Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([CH:18]4[CH2:20][CH2:19]4)[CH:13]=[C:14]([C:15]([OH:17])=O)[C:9]=3[C:8]([CH3:21])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:22][CH2:23][C:24]1[C:25](=[O:32])[NH:26][C:27]([CH3:31])=[CH:28][C:29]=1[CH3:30].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CS(C)=O>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([CH:18]4[CH2:19][CH2:20]4)[CH:13]=[C:14]([C:15]([NH:22][CH2:23][C:24]4[C:25](=[O:32])[NH:26][C:27]([CH3:31])=[CH:28][C:29]=4[CH3:30])=[O:17])[C:9]=3[C:8]([CH3:21])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: Cc1nn(C2CCCC2)c2nc(C3CC3)cc(C(=O)O)c12
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CC3)nc3c2c(C)nn3C2CCCC2)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described for intermediate 56 using 1-cyclopentyl-6-cyclopropyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (160 mg, 0.561 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (119 mg, 0.785 mmol), 1-hydroxy-7-azabenzotriazole (153 mg, 1.121 mmol), EDC (215 mg, 1.121 mmol), N-methylmorpholine (0.247 mL, 2.243 mmol) and DMSO (10 mL). The final product was collected as 0.205 g (87%). LCMS E-S (M+H)=420.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (d, J=6.06 Hz, 4H), 1.85 (dd, J=9.35, 5.05 Hz, 3H), 2.12 (s, 4H), 2.16-2.28 (m, 6H), 2.30-2.44 (m, 7H), 2.63 (d, J=19.96 Hz, 3H), 4.34 (d, J=4.29 Hz, 2H), 5.31 (t, J=8.34 Hz, 1H), 5.87 (s, 1H), 7.01 (s, 1H), 8.59 (br. s., 1H), 11.52 (br. s., 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1Cl)[CH2:5][CH:6]1[C:15]2[CH:14]=[C:13]([CH2:16][CH2:17][CH2:18][NH:19][S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21])[CH:12]=[CH:11][C:10]=2[CH2:9][CH2:8][CH:7]1[NH:26][CH:27]([CH3:29])[CH3:28].[H][H]>CO.[OH-].[Pd+2].[OH-]>[ClH:1].[CH2:5]([CH:6]1[C:15]2[CH:14]=[C:13]([CH2:16][CH2:17][CH2:18][NH:19][S:20]([CH2:23][CH2:24][CH3:25])(=[O:21])=[O:22])[CH:12]=[CH:11][C:10]=2[CH2:9][CH2:8][CH:7]1[NH:26][CH:27]([CH3:28])[CH3:29])[C:4]1[CH:30]=[CH:31][CH:32]=[CH:2][CH:3]=1
Reactant: CCCS(=O)(=O)NCCCc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(NC(C)C)CC2
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)NCCCc1ccc2c(c1)C(Cc1ccccc1)C(NC(C)C)CC2
Product: Cl

Procedure:
N-{3-[8-(3,4-Dichlorobenzyl)-7-(propan-2-ylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]propyl}propane-1-sulfonamide (70 mg, 0.137 mmol) was dissolved in methanol (1.5 mL) and palladium hydroxide (30 mg, 0.214 mmol) was added. The reaction mixture was heated under reflux in an atmosphere of hydrogen for 6 h. The catalyst was removed by filtration and the crude product was purified by flash chromatography (silica gel, dichloromethane, methanol). The obtained amine was dissolved in dichloromethane (2 mL) and 5 N hydrochloric acid in isopropanol (0.3 mL) was added. The solvent was evaporated and the product dried in vacuo. Yield: 30 mg (0.63 mmol, 46%).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]([C:12](=[S:14])[NH2:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.Cl[CH:16]([C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CC(O)C>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:22]1[N:13]=[C:12]([C:11]2[C:3]([CH3:2])=[N:4][N:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=23)[S:14][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Cc1nn2ccccc2c1C(N)=S
Reactant: CCOC(=O)C(Cl)C(=O)c1ccccc1Cl
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1-c1ccccc1Cl
Yield: 91.8 %

