Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][C:15](O)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:18]([NH:21][NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:20])[CH3:19].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH:1]1[C:13]2[CH:12]([CH2:14][C:15]([N:21]([CH:18]([CH3:20])[CH3:19])[NH:22][C:23](=[O:30])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC1c2ccccc2-c2ccccc21
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CC1c2ccccc2-c2ccccc21
Yield: 40.4 %

Procedure:
A solution of 9-fluoreneacetic acid (126 mg, 0.56 mmoles) and benzoic acid N′-isopropyl-hydrazide (100 mg, 0.56 mmoles) in DMF (5 mL) was treated with triethylamine (0.23 mL, 1.68 mmol), HOBT (91 mg, 0.67 mmoles) and EDCI (129 mg, 0.67 mmol) at room temperature for 72 h. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with water and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 10-30% ethyl acetate/hexanes gradient to afford the product as a solid (87 mg, 40%). LC-MS m/e 385.19 (M+H+)
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][CH2:8][NH2:9])[CH2:4][CH3:5])[CH3:2].[CH2:10]1[CH2:15][C@@H:14]2[CH2:16][CH2:17][CH2:18][C:19](=O)[C@H:13]2[CH2:12][CH2:11]1>>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:6][CH2:7][CH2:8][NH:9][CH:15]1[CH:14]2[CH:13]([CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:12][CH2:11][CH2:10]1)[CH3:2]
Reactant: CCN(CC)CCCN
Reactant: O=C1CCC[C@H]2CCCC[C@H]12
Product: CCN(CC)CCCNC1CCCC2CCCCC21

Procedure:
Following the general procedure of Example 46, but starting with diethylaminopropylamine and trans-1-decalone, the title compound is produced. IR (liquid film) 3307, 2968, 2920, 2853, 2799, 1455, 1447, 1383, 1369, 1201, 1164, 1159, 1128, 1105, 1085, 1070. (PLA 2, diabetes-)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2].Cl.[CH3:19][O:20][C@@H:21]([CH3:24])[CH2:22][NH2:23].C(N(C(C)C)CC)(C)C>C(O)C>[Br:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:15]2[NH:23][CH2:22][C@@H:21]([O:20][CH3:19])[CH3:24]
Reactant: CCOC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CO[C@@H](C)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(Br)cc2c1NC[C@H](C)OC
Reaction time: 16 h

Procedure:
Suspend ethyl-6-bromo-4-chloro-quinoline-3-carboxylate (389 g, 1.24 mol) and (2S)-2-methoxypropan-1-amine, hydrochloride (171 g, 1.36 mol, 1.1 eq.) in ethanol (5.84 L). Add diisopropylethylamine (474 mL) and heat the mixture at 50° C. overnight. After 16 hours, cool the reaction to room temperature and concentrate in vacuo. Add methyl tert-butyl ether (2 L) to the residue and stir for 20 min. Filter the precipitate and wash it with methyl tert-butyl ether (2×250 mL). Concentrate the filtrate in vacuo to afford the titled compound in almost quantitative yield. The compound will be used in the next step without further purification. MS (ESI) m/z (M+H)+ 367.0, 369.0.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:20]([C:22]1[S:26][C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:24][C:23]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:21].C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]([N:30]2[CH2:31][CH2:32][N:27]([C:25]3[S:26][C:22]([CH2:20][CH3:21])=[C:23]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:24]=3)[CH2:28][CH2:29]2)=[O:19])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCc1sc(N2CCNCC2)nc1-c1ccccc1
Reactant: CC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CCc1sc(N2CCN(C(=O)Nc3ccc(NC(C)=O)nc3)CC2)nc1-c1ccccc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 27.3 %

