Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:12])=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][OH:11].[H-].[Li+]>O1CCOCC1>[Cl:12][C:5]1[N:4]=[N:3][C:2]2[O:11][CH2:10][CH2:9][O:8][C:7]=2[CH:6]=1
Reactant: OCCOc1cc(Cl)nnc1Cl
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: Clc1cc2c(nn1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-[(3,6-dichloro-4-pyridazinyl)oxy]ethanol containing some bromo-derivative (15.46 g; 0.0703 mol) in dry 1,4-dioxane (1.2 L) was treated with lithium hydride (2.3 g; 0.28 mol) in portions and stirred at room temperature for 1 hour under argon, then heated at 110° C. overnight. The reaction mixture was quenched with wet 1,4-dioxane, then iced-water. The solution was evaporated to half volume, taken to pH 8 with 5M hydrochloric acid and evaporated to dryness. Water was added and the residue was extracted 5× with chloroform, dried (sodium sulphate) and evaporated to afford a white solid (12.4 g, ca. 77%) (containing ca. 15% of a bromo species).
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:9]=[CH:10][C:11]([O:14]C)=[N:12][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CI.[C:18](=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:1][C:2]1([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[N:12]([CH3:18])[CH:13]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C2(O)CCCCC2)cn1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: Cn1cc(C2(O)CCCCC2)ccc1=O
Yield: 81.9 %

Procedure:
A mixture of 5-(1-hydroxycyclohexyl)-2-methoxypyridine (17.1 g), methyl iodide (11.7 g) and potassium carbonate (22.8 g) was heated in 330 mL of refluxing acetonitrile for 18 hours. The mixture was cooled and filtered, and the solids were washed with methanol. The filtrate was concentrated to yield 14.0 g of powder, which was used in subsequent reactions without further purification.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]([O:28][C:29]([N:31]1CCN(CCCCl)CC1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:24]([O:28][C:29]([N:31]1[CH2:4][CH2:5][N:1]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:2][CH2:3]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCCl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C3(C#N)CCOCC3)cc2)CC1
Yield: 83.3 %

Procedure:
4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (200 mg, 0.99 mmol), 4-(3-chloro-propyl)-piperazine-1-carboxylic acid tert-butyl ester (203 mg, 0.76 mmol), DMF (4 ml) and K2CO3 (553 g, 4.00 mmol) was heated to 70° C. and work up according to general procedure E. The organic phase was washed with 2M NaOH (3.×20 ml), water (2×20 ml), dried over MgSO4, fitered and concentrate in vacuo at 35° C. to provided the title compound (272 mg, 64%) as an off white solid. 1H NMR (400 MHz, CDCl3), δ 7.38 (d, 2H), 6.93 (d, 2H), 4.11-4.04 (m, 2H), 4.03 (t, 2H), 3.89 (td, 2H), 3.50-3.37 (m, 4H), 2.53 (t, 2H), 2.45-2.34 (m, 4H), 2.15-2.00 (m, 4H), 1.97 (p, 2H), 1.46 (s, 9H).
Reaction SMILES: C([O:5][C:6](=[O:25])[CH:7]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)CCC.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[C:21]([O:20][C:18]([NH:17][CH:7]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[C:6]([OH:25])=[O:5])=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC(C(=O)O)c1c[nH]c2ccccc12

Procedure:
A suspension of 5.9 g. (0.017 mol.) of the ester in 70 ml. of 5% aqueous sodium carbonate and 30 ml. of dioxane was refluxed for 2.5 hours. The cooled reaction mixture was concentrated in vacuo and 30 ml. of water was added to the residue. The aqueous solution was extracted with methylene chloride, cooled and acidified to pH 2.0 with hydrochloric acid. The resulting solid was collected and recrystallized from ethyl acetate-hexane to give the title compound, m.p. 143.5°.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([F:11])([F:20])[F:21])[CH:14]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 120 °C

