Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:14]#[N:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][CH2:14][NH2:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCc1ccccc1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCCc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine 2-phenylphenylacetonitrile (4.69 g, 24.26 mmol) and diethyl ether (10 ml) and add dropwise to a cooled (−10°) solution of LiAlH4 (2.76 g, 72.81 mmol) in diethyl ether (100 ml). Warm to ambient temperature. After 2 hours, quench with saturated sodium sulfate (100 ml/mol). Filter to remove the precipitate, dry (Na2SO4) the filtrate, filter, and concentrate to residue. Chromatograph the residue on silica gel eluting with dichloromethane/2N NH3(methanol) (95/5) to give the title compound as a yellow oil. Prepare the HCl salt in diethyl ether: mp 197–199° C. MS (ACPI): m/e 198.1 (M+1). Analysis for C14H16ClN: Calcd: C, 71.94; H, 6.90; N, 5.99; found: C, 72.15; H, 6.84; N, 6.09.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([CH3:12])=[CH:4][C:3]=1[N:13]1[N+:17]([O-])=[C:16]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:15]2=[N:14]1.S(=O)(=O)(O)O>O>[OH:1][C:2]1[C:7]([C:8]([CH3:10])([CH3:9])[CH3:11])=[CH:6][C:5]([CH3:12])=[CH:4][C:3]=1[N:13]1[N:17]=[C:16]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:15]2=[N:14]1
Reactant: Cc1cc(-n2nc3cc(Cl)ccc3[n+]2[O-])c(O)c(C(C)(C)C)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Reaction time: 5 h
Yield: 82.9 %

Procedure:
Example 4 from U.S. Pat. No. 4,835,284 is duplicated. 97% sodium hydroxide (8.2 g) is added and dissolved in a mixture of methanol (60 ml) and water (20 ml). 2-nitro-4-chloro-2'-hydroxy-3'-t-butyl-5'-methylazobenzene (11.6 g) is then added to the resultant solution at 50° to 60° C. over 30 minutes while stirring, and thereafter 2,3-dichloro-1,4-naphthoquinone (0.3 g) and 9-fluorenone (0.4 g) are added to the solution. Glucose (8 g) is then added to the resultant mixture at 40° to 50° C. over two hours, and the mixture is stirred for one hour at the same temperature. As this result, almost all of the azobenzene disappears to produce 2-(2-hydroxy-3-t-butyl-5-methylphenyl)-5-chlorobenzotriazole-N-oxide. The system is heated, and is stirred at 66° to 68° C. (boiling point) for 5 hours. As this result, the N-oxide disappears. Thereafter, water (50 ml) is added to the reaction liquor, and the resultant reaction liquor is neutralized with 62% sulfuric acid (10 g) to precipitate a crystal. The precipitated crystal is separated by filtration, and the separated crystal is fully washed with hot water of 60° to 70° C. and further with a small amount of methanol. The washed crystal is then dried, thus obtaining 8.7 g of 2-(2'-hydroxy-3'-t-butyl-5'-methylphenyl)-5-chlorobenzotriazole having a melting point of 138° to 140° C. at the yield of 82.9%. One can see that the reaction using an aromatic ketone takes over 71/2 hours.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[Cl:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:38][CH3:39])[C:30]=2[C:34]([F:37])([F:36])[F:35])[C:25]=1[C:40]([N:42]([CH3:48])[CH2:43][C:44]([O:46][CH3:47])=[O:45])=O>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:38][CH3:39])[C:30]=2[C:34]([F:37])([F:36])[F:35])[C:25]=1[C:40](=[S:10])[N:42]([CH3:48])[CH2:43][C:44]([O:46][CH3:47])=[O:45]
Reactant: COC(=O)CN(C)C(=O)c1c(Cl)ccc2c(C(F)(F)F)c(OC)ccc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)CN(C)C(=S)c1c(Cl)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 25 °C
Yield: 51.4 %

