Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[CH3:5][O:6][CH2:7][C:8]1([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C>CN(C)C(=O)C>[CH3:5][O:6][CH2:7][C:8]1([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][N:11]([CH:2]([CH3:4])[CH3:3])[CH2:10][CH2:9]1
Reactant: COCC1(Nc2ccccc2)CCNCC1
Reactant: CC(C)Br
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COCC1(Nc2ccccc2)CCN(C(C)C)CC1
Yield: 42.6 %

Procedure:
A mixture of 10 parts of 2-bromopropane, 9 parts of 4-(methoxymethyl)-N-phenyl-4-piperidinamine, 4.9 parts of N,N-diethylethanamine and 72 parts of N,N-dimethylacetamide is stirred and refluxed for 10.25 hours. After cooling, the formed N,N-diethylethanamine hydrobromide is filtered off and the filtrate is diluted with water. The product is extracted with methylbenzene. The extract is washed thoroughly with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 5.7 parts (42.6%) of 4-(methoxymethyl)-1-(1-methylethyl)-N-phenyl-4-piperidinamine as an oily residue.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:7][CH3:8])[C:4](=[O:6])[CH3:5].[C:9](OC(=O)C)(=[O:11])[CH3:10].CO.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:7]([CH:3]([C:4](=[O:6])[CH3:5])[CH2:2][O:1][C:9](=[O:11])[CH3:10])[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(CO)C(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCC(COC(C)=O)C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Hydroxymethyl-pentan-2-one (20.7 g) was dissolved in CHCl3 (150 mL) and cooled in an ice bath. Acetic anhydride (80 mL) was added, followed by DMAP (2.18 g), and the mixture was stirred overnight at room temperature. After cooling in an ice bath, MeOH (120 mL) was added dropwise, and the mixture was poured into a saturated aqueous NaHCO3 solution. After extraction with DCM twice, the combined organic phases were dried over Na2SO4 and evaporated under reduced pressure to give 28.0 g of a light-yellow liquid. 1H NMR (400 MHz, CDCl3) δ 0.93 (t, J=8 Hz, 3H), 1.46-1.75 (m, 2H), 2.03 (s, 3H), 2.20 (s, 3H), 2.77 (quint., J=6.5 Hz, 1H), 4.20 (d, J=7 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8]O)[CH:7]=1.[Br:12]P(Br)Br>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8][Br:12])[CH:7]=1
Reactant: COc1ccc(Br)cc1CO
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: COc1ccc(Br)cc1CBr
Reaction time: 0.25 h

Procedure:
To a solution of (5-bromo-2-methoxyphenyl)methanol (1.0 g, 4.6 mmol) in dichloromethane (10 mL) at 0° C. was added tribromophosphine (1 M in dichloromethane, 9.2 mL, 9.2 mmol). The ice bath was removed and the reaction stirred for 15 min. The reaction was concentrated, poured onto cold saturated sodium bicarbonate, extracted with pentane, dried over magnesium sulfate, and concentrated to give 1.15 g (89%) as a white crystalline solid. 1H NMR (500 MHz, CDCl3) δ ppm 7.44 (d, J=2.5 Hz, 1H), 7.38 (dd, J=8.9, 6.1 Hz, 1H), 4.47 (s, 2H), 3.87 (s, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 156.7, 133.6, 132.8, 128.4, 112.8, 112.7, 56.0, 27.5.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:6][C:5]2[C:7]([CH3:21])=[CH:8][CH:9]=[C:10]([N:11]3[N:15]=[C:14]([N:16](OC)[CH3:17])[O:13][C:12]3=[O:20])[C:4]=2[O:3]1.C(N(C(C)C)CC)(C)C>CO>[CH3:1][C:2]1([CH3:22])[CH2:6][C:5]2[C:7]([CH3:21])=[CH:8][CH:9]=[C:10]([N:11]3[N:15]=[C:14]([NH:16][CH3:17])[O:13][C:12]3=[O:20])[C:4]=2[O:3]1
Reactant: CON(C)c1nn(-c2ccc(C)c3c2OC(C)(C)C3)c(=O)o1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nn(-c2ccc(C)c3c2OC(C)(C)C3)c(=O)o1