Procedure:
Using 2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide hydrochloride (300 mg, 1.3 mmol) produced in Example 11(v), ethyl 2-chloro-3-(2-chlorophenyl)-3-oxopropanoate (1.0 g, 3.9 mmol) produced in the above and 2-propanol (20 mL) as starting materials and in the same manner as in Example 11-B(vi), the title compound (475 mg, 91%) was obtained as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:2].[H-].[Na+].[CH:28](OCC)=[O:29]>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]([C:6]1[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:28][OH:29])=[O:25])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)ccn1Cc1ccc(OC)cc1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=CO)c1c(C(=O)OCC)ccn1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Ethyl 2-[2-(ethyloxy)-2-oxoethyl]-1-{[4-(methyloxy)phenyl]methyl}-1H-pyrrole-3-carboxylate (6.1 g) in dry tetrahydrofuran (100 ml) was stirred at room temperature under argon. Sodium hydride (60% dispersion in mineral oil, 23.0 g) was added portionwise and stirring continued for 20 minutes after complete addition. Ethyl formate (3 ml) was added to the reaction mixture and stirred for 45 minutes after which time an exotherm was observed and controlled by cooling the reaction mixture to room temperature with an ice bath. The reaction mixture was stirred for a further 90 minutes then ethyl formate (3 ml) was added and the mixture stirred overnight. The reaction mixture was cooled in an ice bath and quenched by addition of the minimum amount of ethanol then evaporated. The residue was partitioned between ethyl acetate and saturated ammonium chloride, the aqueous layer was removed and acidified to pH 1 with a 2M solution of aqueous hydrochloric acid. The aqueous layer was extracted three times with ethyl acetate and the combined organic layers were washed with brine and dried (MgSO4). The solvent was evaporated to afford an oil consisting of two layers. The top layer was discarded and the lower layer isolated to afford the title compound as a brown oil (6.59 g).
Reaction SMILES: [C:1]1([C:16]([OH:17])=[C:12]([N+:13]([O-:15])=[O:14])[CH:11]=[C:7]([N+:8]([O-:10])=[O:9])[C:5]=1[OH:6])[N+:2]([O-:4])=[O:3]>N1C=CC=CC=1>[C:1]1([C:5]([O-:6])=[C:7]([N+:8]([O-:10])=[O:9])[CH:11]=[C:12]([N+:13]([O-:15])=[O:14])[C:16]=1[O-:17])[N+:2]([O-:4])=[O:3].[NH+:8]1[CH:7]=[CH:11][CH:12]=[CH:16][CH:1]=1.[NH+:8]1[CH:7]=[CH:11][CH:12]=[CH:16][CH:1]=1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c([O-])c([N+](=O)[O-])c1[O-]
Product: c1cc[nH+]cc1

Procedure:
500 grams (2.04 moles) of dry styphnic acid are added in portions, with vigorous stirring, to two liters of dry pyridine. The mixture warms up slightly and a yellow reaction product precipitates. The mixture is stirred for another hour in the warm state, and then the cooled mixture is freed of solids by filtration. The solids are washed with one liter of ether, suspended in two liters of ether, freed of the solvent by filtration, again washed with 500 ml of ether, and dried in air.
Reaction SMILES: Cl.Cl.[OH:3][CH:4]([CH3:16])[CH2:5][C:6]1[N:7]=[N:8][C:9]([NH:14][NH2:15])=[CH:10][C:11]=1[NH:12][CH3:13].C[O-:18].[Na+].N1[CH:25]=[CH:24]C=CC=1>C(Cl)(=O)C>[OH:3][CH:4]([CH3:16])[CH2:5][C:6]1[N:7]=[N:8][C:9]([NH:14][NH:15][C:24](=[O:18])[CH3:25])=[CH:10][C:11]=1[NH:12][CH3:13]
Reactant: c1ccncc1
Reactant: CNc1cc(NN)nnc1CC(C)O
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)Cl
Product: CNc1cc(NNC(C)=O)nnc1CC(C)O
Reaction time: 2 h