Procedure:
Lawesson's reagent (1.9 g, 0.6 eq) was added to a stirred suspension of N-[[2-chloro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-methylglycine, methyl ester (3.00 g, 7.70 mmole) in toluene (30 mL) at room temperature under nitrogen. The reaction was heated to reflux for 42 hours with more Lawesson's reagent (3.9 g, 1.2 eq) added in three equal portions after 11/4, 171/2 and 231/2 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate absorbed onto silica gel and flash chromatographed (gradient elution:eluant 60/40, chloroform/petroleum ether →9/1 chloroform/acetonitrile) to provide the desired product as a foamy solid (0.98 g) and recovered starting material (1.23 g). The starting material (1.23 g, 3.08 mmole) was suspended in toluene (~15 mL) and treated with Lawesson's reagent as described above to give additional product (0.351 g, combined yield 43%), m.p. 67°-73° C. (softens at 50° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH:6]=[CH:5]2.C([Li])(C)(C)C.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[O:24]>>[CH3:12][C:7]1([CH3:13])[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:23]([OH:24])[C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[C:20]([F:19])([F:29])[F:30])[CH:3]=2)[O:8]1
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: CC1(C)C=Cc2cc(Br)ccc2O1
Agent: [Li]C(C)(C)C
Product: CC1(C)C=Cc2cc(C(O)c3ccccc3C(F)(F)F)ccc2O1

Procedure:
6-Bromo-2,2-dimethyl-2H-chromene is metallated at -78° C. using 2 equivalents of tert.-butyllithium and subsequently reacted with 2-trifluoromethylbenzaldehyde to give 2,2-dimethyl-6-(2-trifluoromethyl-hydroxybenzyl)-2H-chromene which is produced as an oil.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1.[NH2:14][CH:15]([CH3:18])[CH2:16][OH:17]>>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[N:4]=[N:3][C:2]([NH:14][CH:15]([CH3:18])[CH2:16][OH:17])=[CH:7][CH:6]=2)[CH:9]=1
Reactant: Clc1ccc(-c2cccnc2)nn1
Reactant: CC(N)CO
Product: CC(CO)Nc1ccc(-c2cccnc2)nn1
Temperature: 130 °C