Procedure:
A solution of 3.0 g of 3, 75 ml of methanol and 1.3 g of N,N-diisopropyl-N-ethylamine was warmed on a steam bath for 18 hours. The solvent was evaporated under reduced pressure, the residue was mixed with 75 ml of water and the mixture was extracted with ether. The extract was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was flash-chromatographed over silica gel, using a 2:15:33 v:v:v mixture of THF, ethyl acetate and hexane as eluent. Two products were obtained: one, a light amber syrup, Rf=0.49, was identified as 3; the second, a solid (Rf=0.24) was recrystallized from ether to give 4, as a colorless solid, m.p.: 183°-184° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[CH3:25][O:26][C:27]1[CH:40]=[CH:39][C:30]([CH2:31][N:32]2[CH2:36][C@H:35]([CH3:37])[NH:34][C:33]2=[O:38])=[CH:29][CH:28]=1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:34]4[C@@H:35]([CH3:37])[CH2:36][N:32]([CH2:31][C:30]5[CH:39]=[CH:40][C:27]([O:26][CH3:25])=[CH:28][CH:29]=5)[C:33]4=[O:38])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: COc1ccc(CN2C[C@H](C)NC2=O)cc1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: COc1ccc(CN2C[C@H](C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)c(F)c3)C2=O)cc1
Yield: 84.6 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (157 mg) described in Preparation Example 114 and (S)-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (106 mg) described in Preparation Example 204 and by the reaction and treatment in the same manner as in Example 1, (S)-3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (180 mg) was obtained. Using the obtained (S)-3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (180 mg) and by the reaction and treatment in the same manner as in Example 421, the title compound (108 mg) was obtained.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:5])[CH3:4].[H-].[Na+].[Cl:8][C:9]1[C:10]([F:43])=[C:11]([CH:40]=[CH:41][CH:42]=1)[C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:22]=[C:23]([CH:28]=[C:29]([N:31]=[C:32]3[N:36]([CH2:37][O:38][CH3:39])[CH:35]=[CH:34][S:33]3)[N:30]=2)[C:24](OC)=O)[CH2:16][CH2:15]1)=[O:13]>O1CCCC1.C(OCC)(=O)C>[Cl:8][C:9]1[C:10]([F:43])=[C:11]([CH:40]=[CH:41][CH:42]=1)[C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[N:30]=[C:29]([N:31]=[C:32]3[N:36]([CH2:37][O:38][CH3:39])[CH:35]=[CH:34][S:33]3)[CH:28]=[C:23]([C:24]3[O:1][N:2]=[C:3]([CH3:4])[N:5]=3)[CH:22]=2)[CH2:16][CH2:15]1)=[O:13]
Reactant: COCn1ccsc1=Nc1cc(C(=O)OC)cc(CN2CCN(C(=O)c3cccc(Cl)c3F)CC2)n1
Reactant: CC(=N)NO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCn1ccsc1=Nc1cc(-c2nc(C)no2)cc(CN2CCN(C(=O)c3cccc(Cl)c3F)CC2)n1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To a mixture of 9.4 mg of N-hydroxyacetamidine, molecular sieves 4A and 1 ml of tetrahydrofuran was added sodium hydride followed by stirring at 65° C. for 1 hour. To the reaction solution was added a solution of 22.6 mg of methyl 2-((4-(3-chloro-2-fluorobenzoyl)piperazin-1-yl)methyl)6-((3-(methoxymethyl)-thiazol-2(3H)-ylidene)amino)isonicotinate in 1 ml of tetrahydrofuran, followed by heating under reflux for 6 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and washed with saturated sodium bicarbonate and brine. The resulting organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The resulting residue was purified by a thin-layer chromatography for fractionation (eluent: chloroform/methanol=10/1) to give the title compound.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:24])[NH:6][C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:9]=1)(=[O:3])[CH3:2].[CH2:25]([O:32][CH2:33][C:34](C)=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([O:32][C:33]1([CH3:34])[O:24][C:5]2=[N:6][C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[CH:9]=[C:4]2[C:1](=[O:3])[CH2:2]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)COCc1ccccc1
Reactant: CC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Product: CC1(OCc2ccccc2)CC(=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nc2O1

