Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([N+:9]#[C-:10])[CH2:7][CH3:8].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:23][CH2:24][CH2:25]Cl)[CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20].C(O)(=O)C.C(OCC)(=O)C>O1CCCC1.O>[CH2:7]([C:6]([N+:9]#[C-:10])([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:25][CH2:24][CH2:23][C:15]1[CH:16]=[C:17]([O:21][CH3:22])[C:18]([O:19][CH3:20])=[C:13]([O:12][CH3:11])[CH:14]=1)[CH3:8]
Reactant: COc1cc(CCCCl)cc(OC)c1OC
Reactant: [C-]#[N+]C(CC)c1cccs1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: [C-]#[N+]C(CC)(CCCc1cc(OC)c(OC)c(OC)c1)c1cccs1
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
A solution of 2 g of diisopropylamine in 10 ml of tetrahydrofuran is cooled at -60° C and 10 ml of 1.6 M n-butyl lithium in hexane are added dropwise to the solution. The mixture is stirred at the same temperature for 30 minutes to give a solution of lithium diisopropylamide. A solution of 2 g of 1-(2-thienyl)propyl isocyanide in 10 ml of tetrahydrofuran is added dropwise at -60° C. to the solution obtained above and the mixture is stirred at the same temperature for 30 minutes. A solution of 3.8 g of 3-(3,4,5-trimethoxyphenyl)propyl chloride in 5 ml of tetrahydrofuran is added dropwise to the mixture at the same temperature, and said mixture is stirred for 1 hour. The reaction mixture is neutralized with acetic acid, and ethyl acetate and water are added thereto. The organic layer is separated therefrom, washed with an aqueous saturated sodium chloride solution, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=4:1) to give 3.4 g of 1-ethyl-4-(3,4,5-trimethoxyphenyl)-1-(2-thienyl)butyl isocyanide as a colorless oil. yield: 71.5%
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1.[H-].[Na+].[N+:20]([C:23]1[CH:28]=[C:27]([S:29]([C:32]([F:35])([F:34])[F:33])(=[O:31])=[O:30])[CH:26]=[CH:25][C:24]=1Cl)([O-:22])=[O:21]>>[N+:20]([C:23]1[CH:28]=[C:27]([S:29]([C:32]([F:35])([F:33])[F:34])(=[O:30])=[O:31])[CH:26]=[CH:25][C:24]=1[O:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Reactant: O=C(O)c1ccc(Oc2cccc(O)c2)cc1
Agent: [H-]
Agent: [Na+]
Product: O=C(O)c1ccc(Oc2cccc(Oc3ccc(S(=O)(=O)C(F)(F)F)cc3[N+](=O)[O-])c2)cc1

