Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[CH:9])[CH:3]=1.C(Br)C.[Mg].[CH3:14][Si:15](Cl)([CH3:17])[CH3:16].[NH4+].[Cl-]>O1CCCC1>[CH3:14][Si:15]([C:9]#[C:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1)([CH3:17])[CH3:16]
Reactant: C[Si](C)(C)Cl
Reactant: C#Cc1cccc(Br)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCBr
Product: C[Si](C)(C)C#Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under an inert atmosphere, 9.5 g of the compound of Step A were introduced into 100 g of tetrahydrofuran, and at 25° C.±3° C., over 15 minutes, 69 ml of a 0.8M solution of magnesium ethyl bromide were added, with stirring for 15 minutes at 25° C. Then, over 2 minutes and without cooling, 8 ml of trimethylsilyl chloride were added with stirring for 30 minutes at 25° C. The reaction mixture was poured into a 2M aqueous solution of NH4Cl and was extracted with ether, dried, filtered, and the filtrate was concentrated to dryness by distilling under reduced pressure then rectified to obtain 12.1 g of 3-(trimethylsilylethynyl)bromobenzene with a boiling point at 0.05 mm/Hg=78° to 84° C.
Reaction SMILES: [H-].[Na+:2].C[O:4][C:5]([C:7]1[S:8][C:9]([C:29]#[C:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:10][C:11]=1[N:12]([CH:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)[C:13]([CH:15]1[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16]1)=[O:14])=[O:6].F[C:36]1[CH:41]=[C:40]([CH2:42][N:43]([CH3:45])[CH3:44])[CH:39]=[CH:38][N:37]=1.[OH-].[Na+]>CN(C=O)C>[CH3:44][N:43]([CH2:42][C:40]1[CH:39]=[CH:38][N:37]=[C:36]([O:28][CH:25]2[CH2:26][CH2:27][CH:22]([N:12]([C:11]3[CH:10]=[C:9]([C:29]#[C:30][C:31]([CH3:32])([CH3:33])[CH3:34])[S:8][C:7]=3[C:5]([O-:4])=[O:6])[C:13]([CH:15]3[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16]3)=[O:14])[CH2:23][CH2:24]2)[CH:41]=1)[CH3:45].[Na+:2]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1
Reactant: CN(C)Cc1ccnc(F)c1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)[O-])C2CCC(Oc3cc(CN(C)C)ccn3)CC2)CC1
Temperature: 25 °C
Yield: 31 %

Procedure:
NaH (65 mg of a 60% oil dispersion, 1.62 mmol) was added to solution 5-(3,3-dimethyl-but-1-ynyl)-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (155 mg, 0.34 mmol) and (2-fluoro-pyridin-4-ylmethyl)-dimethyl-amine (130 mg, 0.84 mmol) in DMF (4.0 mL) at 0° C. After 5 min the reaction was warmed to room temperature and then heated at 65° C. for 2 h. The reaction was cooled, aqueous NaOH (0.5 mL of a 1.0 N solution) was added and the reaction mixture evaporated to dryness. Purification by column chromatography on reverse phase C18 silica gel (100% water to 20% acetonitrile/water) provided the desired product as a colorless solid (62 mg, 31%) after lyophilization. MS (m/z): 580.2 [M+H]; HPLC retention time: 5.05 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.Cl.[NH2:13][CH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[N:19]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:18]2=[O:33].[O:34]=[C:35]1[N:39]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45](O)=[O:46])[CH2:38][CH2:37][O:36]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(#N)C>[O:32]=[C:26]1[CH:25]([N:19]2[C:18](=[O:33])[C:17]3[C:21](=[CH:22][CH:23]=[C:15]([CH2:14][NH:13][C:45](=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][N:39]4[CH2:38][CH2:37][O:36][C:35]4=[O:34])[CH:16]=3)[C:20]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C(O)CCCCCN1CCOC1=O
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(CCCCCN1CCOC1=O)NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42 %