Procedure:
A mixture of 1-chloro-4-nitrobenzene (11 g), 3-(trifluoromethyl)phenol (12 g), and potassium carbonate (21 g) in dimethyl formamide (175 mL) was heated at 120° C. for about 16 hours. The reaction mixture was cooled to room temperature and poured over ice-water. The mixture was filtered and the solid collected was washed with water and dried under vacuum (25 g).
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[F:20][C:21]1([F:32])[CH2:24][N:23]([C:25](=[O:31])[C:26]([OH:30])([CH3:29])[C:27]#[CH:28])[CH2:22]1>>[F:32][C:21]1([F:20])[CH2:24][N:23]([C:25](=[O:31])[C:26]([OH:30])([CH3:29])[C:27]#[C:28][C:2]2[C:3]([F:19])=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]4[C:6]=3[CH:18]=2)[CH2:22]1
Reactant: C#CC(C)(O)C(=O)N1CC(F)(F)C1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)C(=O)N1CC(F)(F)C1
Yield: 5 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 1-(3,3-difluoroazetidin-1-yl)-2-hydroxy-2-methylbut-3-yn-1-one to give the titled compound as an off-white solid (14 mg, 5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[C:21]([O-])([O-])(OCC)[CH2:22][CH3:23].S(=O)(=O)(O)O>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:21]([CH2:22][CH3:23])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: CCOC([O-])([O-])CC
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1.4 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine prepared in Example 1, 50 parts by volume of ethanol and 4 parts by volume of ethyl orthopropionate is added 0.5 part by volume of concentrated sulfuric acid. The mixture is stirred for 30 minutes at room temperature and then treated in a similar manner to Example 14, whereby 8-chloro-1-ethyl-6-phenyl-4H-s-triazolo- [4,3-a] [1,4] benzodiazepine is yielded as crystals. Recrystallization from acetone yields colorless prisms melting at 229° C to 230° C.
Reaction SMILES: [O:1]=[C:2]([C:9]#[C:10][Si](C)(C)C)[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7]>CO.O>[O:1]=[C:2]([C:9]#[CH:10])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: C[Si](C)(C)C#CC(=O)CCCC(=O)O
Solvent: CO
Solvent: O
Product: C#CC(=O)CCCC(=O)O
Temperature: 45 °C
Reaction time: 18 h

Procedure:
The known 5-oxo-7-(trimethylsilyl)hept-6-ynoic acid (1.15 g, 2; prepared using the procedure described in J. Org. Chem., Vol. 62, No. 4, 1997, pp. 982-991) was dissolved in methanol (40 ml) and a solution of Borax (Na2B4O7×10H2O, 2.7 g) in water (6 ml) was added. The resulting reaction mixture was stirred for 18 h at 45° C. under argon. The reaction mixture was then quenched by the addition of 1 M HCl (20 ml) and methanol removed in vacuo. The remaining aqueous solution was then extracted with ethyl acetate (4×35 ml). After washing the pooled organic extracts with brine (2×40 ml), drying with MgSO4 and then filtering, volatiles were removed in vacuo. The crude orange oil remaining was purified by flash chromatography (5% ethyl acetate→10%→15% ethyl acetate/hexane) yielding a pale yellow oil product, 5-oxohept-6-ynoic acid (328 mg, J), which crystallized under storage. 1H NMR (400 MHz, CDCl3): δ1.75 (m, 2H), 2.22 (t, 2H), 2.63 (t, 2H), 4.8 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:9].Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1>CN(C)C1C=CN=CC=1.C1(C)C(C)=CC=CC=1>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][CH:19]=[C:18]2[O:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[O:9])=[CH:15][CH:14]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1ccccc1C(=O)c1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Product: COc1cc2nccc(Oc3ccc(C(=O)c4ccccc4C)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
Under argon, 4-hydroxyphenyl 2-methylphenyl ketone (1.334 g) obtained in Example 126 and 4-dimethylaminopyridine (845 mg) were added to xylene (15 ml), and the admixture was stirred at room temperature for 1 hour. 4-Chloro-6,7-dimethoxyquinoline (1.406 g) was added, and the admixture was refluxed with heat for 23 hours. The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and chloroform, and the chloroform layer was then dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by chromatography on silica gel eluting with hexane/ethyl acetate and then with chloroform, followed by thin layer chromatography on silica gel eluting with hexane/acetone (2/1), to obtain 1.258 g of the title compound (yield: 50%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:5][C:6]1([CH2:29][OH:30])[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][C:24]([CH3:26])=[N:23][CH:22]=4)=[C:17]([O:27][CH3:28])[CH:16]=3)=[N:13][N:14]=[C:7]12.[H-].[Na+].[CH3:37]I>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:5][C:6]1([CH2:29][O:30][CH3:37])[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][C:24]([CH3:26])=[N:23][CH:22]=4)=[C:17]([O:27][CH3:28])[CH:16]=3)=[N:13][N:14]=[C:7]12
Reactant: COc1cc(-c2nnc3n2CCCC3(CO)Cc2ccc(F)c(F)c2)ccc1-c1cnc(C)o1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCC1(Cc2ccc(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Reaction time: 0.5 h

