Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:35])[CH2:4][C@@:5]1([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.Cl.[NH2:37][C:38](N)=[O:39].C([O-])(O)=O.[Na+]>O.CCO>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[C:17]1[CH:16]=[CH:15][C:14]([C@@H:12]([N:8]2[CH2:7][CH2:6][C@:5]([CH2:4][CH:3]([OH:35])[CH2:2][NH:1][C:38]([NH2:37])=[O:39])([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[O:10][C:9]2=[O:11])[CH3:13])=[CH:19][CH:18]=1
Reactant: NC(N)=O
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CC(O)CN)(c2ccc(F)cc2)OC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CC(O)CNC(N)=O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C

Procedure:
To a solution of (6S)-6-(3-amino-2-hydroxypropyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (300 mg, 0.62 mmol) in H2O (10 mL) was added HCl (12 N, 0.05 mL), urea (372 mg, 6.2 mmol) and EtOH (2 mL). Then the mixture was heated to reflux overnight. The reaction mixture was cooled to rt and adjusted pH to 9˜10 by saturated NaHCO3 solution. The mixture was concentrated and extracted by CH2Cl2. The combined organic layer was dried and concentrated to give the residue, which was purified by preparative HPLC followed by chiral preparative HPLC to give two isomers.
Reaction SMILES: COC1C=CC(C2CCN(C3C=CC=C(OC)C=3)C2)=C(N)C=1.Cl.[N:24]1([CH2:31][CH2:32][O:33][C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=O)=[CH:36][CH:35]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.N1(CCOC2C=C[C:56]([CH2:57][NH:58][C:59]3[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:60]=3[CH:67]3[CH2:71][CH2:70][N:69]([C:72]4[CH:77]=[CH:76][CH:75]=[C:74]([O:78][CH3:79])[CH:73]=4)[CH2:68]3)=CC=2)CCCCCC1>>[N:24]1([CH2:31][CH2:32][O:33][C:34]2[CH:42]=[CH:41][C:37]([CH2:38][CH2:56][CH2:57][NH:58][C:59]3[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:60]=3[CH:67]3[CH2:71][CH2:70][N:69]([C:72]4[CH:77]=[CH:76][CH:75]=[C:74]([O:78][CH3:79])[CH:73]=4)[CH2:68]3)=[CH:36][CH:35]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Reactant: COc1cccc(N2CCC(c3ccc(OC)cc3NCc3ccc(OCCN4CCCCCC4)cc3)C2)c1
Agent: COc1cccc(N2CCC(c3ccc(OC)cc3N)C2)c1
Agent: Cl
Product: COc1cccc(N2CCC(c3ccc(OC)cc3NCCCc3ccc(OCCN4CCCCCC4)cc3)C2)c1

Procedure:
Synthesized from 5-methoxy-2-[1-(3-methoxyphenyl)pyrrolidin-3-yl]phenylamine and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl]{5-methoxy-2-[1-(3-methoxyphenyl)pyrrolidin-3-yl]phenyl}amine (202 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-azepan-1-ylethoxy)benzyl]ethyl {5-methoxy-2-[1-(3-methoxyphenyl)pyrrolidin-3-yl]phenyl}amine (188 mg). The total amount of this compound was used according to an analogous synthetic method to Example 111 to provide the title compound (153 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([NH:13][CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)([OH:20])[C:16]([F:19])([F:18])[F:17])[CH3:12]>>[CH2:11]([N:13]([CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:33]1[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=1)([OH:20])[C:16]([F:18])([F:19])[F:17])[C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[F:1])[CH3:12]
Reactant: O=C(O)c1ccccc1F
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Product: CCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1F

