]=[N:23][C:22]3[C:21](=[O:25])[NH:20][C:19]([NH2:26])=[N:18][C:17]2=3)[O:7]1)(=[O:2])=[O:3]
Reactant: CC1(C)OC2C(COS(=O)(=O)O)OC(n3cnc4c(=O)[nH]c(N)nc43)C2O1
Solvent: O
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](COS(=O)(=O)O)[C@H](O)[C@@H]2O)c(=O)[nH]1
Temperature: 70 °C

Procedure:
To a solution of crude 12 (8.11 mmol) in water (8 mL) was added Amberlite 120 acidic resin (0.300 g). The mixture was heated to 70° C. for 4 hours, and then filtered while hot through a sintered glass frit. The water was removed under reduced pressure and ambient temperature to yield 5 (0.244 g, 83% for two steps).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-])=O)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].O.NN>[Fe](Cl)(Cl)Cl.CO>[CH3:18][N:2]([CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:15])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:1]
Reactant: CN(C)CC(=O)N1CCc2ccc([N+](=O)[O-])cc21
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: CO
Solvent: O
Product: CN(C)CC(=O)N1CCc2ccc(N)cc21
Temperature: 65 °C
Yield: 80.2 %

Procedure:
A suspension of N,N-dimethyl-2-(6-nitro-2,3-dihydro-1 H-indol-1-yl)-2-oxoethanamine (13.6 g, 54.6 mmol), hydrazine hydrate (21.42 mL, 436 mmol), iron (III) chloride (1.768 g, 10.91 mmol), activated carbon (15 g), and methanol (100 mL) was maintained at 65° C. for 12 hours, cooled, and filtered through celite (rinsed with additional methanol). Filtrates were concentrated, redissolved in ethyl acetate, and washed twice with saturated aqueous sodium chloride and sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, and concentrated to afford 1-[(dimethylamino)acetyl]-2,3-dihydro-1H-indol-6-amine (9.6 g, 80% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.44 (d, J=1.40 Hz, 1 H), 6.83 (d, J=8.03 Hz, 1 H), 6.20 (dd, J=7.93, 2.11 Hz, 1 H), 4.94 (s, 2 H), 4.06 (t, J=8.43 Hz, 2 H), 3.14 (s, 2 H), 2.91 (t, J=8.33 Hz, 2 H), 2.25 (s, 6 H).
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=O)[CH2:14][C:15](=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[C:1]12([CH2:11][NH:12][CH2:13][CH2:14][CH:15]([OH:20])[CH2:16][CH:17]([CH3:18])[CH3:19])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(C)CC(=O)CC(=O)NCC12CC3CC(CC(C3)C1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(O)CCNCC12CC3CC(CC(C3)C1)C2
Temperature: 70 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
A solution of N-(1-adamantylmethyl)-5-methyl-3-oxohexanamide (1.5 g, 5.1 mmol) in anhydrous THF (15 mL) was added slowly to a suspension of LAH (500 mg, 13.1 mmol) in anhydrous THF (5 mL) under N2 at 0° C. The reaction mixture was heated to 70° C. and stirred at this temperature overnight. Water (0.5 mL) and 10% aq NaOH (0.5 mL) were added to quench the reaction. The resulting slurry was filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on a silica gel column eluted with 10:1 PE/EtOAc to give 1-(1-adamantylmethylamino)-5-methylhexan-3-ol (900 mg, 63.3%). MS (M+1): 280.
Reaction SMILES: [CH:1]1([C:6]([NH:8][C@H:9]([C:22]([NH:24][C@H:25]([C:29]([OH:31])=O)[CH2:26][CH2:27][CH3:28])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[SH:44][CH2:45][CH2:46][C:47]([NH:49][C:50]([CH3:55])([CH3:54])[C:51]([OH:53])=[O:52])=[O:48].C(N1CCOCC1)C>CN(C)C=O>[CH:1]1([C:6]([NH:8][C@H:9]([C:22]([NH:24][C@H:25]([C:29]([S:44][CH2:45][CH2:46][C:47]([NH:49][C:50]([CH3:55])([CH3:54])[C:51]([OH:53])=[O:52])=[O:48])=[O:31])[CH2:26][CH2:27][CH3:28])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCC[C@H](NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)C1CCCC1)C(=O)O
Reactant: CC(C)(NC(=O)CCS)C(=O)O
Agent: CCN1CCOCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCC[C@H](NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)C1CCCC1)C(=O)SCCC(=O)NC(C)(C)C(=O)O
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A solution of 10 mmoles of Nα -(Nα -cyclopentanecarbonyl-Nε -tert-butyloxycarbonyl-L-lysyl-norvaline in redistilled dimethylformamide (DMF) is cooled in an ice-dry ice-acetone bath at -20° C. To this solution is added a cold solution of 10 mmoles of 1,1'-carbonyldiimidazole in DMF. The solution is stirred at -10° C. for two hours and then mixed with a cold solution of 10 mmoles of 2-[(3-mercaptopropanoyl)amino]-2-methylpropanoic acid (from Example 46) in DMF which is neutralized with N-ethyl morpholine. The reaction mixture is storred at -10° C. for an additional hour and then slowly warmed to room temperature. The solvent is removed under reduced pressure at 40° C. and ethyl acetate is added to the residue. The mixture is cooled in an ice water bath and washed with 1N citric acid and then three times with saturated NaCl solution. The solvent is removed with a rotary evaporator after drying over anhydrous MgSO4. The product is purified by LH-20 column chromatography using a 1.2 cm by 95 cm column and eluted with THF:isopropanol, 3:7 (parts by volume). The peak fractions are pooled and the solvent is removed under reduced pressure yielding the named product.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[CH3:23])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.CC1(C)C(C)(C)OB([C:32]2[CH:40]=[C:39]3[C:35]([CH:36]=[N:37][NH:38]3)=[CH:34][CH:33]=2)O1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH:38]1[C:39]2[C:35](=[CH:34][CH:33]=[C:32]([C:2]3[CH:3]=[C:4]([NH:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([N:18]5[CH2:22][CH2:21][CH2:20][CH:19]5[CH3:23])[N:13]=4)[C:5]4[N:6]([CH:8]=[CH:9][N:10]=4)[N:7]=3)[CH:40]=2)[CH:36]=[N:37]1
Reactant: CC1(C)OB(c2ccc3cn[nH]c3c2)OC1(C)C
Reactant: CC1CCCN1c1cccc(Nc2cc(Cl)nn3ccnc23)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC1CCCN1c1cccc(Nc2cc(-c3ccc4cn[nH]c4c3)nn3ccnc23)n1
Temperature: 100 °C
Reaction time: 16 h
Yield: 24.7 %