Procedure:
To a solution of 27g of 3-(2'-hydroxypropyl)methylamino-6-hydrazinopyridazine dihydrochloride in 200 ml of anhydrous pyridine, 7 ml of acetyl chloride are slowly added dropwise at 0° C. When addition is completed, the reaction mixture is left to stand under stirring for two hours at 0°-5° C and then overnight at 0° C. The pyridine is removed by distillation in the rotating evaporator under vacuum at approximately 10° C and an oily residue is obtained which is treated at 0° C and under stirring with a solution of sodium methylate. The product obtained is dried at 10° C, the residue taken up with isopropyl alcohol, filtered on cellite cake and the filtrate, dried under vacuum, gives 3-(2'-hydroxypropyl) methylamino-6-(2'-acetylhydrazino)pyridazine which, recrystallized from ethyl alcohol, melts at 168° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[C:3]#[CH:4].[Li]CCCC.[C:11]([C:15](OCC)=O)([F:14])([F:13])[F:12].B(F)(F)F.O(CC)CC.[NH2:29][NH2:30]>C1COCC1.C1C=CC=CC=1>[CH:2]([C:3]1[NH:30][N:29]=[C:15]([C:11]([F:14])([F:13])[F:12])[CH:4]=1)([CH3:5])[CH3:1]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NN
Reactant: C#CC(C)C
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)c1cc(C(F)(F)F)n[nH]1

Procedure:
Following protocol H, 3-methylbutyne was treated with n-BuLi, CF3CO2Et and BF3-OEt2 in THF. Reaction with hydrazine in benzene under similar reaction conditions yielded title compound.
Reaction SMILES: [N:1]#[C:2][Br:3].[CH2:4]([NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]([Cl:22])[C:13]=1[NH2:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C>[BrH:3].[CH2:4]([N:11]1[C:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([Cl:22])[C:13]=2[N:23]=[C:2]1[NH2:1])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Nc1c(Cl)nc2ccccc2c1NCc1ccccc1
Reactant: N#CBr
Solvent: CCO
Product: Br
Product: Nc1nc2c(Cl)nc3ccccc3c2n1Cc1ccccc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 103.3 %

Procedure:
Cyanogen bromide (2.2 g, 21 mmol) was added to a solution of N4-benzyl-2-chloroquinoline-3,4-diamine (5.0 g, 17 mmol) in ethanol (50 mL), and the solution was heated at 90° C. for two hours. An analysis by liquid chromatography/mass spectrometry (LC/MS) indicated the presence of starting material. Additional cyanogen bromide (2.2 g, 21 mmol) was added, and the reaction was stirred for one hour at 90° C., stirred for three days at 50° C., and allowed to cool to ambient temperature. The solvent was removed under reduced pressure, and the resulting solid was washed with diethyl ether (1 L) to provide 6.84 g of 1-benzyl-4-chloro-1H-imidazo[4,5-c]quinoline-2-amine hydrobromide as a dark gray powder.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:27])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:15][C:14]=2[O:25][CH3:26])[N:10]=1.[CH:28](I)([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:27])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH:28]([CH3:30])[CH3:29])=[O:23])=[CH:15][C:14]=2[O:25][CH3:26])[N:10]=1
Reactant: COc1cc(CCCC(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(CCCC(=O)OC(C)C)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 0 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
A mixture of 4-[4-[2-(2-furyl)-5-methyl-4-oxazolyl methoxy]-3-methoxyphenyl]butanoic acid (106 g), isopropyl iodide (58.2 g), potassium carbonate (47.3 g) and N,N-dimethylformamide (DMF) (100 ml) was stirred for 4 hours at temperatures ranging from 65 to 70° C. The reaction mixture was poured into ice-water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and then concentrated. The concentrate was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate-hexane (1:2), was obtained isopropyl 4-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]butanoate (107 g, 91%), which was recrystallized from acetone-hexane to give colorless needles, m.p.45-46° C.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br.[NH2:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1>CN(C)P(N(C)C)(N(C)C)=O>[CH3:1][C:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28][CH:29]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)CCCCCCCCCCCCBr
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCCCCCCCCCCC(C)(C)C)cc1