Procedure:
Prepared similarly to Example 1 from 2-fluorobenzoic acid and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}methyl)-2-propanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:15])[C:5]([C:8](=[O:14])[CH:9](C)[C:10](O)=O)=[N:6][CH:7]=1.C(O)(=O)C.[Cl:20]Cl>O>[Cl:20][CH:9]([CH3:10])[C:8]([C:5]1[C:4]([F:15])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:14]
Reactant: CC(C(=O)O)C(=O)c1ncc(Cl)cc1F
Reactant: ClCl
Solvent: CC(=O)O
Solvent: O
Product: CC(Cl)C(=O)c1ncc(Cl)cc1F
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
20.8 g of 3-(5-chloro-3-fluoropyridin-2-yl)-2-methyl-3-oxopropionic acid (Example P35) are introduced into 125 ml of glacial acetic acid. 6.3 g of chlorine gas are introduced into the solution in the course of 1 hour . The mixture is then poured into 700 ml of water and extracted with tert-butyl methyl ether. The combined ethereal phases a rewashed with water and dried over magnesium sulfate, filtered and concentrated by evaporation in vacuo. The crude product is dissolved in 180 ml of tert-butyl methyl ether, 45 g of silica gel are added and the mixture is stirred for 30 minutes, in the course of which the evolution of gas observed initially comes to a halt. The silica gel is then filtered off and subsequently washed and the combined ethereal phases are concentrated to dryness in vacuo. 20.1 g of an oily crude product are obtained, which is purified over a flash chromatography column (silica gel; eluant: n-hexane/ethyl acetate 411 (v/v)). 17.0 g of the desired title compound are obtained in the form of a solid having a melting point of 29-32° C.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:12]([C:15]1[CH:16]=[C:17]([C:24]([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:27])=[O:25])[CH:18]=[C:19]([N+:21]([O-])=O)[CH:20]=1)([O-])=O.C>O1CCOCC1>[C:1]([OH:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[NH2:12][C:15]1[CH:16]=[C:17]([C:24]([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:27])=[O:25])[CH:18]=[C:19]([NH2:21])[CH:20]=1
Reactant: O=C(C(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1ccccc1
Agent: C
Agent: O=C(O)C=Cc1ccccc1
Solvent: C1COCCO1
Product: Nc1cc(N)cc(C(=O)C(=O)c2ccccc2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
65.6 g (200 milimole) of 3,5-dinitrobenzil cinnamate, 10 g carbon black contained 5% Pt (product with water content of about 50%), and 500 ml of 1,4-dioxane were placed in a reaction vessel (hydrogenating apparatus). Then the reaction mixture were heated at 60° C. with stirring under a hydrogen atmosphere. In approximately two hours, 29 L of hydrogen was absorbed and the reaction was completed when the absorption of hydrogen stopped, and the filtrate was concentrated. The carbon black contained Pt was isolated by filtration. Thus, 53.6 g of 3, 5-diaminobenzil cinnamate was yielded. The exothermic peak temperature was 230° C.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH:8]([C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)([CH3:10])[CH3:9]>C(Cl)(Cl)Cl>[C:5]([NH:15][C:14]1[CH:16]=[CH:17][C:11]([CH:8]([CH3:10])[CH3:9])=[CH:12][CH:13]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)c1ccc(N)cc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (26.0 g, 254 mmol) is slowly added dropwise to a solution of 4-isopropylaniline (17.2 g, 127 mmol) in 80 ml of chloroform. In the course of this, intense heating of the reaction mixture occurs. On completion of the dropwise addition, the mixture is stirred at room temperature for another 2 h. The reaction mixture is concentrated to dryness and the resulting, reddish-white solid is recrystallized from hexane.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.Cl[CH2:21][C:22]1[N:23]([CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:24]2[C:29]([CH3:30])=[C:28]([CH3:31])[N:27]3[N:32]=[N:33][N:34]=[C:26]3[C:25]=2[N:35]=1>CN(C=O)C>[O:7]=[C:6]1[C:5]2[C:4](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:12])[N:2]1[O:1][CH2:21][C:22]1[N:23]([CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41](=[O:48])[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:24]2[C:29]([CH3:30])=[C:28]([CH3:31])[N:27]3[N:32]=[N:33][N:34]=[C:26]3[C:25]=2[N:35]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Cc1c(C)n2nnnc2c2nc(CCl)n(CCCCNC(=O)c3ccccc3)c12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(C)n2nnnc2c2nc(CON3C(=O)c4ccccc4C3=O)n(CCCCNC(=O)c3ccccc3)c12
Reaction time: 72 h
Yield: 92.8 %