Procedure:
A mixture of 6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (120 mg, 0.365 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (134 mg, 0.547 mmol), Pd2(dba)3 (21 mg, 0.037 mmol), X-phos (70 mg, 0.146 mmol) and Na2CO3 (117 mg, 1.1 mmol) in dioxane (5 mL) and water (0.5 mL) was heated to 100° C. with stirring for 16 h under N2. The solvent was removed in vacuo and the resulting mixture was first purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=20:1), and then again (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give 6-(1H-indazol-6-yl)-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (37 mg, 25%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 13.31 (s, 1H), 9.69 (s, 1H), 8.87 (s, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 8.03 (s, 1H), 7.91 (d, 1H, J=8.4 Hz), 7.69-7.67 (m, 2H), 7.45 (t, 1H, J=7.8 Hz), 6.75 (d, 1H, J=7.8 Hz), 6.08 (d, 1H, J=8.1 Hz), 4.21 (brs, 1H), 3.58 (brs, 1H), 3.45-3.38 (m, 1H), 2.06-1.97 (m, 3H), 1.69 (brs, 1H), 1.11 (d, 3H, J=6.0 Hz). LC-MS: [M+H]+, 411, tR=1.672 min, HPLC: 95.88% at 214 nm, 98.36% at 254 nm, tR=5.913 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1([NH2:12])[CH2:11][CH2:10]1.[Br:13][C:14]1[S:18][C:17]2=[N:19][C:20]([C:22](O)=[O:23])=[CH:21][N:16]2[CH:15]=1>>[Br:13][C:14]1[S:18][C:17]2=[N:19][C:20]([C:22]([NH:12][C:9]3([C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[F:1])[CH2:10][CH2:11]3)=[O:23])=[CH:21][N:16]2[CH:15]=1
Reactant: NC1(c2cc(F)ccc2F)CC1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Product: O=C(NC1(c2cc(F)ccc2F)CC1)c1cn2cc(Br)sc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLIV, using 1-(2,5-difluorophenyl)cyclopropanamine and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=3)[NH2:21])=[N:10][N:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.ClC1N=C(C2C(C3C=C(NC(=O)C(F)(F)F)C=CC=3)=NN3C=CC=C(F)C=23)C=CN=1.[F:55][C:56]1[CH:64]=[CH:63][CH:62]=[C:61]([F:65])[C:57]=1[C:58](Cl)=[O:59].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH:21][C:58](=[O:59])[C:57]4[C:56]([F:55])=[CH:64][CH:63]=[CH:62][C:61]=4[F:65])[CH:22]=[CH:23][CH:24]=3)=[N:10][N:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccc(-c2nn3cc(F)ccc3c2-c2ccnc(Cl)n2)c1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: O=C(Nc1cccc(-c2nn3cccc(F)c3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1cccc(-c2nn3cc(F)ccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
To the solution of 3-[3-(2-chloro-4-pyrimidinyl)-6-fluoropyrazolo[1,5-a]pyridin-2-yl]aniline (0.31 g) (prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)-4-fluoropyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide obtained Example 168, Step B using a protocol similar to that described in Example 168, Step C) in THF (10 mL) was added 2,6-difluorobenzoyl chloride (0.19 g). The reaction was kept stirring at rt for 0.5 h and worked up with sat. NaHCO3 solution (8 mL). After extraction with EtOAc (2×10 mL), drying with Na2SO4, and concentration, the crude mixture was purified through silica gel column chromatography to afford N-{3-[3-(2-chloro-4-pyrimidinyl)-6-fluoropyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide as a yellow solid (0.43 g, 96%). ESIMS (M+H)+=480.
Reaction SMILES: Cl.[NH2:2][OH:3].[H-].[Na+].[CH2:6]([N:13]1[C:17](=[O:18])[CH:16]2[C:19]([CH3:33])([CH3:32])[N:20]([CH3:31])[CH:21]([CH2:22][C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=3)[CH:15]2[C:14]1=[O:34])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[NH2:28][C:27](=[N:2][OH:3])[C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH:21]2[N:20]([CH3:31])[C:19]([CH3:32])([CH3:33])[CH:16]3[C:17](=[O:18])[N:13]([CH2:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:14](=[O:34])[CH:15]23)=[CH:30][CH:29]=1
Reactant: NO
Reactant: CN1C(Cc2ccc(C#N)cc2)C2C(=O)N(Cc3ccccc3)C(=O)C2C1(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(Cc2ccc(C(N)=NO)cc2)C2C(=O)N(Cc3ccccc3)C(=O)C2C1(C)C
Temperature: 0 °C
Reaction time: 48 h
Yield: 97.7 %

