Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH2:12][CH2:13][CH3:14])[C:7]=2[C:6](=[O:15])[NH:5][C:4]1=[O:16])[CH3:2].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][P:23]([O:28][CH2:29][CH3:30])(=[O:27])[O:24][CH2:25][CH3:26]>>[CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH2:12][CH2:13][CH3:14])[C:7]=2[C:6](=[O:15])[N:5]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][P:23](=[O:27])([O:28][CH2:29][CH3:30])[O:24][CH2:25][CH3:26])[C:4]1=[O:16])[CH3:2]
Reactant: CCCn1cnc2c1c(=O)[nH]c(=O)n2CC
Reactant: CCOP(=O)(CCCCCBr)OCC
Product: CCCn1cnc2c1c(=O)n(CCCCCP(=O)(OCC)OCC)c(=O)n2CC

Procedure:
The title substance was prepared from 0.0225 mol of 3-ethyl-7-propyl-xanthine and 0.027 mol of diethyl 5-bromopentanephosphonate analogously to Example 46.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[CH3:5][O:6][CH2:7][CH2:8][NH:9][CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:5][O:6][CH2:7][CH2:8][N:9]([CH3:10])[CH2:1][C:2]#[CH:3]
Reactant: CNCCOC
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C#CCN(C)CCOC
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
Propargyl bromide (26.8 g, 225 mmol) was added dropwise to a mixture of N-(2-methoxyethyl)methyl amine (20 g, 225 mmol) and cesium carbonate (73 g, 225 mmol) in 350 mL of acetone. The mixture was stirred overnight under nitrogen at room temperature. The inorganic salts were then filtered off, and the solvent was removed. The residue was dissolved in saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic extracts were then evaporated to give 14 g of (2-methoxy-ethyl)-methyl-prop-2-ynyl-amine: mass spectrum (m/e): M+H 127.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[CH:15][CH2:16][CH2:17][C:18]1[N:22]([CH2:23][CH2:24][C:25]#[N:26])[C:21]2[CH:27]=[CH:28][CH:29]=[CH:30][C:20]=2[N:19]=1.Cl[CH2:32]CCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH:17]([C:18]2[N:22]([CH2:23][CH2:24][C:25]#[N:26])[C:21]3[CH:27]=[CH:28][CH:29]=[CH:30][C:20]=3[N:19]=2)[CH3:32])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCl
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: N#CCCn1c(CCC=O)nc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(CCN1CCC(Cc2ccccc2)CC1)c1nc2ccccc2n1CCC#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 0.3 g of 4-benzyl-piperidine, 0.2 g of 3-[2-(3-oxo-propyl)-benzimidazol-1-yl]-propionitrile, 5 mL of 1,2-dichloroethane and 0.3 g of sodium triacetoxyborohydride was stirred at room temperature for 24 h. The reaction mixture was diluted with 50 mL chloroform and 10 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 2×25 mL of chloroform and the combined organic layers dried over magnesium sulfate and concentrated under reduced pressure. Low pressure chromatography eluting with a gradient of 70:30 ethyl acetate:methanol to 80:20:2 ethyl acetate:methanol:triethylamine gave 205 mg of 3-{2-[3-(4-benzyl-piperidin-1-yl)-1-methyl-propyl]-benzimidazol-1-yl }-propionitrile as a gum.
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][C:7]([OH:9])=[O:8])[C:3]([OH:5])=[O:4].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)C>CO>[OH:1][C@@H:2]([CH2:6][C:7]([O-:9])=[O:8])[C:3]([O-:5])=[O:4].[CH2:10]([NH3+:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:10]([NH3+:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)C[C@H](O)C(=O)O
Solvent: CO
Solvent: CCO
Product: O=C([O-])C[C@H](O)C(=O)[O-]
Product: [NH3+]Cc1ccccc1