Procedure:
N-Hydroxyphthalimide (2.60 g, 16.0 mmol) and triethylamine (2.20 mL, 16.0 mmol) were added to a suspension of N-{4-[8-(chloromethyl)-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]butyl}benzamide (4.70 g, 11.4 mmol) in DMF (285 mL). The reaction mixture was allowed to stir for 3 days, then was concentrated under reduced pressure to a white slurry. Methanol was added and a white solid was isolated by filtration, washed with methanol, and dried under vacuum to afford 5.70 g of N-[4-(8-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl)butyl]benzamide.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].I[CH3:19]>C(Cl)(Cl)Cl.[Ag-]=O>[CH3:19][O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: CI
Reactant: COC(=O)c1cc(CO)cc(-n2cccc2)c1
Agent: O=[Ag-]
Solvent: ClC(Cl)Cl
Product: COCc1cc(C(=O)OC)cc(-n2cccc2)c1
Temperature: 50 °C
Reaction time: 4.5 h

Procedure:
To a solution of methyl 3-hydroxymethyl-5-(pyrrol-1-yl)benzoate (2.0 g) in chloroform (30 ml) was added silver(I) oxide (8.0 g) and iodomethane (4.3 ml). The reaction mixture was stirred at 50° C. for 4.5 hours. After being cooled to room temperature, the slurry was filtered and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (10:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to afford methyl 3-methoxymethyl-5-(pyrrol-1-yl)benzoate (1.72 g)) as an oil.
Reaction SMILES: OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)N=1)=O.[CH2:39]([O:46][C:47]1[C:48]([C:70]([N:72]([CH2:76][CH2:77][O:78][Si](C(C)(C)C)(C)C)[CH:73]([CH3:75])[CH3:74])=[O:71])=[N:49][C:50]([CH2:54][C:55]2([C:60]3[C:69]4[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=4)[CH:63]=[CH:62][CH:61]=3)[CH2:59][CH2:58][CH2:57][CH2:56]2)=[N:51][C:52]=1[OH:53])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH2:39]([O:46][C:47]1[C:48]([C:70]([N:72]([CH2:76][CH2:77][OH:78])[CH:73]([CH3:75])[CH3:74])=[O:71])=[N:49][C:50]([CH2:54][C:55]2([C:60]3[C:69]4[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=4)[CH:63]=[CH:62][CH:61]=3)[CH2:56][CH2:57][CH2:58][CH2:59]2)=[N:51][C:52]=1[OH:53])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Agent: CN(CCO)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Product: CC(C)N(CCO)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
This compound was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-methyl-amide (351) from 5-(benzyloxy)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-hydroxy-N-isopropyl-2-((1-(naphthalen-1-yl)cyclopentyl)methyl)pyrimidine-4-carboxamide (510).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[N:10]=[C:11]3[CH:20]=[CH:19][C:18]4([CH2:24][CH:17]4[N:12]3[C:13](=[O:16])[C:14]=2[CH3:15])[C:21]([OH:23])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[C:27]([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[N:10]=[C:11]3[CH:20]=[CH:19][C:18]4([CH2:24][CH:17]4[N:12]3[C:13](=[O:16])[C:14]=2[CH3:15])[C:21]([O:23][CH3:27])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1c(/C=C/c2ccccc2)nc2n(c1=O)C1CC1(C(=O)O)C=C2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C12C=Cc3nc(/C=C/c4ccccc4)c(C)c(=O)n3C1C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.9 %