Procedure:
2.19 g (31.56 mmol) of hydroxylamine hydrochloride were suspended in 8 ml of DMF and cooled to 0° C. 0.79 g (26.3 mmol) of 80% sodium hydride was added slowly. 1.02 g (2.63 mmol) of (1RS, 3aSR,6aRS)-4-(5-benzyl-2,3,3-trimethyl-4,6-dioxo-octahydro-pyrrolo[3,4-c]pyrrol-1-ylmethyl)-benzonitrile were dissolved in DMF and added to the reaction mixture. The cooling was then no longer applied. The mixture was stirred at room temperature for 2 days. Thereafter, it was filtered and the DMF was removed in a high vacuum. The mixture was purified chromatographically (RP18, gradient from water to methanol). 1.08 g (97%) of (3aRS,4RS,6aSR)-4-[4-(amino-hydroxyimino-methyl)-benzyl]-2-benzyl-5,6,6-trimethyl-tetrahydro-pyrrolo[3,4-c]pyrrole-1,3-dione were isolated as a colourless powder. M.p.: 189°-192° C. ISP-MS: 421.5 ([M+H]+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[CH3:34][C:35](OC(C)=O)=[O:36]>C(Cl)Cl.O>[CH3:14][C:11]1([CH3:13])[O:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:35](=[O:36])[CH3:34])=[CH:3][CH:4]=2)=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)[C:10]1=[O:15]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)OC(c2ccc(N)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 26.1 %