Procedure:
A mixture of 5 g of 3-chloro-6-(3-pyridinyl)pyridazine and 30 ml of 2-amino-1-propanol is heated at 130° C. for 24 hours and the volatiles removed by bulb to bulb distillation under high vacuum to obtain the product 2-[[6-(3-pyridinyl)-3-pyridazinyl]amino]-1-propanol. As for Example 5, the preceding product is reacted with thionyl chloride and the obtained product is ring closed with potassium carbonate in ethanol to give 2,3-dihydro-2-methyl-6-(3-pyridinyl)imidazo[1,2-b]pyridazine which is dehydrogenated with lead tetraacetate to give 2-methyl-6-(3-pyridinyl)imidazo[1,2-b]pyridazine.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:17]1[C:18]([N:34]([CH3:38])[CH2:35][CH2:36][CH3:37])=[N:19][C:20]([NH:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[N:21][CH:22]=1.[OH-:39].[Na+].Cl>O1CCCC1>[C:28]([C:27]1[CH:32]=[CH:33][C:24]([NH:23][C:20]2[N:19]=[C:18]([N:34]([CH3:38])[CH2:35][CH2:36][CH3:37])[C:17]([C:16]#[C:15][CH2:14][CH2:13][CH2:12][NH:3][C:2]([C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[C:4]([OH:39])=[O:11])=[O:1])=[CH:22][N:21]=2)=[CH:25][CH:26]=1)([OH:30])=[O:29]
Reactant: [OH-]
Reactant: CCCN(C)c1nc(Nc2ccc(C(=O)OC)cc2)ncc1C#CCCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCN(C)c1nc(Nc2ccc(C(=O)O)cc2)ncc1C#CCCCNC(=O)c1ccccc1C(=O)O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 4-((5-(5-(1,3-dioxoisoindolin-2-yl)-1-pentyn-1-yl)-4-(methyl(propyl)amino)pyrimidin-2-yl)amino)benzoate (H7, 634 mg) in tetrahydrofuran (6.2 mL), 2.0 mol/L aqueous sodium hydroxide (3.1 mL) was added at room temperature, and the mixture was stirred at 80° C. for 4 hours. The reaction mixture was cooled to room temperature, and then 1.0 mol/L aqueous hydrochloric acid was added to the reaction mixture until the mixture became acidic. The solid matter was taken by filtration, washed with water, and then dried under reduced pressure to obtain 2-((5-(2-((4-carboxyphenyl)amino)-4-(methyl(propyl)amino)pyrimidin-5-yl)-4-pentyn-1-yl)carbamoyl)benzoic acid (H8, 526 mg) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[NH2:5].[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:19]=1[C:20]([N:22]=[C:23]=[O:24])=[O:21]>C1(C)C=CC=CC=1>[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:19]=1[C:20]([NH:22][C:23]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[C:2]([Cl:1])[CH:3]=1)=[O:24])=[O:21]
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)c(Cl)c1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(Oc2ccc(Cl)cc2)c(Cl)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
At room temperature, 6.4 g of 3-chloro-4-(4-chlorophenoxy)aniline is dissolved in 50 ml of toluene. Subsequently, 4.7 g of 2,6-difluorobenzoyl isocyanate is dripped in, whereupon the temperature rises by 15° C. The mixture is then stirred for 1 hour at 50° C. and allowed to cool; the precipitate is then filtered off. There is obtained 8.5 g of N-(2,6-difluorobenzoyl)-N'-[4-(4-chlorophenoxy)-3-chlorophenyl]-urea of m.p. 194°-196° C.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Cl:21][CH2:22][C:23]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1
Temperature: 3 °C
Reaction time: 1 h

Procedure:
2.00 g (10.74 mmol) tert-butyl 1-piperazinecarboxylate, 1.30 g (12.89 mmol, 1.2 eq.) triethylamine were dissolved into 25 ml dichloromethan under argon gas. After cooling to 3° C., 1.33 g (11.81 mmol, 1.1 eq.) chloroacetyl chloride was diluted with 5 ml dichloromethane and added dropwise slowly into reaction solution. After stirring at 3° C. for 1 hour, 20 ml purified water was added, organic layer was separated and aqueous layer was extracted once with 40 ml dichloromethane again. Organic layer was collected, dried with magnesium sulfate and concentrated with decompression. Purifying residues by chromatography using silicagel, 2.00 g (71%) target compound as yellow syrup was yielded.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH:12]1C=CC=CC=1.C(OCC)C>O>[CH2:12]=[C:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: c1ccccc1
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: O
Solvent: CCOCC
Product: C=C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
1,4-Dioxaspiro[4.5]decan-8-one (21 g, 0.13 mol) in dry benzene (50 mL, 0.6 mol) was added to ethylenetriphenylphosphorane [prepared from dimsyl sodium and methyltriphenylphosphonium bromide (106 g, 0.291 mol) in dimethyl sulfoxide (600 mL, 8 mol)] The mixture was stirred at room temperature overnight and poured into a separating funnel containing ethyl ether (500 mL) and water (500 mL). The organic layer was separated and the aqueous phase was extracted with ethyl ether (2×500 mL). The combined ether layers were washed with water (500 mL) and brine (500 mL), and dried. The solvents were removed under reduced pressure and the residue was purified by flash chromatography to afford the desired product (18.0 g, 85%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][NH2:17])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:19][C:20]1[C:25]([CH2:26][C:27](O)=[O:28])=[CH:24][CH:23]=[C:22]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[N:21]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([CH3:7])([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][NH:17][C:27](=[O:28])[CH2:26][C:25]2[C:20]([CH3:19])=[N:21][C:22]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:39])[F:38])=[CH:32][CH:31]=3)=[CH:23][CH:24]=2)[CH:10]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(CCN)c1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CC(=O)O
Product: CCOC(=O)C(C)(C)Oc1cccc(CCNC(=O)Cc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-[3-(2-amino-ethyl)-phenoxy]-2-methyl-propionic acid ethyl ester was reacted with [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid (example 26E]) to give 2-methyl-2-[3-(2-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetylamino}-ethyl)-phenoxy]-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH2:13][CH2:14][OH:15]>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][CH2:13][CH2:14][OH:15])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: NCCO
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Product: O=[N+]([O-])c1cc(F)ccc1NCCO