Procedure:
2-trans-(2-phenyl-ethenyl)-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid (0.8 g) was reacted with methyl iodide (0.55 g) and anhydrous K2CO3 (0.65 g) in dimethylformamide (7 ml) under stirring at room temperature for 4 hours. After dilution with ice water the precipitate was filtered off: crystallization from acetone gave 0.5 g of 2-trans-(2-phenyl-ethenyl)-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid, methyl ester, m.p. 164°-165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[C:17]([NH2:19])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[C@H:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[C:17]([NH2:19])=[O:18])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: NC(=O)[C@@H]1CCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: NC(=O)[C@@H]1CCC[C@@H]1N(Cc1ccc(C(F)(F)F)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 50 %

Procedure:
The titled compound (191 mg) was prepared in 50% yield from cis-2-(4-chlorobenzenesulfonylamino)-cyclopentanecarboxylic acid amide (250 mg, 0.83 mmol) and 1-bromomethyl-4-trifluoromethyl-benzene according to the N-alkylation procedure described in Example 11: 1 H NMR (DMSO-d6) δ 7.73 (d, 2 H, J=8.0 Hz), 7.56 (m, 4 H), 7.41 (d, 2 H, J=8.0 Hz), 7.08 (s br, 1 H), 6.77 (s br, 1 H), 4.66 (AB2,2 H,Δv=20,Jab=24 Hz), 4.37 (m, 1 H), 2.85 (m, 1 H), 1.76 (m, 4 H), 1.51 (m, 2 H); MS m/e 460.98 (M+H)+.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]([N:7]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6]>O1CCCC1>[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][N:7]([C:5]([O:2][CH3:1])=[O:6])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[O-]
Reactant: COc1ccccc1CN(C(=O)Cl)c1ccccc1Oc1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N(Cc1ccccc1OC)c1ccccc1Oc1ccccc1
Yield: 97.9 %

Procedure:
To a solution of 226 mg of sodium methoxide in 5 ml of tetrahydrofuran was added dropwise a solution of 1.22 g of N-chlorocarbonyl-N-(2-methoxybenzyl)-2-phenoxyaniline in 5 ml of tetrahydrofuran under ice-cooling with stirring, followed by stirring at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure, poured into water and extracted with ethyl acetate, and the extract was washed with 5% hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:6) and recrystallized from ethyl acetate to give 1.18 g of N-(2-methoxybenzyl)-N-methoxycarbonyl-2-phenoxyaniline.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH2:13])=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1)[C:27](Cl)=[O:28]>>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:27](=[O:28])[C:26]2[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=[C:24]([O:23][CH3:22])[CH:25]=2)=[N:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccccc2)cc1
Product: COc1ccc(-c2nc(NC(=O)c3cc(OC)cc(OC)c3)sc2Cc2ccccc2)cc1
Yield: 65.7 %

Procedure:
A procedure similar to that in Example 4 was used. 5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 1 and 3,5-dimethoxy-benzoyl chloride prepared in the step 1 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (100:0-10:1) to obtain a product as a white solid in a yield of 65.7%, mp: 152-153 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.78 (6H, s, 2×OCH3), 3.80 (3H, s, OCH3), 4.22 (2H, s, CH2), 6.55 (1H, t, J=2.12 Hz, ArH), 6.83 (2H, d, J=8.68 Hz, ArH), 6.90 (2H, t, J=2.12 Hz, ArH), 7.25˜7.33 (5H, m, ArH), 7.39 (2H, d, J=8.68 Hz, ArH), 10.75 (1H, br, CONH); EI-MS m/e (%): 460.2 (M+, 100), 165.0 (84); HREI-MS Calcd. for C26H24N2O4S: 460.1457. found: 460.1464.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C@@H:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][OH:11])=[O:7])=[C:4]([F:20])[CH:3]=1.[NH2:21][C:22]1[N:27]=[CH:26][C:25]([CH:28]2[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]2)=[CH:24][C:23]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C>[NH2:21][C:22]1[C:23]([C:2]2[CH:19]=[CH:18][C:5]([C:6]([NH:8][C@@H:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:10][OH:11])=[O:7])=[C:4]([F:20])[CH:3]=2)=[CH:24][C:25]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:26][N:27]=1
Reactant: O=C(N[C@H](CO)c1ccccc1)c1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(c2cnc(N)c(B3OC(C)(C)C(C)(C)O3)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Nc1ncc(C2CCNCC2)cc1-c1ccc(C(=O)N[C@H](CO)c2ccccc2)c(F)c1
Temperature: 120 °C
Yield: 20.9 %