Procedure:
Using procedure as in example 10, a reaction of 4-(3-hydroxyphenoxy)benzoic acid (100 mg, 0.4334 mmol), NaH (38 mg, 2.2 equiv.) and 2-nitro-4-(trifluoromethylsulfonyl)chlorobenzene (126 mg, 1 equiv.) afforded 4-[3-(2-nitro-4-trifluoromethanesulfonyl-phenoxy)-phenoxy]-benzoic acid. 1HNMR (360 MHz, DMSO-d6) δ 12.8 (br s, 1H, COOH), 8.75 (d, J=2.7 Hz, 1H), 8.30 (dd, J=2.7 & 9.0 Hz, 1H), 7.95 (m, 2H), 7.6 (m, 1H), 7.37 (d, J=9.0 Hz, 1H), 7.17-7.21 (m, 2H), 7.12 (m, 3H). MS-EI m/z 483 [M+].
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:25]([O:29][C:30](=[O:41])[CH2:31][C@@:32]1([C:38]([OH:40])=[O:39])[C@H:36]([CH3:37])[CH2:35][NH:34][CH2:33]1)([CH3:28])([CH3:27])[CH3:26].C(O)(=O)C>O.CO>[C:25]([O:29][C:30](=[O:41])[CH2:31][C@@:32]1([C:38]([OH:40])=[O:39])[C@H:36]([CH3:37])[CH2:35][N:34]([CH2:4][C:3]2[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=2[Cl:10])[CH2:33]1)([CH3:26])([CH3:27])[CH3:28]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: C[C@@H]1CNC[C@]1(CC(=O)OC(C)(C)C)C(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: C[C@@H]1CN(Cc2c(Cl)cccc2Cl)C[C@]1(CC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,6-Dichlorobenzaldehyde (646 mg, 3.7 mmol) and sodium triacetoxyborohydride (782 mg, 3.7 mmol) were added to a mixture of (3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidine-3-carboxylic acid obtained by the method of Example 2j (600 mg, 2.47 mmol), acetic acid (0.14 ml, 2.47 mmol) and methanol (10 ml), and the reaction mixture was stirred at room temperature for two hours. 2,6-Dichlorobenzaldehyde (430 mg, 2.5 mmol) and sodium triacetoxyborohydride (522 mg, 2.5 mmol) were further added, followed by stirring at an external temperature of 40° C. for 10.5 hours. Water was added to the reaction mixture, which was extracted with dichloromethane five times, and the organic layer was concentrated. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol) to give Lot A (32 mg) and Lot B (551 mg) of the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1.[H-].[Na+].Cl[CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].O>C1COCC1.CCCCCC>[F:18][C:2]([F:1])([F:17])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]3=[N:16][S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][N:12]3[CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: Nc1ncccc1-c1ccc(OC(F)(F)F)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc(OC(F)(F)F)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
A mixture of 3-[4-(trifluoromethoxy)phenyl]pyridin-2-amine (350 mg) in dehydrated THF (5 mL) was added to a mixture of sodium hydride (60%, 275 mg) and 2-chloroethanesulfonyl chloride (673 mg) in dehydrated THF (5 mL) under ice-cooling. The reaction mixture was stirred at room temperature overnight, and water and hexane were added. The resulting precipitate was collected by filtration, and washed with water and diisopropyl ether to give the title compound (333 mg) as a white solid. The obtained solid was crystallized from THF, acetonitrile and diisopropyl ether to give a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[O:11]1[CH:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12]1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:12][CH:13]([OH:11])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CCCCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCC(O)CSc1ccc(Cl)cc1

Procedure:
To 28.9 g (0.2 mole) the p-chlorothiophenol and 8.0 g (0.2 mole) of sodium hydroxide in 100 ml of water is added 22.0 g (0.22 mole) of 1,2-epoxyhexane over 10 minutes. When addition is completed, the mixture is heated to reflux for 16 hours. The mixture is cooled, combined with 300 ml of water and the organic phase is separated.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH2:25]([CH2:27][NH2:28])[OH:26]>>[CH:18]1([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:28][CH2:27][CH2:25][OH:26])=[O:24])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: COC(=O)c1ccc(OCc2c(C3CCCCC3)noc2C)nc1
Reactant: NCCO
Product: Cc1onc(C2CCCCC2)c1COc1ccc(C(=O)NCCO)cn1
Yield: 10 %

Procedure:
As described for example 31e, 6-(3-cyclohexyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (708 mg, 1.5 mmol) was converted, using ethanolamine instead of isopropylamine, to the title compound (55 mg, 10%) which was obtained as a light yellow oil after purification by chromatography (silica, 0 to 5% methanol in dichloromethane). MS: m/e=360.4 [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:23]=[CH:22][C:10]([CH2:11][CH:12]2[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[C:13]2([OH:21])[CH2:19][OH:20])=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][CH:12]2[CH2:16][CH2:15][C:14]([CH3:17])([CH3:18])[C:13]2([OH:21])[CH2:19][O:20][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:22][CH:23]=1
Reactant: CC1(C)CCC(Cc2ccc(Cl)cc2)C1(O)CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CCC(Cc2ccc(Cl)cc2)C1(O)COS(C)(=O)=O
Reaction time: 2 h
Yield: 79.8 %