Procedure:
This compound was prepared from 1,4-difluoro-2-nitrobenzene (21.8 ml, 100 mmol) and 2-amino ethanol (10 ml, 300 mmol) using analogous procedure described in Step A of Example 3. Yield (19.2 g, 96%).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:20]=[C:19]3[C:14]([N:15]=[CH:16][C:17]([N:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[N:18]3)=[CH:13][CH:12]=2)[CH:8]=[N:9][CH:10]=1)(=[O:4])=[O:3].FC(F)(F)C(O)=O>C(#N)C>[N:21]1([C:17]2[CH:16]=[N:15][C:14]3[C:19]([N:18]=2)=[CH:20][C:11]([C:7]2[CH:6]=[C:5]([S:2]([NH2:1])(=[O:4])=[O:3])[CH:10]=[N:9][CH:8]=2)=[CH:12][CH:13]=3)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc3ccc(-c4cncc(S(N)(=O)=O)c4)cc3n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: NS(=O)(=O)c1cncc(-c2ccc3ncc(N4CCNCC4)nc3c2)c1

Procedure:
A solution of 1,1-dimethylethyl 4-{7-[5-(aminosulfonyl)-3-pyridinyl]-2-quinoxalinyl}-1-piperazinecarboxylate (0.21 mmol) (prepared according to Scheme 1) in acetonitrile (4 mL) was treated with concentrated trifluoroacetic acid (4 mL) for 2 hours. The reaction mixture was then concentrate and neutralized with saturated sodium bicarbonate (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to yield the title product. MS(ES)+ m/e 371.0 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][O:4][C@H:5]1[C@@H:10]([NH2:11])[CH2:9][CH2:8][N:7]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:6]1.[Cl:19][C:20]1[N:21]=[C:22]([C:27](O)=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[Cl:19][C:20]1[N:21]=[C:22]([C:27]([NH:11][C@H:10]2[CH2:9][CH2:8][N:7]([C:12](=[O:17])[C:13]([F:16])([F:14])[F:15])[CH2:6][C@H:5]2[O:4][CH2:3][CH:2]([F:1])[F:18])=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: N[C@H]1CCN(C(=O)C(F)(F)F)C[C@H]1OCC(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)C(F)(F)F)C[C@H]2OCC(F)F)nc1Cl
Yield: 66.3 %

Procedure:
The same operation as in Example (106d) was performed using cis(±)-3-(2,2-difluoroethoxy)-1-(trifluoroacetyl)piperidin-4-amine obtained in Example (121e) (0.79 g, 2.86 mmol), 4-chloro-5-ethyl-1H-imidazole 2-carboxylic acid (85% content, 0.62 g, 3 mmol), WSC hydrochloride (1.15 g, 6 mmol), HOBt (0.61 g, 4.5 mmol), DMA (15 mL) and dichloromethane (15 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 3/2, 4/1) to obtain 0.82 g of the title compound as a colorless amorphous solid (63%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:27])=[C:7]([C:9]2[NH:10][C:11](=[O:26])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]#[C:21][CH:22]4[CH2:24][CH2:23]4)=[CH:16][C:15]=3[F:25])[N:13]=2)[CH:8]=1.[C:28](Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[Cl:27][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:7]=1[C:9]1[NH:10][C:11](=[O:26])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][CH:22]3[CH2:24][CH2:23]3)=[CH:16][C:15]=2[F:25])[N:13]=1
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C#CC4CC4)cc3F)c(=O)[nH]2)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C#CC4CC4)cc3F)c(=O)[nH]2)c1
Yield: 32.2 %