Procedure:
{8-(3,4-Difluorobenzyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl}methanol (100 mg) was added to a suspension of sodium hydride (60%, 9.4 mg) in DMF (1 mL) under ice-cooling, and the mixture was stirred for 30 min. Methyl iodide (14.7 μL) was added to the reaction mixture under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hr, and diluted with ethyl acetate, and the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (80.0 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28]>CN(C=O)C>[Cl:2][C:3]1[C:8]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[N:13]([CH2:24][CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28])[CH:14]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COC(CCBr)OC
Reactant: O=c1[nH]cc(-c2cccnc2Cl)c(=O)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(CCn1cc(-c2cccnc2Cl)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Yield: 39.6 %

Procedure:
To a suspension of 5-(2-chloro-pyridin-3-yl)-1H-pyrimidine-2,4-dione hydrochloride salt (Prep95, 803 mg, 3.10 mmol) and K2CO3 (428 mg, 3.10 mmol) in DMF (15 ml), 90% 3-bromo-1,1dimethoxy-propane (516 μl, 3.41 mmol) was added in three portions over 5 days. The mixture was contemporarily stirred at room temperature. Solvent was then removed in vacuum at 40° C. The residue washed with petroleum ether and then with ethyl acetate. Ethyl acetate phase was dried (Na2SO4), filtered and evaporated. The crude was purified by flash chromatography eluting with DCM-MeOH—NH4OH (98:2:0.2) to give 400 mg of the final compound as a white solid (40% yield)
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([NH:11][CH:12]3[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH2:19]([NH2:22])[CH2:20][CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[CH:1]1[C:10]2[C:5](=[C:6]([NH:11][CH:12]3[CH2:17][CH2:16][CH:15]([NH:22][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CCCN
Reactant: O=C1CCC(Nc2cccc3cnccc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCNC1CCC(Nc2cccc3cnccc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.4 %

Procedure:
4-(5-Isoquinolylamino)-1-cyclohexanone (intermediate 4) (60 mg) and propylamine (30 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was then added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (18 mg) and a syn-form compound (22 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][SH:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].O1CCOCC1.[F:26][CH:27](Cl)[F:28]>O>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][S:15][CH:27]([F:28])[F:26])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CS)cc1
Reactant: FC(F)Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccc(Cl)cc1)c1ccc(CSC(F)F)cc1
Temperature: 25 °C
Yield: 36 %