Procedure:
To a stirred solution of 5-(4-aminophenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (0.07 g, 0.16 mmol) in DCM (5 mL) were added Ac2O (0.018 mL, 0.19 mmol) and TEA (0.04 mL, 0.32 mmol) at 0° C. under N2 atmosphere. The reaction mixture was stirred at RT for 14 h. The reaction mixture was diluted with water and extracted with DCM (2×15 mL). Combined organic layers were washed with water (2×5 mL), brine and dried over anhydrous Na2SO4. After filtration and evaporation, the crude material was purified by silica gel column chromatography to afford N-(4-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-dihydrofuran-2-yl) phenyl)acetamide (20 mg, 26%), as an off white solid. 1H NMR (500 MHz, CDCl3): δ 8.22 (d, J=8.5 Hz, 1H), 8.08 (d, J=7.9 Hz, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.74 (t, J=8.2 Hz, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.64 (d, J=8.2 Hz, 2H), 7.56 (t, J=8.5 Hz, 1H), 7.48 (d, J=7.4 Hz, 2H), 7.22 (d, J=7.5 Hz, 2H), 7.08 (d, J=8.9 Hz, 2H), 5.42 (s, 2H), 2.22 (s, 3H), 1.58 (s, 6H). MS: [M+Na]: m/z=501.3, [M+H]: m/z=479.3. HPLC: 95.9% (RT-2.32 min), Column: Acquity BEH-C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[NH4+].[OH-]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:9]([C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1)#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: Nc1ccc(I)cc1
Reactant: C#CCCCCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCCCC#Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 85.9 %

Procedure:
To a mixture of 4-iodoaniline (2.19 g, 10 mmol), CuI (38 mg, 0.2 mmol, 2 mol %) and Pd(PPh3)2Cl2 (70 mg, 0.1 mmol, 1 mol %) under argon was added THF (60 mL), followed by non-1-yne (1.49 g, 12 mmol, 1.2 equiv.). After stirring for 1 min at rt, 0.5 M NH4OH (40 mL) was added dropwise. After addition, the resulting mixture was stirred 0/N at rt. It was extracted with ether (60 mL+30 mL) and combined extracts were dried (Na2SO4) and purified by flash chromatography (eluent: EtOAc/Hex=1:6) to give 4-(non-1-ynyl) aniline as a light yellow oil (1.85 g, 86%). 1H NMR (400 MHz, CDCl3) δ 7.22 (d, 2H, J=8.4 Hz), 6.60 (d, 2H, J=8.4 Hz), 3.65 (s, br, 2H, NH2), 2.38 (t, 2H, J=7.0 Hz), 1.59 (quint, 2H, J=7.2 Hz), 1.44 (quint, 2H, J=6.8 Hz), 1.38-1.25 (m, 6H), 0.90 (t, 3H, J=6.4 Hz).
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][CH:8]=1.F.F.F.C(N(CC)CC)C.[F:23]C(F)(C(F)(F)F)C(F)(F)C(F)(F)S(F)(=O)=O.C([O-])(O)=O.[Na+]>C1COCC1.C(N(CC)CC)C>[F:23][CH2:2][C:3]1[N:4]=[CH:5][C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][CH:8]=1
Reactant: COC(=O)c1cnc(CO)cn1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cnc(CF)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 14.5 %

Procedure:
To a solution of methyl 5-(hydroxymethyl)pyrazine-2-carboxylate (0.64 g) in THF (20 mL) was added triethylamine (2.30 g) and the solution was cooled to 0° C. Triethylamine trihydrofluoride (1.22 g) was then added followed by nonafluorobutanesulfonyl fluoride (2.28 g) dropwise over 5 mins. After warming to RT and stirring for 2 h, NaHCO3 (sat., aq., 100 mL) was added, and the mixture was extracted with EtOAc (2×50 mL). The combined organic portions were dried over MgSO4, evaporated, and purified by silica gel chromatography (5% to 50% EtOAc in hexane) to afford the title compound (94 mg). 1H NMR (400 MHz, CDCl3) δ ppm 4.07 (s, 3H), 5.67 (d, J=46.5 Hz, 2H), 8.89 (s, 1H), 9.28 (s, 1H)
Reaction SMILES: O[CH:2]([CH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])[CH2:3][CH2:4][CH2:5][CH3:6].II.C1(C)C(C)=CC=CC=1>O>[CH2:2]([C:7]1[C:8](=[O:12])[CH2:9][CH2:10][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(O)C1CCCC1=O
Agent: II
Solvent: O
Solvent: Cc1ccccc1C
Product: CCCCCC1=CCCC1=O
Yield: 97.3 %

