Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8](=[O:26])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15][C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][C:21](=[O:25])[NH:22]3)=[CH:18][CH:17]=2)=[CH:5][C:4]([CH3:27])=[N:3]1.[CH:28](OCC)=[O:29].[O-]CC.[Na+].Cl>C(O)C.CCOC(C)=O>[CH3:1][N:2]1[C:6]([NH:7][C:8](=[O:26])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15][C:16]2[CH:24]=[C:23]3[C:19](/[C:20](=[CH:28]/[OH:29])/[C:21](=[O:25])[NH:22]3)=[CH:18][CH:17]=2)=[CH:5][C:4]([CH3:27])=[N:3]1
Reactant: Cc1cc(NC(=O)c2ccccc2Sc2ccc3c(c2)NC(=O)C3)n(C)n1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(NC(=O)c2ccccc2Sc2ccc3c(c2)NC(=O)/C3=C\O)n(C)n1
Temperature: 78 °C
Yield: 19 %

Procedure:
N-(2,5-Dimethyl-2H-pyrazol-3-yl)-2-(2-oxo-2,3-dihydro-1H-indol-6-ylsulfanyl)-benzamide (as prepared above in Step 4; 0.300 g, 0.793 mmol) was dissolved in anhydrous ethanol (8 mL) and the resulting solution was treated with ethyl formate (0.058 mL, 0.717 mmol) The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (1.48 mL, 3.97 mmol). This reaction mixture was heated at 78° C. for 0.5 h, which caused the reaction mixture to turn black in color. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH=1 with dropwise addition of 1M HCl(aq). The reaction mixture was diluted with EtOAc (25 mL) and extracted with brine (2×25 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified via flash silica gel chromatography (5% MeOH in CHCl3) affording the title compound in 19% yield (0.061 g, 0.150 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10]([CH2:20][CH2:21][OH:22])=[C:11]([CH3:19])[NH:12]3)=[O:7])=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.OP(O)(O)=O.C(OCC)C>CS(C)=O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10]([CH2:20][CH:21]=[O:22])=[C:11]([CH3:19])[NH:12]3)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc2[nH]c(C)c(CCO)c2c1C(=O)c1ccc(Cl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=P(O)(O)O
Solvent: CS(C)=O
Solvent: CCOCC
Product: COc1ccc2[nH]c(C)c(CC=O)c2c1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.8 %

Procedure:
To a mixture in dry DMSO (11.6 mL) of 2-(4-chlorobenzoyl-5-methoxy-2-methylindol-3-yl) ethanol (2.0 g, 5.8 mmol), prepared as in step 1, and dicyclohexylcarbodiimide (DCC) (1.6 g. 7.8 mmol) was added 1.0 M H3PO4 in DMSO (1.0 mL) and the reaction mixture was stirred at room temperature for 48 hours. Diethyl ether (100 mL) was added and the solid dicyclohexylurea byproduct was removed by filtration. The filtrate was washed with water, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was triturated with hexane/ether to give 1.9 g (95%) of (4-chlorobenzoyl-5-methoxy-2-methylindol-3-yl) acetaldehyde.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[C:18]([F:24])=[C:19]([F:23])[CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[C:18]([F:24])=[C:19]([F:23])[CH:20]=[C:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(F)c(F)cc(Br)c3O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3c(F)c(F)cc(-c4ccccc4)c3O2)cc1
Yield: 79.6 %

Procedure:
To a solution of (±)-(7-bromo-4,5-difluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.59 mmol) in dioxane (30 mL) was added phenylboronic acid (0.656 g, 5.38 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (0.293 g, 0.359 mmol), and potassium carbonate (0.993 g, 7.18 mmol) and the reaction mixture was heated at reflux for 48 h. The reaction mixture was filtered (celite), rinsed (ethyl acetate), and the combined organic layers were washed with water (100 mL), aqueous sodium chloride (75 mL), dried (sodium sulfate) and the solvent was removed in vacuo to provide a crude solid. Purification by column chromatography (silica, ethyl acetate:hexane 1:9) afforded 1.19 g (80%) of (±)-(4,5-difluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Rf=0.76 (silica, ethyl acetate:hexanes 1:9); 1H NMR (DMSO-d6) δH 7.69 (d, 2H); 7.50 (dd, 1H); 7.56 (d, 2H); 7.35 (m, 6H); 5.14 (m, 1H); 4.30 (dd, 1H); 4.20 (dd, 1H); 3.39 (dd, 1H); 3.05 (dd, 1H).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:5]=1)(=[O:3])[CH3:2].[Br:20]Br>C1COCC1>[Br:20][CH2:2][C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:5]=1)=[O:3]
Reactant: CC(=O)c1cn(C(=O)OC(C)(C)C)c2ccccc12
Reactant: BrBr
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1cc(C(=O)CBr)c2ccccc21