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chlorophenyl)-2-(4-(2-cyclopropylethynyl)-2-fluorophenyl)-2H-1,2,4-triazol-3(4H)-one (0.100 g, 0.266 mmol), pivaloyl chloride (0.040 g, 0.319 mmol), THF (10.0 mL) and TEA (2 mL) to afford 0.040 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 0.78 (m, 2H), 0.919 (m, 2H), 1.11 (br s, 9H), 1.56 (m, 1H), 4.28 (br d, 2H), 7.32-7.41 (m, 3H), 7.56 (br s, 3H), 8.16 (s, 1H), 12.46 (s, 1H); MS (m/z): 467.22 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3](O)=[O:4].C(Cl)(=O)C([Cl:16])=O>ClCCl>[CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([Cl:16])=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C(=O)O)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C(=O)Cl)c1ccccc1

Procedure:
A solution of 2-Methyl-2-phenylpropionic acid (10 mmol, 1.0 eq.) and oxalyl chloride (40 mmol, 4.0 eq.) in dichloromethane (30 mL) was stirred at room temperature for 18 h. The mixture was concentrated in vacuo to afford the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.Cl[CH2:13][CH:14]=O.C(=O)(O)[O-].[Na+]>O>[CH3:11][O:10][C:4]1[N:3]2[CH:13]=[CH:14][N:1]=[C:2]2[CH:7]=[C:6]([O:8][CH3:9])[N:5]=1
Reactant: COc1cc(N)nc(OC)n1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1cc2nccn2c(OC)n1
Temperature: 80 °C

Procedure:
A mixture of 1.5 g (0.01 mole) of 4-amino-2,6-dimethoxypyrimidine and 3.0 g (0.015 mole) of 50% aqueous chloroacetaldehyde in 20 ml of water was heated at 80° C. for one hour, and was then cooled with an ice bath with concomitant neutralization with sodium bicarbonate. The solid which formed was separated by filtration and recrystallized from cyclohexane with treatment with decolorizing charcoal. White crystals of 5,7-dimethoxyimidazo[1,2-c]pyrimidine, m.p. 120°-121° C., were obtained. Analysis: Calculated for C8H9N3O2 : %C, 53.6; %H, 5.1; %N, 23.5; Found: %C, 53.5; %H, 5.0; %N, 23.6. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [Br:1][C:2]1[CH2:6][CH:5]([C:7]([O:9]CCCCC)=[O:8])[N:4]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:3]=1.C(O)C.[OH-].[Na+]>O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[N:4]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:3]=1
Reactant: CCCCCOC(=O)C1CC(Br)=NN1c1ncccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
To a 100 mL flask, pentyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (5.00 g, 97%, 12.94 mmol), ethanol (30 mL), water (30 mL) and sodium hydroxide (0.52 g, 12.94 mmol) were added. The reaction mixture was stirred for 6 hours at room temperature. The reaction mixture was concentrated by rotary evaporator to remove ethanol. Then water (250 mL) was added. Aqueous solution was extracted with ethyl acetate (100 mL), acidified with concentrated hydrochloric acid to pH=2 and extracted with dichloromethane (3×200 mL) again. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated by rotary evaporator to give 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (3.60 g) as a white solid in 90% yield. HPLC area normalization method content is 98% (Analytical condition: chromatographic column: ZORBAX Eclipse XDB-C8 4.6×150 mm 5 μm, mobile phase:the ratio of acetonitrile to water is 70:30).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]([C:13](=O)[CH2:14][C:15](=O)[CH3:16])[C:9]([CH3:19])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:21]([NH:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:28]1[C:13]([C:10]2[C:9]([CH3:19])=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]=2[OH:12])=[CH:14][C:15]([CH3:16])=[N:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NNCc1ccccc1
Reactant: CC(=O)CC(=O)C1C(=O)N(c2ccccc2)N=C1C
Agent: Cl
Product: Cc1cc(-c2c(C)nn(-c3ccccc3)c2O)n(Cc2ccccc2)n1