Procedure:
To a suspension of (S)-4-bromo-2-fluoro-N-(2-hydroxy-1-phenylethyl)benzamide (67.1 mg, 0.20 mmol) in DME (5 mL) was added tert-butyl 4-(6-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)piperidine-1-carboxylate (40 mg, 0.099 mmol) and sodium carbonate (0.24 mL, 0.49 mmol). The mixture was purged with nitrogen for 10 min, then PdCl2(dppf)-CH2Cl2Adduct (12.15 mg, 0.015 mmol) was added. The reaction mixture was heated to 120° C. in an oil bath for 3 h. The reaction mixture was diluted with ethyl acetate. The organic solution was washed with water, brine, dried over sodium sulfate and concentrated. The resulting residue was treated with 30% TFA in DCM (20 mL) for 15 min. The reaction mixture was concentrated and the crude product was purified by HPLC to give (S)-4-(2-amino-5-(piperidin-4-yl)pyridin-3-yl)-2-fluoro-N-(2-hydroxy-1-phenylethyl)benzamide (9 mg, 20.8%) as TFA salt. LCMS (m/z): 435 (MH+), 0.44 min; 1H NMR (300 MHz, CD3OD) δ ppm 8.63 (br. s., 1H) 7.90 (t, J=7.77 Hz, 1H) 7.84 (s, 2H) 7.47-7.24 (m, 7H), 5.27-5.17 (m, 1H) 3.93-3.79 (m, 2H) 3.52 (d, J=12.60 Hz, 2H) 3.21-3.05 (m, 2H) 2.96 (t, J=12.31 Hz, 1H) 2.15 (d, J=14.07 Hz, 2H) 1.96-1.78 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[C:10]([N:14]=[C:15]=[S:16])([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>CCOC(C)=O.O>[C:10]([NH:14][C:15]1[S:16][C:3]2[N:4]=[CH:5][N:6]=[C:7]([Cl:8])[C:2]=2[N:1]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)N=C=S
Reactant: Nc1c(Cl)ncnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)Nc1nc2c(Cl)ncnc2s1
Temperature: 50 °C
Reaction time: 16 h
Yield: 48.3 %

Procedure:
A mixture of 5-Amino-4,6-dichloropyrimidine (9.0 g, 55 mmol), tert-butylisothiocyanate (7.02 g, 61.0 mmol), Cesium Carbonate (39.7 g, 122 mmol) and acetonitrile (200 mL) was stirred at 50° C. for 16 hours. The mixture was allowed to cool to rt. To the mixture, were added water and EtOAc. After being stirred for 30 min, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (6.45 g, 48%) as a white solid. LCMS: (AA) ES+ 243, 245. 1H NMR (400 MHz, d6-DMSO) δ: 8.71 (bs, 1H), 8.49 (s, 1H), 1.45 (s, 9H).
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:32])=[C:6]([CH:29]=[CH:30][CH:31]=1)[C:7](=[O:28])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)=[CH:12][CH:11]=1)([OH:3])=[O:2].[OH-:33].[K+].OO.Cl>CO>[C:1]([C:4]1[CH:31]=[CH:30][CH:29]=[C:6]2[C:5]=1[O:32][C:9]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:12][CH:11]=1)=[C:8]([OH:33])[C:7]2=[O:28])([OH:3])=[O:2]
Reactant: [OH-]
Reactant: O=C(O)c1cccc(C(=O)C=Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1O
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CO
Product: O=C(O)c1cccc2c(=O)c(O)c(-c3ccc(OCc4ccc5ccccc5n4)cc3)oc12
Reaction time: 24 h
Yield: 49 %