Procedure:
(S)-Hydroxysuccinic acid (3.0 g; 22 mmol) was dissolved in methanol (10 cm3) and added to a mixture of benzylamine (2.2 g; 22 mmol) and ethanol (5 cm3). The resulting white solid was collected by filtration, recrystallized from water and dried in vacuo. Found: C, 54.6%; H, 6.3%; N, 5.8%. Calculated for C11H15NO4 : C, 64.76%; H, 6.28%; N, 5.81%. M.pt. 149°-150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([CH2:17][CH3:18])[C:11]=2[C:10](=O)[CH2:9]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([CH2:17][CH3:18])[C:11]=2[C:10](=[N:24][NH:23][C:20]([NH2:22])=[NH:21])[CH2:9]1
Reactant: N=C(N)NN
Reactant: CCc1n[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCc1n[nH]c2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Yield: 204 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-ethyl-4,5,6,7-tetrahydroindazol-4-one (0.44 g), aminoguanidine hydrochloride (0.19 g), concentrated hydrochloric acid (0.24 ml), water (0.24 ml) and ethanol (40 ml) was refluxed for 4 hours. Under reduced pressure, the solvent was evaporated. The resulting crystals were recrystallized from ethanol-water to give 6-(2-chlorophenyl)-3-ethyl-4-guanidinoimino-4,5,6,7-tetrahydroindazole hydrochloride (Compound 27) (0.6 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH:10]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:9]=1.Cl.C(=O)([O-])[OH:33].[Na+].[Cl:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][C:46]=1[Cl:47])[C:41](Cl)=[O:42]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:14]1[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=1[N:12]1[C:20]([CH3:23])=[N:21][N:22]=[C:11]1[CH:10]([NH:9][C:41](=[O:42])[C:40]1[CH:44]=[CH:45][C:46]([Cl:47])=[C:38]([Cl:37])[CH:39]=1)[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:33]
Reactant: CCOC(=O)CCC1N=C(c2ccccc2Cl)c2cc(CC)sc2-n2c(C)nnc21
Reactant: O=C([O-])O
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCC(NC(=O)c1ccc(Cl)c(Cl)c1)c1nnc(C)n1-c1sc(CC)cc1C(=O)c1ccccc1Cl
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Ethyl 3-(4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-6-yl)propionate (4.0 g) was added to 2M hydrochloric acid (100 ml), and the mixture was stirred at 60° C. for 1 hour. The reaction mixture was cooled to 0° C. A saturated aqueous sodium hydrogencarbonate solution, chloroform and 3,4-dichlorobenzoyl chloride (2.1 g) were added, and the mixture was stirred for 0.5 hour. The organic layer was taken out, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate) and crystallized from a mixed solvent of ethyl acetate-diisopropyl ether to give 0.56 g of ethyl 4-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-yl)-4-(3,4-dichlorobenzoylamino)butanoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:6]([CH3:24])=[N:7][C:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[N:9][C:10]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH:59]1[C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:62]=[CH:61][C:60]=1[C:69](O)=[O:70].C(N(CC)C(C)C)(C)C>C1COCC1.O>[CH3:24][C:6]1[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:25])=[C:10]([N:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)[N:9]=[C:8]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:69]([C:60]3[CH:61]=[CH:62][C:63]4[C:68](=[CH:67][CH:66]=[CH:65][CH:64]=4)[CH:59]=3)=[O:70])=[CH:21][CH:22]=2)[N:7]=1
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: COC(=O)Cc1c(C)nc(Cc2ccc(N)cc2)nc1N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Cc1c(C)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N1CCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 36.4 %

Procedure:
A solution of methyl[2-(4-aminobenzyl)-4-methyl-6-pyrrolidin-1-ylpyrimidin-5-yl]acetate (0.034 g, 0.10 mmol) in THF (1 mL) at room temperature was treated with PyBOP (0.052 g, 0.10 mmol), 2-naphthoic acid (0.019 g, 0.11 mmol), and N,N-diisopropylethylamine (0.017 mL, 0.10 mmol). After stirring at room temperature for 17 hours, the reaction mixture was poured into water and extracted with EtOAc. The combined organic extracts was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The remaining residue was chromatographed over silica gel eluting with 60% EtOAc in CH2Cl2 to give methyl {4-methyl-2-[4-(2-naphthoylamino)benzyl]-6-pyrrolidin-1-ylpyrimidin-5-yl}acetate (0.018 g, 36% yield) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[C:15]([O-])(O)=O.[Na+]>CO>[CH3:15][O:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C)cc1
Yield: 93 %

Procedure:
To a solution of p-toluic acid (175 g, 1.28 mol) in methanol (2 L) was added dropwise thionylchloride (612 g, 5.14 mol) under stiring at 5° C. The mixture was refluxed overnight, then the solvent evaporated. The residue obtained was treated with a 10% aqueous NaHCO3 solution (pH˜8) The product was extracted with ethyl acetate, washed-with water and dried. The solvent was removed and the crude was purified by column chromatography (pet ether/ethyl acetate) to give methyl-p-toluate as colorless liquid (180 g, 93%).
Reaction SMILES: [CH:1]1([C:6]2([CH3:19])[CH2:14][C:13]3[C:8](=[C:9]([Cl:17])[C:10]([Cl:16])=[C:11]([OH:15])[CH:12]=3)[CH:7]2[OH:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:20].[Na+].C(Cl)(Cl)Cl>CC(C)=O>[CH3:1][C:6]([O:15][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([Cl:17])[C:10]=1[Cl:16])[C:7](=[O:18])[C:6]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)([CH3:19])[CH2:14]2)([CH3:14])[C:7]([OH:18])=[O:20]
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1O
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)(Oc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2)C(=O)O