Procedure:
4-chloro-4'-mercaptomethylbenzophenone (14.7 g) and potassium hydroxide (15 g) was added to a solvent comprising dioxane (100 ml) and water (100 ml). Difluoromethyl chloride was blown into this solution at 60° C. until the starting material 4-chloro-4'-mercaptomethylbenzophenone disappeared. The reaction product was cooled to room temperature and then subjected to filtration. The organic layer as the filtrate was dried over anhydrous magnesium sulfate add concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain the desired product (6.4 g, melting point: 34° to 35° C., yield: 36%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[C:13]([N:15]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@H:16]1[CH2:21][C@@H:20]([C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:19][N:18]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:17]1)=[O:14].C(N(CC)CC)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>C1COCC1.C(=O)(O)[O-].[Na+]>[CH3:39][CH:38]([CH3:40])[CH2:37][N:15]([C:13]([C:5]1[N:4]([CH2:3][CH2:2][O:1][S:49]([CH3:48])(=[O:51])=[O:50])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=1)=[O:14])[C@H:16]1[CH2:21][C@@H:20]([C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:19][N:18]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:17]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CN(C(=O)c1nc2ccccc2n1CCO)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCOS(C)(=O)=O)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (3S,5R)-3-[[[1-(2-hydroxyethyl)-1H-benzimidazol-2-yl]carbonyl](2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (223 mg) and triethylamine (84 μl) in THF (5 ml) was added dropwise methanesulfonyl chloride (37 μl) at room temperature. The reaction mixture was stirred at room temperature for 3 hr, diluted with aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object product (288 mg).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:5]=[C:6]2[C:29](=[CH:30][CH:31]=1)[C:10]1=[N:11][O:12][C:13]([C:14]3C(C(F)(F)F)=C(C4C=CC=CC=4)ON=3)=[C:9]1[CH2:8][CH2:7]2.[CH2:32]([O:34][C:35]1[CH:36]=[C:37](C2ON=C3C4C(CCC=23)=CC(C=C)=CC=4)C=[CH:39][C:40]=1[O:41][CH2:42][CH3:43])[CH3:33]>>[CH2:42]([O:41][C:40]1[CH:39]=[C:14]([C:13]2[O:12][N:11]=[C:10]3[C:29]4[C:6]([CH2:7][CH2:8][C:9]=23)=[CH:5][C:4]([CH:2]2[CH2:3][O:1]2)=[CH:31][CH:30]=4)[CH:37]=[CH:36][C:35]=1[O:34][CH2:32][CH3:33])[CH3:43]
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(OCC)c(OCC)c1
Reactant: FC(F)(F)c1c(-c2onc3c2CCc2cc(C4CO4)ccc2-3)noc1-c1ccccc1
Product: CCOc1ccc(-c2onc3c2CCc2cc(C4CO4)ccc2-3)cc1OCC

Procedure:
This compound was prepared according to the procedure described for Preparation 13A, employing 70 mgs of 3-(3,4-diethoxyphenyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (80A). Yield: 80 mgs (25%); LC/MS M+1=378.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][CH:20]([CH3:22])[CH3:21])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:23]([NH2:25])[CH3:24]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:25][CH2:23][CH3:24])[N:15]=[C:14]([NH:19][CH:20]([CH3:22])[CH3:21])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCN
Reactant: CC(C)Nc1nc(Cl)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Solvent: CCO
Product: CCNc1cc(NS(=O)(=O)c2ccc(N)cc2)nc(NC(C)C)n1
Temperature: 130 °C
Reaction time: 4 h
Yield: 42.9 %