Procedure:
A mixture of 2,2,2-trichloroethyl [6-(acetylamino)pyridin-3-yl]carbamate (263 mg, 0.805 mmol), 1-(5-ethyl-4-phenyl-1,3-thiazol-2-yl)piperazine (200 mg, 0.732 mmol) and diisopropylethylamine (0.255 ml, 1.46 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the desired product (90.1 mg, 27.3%) as a solid.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]([OH:14])[CH2:10][C:11]([OH:13])=[O:12])[C:2]([NH2:4])=[NH:3].Cl.[C:16](O)(=[O:18])[CH3:17]>>[NH:1]([CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]([O:14][C:16](=[O:18])[CH3:17])[CH2:10][C:11]([OH:13])=[O:12])[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)NCCCC[C@H](O)CC(=O)O
Reactant: CC(=O)O
Agent: Cl
Product: CC(=O)O[C@@H](CCCCNC(=N)N)CC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.55 g (14.8 mmols) of 7-guanidino-3(S)-hydroxyheptanoic acid was dissolved in 100 ml of glacial acetic acid, and hydrogen chloride gas was introduced to saturation at a temperature lower than room temperature. The reaction mixture was stirred for 2 hours at room temperature, and concentrated under reduced pressure. The above procedure was carried out two more times, and the residue was sufficiently dried to obtain the desired product in a quantitative yield.
Reaction SMILES: F[B-](F)(F)F.C([O+](CC)CC)C.[Cl:13][C:14]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][C:26](=O)[CH2:25]1)=[O:23].[S:31]1[N:35]=[CH:34][C:33]([C:36]([NH:38][NH2:39])=O)=[N:32]1>ClCCl.C(OCC)(=O)C>[Cl:13][C:14]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]2[C:36]([C:33]3[CH:34]=[N:35][S:31][N:32]=3)=[N:38][N:39]=[C:26]2[CH2:25]1)=[O:23]
Reactant: NNC(=O)c1cnsn1
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Cl)c(F)c1Cl)N1CCn2c(nnc2-c2cnsn2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethyloxonium tetrafluoroborate (144 mg, 0.756 mmol) was added under argon to a suspension of 4-[(2,4-dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37) (200 mg, 0.687 mmol) in dry dichloromethane (DCM) (1.7 ml). The reaction mixture was stirred at room temperature for 1 h—everything dissolved. 1,2,5-thiadiazole-3-carbohydrazide (I119)(119 mg, 0.824 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and 1-butanol (1.700 ml) was added to the residue. The resulting reaction mixture was stirred at reflux for 5 h. The reaction mixture was diluted with ethyl acetate (I25 mL) and washed with water (2×25 mL), sat. NaHCO3 (25 mL) and brine (2×25 mL). The resulting organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by MDAP (basic method). The resulting residue was triturated with Et2O and dried 3 days at 50° C. under vacuum. The resulting solid was triturated with n-hexane and dried at 50° C. under vacuum for 20 h. The resulting solid was triturated again with n-hexane and dried at 50° C. under vacuum overnight to afford the desired product in 37.5 mg as a white powder.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH:11]=[CH:10]2.[CH2:23]([CH2:26][NH2:27])[CH:24]=C.[CH3:28]N(C=O)C>>[CH2:26]([N:27]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH:11]=[CH:10]2)[CH3:28])[CH:23]=[CH2:24]
Reactant: C=CCCN
Reactant: Fc1ccc(-n2ccc3cc(OCCCCBr)ccc32)cc1
Reactant: CN(C)C=O
Product: C=CCN(C)CCCCOc1ccc2c(ccn2-c2ccc(F)cc2)c1
Temperature: 60 °C
Yield: 77 %

Procedure:
To 160 mg (0.44 mmol) 5-(4-Bromo-butoxy)-1-(4-fluoro-phenyl)-1H-indole in 2 ml DMF were added 0.5 ml (5.2 mmol) N-allylmethylamine and the solution was heated to 60° C. for 30 min. After concentration in vacuo, the residue was dissolved in water and ether. 2M NaOH was added, and the inorganic phase was extracted with ether, the combined organic phases were washed with water and dried over Na2SO4. Column chromatography on silica gel with CH2Cl2/MeOH 9:1 yielded 120 mg (77%) Allyl-{4-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-amine as yellow oil, MS: 353 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24](I)[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][N:40]=1.CN(C)[CH:47]=[O:48]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([C:47](=[O:48])[NH:38][C:39]3[CH:44]=[CH:43][N:42]=[CH:41][N:40]=3)[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(I)c(Cl)cc3[nH]c2=O)c1
Reactant: Nc1ccncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(C(=O)Nc4ccncn4)c(Cl)cc3[nH]c2=O)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a suspension of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-iodo-2-oxo -1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (0.10 g in a mixture of 1 mL N,N-dimethylformamide and 0.04 mL triethylamine) was added 75 mg of 4-aminopyrimidine followed by 0.8 mg dichlorobis(triphenylphosphine)palladium(II) and the flask flushed (5×) with carbon monoxide. The mixture was then heated to 90° C. on an oil bath under a carbon monoxide atmosphere. After 16 hours, the mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic portion was dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography on silica gel (ethyl acetate:hexane, 35:65; then methylene chloride:methanol, 95:5) gave the title compound (70 mg).
Reaction SMILES: [CH2:1]([O:17][C:18]1[CH:35]=[CH:34][C:21]([O:22][CH2:23][C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:36](OC(=O)C)(=[O:38])[CH3:37].N1C=CC=CC=1>O>[C:36]([N:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:24](=[O:25])[CH2:23][O:22][C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:35][CH:34]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)NCc2ccccn2)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)N(Cc2ccccn2)C(C)=O)cc1
Temperature: 110 °C
Yield: 48.1 %