Procedure:
To a refluxing solution of 2-cyclopentyl-2-methyl-6,7-dichloro-1,5-indandiol (Example 5, Step C), (15.6 g., 0.05 mole) in acetone (500 ml.) in an inert atmosphere is added solid sodium hydroxide (12.6 g., 0.25 mole). Chloroform (7.6 g., 0.69 mole) in acetone (50 ml.) is added dropwise during a ten-minute period. The reaction mixture is refluxed for 5 hours, then evaporated to dryness at reduced pressure. The residue is dissolved in water, filtered and acidified with hydrochloric acid affording α,α-dimethyl-(1-oxo-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]3[O:11][CH2:12][C:13](=[O:17])[NH:14][C:15]=3[N:16]=2)[CH2:5][C@H:4]([CH2:18][N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[O:3]1.Cl[C:26]1[N:35]=[C:34]2[C:29]([C:30](=[O:43])[C:31]3[C:41](=[O:42])[NH:40][S:39][C:32]=3[N:33]2[CH:36]2[CH2:38][CH2:37]2)=[CH:28][C:27]=1[F:44]>>[CH:36]1([N:33]2[C:34]3[C:29](=[CH:28][C:27]([F:44])=[C:26]([N:22]4[CH2:23][CH2:24][N:19]([CH2:18][C@@H:4]5[O:3][C:2](=[O:1])[N:6]([C:7]6[CH:8]=[CH:9][C:10]7[O:11][CH2:12][C:13](=[O:17])[NH:14][C:15]=7[N:16]=6)[CH2:5]5)[CH2:20][CH2:21]4)[N:35]=3)[C:30](=[O:43])[C:31]3[C:41]([OH:42])=[N:40][S:39][C:32]2=3)[CH2:38][CH2:37]1
Reactant: O=c1[nH]sc2c1c(=O)c1cc(F)c(Cl)nc1n2C1CC1
Reactant: O=C1COc2ccc(N3C[C@H](CN4CCNCC4)OC3=O)nc2N1
Product: O=C1COc2ccc(N3C[C@H](CN4CCN(c5nc6c(cc5F)c(=O)c5c(O)nsc5n6C5CC5)CC4)OC3=O)nc2N1
Yield: 49 %

Procedure:
In analogy to Example 2, starting from 6-((S)-2-oxo-5-piperazin-1-ylmethyl-oxazolidin-3-yl)-4H-pyrido[3,2-b][1,4]oxazin-3-one (intermediate 19.1; 133 mg) and 7-chloro-9-cyclopropyl-6-fluoro-isothiazolo[5,4-b][1,8]naphthyridine-3,4(2H,9H)-dione (93 mg; prepared according to Chu et al., J. Heterocycl. Chem. (1990), 27(5), 1191-1195), the title compound was obtained as a beige solid (90 mg; 49% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]([OH:17])[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[H-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]([O:17][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:9]=2[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:6][CH:7]=1
Reactant: ClCCN1CCOCC1
Reactant: On1c(-c2ccncc2)c(-c2ccc(F)cc2)c2ncccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2c(-c3ccncc3)n(OCCN3CCOCC3)c3cccnc23)cc1
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a solution of 3-(4-fluorophenyl)-1-hydroxy-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine (0.20 g, 0.65 mmol) and 2-chloroethylmorpholine hydrochloride (0.24 g, 6.56 mmol) in dimethylformamide (5 ml) was added sodium hydride (100 mg, 60% in oil). The reaction mixture was stiffed overnight and quenched with 10% HCl (2 ml). The pH was adjusted to pH=8-9 by the addition of saturated sodium bicarbonate solution and the product was extracted into ethyl acetate. The combined extracts were dried over anhydrous MgSO4 and concentrated in vacuo to give an oil. Purified by flash column chromatography (50%-80% ethyl acetate/hexanes, followed by 95/5% methylene chloride/methanol gradient) gave 3-(4-fluorophenyl)-1-[2-(morpholin-4-yl)ethoxy]-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine (180 mg) which recrystallized from hexanes/ethyl acetate to give a white solid.
Reaction SMILES: CC([O-])(C)C.[K+].[N+:7]([C:10]1[S:14][C:13]([C:15]2[N:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:16]=2)=[CH:12][CH:11]=1)([O-:9])=[O:8].[CH:28](Cl)([Cl:30])[Cl:29]>C1COCC1.CN(C=O)C>[Cl:29][CH:28]([Cl:30])[C:11]1[CH:12]=[C:13]([C:15]2[N:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:16]=2)[S:14][C:10]=1[N+:7]([O-:9])=[O:8]
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc([N+](=O)[O-])s2)n1
Reactant: ClC(Cl)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnc(-c2cc(C(Cl)Cl)c([N+](=O)[O-])s2)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of t-BuOK (9.07 g, 81 mmol) in THF (50 mL) was cooled to −78° C. before adding DMF (70 mL). A solution of 3-(5-nitro-2-thienyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazole (6.60 g, 20.22 mmol) and CHCl3 (1.79 mL, 22.24 mmol) in DMF (35 mL) was added dropwise over 1 h. After complete addition, the reaction was stirred at −78° C. for 30 min, quenched with 2 N HCl, allowed to warm to room temperature, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Purification of the crude residue by flash chromatography (0-25% EtOAc/hexanes) afforded the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[N:31]=[C:30]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[CH:28][CH:29]=[C:30]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[N:31]=4)[CH2:22][CH2:21]3)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCCC3)CC2)n1