Procedure:
A solution of 10 g. of 13,13-dimethyltetradecyl bromide and 10.8 g. of ethyl 4-aminobenzoate in 75 ml. hexamethylphosphoramide is heated at 110° C. for 17 hours. The cooled solution is diluted with 100 ml. water, filtered, and the residue is washed in portions with 100 ml. 50% ethanol-water. After drying, the product is crystallized from ethanol-water. After drying, the product is crystallized from ethanol to yield ethyl 4-(13,13-dimethyltetradecyl)aminobenzoate as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:11])[O:10][CH2:9]2)=[CH:4][CH:3]=1.C(O)[CH2:13][CH2:14][CH3:15].B(F)(F)F.C[CH2:22][O:23]CC>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:9][CH2:13][CH2:14][CH3:15])([CH3:11])[CH2:22][OH:23])=[CH:6][CH:7]=1
Reactant: CC1(c2ccc(F)cc2)CO1
Reactant: CCOCC
Reactant: CCCCO
Agent: FB(F)F
Product: CCCCOC(C)(CO)c1ccc(F)cc1
Reaction time: 4 h

Procedure:
A solution of 4.56 g (30 mmoles) of 2-(4-fluorophenyl)-1,2-epoxypropane in 5.55 g (75 mmoles) of n-butanol is added dropwise slowly at an internal temperature of 5°-7° C., with cooling, to a solution of 2.13 g (0.016 mole) of boron trifluoride ethyl etherate in 5.55 g (75 mmoles) of n-butanol, and the temperature is kept at +7° C. for a further 4 hours. The reaction mixture is then worked up by extraction (methylene chloride) and washing with water. The organic phase is dried over sodium sulfate, filtered and concentrated in vacuo. Distillation of the crude product gives 4.48 g (=66% of theory) of the pure end product in the form of a colourless oil. Boiling point 120°-125° C./20 mbar. 100 MHz-1H-NMR (CDCl3): δ=6.8-7.5 ppm (m, 4H aromatic); 3.5 ppm (q, 2H, --CH2OH); 3.2 ppm (m, 2H, --OCH2 --); 2.3 ppm (broad, 1H, --OH); 1.6 ppm (s, 3H, --CH3); 1.4 ppm (m, 4H, --CH2CH2 --); 0.9 ppm (t, 3H, --CH3).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][CH:10](OCC)[O:11]CC)=[O:7])=[C:4]([Cl:19])[CH:3]=1.Cl.O>C1COCC1>[Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][CH:10]=[O:11])=[O:7])=[C:4]([Cl:19])[CH:3]=1
Reactant: CCOC(CNC(=O)c1ccc(Br)cc1Cl)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=CCNC(=O)c1ccc(Br)cc1Cl
Reaction time: 24 h
Yield: 59.5 %

Procedure:
To a solution of 4-bromo-2-chloro-N-(2,2-diethoxyethyl)benzamide (14.88 g, 42.44 mmol) in THF (50 mL) was added 2N HCl (50 mL) at room temperature. After 24 hours, water (100 mL) was added to the mixture, then the mixture was extracted with ethyl acetate (100 mL×2), the organic layer was washed with water (50 mL), dried over MgSO4. Removal of the solvent, gave a title compound (6.98 g, 60% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:3]=1[CH3:20].[Br:21][C:22]1[CH:23]=[CH:24][C:25]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[C:26]([NH2:28])[CH:27]=1.Cl>O1CCOCC1.CO>[Br:21][C:22]1[CH:23]=[CH:24][C:25]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)=[C:26]([NH:28][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:3]=2[CH3:20])[CH:27]=1
Reactant: Cc1c(-c2ccccc2F)nc2cc(F)ccc2c1Cl
Reactant: Nc1cc(Br)ccc1N1CCOCC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2F)nc2cc(F)ccc2c1Nc1cc(Br)ccc1N1CCOCC1

Procedure:
Prepared according to Procedure K, Method 1 using 4-chloro-7-fluoro-2-(2-fluorophenyl)-3-methylquinoline (118 mg, 407 μmol), 5-bromo-2-morpholinobenzenamine (105 mg, 407 μmol) and 4.0N hydrochloric acid (0.10 mL, 407 μmol) in 1,4-dioxane in MeOH (1.00 mL) to afford a yellow solid after purification by chromatography on silica gel, eluting with EtOAc-DCM-hexane solvent mixture. Mass Spectrum (ESI) m/e=510.0 & 512.0 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1)=[O:3].N1C=CC=CC=1.[CH2:17]([S:20](Cl)(=[O:22])=[O:21])[CH2:18][CH3:19].O>ClCCl>[C:2]([C:4]1[CH:5]=[C:6]([NH:10][S:20]([CH2:17][CH2:18][CH3:19])(=[O:22])=[O:21])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:1]
Reactant: CCCS(=O)(=O)Cl
Reactant: CC(=O)c1cccc(N)c1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1cccc(C(C)=O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.8 %