Procedure:
The product of Example 4 Step A and 1-(benzyloxy)acetone were combined in a procedure similar to Example 4 Step B to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:14]([F:39])=[C:15]([C:19]2[N:20]=[C:21]([C:35]([CH3:38])([CH3:37])[CH3:36])[S:22][C:23]=2[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH2:30][CH2:31][C:32](O)=[O:33])[N:25]=2)[CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:10].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:73]1[CH2:78][CH2:77][O:76][CH2:75][CH2:74]1>CN(C)C=O>[CH3:38][C:35]([C:21]1[S:22][C:23]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH2:30][CH2:31][C:32]([N:73]3[CH2:78][CH2:77][O:76][CH2:75][CH2:74]3)=[O:33])[N:25]=2)=[C:19]([C:15]2[C:14]([F:39])=[C:13]([NH:12][S:9]([C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])(=[O:11])=[O:10])[CH:18]=[CH:17][CH:16]=2)[N:20]=1)([CH3:37])[CH3:36]
Reactant: C1COCCN1
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(CCC(=O)O)n2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(CCC(=O)N3CCOCC3)n2)s1
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
3-{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinyl}propanoic acid (200 mg, 0.347 mmol) was taken up in N,N-dimethylformamide (DMF) (2 ml). HATU (0.158 g, 0.416), DIEA (0.134 g, 1.041 mmol), and morpholine (0.060 g, 0.694) were added. After 30 min, the reaction mixture was concentrated and residue was purified via Gilson Acidic HPLC (10 to 90% gradient, Acetonitrile/H2O+TFA; C18 column) to obtain the title compound (147 mg, 53%) as white solid. MS (ESI): 646 [M+H]+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([C:18](O)([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[C:13]([CH3:17])[S:14][C:15]=3[CH3:16])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([C:18](=[CH2:23])[C:19]([O:21][CH3:22])=[O:20])=[C:13]([CH3:17])[S:14][C:15]=3[CH3:16])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C(C)(O)c1c(C)sc(C)c1-c1ccc2c(c1)CCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C(=O)OC)c1c(C)sc(C)c1-c1ccc2c(c1)CCCO2
Temperature: 25 °C
Yield: 92.1 %

Procedure:
A mixture of methyl 2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-2,5-dimethylthiophen-3-yl]-2-hydroxypropanoate (42b) (130 mg, 0.38 mmol), p-toluenesulfonic acid monohydrate (357 mg, 1.88 mmol) and a spoon of sodium sulfate, in anhydrous toluene (3 mL), was refluxed for 16 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was successively washed with a saturated solution of sodium bicarbonate (2×5 mL) and brine (5 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide the desired product (42c) (114 mg, 0.35 mmol, 93%) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:26]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCCC[C@H](NS(=O)(=O)c1ccc(Br)cc1)C(=O)O
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC[C@H](NS(=O)(=O)c1ccc(Br)cc1)C(=O)Nc1ccc(CC(=O)OCC)cc1
Yield: 73.1 %

Procedure:
The procedure described in Example 180 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)hexanoic acid (3.50 g) and ethyl 4-aminophenylacetate (1.61 g) were condensed in dichloromethane (40 ml) in the presence of N,N'-dicyclohexylcarbodiimide (2.47 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from isopropyl alcohol to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)hexanamide (3.36 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10][S:11][C:12]2[NH:13][C:14]3[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)[C:4]=1[CH3:25].C[OH:27]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10][S:11]([C:12]2[NH:13][C:14]3[CH:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)=[O:27])[C:4]=1[CH3:25]
Reactant: COc1c(C)cnc(CSc2nc3ccc(C(F)(F)F)cc3[nH]2)c1C
Reactant: CO
Solvent: ClCCl
Product: COc1c(C)cnc(CS(=O)c2nc3ccc(C(F)(F)F)cc3[nH]2)c1C
Reaction time: 1 h