Procedure:
0.1 g (0.000293 mol) of 4-amino-N-(6-chloro-2-isopropylamino-pyrimidin-4-yl)-benzenesulfonamide was dissolved in 20 ml of ethanol, treated with 1.93 ml (0.0293 mol) of ethylamine and stirred in an autoclave at 130° C. for 4 hours. The reaction mixture was freed from solvent, the residue was suspended in 5 ml of ethanol and treated in an ultrasound bath for 15 min. The precipitate was filtered off, dissolved in 10 ml of 0.1N NaOH and filtered. The filtrate was adjusted to pH 6 with 0.1N HCl. The precipitate was filtered off under suction, washed with water and dried. There was obtained 0.044 g (43%) of 4-amino-N-(6-ethylamino-2-isopropylamino-pyrimidin-4-yl)-benzenesulfonamide as white crystals; m.p.: 266-267° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:32][CH3:33])[C:30]=1[CH3:31])[C:6]([N:8]([CH2:18][C:19]1[S:20][C:21]([CH3:27])=[C:22]([C:24](O)=[O:25])[N:23]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:46][N:47]([CH3:52])[S:48]([NH2:51])(=[O:50])=[O:49].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:32][CH3:33])[C:30]=1[CH3:31])[C:6]([N:8]([CH2:18][C:19]1[S:20][C:21]([CH3:27])=[C:22]([C:24]([NH:51][S:48]([N:47]([CH3:52])[CH3:46])(=[O:50])=[O:49])=[O:25])[N:23]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7]
Reactant: COc1cc(C(=O)N(CCCc2ccccc2)Cc2nc(C(=O)O)c(C)s2)cc(OC)c1C
Reactant: CN(C)S(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(C(=O)N(CCCc2ccccc2)Cc2nc(C(=O)NS(=O)(=O)N(C)C)c(C)s2)cc(OC)c1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
2-{[(3,5-Dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-5-methyl-1,3-thiazole-4-carboxylic acid (150 mg) and CDI (78 mg) was added to anhydrous THF (5 mL), followed by heating at 60° C. for about 1 hour. To the reaction mixture were added N,N-dimethylsulfamide (60 mg) and DBU (73 mg) under ice-cooling, respectively, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and neutralized by the addition of an appropriate amount of purified water and 1 M hydrochloric acid, and then extracted from chloroform. The obtained organic layer was dried over MgSO4, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1:2) to obtain 2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-[(dimethylamino)sulfonyl]-5-methyl-1,3-thiazole-4-carboxamide (111 mg) as a white solid.
Reaction SMILES: [Br:1]Br.[CH:3]1([O:9]/[N:10]=[C:11](/[C:17](=[O:19])[CH3:18])\[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br>C(Cl)(Cl)(Cl)Cl.C(O)(=O)C>[CH2:15]([O:14][C:12](=[O:13])/[C:11](=[N:10]\[O:9][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1)/[C:17](=[O:19])[CH2:18][Br:1])[CH3:16]
Reactant: BrBr
Reactant: CCOC(=O)/C(=N\OC1CCCCC1)C(C)=O
Agent: Br
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C(=N\OC1CCCCC1)C(=O)CBr
Reaction time: 2 h

Procedure:
A solution of bromine (4.5 ml) in carbon tetrachloride (50 ml) was added dropwise to a mixture of ethyl (Z)-2-(cyclohexyloxyimino)-3-oxobutyrate (20.0 g), hydrogen bromide in acetic acid (45%, 1.0 ml) and carbon tetrachloride (150 ml) over 1.5 h, at room temperature. The mixture was stirred for 2 h, then the solvent removed in vacuo.
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[N:8]([CH3:9])[N:7]=[C:6]([CH:10]([F:12])[F:11])[C:5]=1[CH:13]=[O:14].O>CN(C)C=O>[F:1][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([CH:10]([F:12])[F:11])[C:5]=1[CH:13]=[O:14]
Reactant: Cn1nc(C(F)F)c(C=O)c1Cl
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(C(F)F)c(C=O)c1F
Temperature: 150 °C
Reaction time: 3 h

Procedure:
To 96.3 g (1660 mmol) of spray-dried potassium fluoride, was added a solution of 129.2 g (664 mmol) of 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde in 1000 ml of dimethylformamide. The resulting reaction mixture was stirred at 150° C. for 3 hours. The reaction mixture was cooled to room temperature and to it was added 4 L of water. The aqueous phase was extracted with ethyl acetate. The combined organic phase were washed with brine, dried over sodium sulphate and evaporated under vacuum to give the expected product.