Procedure:
Example 84 was prepared from 1-(4-chlorophenyl)cyclopentanecarboxylic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.07 (d, 1H, J=8.4 Hz), 7.81 (s, 1H), 7.66 (t, 1H, J=7.6 Hz), 7.36–7.33 (m, 2H), 7.30–7.27 (m, 2H), 6.90 (d, 1H, J=6.8 Hz), 6.60 (br s, 1H), 3.28 (dd, 2H, J=5.6, 12.0 Hz), 2.95 (d, 2H, J=11.6 Hz), 2.55–2.49 (m, 4H), 2.33 (t, 2H, J=6.4 Hz), 2.00–1.61 (m, 14H), 1.26 (d, 6H, J=6.8 Hz); ESMS m/e: 511.3 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[S:14][CH:15]=[C:16]([C:18]([OH:20])=O)[N:17]=3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:42][O:43][CH2:44][CH2:45][CH2:46][NH2:47].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:42][O:43][CH2:44][CH2:45][CH2:46][NH:47][C:18]([C:16]1[N:17]=[C:13]([C:10]2[CH:11]=[N:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][CH:9]=2)[S:14][CH:15]=1)=[O:20]
Reactant: COCCCN
Reactant: O=C(O)c1csc(-c2cnc(-c3ccccc3)nc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCCNC(=O)c1csc(-c2cnc(-c3ccccc3)nc2)n1
Reaction time: 18 h

Procedure:
To a solution consisting of 2-(2-phenylpyrimidin-5-yl)thiazole-4-carboxylic acid (Example 63, 80 mg, 0.28 mmol) in dichloromethane (10 mL) was added EDAC (75 mg, 0.39 mmol) and HOBt (53 mg, 0.39 mmol) at 0° C. To this mixture was added 3-methoxypropylamine (25 mg, 0.28 mmol) dissolved in dichloromethane (2 mL) and diisopropylethylamine (0.52 mL, 390 mg, 3.0 mmol). The solution was allowed to reach room temperature and stirred for 18 hours. The solvent was evaporated away under reduced pressure and the residue was purified by silica gel flash chromatography (1:1 v/v hexane-ethyl acetate to 100% ethyl acetate gradient) through a 25-g Silicycle® flash silica cartridge. The title compound was obtained as an off-white solid (21 mg, 21% yield); Rf 0.70 with 4:1 v/v ethyl acetate-hexane; melting point 134-136° C.; 1H-NMR (300 MHz; CDCl3) δ 9.31 (s, 2H), 8.52 (dd, 2H), 8.20 (s, 1H), 7.88 (br t, 1H), 7.53 (m, 3H), 3.62 (t, 2H); 3.59 (t, 2H); 3.41 (s, 3H), 1.96 (m, 2H); MS (ESI+) m/z 355 (M+1); H-PGDS FPBA IC50: 3.4 μM.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:14]=3)[CH:9]=2)=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[B:35](OC(C)C)([O:40]C(C)C)[O:36]C(C)C.Cl>C1(C)C=CC=CC=1.C1COCC1>[C:18]1([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([B:35]([OH:40])[OH:36])=[CH:3][CH:4]=2)[CH:17]=[CH:16]3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc(-c2ccc3cc(-c4ccccc4)ccc3c2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2ccc3cc(-c4ccccc4)ccc3c2)cc1
Temperature: -60 °C
Yield: 63 %