Procedure:
31.4 g of 2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-5-(trifluoromethyl)benzimidazole are dissolved in 1.3 l of methylene chloride and 50 ml of methanol and then cooled to -20°. 16.9 g of m-chloroperbenzoic acid, recrystallized from a methyene chloride/petroleum ether, are then introduced within 10 minutes. The solution is stirred further at -20° for 60 minutes and then poured into a mixture of 120 ml of 2N sodium carbonate solution and ice. The organic phase is washed neutral with water, dried over sodium sulphate and evaporated in vacuo. Crystallization from methylene chloride/methanol/petroleum ether gives 2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulphinyl]-5-(trifluoromethyl)benzimidazole of melting point 152°-154°.
Reaction SMILES: [NH2:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:24][CH3:25])[CH:3]=1.[C:26](O)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[NH2:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:24][CH3:25])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCN)CC1
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCNC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 20.7 %

Procedure:
4-Amino-N-(1-(4-aminobutyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (0.8 g) was dissolved in dimethylformamide (10 ml), and benzoic acid (0.25 g) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.44 g) were added. The mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure. Aqueous potassium carbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 0.2 g of 4-amino-N-(1-(4-benzoylaminobutyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)[S:9][CH:10]=1)=O)C.[NH3:16]>CO>[NH:15]1[CH:14]=[CH:13][N:12]=[C:11]1[C:8]1[S:9][CH:10]=[C:6]([C:4]([NH2:16])=[O:3])[N:7]=1
Reactant: N
Reactant: CCOC(=O)c1csc(-c2ncc[nH]2)n1
Solvent: CO
Product: NC(=O)c1csc(-c2ncc[nH]2)n1
Temperature: 60 °C

Procedure:
A solution of 2-(1H-Imidazole-2-yl)-thiazole-4-carboxylic acid ethyl ester (190 mg) in 5 mL of MeOH is saturated with NH3 gas, and heated at 60° C. in a sealed tube overnight. After cooled, the reaction mixture is transferred to a round bottle flask and evaporated in vacuo to a solid. LRMS calcd 194. found 195 (MH+).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:8][C:9]([NH:11][CH3:12])=[O:10])([O:5][CH2:6][CH3:7])=[O:4].[C:13](O)(=O)C>C(O)(C)C>[C:3]([CH2:8][C:9]([NH:11][CH3:12])=[O:10])([O:5][CH:6]([CH3:13])[CH3:7])=[O:4]
Reactant: CCOC(=O)CC(=O)NC
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Product: CNC(=O)CC(=O)OC(C)C
Temperature: 25 °C
Yield: 82 %

Procedure:
1.4 g sodium hydride (60% in mineral oil) are added to a solution prepared by dissolving 101.5 g of 2-carboethoxy-N-methyl-acetamide in 11 of isopropanol. The reaction is maintained at room temperature for 5 hours. The mixture is neutralised with acetic acid, then the solvent is removed at reduced pressure, and the product is isolated by distillation at 6 mmHg (Teb 115° C.). 91.4 g of 2-carboisopropoxy-N-methyl-acetamide are obtained (yield 82%).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=1.O>CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=3[C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:23]=2)[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 2-butylbenzimidazole (0.52 g) in DMF (4 ml) was added, under cooling with ice, sodium hydride (60% oil, 0.13 g), and then the mixture was stirred for 20 minutes. To the resultant mixture was added methyl 2-(4-bromomethylphenyl)benzoate (1.0 g), which was stirred for 1.5 hour at room temperature. To the mixture was added water, followed by extraction with ethyl acetate. The solvent was evaporated to dryness to give an oily residue. The oil was purified by column chromatography on silica gel to obtain a colorless oil (1.2 g, quantitatively).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([C:8](=[O:20])[CH2:9][CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12](=O)[O:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:25])=O.Cl>C1C=CC=CC=1>[N+:1]([C:4]1[CH:22]=[CH:21][C:7]([C:8]([CH:9]=[CH:10][C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:12]([Cl:25])=[O:11])=[O:20])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(CC1OC(=O)c2ccccc21)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: c1ccccc1
Product: O=C(C=Cc1ccccc1C(=O)Cl)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
A 500 ml flask fitted with a reflux condenser was charged with 29.7 grams (0.1 mol) of 3-(4-nitrophenacyl)phthalide, 0.12 mol of freshly distilled thionyl chloride and 100 ml of benzene. The mixture was heated to reflux temperature on a steambath, and a clear solution formed on initiation of refluxing, with evolution of HCl. The evolution ceased after 1 hour, after which benzene and excess unreacted thionyl chloride were distilled off under reduced pressure. The residual solid in the flask was triturated with ligroin, filtered and dried to yield o-(4'-nitrobenzoylvinyl)benzoyl chloride, m.p. 133°-134° C. Analysis shows 59.4% carbon, 3.36% hydrogen, 4.56% nitrogen and 11.72% chlorine as against calculated values of 60.87%, 3.19%, 4.44% and 11.23% for C16H10ClNO4.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[OH:12].[Cl:13][C:14]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:15]=1[NH2:16]>>[Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([NH:16][C:15]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:14]=1[Cl:13])=[O:7]
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1Cl)c1cc(Cl)cc(Cl)c1O