Procedure:
A mixture of 0.70 g of product from Example 88, 2.96 g of acetic anhydride, 0.027 g of 4-N,N-dimethylaminopyridine and 15 ml of pyridine is heated at 110° C. for 35 hours and at reflux temperature for 57 hours. The reaction is poured into water and extracted with methylene chloride. The organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel: 35% ethyl acetate/hexane) to give 0.366 g of product as light yellow crystals.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:16]([O:19][CH2:20][CH3:21])(=[O:18])[CH3:17]>>[C:16]([O:19][CH2:20][CH3:21])(=[O:18])/[CH:17]=[CH:14]/[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCOC(C)=O
Reactant: CCCCCCCCCCCCCC=O
Product: CCCCCCCCCCCCC/C=C/C(=O)OCC

Procedure:
IR (thin film) 2920, 2850, 1725, 1465, 1265, 1175, 1045 cm-1 ; 1H NMR (CDCl3, 300 MHz) δ7.00 (dt, 1, J=15.5, 6.8 Hz, CH2CH=), 5.84 (dt, 1, J=15.5, 1.2 Hz, COCH=), 4.21 (dd, 2, J=14.2, 7.2 Hz, CH2O), 2.23 (qd, 2, J=6.9, 1.2 Hz, CH2CH=), 1.49 (t, 2, J=7 Hz, CH2CH2CH3), 1.3 (m, 20, CH2CH2CH2), 0.92 (t, 3, J=7 Hz, CH2CH2CH3). Rf (5% ethyl acetate:hexanes):tetradecanal, 0.29; ester product, 0.31. MS (FD): m/e 282 (M+).
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9].[C:12](O)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC=CC=1>C(=O)([O-])[O-].[Zr+4].C(=O)([O-])[O-].O>[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH3:9])[CH3:10])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)CCCCCCCO
Agent: [Zr+4]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)CCCCCCCOC(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
Isodecyl alcohol (791.4 grams; 5.-0 mol), benzoic acid (622.8 grams; 5.1 mol), zirconium carbonate (3.3 grams) and toluene (75 ml) were placed into a three-necked, round bottom flask equipped with stirrer, thermometer, 10" Vigeraux column, water trap and condenser. The reaction temperature was 184° C., washed first with water (25 mls) at 90°-95° C. for 30 minutes, then with sodium carbonate (15%) at 90°-95° C. for 30 minutes and twice with water (300 ml) at 90° C. for five minutes. After being washed, the product was dried at 125° C. and filtered to yield the desired product (1254.6 grams; 95.6% yield). It assayed 99.5% with the following properties:
Reaction SMILES: [C:1]([C:3]([S:13][CH2:14][CH3:15])=[CH:4][C@@H:5]1[C@@H:7]([C:8](O)=[O:9])[C:6]1([CH3:12])[CH3:11])#[N:2].S(Cl)([Cl:18])=O>CN(C)C=O.C1(C)C=CC=CC=1>[C:1]([C:3]([S:13][CH2:14][CH3:15])=[CH:4][C@@H:5]1[C@@H:7]([C:8]([Cl:18])=[O:9])[C:6]1([CH3:12])[CH3:11])#[N:2]
Reactant: O=S(Cl)Cl
Reactant: CCSC(C#N)=C[C@@H]1[C@@H](C(=O)O)C1(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCSC(C#N)=C[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Temperature: 65 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
To methyl=(1R)-trans-3-[(1EZ)-2-cyano-2-(ethylthio)ethenyl]-2,2-dimethylcyclopropanecarboxylic acid (8.98 g, 39.9 mmol), toluene (25 mL) was added and then thionyl chloride (5.0 g, 42.0 mmol) was added. Furthermore, N,N-dimethylformamide (50 mg) was added, followed by stirring at an inner temperature of 60 to 70° C. for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain 9.62 g of (1R)-trans-3-[(1EZ)-2-cyano-2-(ethylthio)ethenyl]-2,2-dimethylcyclopropanecarboxylic acid chloride represented by the following formula:
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl.O>C1(C)C=CC=CC=1>[OH:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2([C:20]3[CH:21]=[CH:22][C:17]([OH:23])=[CH:18][CH:19]=3)[CH2:6][CH2:5][CH:4]([C@H:1]3[CH2:3][CH2:2][C@H:1]([CH2:4][CH2:5][CH3:6])[CH2:3][CH2:2]3)[CH2:9][CH2:8]2)=[CH:11][CH:12]=1
Reactant: Oc1ccccc1
Reactant: CCC[C@H]1CC[C@H](C2CCC(=O)CC2)CC1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H](C2CCC(c3ccc(O)cc3)(c3ccc(O)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 50 h