Procedure:
Under an argon gas atmosphere, a mixture of 15.3 g (42.6 mmol) of 2-(4-bromophenyl)-6-phenylnaphthalene and 200 mL of dehydrated THF was cooled down to −60 degrees C., and added with 32.8 mL (51.1 mmol) of hexane solution of 1.56M n-butyllithium in drops while being stirred. Then, the reaction mixture was stirred for two hours at −60 degrees C. 24.0 g (128 mol) of triisopropyl borate was dropped into the reaction solution at −60 degrees C. Subsequently, the reaction mixture was warmed up to room temperature, and stirred for 17 hours. The reaction mixture was cooled down to 0 degree C. to be further added with solution of hydrochloric acid, and then stirred for one hour at room temperature. After the reaction, the reaction mixture was further added with toluene, so that aqueous phase thereof was eliminated. After organic phase thereof was dried with magnesium sulfate, the solvent was distilled away under reduced pressure. By recrystallizing residue by toluene and hexane, 8.7 g of 4-(6-phenylnaphthalene-2-yl) phenylboronic acid was obtained at an yield of 63%.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][C@@H:6]2[CH2:8][C@:5]32[C@H:9]2[C@H:18]([CH2:19][CH2:20][C@:3]13[CH3:4])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]2.OO.FC1C(=[O:43])CC[C@H]2C=1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@@]31C[C@H]3C[C@H]2O.[OH-].[Na+]>CO.O.ClCCl>[O:43]1[C:12]23[C@H:17]([CH2:16][CH2:15][C:14](=[O:21])[CH:13]12)[C@@H:18]1[C@H:9]([C@:5]24[CH2:8][C@H:6]2[CH2:7][C@H:2]([OH:1])[C@:3]4([CH2:20][CH2:19]1)[CH3:4])[CH2:10][CH2:11]3
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=C(F)C(=O)CC[C@@H]43)[C@@]13C[C@H]3C[C@H]2O
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@]13C[C@H]3C[C@@H]2O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: C[C@]12CC[C@@H]3[C@H]4CCC(=O)C5OC54CC[C@H]3[C@@]13C[C@H]3C[C@@H]2O
Reaction time: 3 h

Procedure:
17β-Hydroxy-14α,15α-methylene-estr-4-ene-3-one (2 g) was dissolved in 50 ml of methanol and treated at 10° C. with hydrogen peroxide solution (35%). While stirring, 5 ml of a 10 sodium hydroxide solution was added and the stirring was continued for 3 hours. The reaction solution is mixed with 50 ml of dichloromethane and 25 ml of water and the organic phase is removed, washed with semi-concentrated thiosulfate solution, dried and evaporated to dryness. The residue obtained consists of a mixture of 4α,5α- and 4β,5β epoxides and is used in the subsequent step without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]#[N:7])=[CH:2]1.[C:8]([Cl:11])(=[O:10])[CH3:9]>ClCCl.C(O)C>[ClH:11].[CH2:8]([O:10][C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[NH:7])[CH3:9]
Reactant: CC(=O)Cl
Reactant: N#Cc1ccsc1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=N)c1ccsc1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of thiophene-3-carbonitrile (10 g, 9.2 mmol) in dichloromethane (100 mL) and ethanol (170 mL) at 0° C. was added acetyl chloride (114 g, 145 mmol). The reaction was allowed to slowly warm to ambient temperature and stir 16 h. The reaction mixture was then concentrated under reduced pressure to yield a solid which was triturated with diethyl ether resulting in 17.1 g of 3-thiophenecarboximidic acid ethyl ester hydrochloride as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[OH:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc(Cl)nn2)cc1
Yield: 86.1 %

Procedure:
3,6-Dichloropyridazine (3.00 g, 20.1 mmol), 4-hydroxybenzaldehyde (2.46 g, 20.1 mmol), potassium carbonate (2.78 g, 20.1 mmol) and 60 mL of N,N-dimethylformamide were mixed and the mixture was refluxed for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The extracted solution was washed with brine, then dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluate n-hexane:ethyl acetate=1:1 v/v) to obtain 4.06 g (86%) of the title compound as colorless crystalline powder.