Procedure:
This material was prepared according to the method of Example 1 using 3,5-dichlorosalicylic acid and 2-chloro-4-nitroaniline, with reagents and solvents employed in similar molar ratios. 1HNMR (500 MHz, DMSO-d6): δ 7.85 (m, 1H, H4), 7.98 (m, 1H, H5), 8.29 (m, 1H, H5′), 8.04 (m, 1H, H6), 8.44 (m, 1H, H3′), 8.55 (m, 1H, H6′).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[Li]C(CC)C.[I:24]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH3:18])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[I:24]
Reactant: CCCc1ccc(CCc2cccc(F)c2)cc1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Li]C(C)CC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1ccc(CCc2ccc(I)c(F)c2)cc1
Temperature: -60 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
In a solution of 4.8 g (19.7 mmol) of the 3-fluoro-(2-(4-propylphenyl)ethyl)benzene obtained in the previous step in 25 ml of THF was added dropwise 23 ml of sec-BuLi (1.04 M, cyclohexane solution, corresponding to 23.7 mmol) while being maintained at a temperature lower than −60° C., and they were stirred at the same temperature for 1 hour. Subsequently, a solution of 7.5 g (29.6 mmol) of iodine in 20 ml of THF was added dropwise to the reaction mixture while being maintained at a temperature lower than −60° C., and they were stirred at the same temperature for 1 hour. The reaction solution was poured into 50 ml of a diluted aqueous sodium thiosulfate solution, and extracted with 50 ml of heptane. The organic layer thus obtained was washed with water thrice and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under a reduced pressure, the residue was subjected to silica gel column chromatography (eluent: heptane) to obtain 6.5 g of a crude 3-fluoro-4-iodo-(2-(4-propylphenyl)ethyl)benzene. This product was used for next reaction without any further purification. (Yield: 90.2%)
Reaction SMILES: C(OC([NH:8][N:9]=[C:10]([C:19]1[C:20](OC2C=CC(F)=CC=2F)=[N:21][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[F:33])=[N:23][CH:24]=1)[NH:11][C@H:12]([CH3:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=O)(C)(C)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.Cl.C(OC(C)C)(=O)C>[F:33][C:27]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=1[O:25][C:22]1[N:21]=[C:20]2[NH:8][N:9]=[C:10]([NH:11][C@H:12]([CH3:18])[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[C:19]2=[CH:24][N:23]=1
Reactant: C[C@H](CS(C)(=O)=O)NC(=NNC(=O)OC(C)(C)C)c1cnc(Oc2ccc(F)cc2F)nc1Oc1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)C
Product: C[C@H](CS(C)(=O)=O)Nc1n[nH]c2nc(Oc3ccc(F)cc3F)ncc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
A solution of 1.02 kg of N′-[[2,4-bis-(2,4-difluoro-phenoxy)-pyrimidin-5-yl]-((R)-2-methanesulfonyl-1-methyl-ethylamino)-methylene]-hydrazinecarboxylic acid tert-butyl ester in toluene (6-8 l) and conc HCl. (500 ml) was stirred at room temperature overnight. The reaction mixture was diluted with iso-propyl acetate (3.5 L) and a saturated aqueous sodium bicarbonate solution was added. The resulting solid precipitate was collected by filtration, washed with aqueous sodium bicarbonate, water, then with methyl t-butyl ether, and dried under vacuum. The material was recrystallized from isobutanol to give 455 g of [6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-((R)-2-methanesulfonyl-1-methyl-ethyl)-amine. Mp=177.7-178.8° C., MS(M+H)=384.