Procedure:
2.76 g (1.05 equivalents) methylsulphonyl chloride were added to a solution of 6.42 g (24 mmols) 1-(4-chlorobenzyl)-3,3-dimethyl-2-hydroxy-2-hydroxymethylcyclopentane prepared as described in Example 1 (i) and 2.55 g (1.1 equivalents) triethylamine in 50 ml dichloromethane at 10°-15° C. The reaction mixture was kept at 10°-15° C. for further 2 hours and then washed with 20 ml water, then 20 ml aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulphate and flashed. Trituration with 60/80 petroleum gave 6.64 g 1-(4-chlorobenzyl)-3,3-dimethyl-2-hydroxy-2-methylsulphonyloxymethylcyclopentane (Isomer A) as a white solid, m.pt. 113°-114° C. Yield: 80%.
Reaction SMILES: [C:1]([O:7][CH2:8]Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[C:16]([O:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]2[C:40]([C:41]([OH:43])=[O:42])=[C:39]([C:44]([OH:47])([CH3:46])[CH3:45])[N:38]=[C:37]2[CH2:48][CH2:49][CH3:50])=[CH:31][CH:30]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(OCC)(=O)C>CN(C)C(=O)C.O>[C:16]([O:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]2[C:40]([C:41]([O:43][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:42])=[C:39]([C:44]([OH:47])([CH3:46])[CH3:45])[N:38]=[C:37]2[CH2:48][CH2:49][CH3:50])=[CH:31][CH:30]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCOC(=O)C(C)(C)C)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.13 ml of chloromethyl pivalate and 3.99 g of potassium carbonate were added to a solution of 6 g of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid [prepared as described in step (b) above] in 70 ml of N,N-dimethylacetamide, and the resulting mixture was stirred at room temperature for 1 hour and then at 50° C. for 2 hours. At the end of this time, the reaction mixture was mixed with ethyl acetate and water. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 6.80 g of the title compound as crystals, melting at 106°-107° C.
Reaction SMILES: [C:1]([O:4]C(=O)C)(=[O:3])[CH3:2].[C:8]1(=[O:18])[O:13][C:11](=O)[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12.C([O-])(=O)C.[K+]>C1(C)C=CC=CC=1>[O:18]=[C:8]1[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)/[C:11](=[CH:2]/[C:1]([OH:4])=[O:3])/[O:13]1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1OC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(O)/C=C1\OC(=O)c2ccccc21
Temperature: 30 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
To 402 ml (4.26 moles) of acetic anhydride was added 150.0 g (1.01 moles) of phthalic anhydride and 124 g (1.26 moles) of potassium acetate in a 2 liter 3 neck flask. The resulting slurry was heated to 130°-135° C. for 1 hour and 20 minutes then cooled to 75°-80° C. and 1500 ml of toluene were added. The slurry was allowed to cool to 30° C. and granulate for 1 hour. The solids were recovered by filtration, washed with 300 ml of methylene chloride and air dried. The dried solids were repulped in 1500 ml H2O at 20°-25° C., allowed to granulate for 1 hour and oven dried at 50° C. overnight with an air bleed to give a yield of 52% (100.0 g) of the title compound: mp 245-250° C.;
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24]Cl>C(Cl)Cl>[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COCCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCOc1ccc(C=O)cc1
Reaction time: 2 h
Yield: 101.1 %

Procedure:
0.16 mol of 4-hydroxybenzaldehyde and 0.32 mol of ethyldiisopropylamine are dissolved in 250 ml of CH2Cl2 (anhydrous), and 0.24 mol of 2-methoxyethoxymethyl chloride are then added dropwise at room temperature. The mixture is stirred at this temperature for 2 hours, then the solvent is removed in vacuo. The residue is taken up using 200 ml of EA and the solution is washed once each with 200 ml of Na2CO3 solution and 200 ml of NaH2PO4 solution, dried over Na2 SO4 and the solvent removed in vacuo. 34 g of a light brown oil are obtained, which is reacted further without purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:21][CH3:22])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([Cl:37])[C:29]=1[C:30](=O)[C:31]([O:33]CC)=O.CC(O)=O>COCCO>[Cl:37][C:28]1[CH:27]=[N:26][CH:25]=[C:24]([Cl:23])[C:29]=1[C:30]1[C:31](=[O:33])[N:21]([CH3:22])[C:3]2[N:4]=[C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:11][CH:10]=3)[N:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CCOC(=O)C(=O)c1c(Cl)cncc1Cl
Reactant: CNc1nc(Nc2ccc(N3CCOCC3)cc2)ncc1N
Solvent: COCCO
Solvent: CC(=O)O
Product: Cn1c(=O)c(-c2c(Cl)cncc2Cl)nc2cnc(Nc3ccc(N4CCOCC4)cc3)nc21
Yield: 17.5 %