Procedure:
1 g (7.4 mmol) of 3-aminoacetophenone were dissolved in 35 ml of dry dichloromethane. To the resultant solution cooled at 0° C. 0.89 ml (11.09 mmol) of anhydrous pyridine and 1.26 g (8.87 mmol) of 1-propanesulfonic acid chloride were added. After stirring the reaction mixture for 20 h at room temperature and under inert atmosphere, 15 ml of water were added. The two layers were separated, and the aqueous layer was washed with 2×15 ml of dichloromethane. The organic layers were washed with 30 ml of water and dried over anhydrous sodium sulfate. The dichloromethane layer was evaporated to dryness to yield a yellow solid, 1.8 g (yield=100%) of N-(3-acetylphenyl)-1-propane-sulfonamide which was directly used for the following reaction.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[CH2:16](O)[CH3:17]>S(=O)(=O)(O)O>[CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][CH:7]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: CCO
Reactant: O=C(O)Cc1ccc(C(=O)C2CC2)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(C(=O)C2CC2)cc1
Reaction time: 24 h
Yield: 88 %

Procedure:
Dissolve 4-(cyclopropylcarbonyl)benzeneacetic acid in ethanol (150 mL) containing concentrated sulfuric acid (10 drops). Stir 24 hours. Add triethylamine (2 mL) and concentrate the solution. Dissolve the residue in water/ethyl acetate. Wash the organic phase with saturated sodium hydrogen carbonate solution, dry over anhydrous magnesium sulfate and concentrate. Purify by silica gel chromatography (400 mL silica gel, 20% ethyl acetate/heptane as eluent) to give the title compound (7.0 g, 88%).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.Cl.[NH:17]1[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=2)=[N:20][N:19]=[N:18]1.C([O-])(=O)C.[Na+]>C(O)CCC.CO>[NH:20]1[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:2]3[C:11]4[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=4[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=3)=[CH:30][CH:29]=2)=[N:17][N:18]=[N:19]1
Reactant: FC(F)(F)c1nc(Cl)c2c(n1)CCCC2
Reactant: NCc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Solvent: CO
Product: FC(F)(F)c1nc2c(c(NCc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)n1)CCCC2
Temperature: 25 °C
Yield: 49.8 %

Procedure:
To 10 mL of a 5:1 mixture of n-butanol/methanol were added 1.42 g of 4-chloro-5,6,7,8-tetrahydro-2-trifluoromethylquinazoline, 1.73 g of N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amine hydrochloride and 2.7 g of sodium acetate. The resulting mixture was heated at reflux for 5 days and then cooled to room temperature. All solvents were removed by evaporation and the resulting residue was purified on silica to yield 1.35 g (50%) of the desired product. The compound was characterized as its potassium salt: 1H NMR (DMSO-d6, 400 MHz) δ 7.78 (t, J=6.0 Hz, 1H), 7.50 (m, 1H), 7.32 (m, 3H), 7.15 (m, 2H), 7.03 (m, 2H), 4.57 (d, J=6.0 Hz, 2H), 2.61 (m, 2H), 2.38 (m, 2H, 1.75 (m, 4H); negative FAB-MS m/e 488(M-H), 450(M-K). Anal. calcd for C23H19F3KN7.0.5H2O: C, 55.41; H, 4.04; N, 19.67. Found: C, 55.66; H, 4.09; N, 19.46.
Reaction SMILES: [Al].[CH2:2](Br)[C:3]#[CH:4].[F:6][C:7]([F:27])([F:26])[C:8](=[O:25])[CH2:9][C:10]1([CH3:24])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:18]=2)[O:13][CH2:12][CH2:11]1>C1COCC1.C1(C)C=CC=CC=1>[F:27][C:7]([F:6])([F:26])[C:8]([CH2:9][C:10]1([CH3:24])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([S:20]([CH3:23])(=[O:21])=[O:22])[CH:18]=2)[O:13][CH2:12][CH2:11]1)([OH:25])[CH2:4][C:3]#[CH:2]
Reactant: CC1(CC(=O)C(F)(F)F)CCOc2ccc(S(C)(=O)=O)cc21
Reactant: C#CCBr
Agent: [Al]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C#CCC(O)(CC1(C)CCOc2ccc(S(C)(=O)=O)cc21)C(F)(F)F
Temperature: 40 °C
Reaction time: 0.33 h