Procedure:
3'-Carboxy-2'-hydroxy-4-[(2-quinolinyl)methoxy]chalcone (1.2 mmol) was dissolved in 35 ml of methanol, followed by the addition of 2 ml of 16% potassium hydroxide. While the resulting mixture was stirred over an ice bath, 2.0 ml of a 15% aqueous solution of hydrogen peroxide were gradually added dropwise. The resulting mixture was allowed to stand for 24 hours at 4° C. The reaction mixture was acidified with 1 N hydrochloric acid. The resulting precipitate was collected by filtration and the recrystallized from DMF, whereby the title compound represented by the following formula was obtained (yield: 49%). ##STR41##
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][C:20]=3[C:21](O)=[O:22])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[NH2:39][C@@H:40]1[CH2:45][CH2:44][C@H:43]([C:46]([O:48][CH2:49]C)=[O:47])[CH2:42][CH2:41]1>>[C:1]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:2]=[CH:3][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][C:20]=3[C:21]([NH:39][C@H:40]3[CH2:41][CH2:42][C@@H:43]([C:46]([O:48][CH3:49])=[O:47])[CH2:44][CH2:45]3)=[O:22])=[CH:11][CH:10]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(OCCCc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2)c(C(=O)O)c1
Reactant: CCOC(=O)[C@H]1CC[C@@H](N)CC1
Product: CCOC(=O)c1ccc(OCCCc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2)c(C(=O)N[C@H]2CC[C@@H](C(=O)OC)CC2)c1

Procedure:
The compound is prepared in analogy to the process described in Example 6 from 2-{3-[4-(1,1′-biphenyl-4-ylmethoxy)phenyl]propoxy}-5-(ethoxycarbonyl)benzoic acid and ethyl cis-4-amino-1-cyclohexanecarboxylate.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][CH2:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1.Br[CH2:39][C:40]([C:42]1[CH:47]=[CH:46][C:45]([Br:48])=[CH:44][CH:43]=1)=[O:41]>C1COCC1.CCOC(C)=O>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][CH2:8][C:9](=[O:13])[N:10]2[CH2:39][C:40]([C:42]2[CH:47]=[CH:46][C:45]([Br:48])=[CH:44][CH:43]=2)=[O:41])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)NC(=O)CN2
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(c1)N(CC(=O)c1ccc(Br)cc1)C(=O)CN2
Reaction time: 16 h
Yield: 37.8 %

Procedure:
To a solution of 7-cyano-3,4-dihydroquinoxalin-2(1H)-one (4 mg, 20 mmol) in THF (100 mL) was added K2CO3 (152 mg, 1.1 mmoL), 18-crown-6 (230 mg), and 2,4′-dibromoacetophenone (5.54 g, 20 mmol), and the resulting mixture was stirred for 16 hours. The mixture was diluted with EtOAc and filtered. The residue was washed with EtOAc and water, and dried by air to give the product (2.8 g, 37.8%). The filtrate was washed with brine (50 mL×4), dried over MgSO4, and concentrated to give a crude material, which was recrystallized in EtOAc (20 mL) to give the product (2 g, 27%) as a white solid. 1H NMR (DMSO-d6) δ 8.02 (d, J=8.4 Hz, 2H), 7.83 (d, J=8.4 Hz, 2H), 7.35 (d, J=1.4 Hz, 1H), 7.26 (dd, J=8.1 Hz, J=1.4 Hz, 1H), 7.10 (s, 1H), 6.81 (d, J=8.4 Hz, 1H), 5.50 (s, 2H), 4.05 (d, J=1.1 Hz, 2H); MS(CI) m/z 370/372 (M+H).