Procedure:
A mixture of 0.30 g (1 mmol) of 5-amino-4-(methylamino)-2-[[4-(morpholin-4-yl)phenyl]amino]pyrimidine, 0.37 g (1.5 mmol) of ethyl 2-(3,5-dichloropyridin-4-yl)-2-oxoacetate, and 0.3 mL HOAc in 15 mL 2-methoxyethanol as heated under reflux for 16 hours, and worked up as above in 2. Chromatography on alumina, eluting with CH2Cl2/EtOAc (4:1), gives 85 mg (18%) of the title compound (Compound 12 in Tables 1 and 2): mp (MeOH) 243–245° C.
Reaction SMILES: CN(C)[CH2:3][CH2:4]N(C)C.[CH2:9]([C:11]1[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=1[C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])[CH3:10].C([Li])(CC)C.C(I)C>C1COCC1.C1CCCCC1.O>[CH:9]([C:11]1[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=1[C:13]([N:15]([CH2:16][CH3:17])[CH2:18][CH3:19])=[O:14])([CH2:3][CH3:4])[CH3:10]
Reactant: CCc1ccccc1C(=O)N(CC)CC
Reactant: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCI
Solvent: C1CCCCC1
Solvent: O
Product: CCC(C)c1ccccc1C(=O)N(CC)CC
Temperature: -78 °C
Yield: 40.9 %

Procedure:
To a solution of 4.74 ml (0.031 mol) of tetramethylethylenediamine in 300 ml of THF (passed through alumina prior to use) was added 5.8 g (0.03 mol) of 2-ethyl-N,N-diethylbenzamide. The solution was cooled to -78° C. and treated with 34.9 ml (0.031 mol) of a 0.9M solution of s-butyl lithium in cyclohexane. When addition was complete, the mixture was stirred for twenty minutes and then treated with a solution of 3.2 ml (0.04 mol) of ethyl iodide while maintaining the temperature at -78° C. The temperature was then allowed to rise to ambient temperature and the mixture stirred for about sixteen hours and then poured into water. The resulting oil was separated and chromatographed on silica gel, eluting with 10% ethyl acetate/hexane to give 2.86 g (43%) of 2-sec.-butyl-N,N-diethylbenzamide as a yellow oil.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[C:17]([F:18])=[CH:16][C:15]([C:19]2[N:20]=[C:21]([N:28]3[CH2:33][CH2:32][NH:31][CH:30]([C:34](OCC)=[O:35])[CH2:29]3)[C:22]3[S:27][CH:26]=[CH:25][C:23]=3[N:24]=2)=[C:14]([F:39])[CH:13]=1.[ClH:40].[OH-].[Na+].Cl.O1CCOCC1>C1COCC1>[ClH:11].[ClH:40].[Cl:11][C:12]1[C:17]([F:18])=[CH:16][C:15]([C:19]2[N:20]=[C:21]([N:28]3[CH2:33][CH2:32][NH:31][CH:30]([CH2:34][OH:35])[CH2:29]3)[C:22]3[S:27][CH:26]=[CH:25][C:23]=3[N:24]=2)=[C:14]([F:39])[CH:13]=1
Reactant: CCOC(=O)C1CN(c2nc(-c3cc(F)c(Cl)cc3F)nc3ccsc23)CCN1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: OCC1CN(c2nc(-c3cc(F)c(Cl)cc3F)nc3ccsc23)CCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.65 ml of THF solution with 1.0M diisobutylaluminum hydride was added dropwise under ice cooling into a mixture of 400 mg of ethyl 4-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]piperazine-2-carboxylate and 10 ml of THF and the resultant was stirred for 3 hours at room temperature. After 10 ml of 1M HCl aq was added to the reaction mixture and stirred for 10 minutes at room temperature, 20 ml of 1M NaOH aq was added and extracted with chloroform. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-MeOH) to give an oily substance. After the obtained oily substance was dissolved in 10 ml of THF and 1 ml of 4M HCl-dioxane solution was added, the resultant was concentrated under reduced pressure to give a solid. This solid washed with EtOH-ether to give 60 mg of {4-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]piperazine-2-yl}methanol dihydrochloride.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/4)=[C:9]3[N:8]=[C:7]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:6]=2)[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.[CH:38]1([CH2:41][C:42](O)=[O:43])[CH2:40][CH2:39]1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN1C(=O)CCC1.CO>[CH:38]1([CH2:41][C:42]([N:25]2[CH2:26][CH2:27][N:22]([C:7]3[CH:6]=[C:5]([NH:4][CH:1]4[CH2:2][CH2:3]4)[N:10]4[N:11]=[CH:12][C:13](/[CH:14]=[C:15]5/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/5)=[C:9]4[N:8]=3)[CH2:23][CH2:24]2)=[O:43])[CH2:40][CH2:39]1
Reactant: O=C(O)CC1CC1
Reactant: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)cc(N4CCNCC4)nc23)N1
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)cc(N4CCN(C(=O)CC5CC5)CC4)nc23)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (Z)-5-((7-(cyclopropylamino)-5-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (step b) (10 mg, 0.027 mmol) in 50.0 uL NMP, was added HOBT (4.4 mg, 0.032 mmol), cyclopropyl acetic acid (60 ul in 0.02M NMP solution), DIPEA (9.5 ul, 0.067 mmol) and EDC (7.8 mg, 0.040 mmol). The reaction mixture was stirred at room temperature for one hour. Diluted the reaction mixture with methanol and prepared by HPLC to yield (Z)-5-((5-(4-(2-cyclopropylacetyl)piperazin-1-yl)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=451)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+].O1CCCC1>C(OCC)(=O)C>[CH2:17]([O:24][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccccc1
Reactant: Fc1ccc(OCc2ccnc(Cl)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(OCc2ccnc(OCc3ccccc3)c2)cc1
Yield: 99.3 %