Procedure:
To a stirred solution of 3-acetyl-1-(tert-butoxycarbonyl)-indole, which may be prepared as described in Step (b) above, (0.01 mol), in THF at a temperature of about −80° C. to about 25° C. is added bromine (0.01 mol), and the mixture is stirred from about 5 minutes to about 24 hours. Reaction progress may be followed by TLC or HPLC. When a sufficient amount of desired product is formed, the mixture (or, optionally, the residue which is obtained after first rotary evaporating off the reaction solvent) is partitioned between ethyl acetate and an excess of an aqueous solution of sodium bisulfite or an aqueous solution of sodium thiosulfate. The organic layer is washed with water, then brine, dried over sodium sulfate, and rotary evaporated to give 3-bromoacetyl-1-(tert-butoxycarbonyl)-indole, which may be purified, if needed or desired, by chromatography on silica gel or crystallization.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)=[O:6].[CH3:22][O:23][C:24](=[O:37])[CH2:25][CH2:26][C:27]1[CH:32]=[C:31](C)[C:30]([CH:34]=O)=[C:29](C)[CH:28]=1.OOS([O-])=O.[K+]>CN(C=O)C.O>[CH3:22][O:23][C:24](=[O:37])[CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([C:34]2[NH:1][C:2]3[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]4[CH:17]=[CH:16][C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[N:9]=4)[CH:18]=[CH:19][C:20]=3[N:21]=2)=[CH:31][CH:32]=1
Reactant: Nc1ccc(C(=O)Nc2ccc3ccccc3n2)cc1N
Reactant: COC(=O)CCc1cc(C)c(C=O)c(C)c1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1ccc(-c2nc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)cc1
Reaction time: 0.33 h

Procedure:
To a mixture of 3,4-diamino-N-quinolin-2-yl-benzamide (1.0 g, 3.92 mmol) and 3-(4-formyl-3,5-dimethyl-phenyl)-propionic acid methyl ester (1.09 g, 3.92 mmol) in DMF (10 mL) and water (1 mL) was added oxone (1.62 g, 2.63 mmol) and the mixture was stirred atambient temperature for 20 min. The mixture was quenched with water and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine, dried with MgSO4, and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane/EtOAc (1:3) to give 3-{4-[6-(quinolin-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-phenyl}-propionic acid methyl ester as a pale yellow solid. 1H NMR (Methanol-d4, 400 MHz): δ 8.45 (d, 1H), 8.38 (d, 1H), 8.29 (s, 1H), 8.04 (d, 1H), 7.93 (d, 2H), 7.83 (s, 1H), 7.75 (m, 1H), 7.55 (m, 1H), 7.09 (s, 2H), 3.67 (s, 3H), 2.97 (t, 2H), 2.71 (t, 2H), 2.16 (s, 6H). MS (m/z) 479.2 (M+1); Retention time: 1.48 min (Method 10).
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>C1COCC1.CN(C=O)C>[Si:21]([O:20][C:9]1[CH:8]=[CH:7][C:6]2[C@@H:5]3[C@H:14]([C@H:15]4[C@@:2]([CH2:3][CH2:4]3)([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 8 h
Yield: 94 %

Procedure:
To a mixture of estrone (1, 29 g, 107.3 mmol) and tert-butyldimethylsilyl chloride (18 g, 118 mmol) in THF (350 mL) at room temperature under argon was added imidazole (18 g, 264 mmol) in DMF (350 mL). After stirring the reaction mixture overnight, the THF was evaporated and the reaction mixture was poured onto ice water. The resulting white precipitate was collected by filtration, dissolved in CH2Cl2, and the solution was dried (MgSO4). The desiccant was filtered and the solvent was evaporated under reduced pressure to afford 38.8 g of 2 as a white, crystalline solid (94% yield), m.p. 171-172° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[OH:8])[CH3:2].[CH:20]1([CH2:25][CH2:26][C:27](O)=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([CH2:25][CH2:26][C:27]([CH2:2][CH2:1][NH:3][CH2:4][CH2:5][CH2:6][CH:7]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=2)[OH:8])=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(O)CCC1CCCC1
Reactant: CCNCCCC(O)c1ccc(NS(C)(=O)=O)cc1
Product: CS(=O)(=O)Nc1ccc(C(O)CCCNCCC(=O)CCC2CCCC2)cc1
Yield: 42.8 %