Procedure:
4-(Trans-4-n-propylcyclohexyl)cyclohexanone (449 g), phenol (756 g) and CaCl (446 g) were mixed, followed by gradually dropwise adding conc. hydrochloric acid (335 ml) with vigorous stirring at room temperature, further agitating the mixture for 30 minutes after completion of the dropwise addition, allowing the resulting material to stand at room temperature, further for 50 hours, adding hot water (2 l) and toluene (3 l), heating the mixture, cooling, filtering off crystals, washing the crystals with water and then with toluene, drying the crystals and recrystallizing from tetrahydrofuran solvent to obtain white crystals of 1,1-bis(4-hydroxyphenyl)-4-(trans-4-n-propylcyclohexyl)cyclohexane as a diol compound of the present invention (436 g). M.P.: 222.0°-222.8° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][O:8][C:4]=2[CH:3]=1.[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2ncoc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2ncoc2c1
Yield: 38.2 %

Procedure:
A mixture of 6-methylbenzoxazole (422 mg, 3.17 mmol), N-bromosuccinimide (677 mg, 3.80 mmol), and 2,2′-azobisisobutyronitrile (78 mg, 0.48 mmol) in CCl4 (6.3 mL) was heated at reflux for 22 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. Purification of the crude material on silica gel (4% EtOAc/hexanes) gave the title compound as colourless crystals (257 mg, 38%). 1H NMR (CDCl3) δ 4.64 (s, 2H), 7.42 (dd, 1H, J=8.1, 1.5 Hz), 7.64 (d, 1H, J=1.2 Hz), 7.76 (d, 1H, J=8.4 Hz), 8.12 (s, 1H).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]12OCC[O:23]1)[CH3:2]>CO.Cl>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:23])[CH3:2]
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4C(C)C[C@H]3[C@@H]1CCC21OCCO1
Agent: Cl
Solvent: CO
Product: CC[C@]12CC[C@@H]3c4ccc(OC)cc4C(C)C[C@H]3[C@@H]1CCC2=O
Yield: 92.4 %