Procedure:
A mixture of 2-chloro-4-[(4-fluorophenoxy)methyl]pyridine (845 mg, 3.55 mmols), benzyl alcohol (0.48 mL, 4.62 mmols), sodium hydride (60% oiliness, 170 mg, 4.26 mmols) and tetrahydrofuran (20 mL) was refluxed for 16 hours. Cooling the reaction liquid to room temperature, ethyl acetate was added thereto, followed by washing with saturated aqueous sodium hydrogencarbonate solution and saturated brine and drying over anhydrous sodium sulfate. Concentrating the solvent under reduced pressure, the residue was purified on silica gel column chromatography (KP-Sil, FLASH 40+M, hexane:ethyl acetate=10:0-17:3) to provide the title compound (1.09 g, 99%).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:49]([O:51][C:52](=[O:55])[CH2:53][NH2:54])[CH3:50]>CN(C=O)C.O>[CH2:49]([O:51][C:52](=[O:55])[CH2:53][NH:54][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:16][CH:15]=1)[CH3:50]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1ccc(Nc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)c1ccc(Nc2ccccc2)cc1
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a stirred solution of 4-phenylamino-benzoic acid (3.0 g, 0.01401 mol) in DMF (10 mL), was added DIPEA (5.4 g, 0.04205 mol), HOBt (2.27 g, 0.01682 mol) and EDCI.HCl (6.69 g, 0.03504 mol) at ambient temperature. After 2 minutes amino-acetic acid ethyl ester hydrochloride (2.33 g, 0.01682 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration, washed with water followed by hexane and dried to afford 4 g (95%) of (4-phenylamino-benzoylamino)-acetic acid ethyl ester. To a stirred solution (4-phenylamino-benzoylamino)-acetic acid ethyl ester (4 g, 0.01337 mol) in a mixture of THF (15 mL), methanol (15 mL) and H2O (8 mL) was added LiOH.H2O (2.24 g, 0.0535 mol). The resulting mixture was stirred at ambient temperature for 3 hours and then concentrated. The residue was diluted with water and acidified with 10% aqueous citric acid solution. The resulting precipitate was isolated by filtration and dried to afford 3.3 g (91%) of (4-phenylamino-benzoylamino)-acetic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7](/[CH:9]=[CH:10]/[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[CH:25](OCC)(OCC)OCC.[BH4-].[Na+].C(=O)(O)[O-].[Na+].[ClH:42]>C(O)C.CO>[ClH:42].[CH3:25][NH:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7](/[CH:9]=[CH:10]/[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: CCO
Product: CNc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Reaction time: 6 h
Yield: 43 %

Procedure:
A mixture of (E)-5-amino-1-(2-pyridyl)-2-styryl-1H-benzimidazole (300 mg, 0.96 mmol) and triethyl orthoformate (3 ml) was refluxed with stirring for 6 h. Excess solvent was removed in vacuo and obtained solids were dissolved in ethanol (5 ml). Sodium borohydride (45 mg, 1.2 mmol) was added to this solution in one portion at 0° C. and the reaction mixture was stirred for 2 h at room temperature. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution (50 ml) and the aqueous mixture was extracted with ethyl acetate (100 ml). The organic extract was washed consecutively with water (50 ml) and brine (50 ml), dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100 g; n-hexane/ethyl acetate (1/1)) to give a brown oil. Then, it was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Volatiles were removed under reduced pressure and the residue was recrystallized from ethanol to afford 151 mg (43%) of the titled compound as yellow solids.