Procedure:
Prepare the compound from 1-[1-phenyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-1,3-dione and benzylhydrazine hydrochloride according to the procedure of Example 28.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].ClC(Cl)(Cl)C(=N)O[C:16]([CH3:19])([CH3:18])[CH3:17].C(=O)(O)[O-].[Na+]>ClCCl.CCCCCC>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:10]
Reactant: O=C(O)CCCCCCCBr
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCCCCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
A 5.00 g (22.4 mmol) portion of 8-bromooctanoic acid was dissolved in a mixed solvent of 2 ml dichloromethane and 10 ml hexane, and the solution was mixed with 8.00 ml (44.8 mmol) of tert-butyl 2,2,2-trichloroacetoimidate and 0.45 ml (3.66 mmol) of boron trifluoride-ether complex and stirred at room temperature for 1 hour. The reaction solution was mixed with 10 ml of hexane and 0.031 g (3.66 mmol) of sodium bicarbonate, the resulting precipitate was separated by filtration, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=5/1) to obtain 2.34 g (yield, 38%) of tert-butyl 8-bromooctanoate.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:11](Cl)([CH3:13])=[O:12]>C(Cl)Cl>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11](=[O:12])[CH3:13])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)Cl
Reactant: Nc1ccc2c(c1)CCC2
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of indan-5-amine (43 g, 0.31 mol) and TEA (51.3 mL, 0.370 mol) in 400 mL of anhydrous DCM was added a solution of AcCl (23.6 mL, 0.340 mol) in 100 mL of anhydrous DCM dropwise at 0° C. then and stirred for 0.5 h at r.t. After the reaction was completed, the reaction mixture was added 500 mL of DCM, washed with water, 10% HCl solution, 10% NaHCO3 and brine. The organic phase was dried over anhydrous Na2SO4 and concentrated to give N-(2,3-dihydro-1H-inden-5-yl)acetamide. 1H-NMR (300 MHz, CDCl3) δ ppm 7.43 (s, 1H), 7.13˜7.14 (m, 2H), 2.86 (q, J=7.9 Hz, 4H), 2.15 (s, 3H), 2.0˜2.10 (m, 2H);
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:35]1[CH:39]=[CH:38][O:37][N:36]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][O:14][C:35]3[CH:39]=[CH:38][O:37][N:36]=3)[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: OCC1CC(c2ccc(Br)cc2)=NO1
Reactant: Oc1ccon1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1ccc(C2=NOC(COc3ccon3)C2)cc1
Reaction time: 18 h
Yield: 55.5 %

Procedure:
(5RS)-3-(4-Bromophenyl)-5-hydroxymethyl-4,5-dihydro-isoxazole (3.07 g, 12 mM), triphenylphosphine (3.78 g, 14.4 mM) and 3-hydroxyisoxazole (1.02 g, 12 mM) were dissolved in anhydrous tetrahydrofuran (50 ml), cooled to 0° with stirring under nitrogen, and treated with diisopropylazodicarboxylate (2.71 g, 13.4 mM). Stirring was continued for 18 hours, and the mixture evaporated to dryness. The residue was chromatographed on a 90 g Biotage silica column, eluting with 25% ethyl acetate in isohexane, appropriate fractions combined, and chromatographed again on a 40 g Biotage silica column, eluting with 5% methanol in dichloromethane. Appropriate fractions were combined to give the desired product (2.15 g). MS (ESP): 323 (MH+) for C13H11BrN2O3