Procedure:
The product from Example 7, Step II was condensed with 3-cyclopentylpropionic acid according to Procedure E (Example 7, Step III). The product was recrystallized from EtOAc-hexane to give N-[4-[4-[(2-Cyclopentylethylcarbonyl)ethylamino]-1-hydroxybutyl]phenyl]methanesulfonamide (42.8%): mp 101°-102° C.; NMR (CDCl3) δ1.13 (m, 5H), 1.63 (m, 13H), 2.3 (m, 2H), 2.99 (d, 3H), 3.39 (m, 4H), 4.72 (m, 1H), 7.07 (s, 1H), 7.24 (m, 4H); MS m/z (relative intensity) 410 (M+, 2.8), 392 (3.2), 331 (11.5), 223 (29.0), 207 (6.3), 200 (2.9), 189 (19.4); IR (Nujol) 3397, 3190, 1591 cm-1. Anal. calc'd for C21H34N2O4S: C, 61.43 ; H, 8.35; N, 6.82; S, 7.81. Found: C, 61.21; H, 8.56; N, 6.59; S, 7.77.
Reaction SMILES: [CH2:1]([C@:8]([OH:17])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:9](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][C:43]1[CH:44]=[C:45]([Cl:50])[CH:46]=[CH:47][C:48]=1[NH2:49].CN(C=O)C>C(OCC)(=O)C.O>[Cl:50][C:45]1[CH:46]=[CH:47][C:48]2[N:49]=[C:9]([C@:8]([OH:17])([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:42][C:43]=2[CH:44]=1
Reactant: Nc1ccc(Cl)cc1N
Reactant: CCOC(=O)[C@@](O)(Cc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@@](O)(Cc1ccccc1)c1nc2ccc(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2R)-2-benzyl-3-ethoxy-2-hydroxy-3-oxopropanoic acid (320 mg), HATU (562 mg), 3,4-diamino-chlorobenzene (230 gm) was added 4 mL of DMF at rt. The mixture was stirred at rt overnight. To this mixture was added water and ethyl acetate. The organic layer was washed with water and then concentrated in vacuo after being dried with mangesium sulfate. The residue, without purification, was dissolved in 3 mL of acetic acid and heated at 75 degrees for 2 h. The mixture was then concentrated and purified by Biotage silica gel column chromatography (8-35% ethyl acetate in hexanes) to give the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:30])[C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[C:17]1=[O:31])(=[O:14])=[O:13])[CH:6]=[CH:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:43][C:44]#[N:45]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH2:43][C:44]#[N:45])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:30])[C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[C:17]1=[O:31])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: N#CCBr
Reactant: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](N(CC#N)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: -78 °C
Reaction time: 16 h
Yield: 27.7 %

Procedure:
A solution of 6-chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide [Example 1] (0.01 g) in THF (2 ml) was cooled to −78° C. under nitrogen, and treated with lithium bis(trimethylsilyl) amide (1.0M solution in THF; 0.026 ml), followed by bromoacetonitrile (0.013 g). The resultant solution was allowed to reach room temperature and stirred for a further 16 h. The mixture was then cooled to −78° C. and further lithium bis(trimethylsilyl) amide (0.026 l) added. After reaching room temperature, the reaction mixture was stirred for a further 18 h and then quenched by the addition of methanol (1 ml). The resultant solution was concentrated under reduced pressure and the residue purified by mass directed preparative h.p.l.c. to give the title compound (0.003 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14](=[S:16])[NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=O.C(=O)([O-])[O-].[Ca+2]>C(O)(C)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[S:16][C:18]2[CH2:26][C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:19]=2[N:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCCC1C(N)=S
Reactant: O=C1c2ccccc2CC1Br
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NC1CCCC1c1nc2c(s1)Cc1ccccc1-2
Yield: 12.1 %