Procedure:
A mixture of 70 mg (2.75 mmol) of aluminum foil and 0.8 mg (0.003 mmol) of mercuric chloride in 3 mL of anhydrous THF was vigorously stirred. After 20 minutes, 0.31 mL (2.75 mmol) of a 80% solution of propargyl bromide in toluene was added and the reaction was warmed at 40° C. for one hour. The dark grey solution was then added to a chilled (0° C.) solution of 300 mg (0.88 mmol) of 1,1,1-trifluoro-3-(6-methanesulfonyl-4-methylchroman-4-yl)propan-2-one in 10 mL of dry tetrahydrofuran. The reaction was warmed to room temperature overnight, concentrated in vacuo, quenched with ice and extracted with diethyl ether. The combined organic fractions were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 330 mg of crude 1,1,1-trifluoro-2-(6-methanesulfonyl-4-methylchroman-4-ylmethyl)pent-4-yn-2-ol as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][OH:27])=[CH:21][CH:20]=1>CN1C(=O)CCC1.O>[CH:13]1([O:12][C:4]2[N:3]=[C:2]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][OH:27])=[CH:21][CH:20]=3)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: FC(F)(F)c1cc(Cl)nc(OC2CCCC2)n1
Reactant: Nc1ccc(CCO)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: OCCc1ccc(Nc2cc(C(F)(F)F)nc(OC3CCCC3)n2)cc1
Temperature: 120 °C
Yield: 69.7 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-(cyclopentyloxy)-6-(trifluoromethyl)pyrimidine (0.090 g, 0.34 mmol) and (4-aminophenyl)ethyl alcohol (0.069 g, 0.51 mmol) in NMP (3 mL). The resulting mixture was heated at 120° C. under microwave irradiation for 1 h. After this time, the reaction mixture was cooled and diluted with water (50 mL) affording a solid. The solid was isolated by filtration and chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent to afford the title compound (0.087 g, 70%) as a white solid. MW=367.37. M.p. 173-175° C. 1H NMR (DMSO-d6, 500 MHz) δ 10.01 (s, 1H), 7.56 (br d, J=7.0 Hz, 2H), 7.22 (d, J=8.5 Hz, 2H), 6.73 (s, 1H), 5.30 (septet, J=3.0 Hz, 1H), 4.61 (t, J=5.0 Hz, 1H), 3.62-3.57 (m, 2H), 2.70 (t, J=7.0 Hz, 2H), 2.00-1.90 (m, 2H), 1.80-1.66 (m, 4H), 1.65-1.55 (m, 2H); APCI MS m/z 368 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH2:3]([SH:6])[CH:4]=[CH2:5].C(O[CH:11]1[NH:14][C:13](=[O:15])[CH:12]1[CH2:16][CH3:17])(=O)C>O>[CH2:3]([S:6][CH:11]1[NH:14][C:13](=[O:15])[CH:12]1[CH2:16][CH3:17])[CH:4]=[CH2:5]
Reactant: C=CCS
Reactant: CCC1C(=O)NC1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCSC1NC(=O)C1CC
Reaction time: 0.33 h

Procedure:
To a stirred solution of 3.2 g of sodium hydroxide in 40 ml of water under an argon atmosphere were added 8 ml of allyl thiol (about 85% pure). After 20 minutes of further stirring, a solution of 12.5 g of 4-acetoxy-3-ethylazetidin-2-one in 20 ml of water was added and the mixture was stirred for a further 15 minutes, and then extracted into dichloromethane. The organic extracts were washed with water, were dried over MgSO4, and evaporated in vacuo to dryness, Chromatography over silica gel, eluting with hexane-ethyl acetate mixtures, afforded the title compound as a yellow oil (3.2 g).