Procedure:
In a 100 ml four-neck flask fitted with a thermometer, a reflux condenser and a stirrer were placed 2-(1-hydroxypentyl)cyclopentanone (20 g) synthesized in Reference Example 1, iodine (0.01 g) and xylene (10 ml), and water was removed under refluxing, followed by 2 hours of the reaction at 170° C. The reaction mixture was washed with water and the layers were separated from each other. Further, the resulting organic layer was washed with saturated brine and separated. The organic layer was evaporated on a rotary evaporator under reduced pressure to recover xylene, whereby a crude product (19.8 g) was obtained. The product was distilled using a Claisen distillation apparatus to obtain 17.4 g of 2-pentyl-2-cyclopentenone (boiling point: 105° C./933 Pa; GC purity: 98.2%).
Reaction SMILES: [I-].[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9](=[N:12][CH3:13])SC)=[CH:5][CH:4]=1.[N:16]1([CH2:21][CH2:22][CH2:23][NH2:24])[CH2:20][CH2:19][CH2:18][CH2:17]1>C(O)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]([NH:12][CH3:13])=[N:24][CH2:23][CH2:22][CH2:21][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:14][CH:15]=1
Reactant: NCCCN1CCCC1
Reactant: CN=C(NCc1ccc(Cl)cc1)SC
Agent: [I-]
Solvent: CCO
Product: CNC(=NCCCN1CCCC1)NCc1ccc(Cl)cc1
Yield: 73 %

Procedure:
A solution of the product from step b (358 mg, 1.00 mmol) and 3-pyrrolidin-1-yl-propylamine (0.19 ml) in ethanol (4 ml) was stirred at ambient temperature for 16 h followed by heating at reflux for 1 h. The solvent was removed at reduced pressure and the residue was partitioned between DCM (20 ml) and aqueous ammonia (880, 20 ml). The aqueous phase was extracted with further DCM (10 ml) and then discarded. The combined organic phases were washed twice with water (20 ml) and once with brine (20 ml). The organic phase was dried over anhydrous sodium sulfate and the filtrate evaporated to afford the title compound (225 mg, 73%). 1H NMR 7.40-7.29 (4H, m), 4.60 (2H, s), 3.42-3.47 (2H, m), 2.97 (3H, s), 2.50-2.44 (6H, m), 1.83-1.63 (6H, m).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:18]2[CH:17]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:14][C:13]=2[S:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2.[Na+].[I-:24]>CC(C)=O>[I:24][CH2:2][CH2:3][CH2:4][N:5]1[C:18]2[CH:17]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:14][C:13]=2[S:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: FC(F)(F)c1ccc2c(c1)N(CCCCl)c1ccccc1S2
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: FC(F)(F)c1ccc2c(c1)N(CCCI)c1ccccc1S2
Temperature: 55 °C

Procedure:
A solution of 10-(3-chloropropyl)-2-(trifluoromethyl)-10H-phenothiazine was mixed with acetone (50 mL) and NaI (4.0 g, 26 mmol) and heated at 55° C. for 48 h. Once no starting material was observed by analytical LCMS, the reaction mixture was partitioned between CH2Cl2 (100 mL) and an aqueous solution of Na2S2O3 (20 ml). The organic layer is dried with MgSO4 and concentrated to afford the title compound.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH2:10]([N:14]=[C:15]=[O:16])[CH2:11][CH2:12][CH3:13]>CN(C)C=O>[CH2:10]([NH:14][C:15]([N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])=[O:16])[CH2:11][CH2:12][CH3:13]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: CCCCN=C=O
Solvent: CN(C)C=O
Product: CCCCNC(=O)n1cc(F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.4 %

Procedure:
13.0g (0.10 mole) of 5-fluorouracil was dissolved in 70 ml of dimethyl formamide, then 11.9g (0.12 mole) of n-butyl isocyanate was added thereto at room temperature and stirred at the same temperature for 24 hours. The reaction mixture was concentrated to 40ml by removing dimethyl formamide and excess n-butyl isocyanate under reduced pressure. The residue was poured into 300ml of water and resultant precipitate was filtered off. The precipitate was washed and dried and 16.6g (72.3% yield) of 1-(n-butylcarbamoyl)-5-fluorouracil was obtained