Procedure:
In 50 ml of isopropanol, 0.63 g of 2-(tert-butoxy-carbonylamino)cyclopentanecarbothioamide and 0.54 g of 2-bromo-1-indanone were dissolved. Then, 0.26 g of calcium carbonate was added, followed by heating under reflux for 3 hours. After cooling, the insoluble matter was removed by filtration, and the solvent was evaporated. The resulting residue was subjected to silica gel column chromatography eluted with chloroform-methanol-29% aqueous ammonia (100:10:1). The resulting crystals were recrystallized from diethyl ether, whereby 0.11 g of 2-[2-(tert-butoxycarbonylamino)cyclopentyl]-8H-indeno[1,2-d]thiazole was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][C:10]2([CH3:18])[CH3:17])[N:3]=1.[CH2:19]([NH:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22].[OH-].[Na+]>C1(C)C(C)=CC=CC=1.O>[CH2:19]([N:23]([CH2:24][CH2:25][CH2:26][CH3:27])[C:2]1[N:7]=[C:6]([N:23]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][CH2:20][CH2:21][CH3:22])[N:5]=[C:4]([N:9]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][C:10]2([CH3:18])[CH3:17])[N:3]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCNCCCC
Reactant: CC1(C)CCCC(C)(C)N1c1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCN(CCCC)c1nc(N(CCCC)CCCC)nc(N2C(C)(C)CCCC2(C)C)n1
Reaction time: 2 h

Procedure:
57.8 g of 2,4-dichloro-6-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine are suspended in 200 ml of xylene at room temperature. 25.8 g of dibutylamine are added dropwise to this during the course of 15 minutes, the temperature climbing to 40°. A solution of 8.87 g of sodium hydroxide in 40 ml of water is added to the reaction mixture in about 15 minutes and it is subsequently stirred at 60° for 2 hours. The aqueous phase is then separated off and 28.4 g of dibutylamine and a solution of 9.6 g of sodium hydroxide in 20 ml of water is added to the clear organic phase. The mixture is then heated in a water separator until an internal temperature of about 135° is reached and is then stirred for 12 hours at this temperature. The contents of the flask are cooled to 90°, a solution of 3 g of sodium hydroxide in 100 ml of water is added and the mixture is vigorously stirred at 90° for 30 minutes. The aqueous phase is then separated off, the xylene solution is washed five times, each with 100 ml of water, and evaporated in vacuo. The yellowish, oily residue is distilled in a high vacuum. 2,4-Bis-dibutylamino-6-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine is obtained as a colorless oil having a boiling point of 173° at 6.5 Pa.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][CH:21]([F:49])[C:22]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:23]=1[CH2:24]N1CCN(C2C=CC3N(C(C(F)(F)F)=NN=3)N=2)CC1>>[F:49][CH:21]([F:20])[C:22]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:23]=1[CH2:24][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:18])([F:17])[F:19])=[N:14][N:15]=3)[CH:12]=2)[CH2:6][CH2:5]1
Reactant: Fc1ccc(C(F)F)c(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)cn12
Product: Fc1ccc(C(F)F)c(CN2CCN(c3ccc4nnc(C(F)(F)F)n4c3)CC2)c1
Yield: 39 %