Procedure:
Suspend dl-13-ethyl-3-methoxy-6-methyl-17,17-ethylenedioxygona-1,3,5(10)-triene (9.0 g) in methanol (200 ml) and concentrated hydrochloric acid (5 ml). Heat the mixture on a steam bath for 15 minutes. Remove the solvent under vacuum and partition the residue between ether and aqueous sodium bicarbonate. Remove the organic solvents and dry to obtain a gum. Recrystallize from methanol to obtain dl-13-ethyl-3-methoxy-6-methylgona-1,3,5(10)-trien-17-one (7.29 g), m.p. 115°-123°. Recrystallize from methanol to obtain an analytical sample with m.p. 123°-127°; ultraviolet absorption peak at 280 mμ (ε2,190), infrared maximum (potassium bromide) at 5.75 μ.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[C:12]([Cl:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[OH:15])[CH:2]=[CH2:3].[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:4]1[CH:13]=[C:12]([Cl:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[O:15][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:2]=[CH2:3]
Reactant: BrCc1ccccc1
Reactant: C=CCc1cc(Cl)c2ccccc2c1O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCc1cc(Cl)c2ccccc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To a solution of 2-allyl-4-chloro-1-naphthol (20.0 g, 0.091 mol) in N,N-dimethylformamide (700 mL) was added sodium hydride (60 wt. %, 4.39 g, 0.11 mol) and the reaction mixture was allowed to stir at room temperature for 30 min. Benzyl bromide (18.8 g, 0.11 mol) was then added and the reaction mixture was allowed to stir at room temperature for 2 h. The solvent was removed in vacuo to provide a crude oil. The residue was re-dissolved in ethyl acetate (500 mL) and the organic layer was washed with water (2×250 mL), saturated aqueous sodium chloride (250 mL), dried (sodium sulfate) and the solvent was removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, dichloromethane:hexanes 1:4) provided 23.0 g (82%) of 2-allyl-1-(benzyloxy)4-chloronaphthalene as a light brown oil. Treatment of the benzyl ether with AD-mix-α (104.3 g) generally according to the procedure described for Intermediate 2 afforded 24.0 g (94%) of (±)-3-[1-(benzyloxy)-4-chloro-2-naphthyl]propane-1,2-diol as a white solid. mp 69-71° C.; Anal. calcd. for C20H19ClO: C, 70.07; H, 5.59. Found: C, 68.01; H, 5.47.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[C:5]([O:10][CH3:11])[C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1B(O)O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:20]2[CH:19]=[CH:18][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)=[C:5]([O:10][CH3:11])[C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: COc1ccc(Br)c(OC)c1-c1ccccn1
Reactant: OB(O)c1ccc2ccccc2c1
Product: COc1ccc(-c2ccc3ccccc3c2)c(OC)c1-c1ccccn1

Procedure:
This compound was prepared by the same procedure as used in EXAMPLE 3 using 1,3-dimethoxy-2-(pyrid-2-yl)-4-bromobenzene 38 and naphth-2-yl boronic acid to yield 39.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[S:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH3:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([CH3:28])[CH:27]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:32]2[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:30][CH2:31]2)=[S:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: COc1nc(C)c(C)nc1NC(=S)Oc1ccccc1
Product: COc1nc(C)c(C)nc1NC(=S)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 68.4 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)thiocarbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 28 to obtain the titled compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30](O)=[O:31])[CH:25]=1)#[N:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:30]([C:26]3[CH:25]=[C:24]([C:22]#[N:23])[CH:29]=[CH:28][N:27]=3)=[O:31])=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)c(F)c2)C1
Reactant: N#Cc1ccnc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cc(C#N)ccn3)c(F)c2)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
(−)-(S)-2-(4-Amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (example 1 h, 70 mg, 236 μmol, Eq: 1.00), 4-cyanopicolinic acid (CAS 640296-19-1, 45.5 mg, 307 μmol, Eq: 1.3) and HBTU (134 mg, 354 μmol, Eq: 1.5) were dissolved in DMF (1.25 ml), treated with N-Methylmorpholin (71.7 mg, 77.9 μl, 709 μmol, Eq: 3) and stirred at r.t. for 17 h. The mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered off and concentrated under vacuo. The solid residue was diluted with a small volume of MeOH, and filtered, leading to 64 mg of a white solid.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][I:22]>CC(C)=O>[I-:22].[CH3:21][N+:8]1[CH2:9][CH2:10][C:11]2[C:16](=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)=NCC2
Reactant: CI
Solvent: CC(C)=O
Product: COc1cc2c(cc1OC)C(c1ccccc1)=[N+](C)CC2
Product: [I-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
To a stirred solution of 1-phenyl-6,7-dimethoxy-3,4-dihydroisoquinoline in acetone was added methyl iodide and the reaction mixture was stirred at room temperature for 16 hours. A pale yellow precipitate was formed. The by-products and unreacted methyl iodide were removed in vacuo to afford the desired compound in 93% yield.