Procedure:
Obtained in 39% yield by General Synthetic Method 9, starting from 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine and 2-difluoromethyl-5-fluorobenzaldehyde (obtained as described in Example 779, preparation of starting materials).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:13])[CH:5]=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[BH4-].[Na+].Cl.O>C(O)C.CCOCC>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([OH:11])[C:6]([CH3:12])=[CH:5][C:4]=1[OH:13]
Reactant: COC1=C(OC)C(=O)C(C)=CC1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: COc1c(O)cc(C)c(O)c1OC
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
In 28 ml of ethanol was dissolved 1.82 g (10 mmol.) of 2,3-dimethoxy-5-methyl-1,4-benzoquinone. To the solution was portionwise added at room temperature 240 mg (6.3 mmol.) of sodium borohydride. The mixture was stirred for 15 min. The mixture was then made acidic by addition of 3-N hydrochloric acid. To the mixture were added 50 ml of water and 100 ml of ether for performing extraction. The ether portion waswashed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill off the solvent to give 1.72 g of 2,3-dimethoxy-5-methylhydroquinone as a yellow oil, yield 93.5%. To the resulting oil were added 1.65 g (9.3 mmol.) of methyl 1-piperazinecarbodithioate and 280 mg (9.3 mmol.) of paraformaldehyde. Themixture was added to 17 ml of chloroform, and the resulting mixture was refluxed under heating for 6 hours. To the heated mixture was added water.The aqueous mixture was then extracted with chloroform. The chloroform extract was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill off the solvent. The residue was dissolved in 10 ml ofethanol. Insolubles were removed by filtration. The filtrate was placed under reduced pressure to distill off ethanol. The residue was then purified by means of silica gel column, to give 1.1 g of a pale yellow oil, yield 31.8%. The oil was crystallized from ethanol. The crystals werecollected by filtration to give 790 mg of the desired compound as a yellow crystalline proudct, m.p. 135°-136° C.
Reaction SMILES: [CH2:1]1[CH2:21][O:20][C:19]2[C:3](=[C:4]([CH:16]=[CH:17][CH:18]=2)[CH2:5][CH:6]([CH2:14][OH:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[O:2]1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>N1C=CC=CC=1>[CH2:1]1[CH2:21][O:20][C:19]2[C:3](=[C:4]([CH:16]=[CH:17][CH:18]=2)[CH2:5][CH:6]([CH2:14][O:15][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[O:2]1
Reactant: CC(C)(C)OC(=O)C(CO)Cc1cccc2c1OCCO2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(Cc2cccc3c2OCCO3)C(=O)OC(C)(C)C)cc1
Yield: 70.9 %

Procedure:
238 mg of tert-butyl 2-(2,3-ethylenedioxybenzyl)-3-hydroxypropionate was dissolved in 4 ml of dry pyridine, and 170 mg of p-toluenesulfonyl chloride was added thereto. The mixture was reacted at room temperature overnight and then concentrated under reduced pressure. The residue was dissolved in 50 ml of ethyl acetate and washed sequentially with 50 ml of a 5% potassium hydrogensulfate aqueous solution, with 50 ml of a 4% sodium hydrogencarbonate aqueous solution and with 50 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous magnesium sulfate, then concentrated under reduced pressure and purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1) to obtain 257 mg of tert-butyl 2-(2,3-ethylenedioxybenzyl)-3-p-toluenesulfonyloxypropionate as colorless transparent syrup.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1.C(N(CC)CC)C.Br[C:19]1[C:20]2[N:21]([C:26]([CH3:29])=[CH:27][N:28]=2)[N:22]=[C:23]([Cl:25])[CH:24]=1.ClC1C=C(Cl)C2N(C(C)=CN=2)N=1>CCO>[Cl:25][C:23]1[CH:24]=[C:19]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:2][CH3:1])=[CH:5][CH:6]=2)[C:20]2[N:21]([C:26]([CH3:29])=[CH:27][N:28]=2)[N:22]=1
Reactant: Cc1cnc2c(Br)cc(Cl)nn12
Reactant: CCOc1ccc(N)cc1
Agent: Cc1cnc2c(Cl)cc(Cl)nn12
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOc1ccc(Nc2cc(Cl)nn3c(C)cnc23)cc1
Temperature: 90 °C
Reaction time: 30 h

Procedure:
p-Phenetidine (0.068 g, 0.5 mmol) and triethylamine (0.15 ml, 1.1 mmol) were added to a mixture of 8-bromo-6-chloro-3-methylimidazo[1,2-b]pyridazine and 6,8-dichloro-3-methylimidazo[1,2-b]pyridazine (0.011 g, 0.5 mmol) both from 1a in EtOH (10 mL). The mixture was heated to 90° C. and stirred for 30 hrs. The solution was then concentrated in vacuo to give crude 6-chloro-N-(4-ethoxyphenyl)-3-methylimidazo[1,2-b]pyridazin-8-amine.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:34][CH2:33][N:32]([C:2]3[C:3]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:4][C:5]4[C:10]([N:11]=3)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=4)[CH2:31][CH2:30]2)=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: Clc1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccc(Cl)cc4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), 1-(4-chlorophenyl)piperazine (172.5 mg, 0.88 mmol, 5.00 equiv), and DIEA (170.3 mg, 1.32 mmol, 3.00 equiv) in DMF (4 mL) was placed in a 8-mL sealed tube, stirred overnight at 100° C. in an oil bath, then concentrated under vacuum. Purification via silica gel column (ethyl acetate/petroleum ether (1:50)) afforded 153.4 mg (69%) of methyl 3-(4-(4-chlorophenyl)piperazin-1-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.