Procedure:
DBU (1.2 g, 8.1 mmol) was added to a stirred suspension of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.0 g, 3.1 mmol) in acetonitrile (35 mL), resulting in the formation of a clear solution. The mixture was stirred at room temperature for 10 minutes, and then, 6-(2-oxo-oxazolidin-3-yl)-hexanoic acid (2.0 g, 10 mmol) and HOBt (0.5 g, 3.7 mmol) were added, followed by EDC (0.89 g, 4.7 mmol). After stirring for an additional 16 hours, the mixture was evaporated under vacuum. The residue was partitioned between ethyl acetate (50 mL) and water (100 mL), and the aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic layers were evaporated. The residue was chromatographed on silica, using a methylene chloride-methanol gradient, eluting 0.61 g of the product at 93:7 methylene chloride-methanol, in 42% yield; mp 178-180° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 25/75 CH3CN/0.1% H3PO4, 3.36 (98.33%); 1H NMR (DMSO-d6) δ 1.26-1.28 (m, 2H), 1.43-1.61 (m, 4H), 2.04-2.08 (m, 1H), 2.18 (t, J=7.4 Hz, 2H), 2.46-2.63 (m, 2H), 2.83-2.96 (m, 1H), 3.12 (t, J=7.1 Hz, 2H), 3.49 (t, J=8.0 Hz, 2H), 4.42 (t, J=8.0 Hz, 2H), 4.43 (d, J=5.8 Hz, 2H), 5.15 (dd, J=12.9 Hz, J=5.4 Hz, 1H), 7.72-7.77 (m, 2H), 7.89 (d, J=7.8 Hz, 1H), 8.51 (t, J=5.8 Hz, 1H), 11.12 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 24.8, 25.7, 26.4, 30.9, 35.1, 41.9, 43.3, 43.8, 49.0, 61.5, 121.8, 123.5, 129.7, 131.6, 133.3, 147.8, 157.8, 167.0, 167.1, 169.8, 172.4, 172.7; Anal. Calcd for C23H26N4O7+0.3H2O: C, 58.05; H, 5.63; N, 11.77. Found: C, 58.05; H, 5.42; N, 11.62.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([CH2:26][OH:27])=[C:24]([CH3:28])[N:23]=[C:22]2[CH2:29][CH2:30][CH3:31])=[CH:16][CH:15]=1)=[O:7])(C)(C)C.[ClH:32]>>[ClH:32].[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([CH2:26][OH:27])=[C:24]([CH3:28])[N:23]=[C:22]2[CH2:29][CH2:30][CH3:31])=[CH:16][CH:15]=1)([OH:7])=[O:5]
Reactant: CCCc1nc(C)c(CO)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Product: CCCc1nc(C)c(CO)n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
A solution of 3.32 g of 1-[(2'-tertbutoxycarbonylbiphenyl-4-yl)methyl]-5-hydroxymethyl-4-methyl-2-propylimidazole in 100 mL of 10% aqueous hydrochloride acid was stirred at 25° C. for 16 hours. The solvent and excess hydrochloric acid then were removed under vacuum to provide 2.22 g of 1-[(2'-carboxybiphenyl-4-yl)methyl]-5-hydroxymethyl-4-methyl-2-propylimidazole.hydrochloride (mp 208°-210° C. (dec.)).
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[F:11][C:12]([F:25])([F:24])[C:13]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=1[NH2:15].P(Cl)(Cl)Cl.ClC1C=CC=CC=1>C(OCC)(=O)C>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([NH:15][C:14]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:13]=1[C:12]([F:11])([F:24])[F:25])=[O:10]
Reactant: O=C(O)c1ccccc1O
Reactant: Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClP(Cl)Cl
Solvent: Clc1ccccc1
Product: O=C(Nc1cc(C(F)(F)F)ccc1C(F)(F)F)c1ccccc1O
Temperature: 25 °C
Yield: 48.1 %

Procedure:
A mixture of salicylic acid (6.90 g, 50 mmol), 2,5-bis(trifluoromethyl)-aniline (11.46 g, 50 mmol), phosphorus trichloride(2.18 ml, 25 mmol) and chlorobenzene(150 mL) was refluxed for 4 hours. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was washed with n-hexane to give the title compound(8.4 g, 47.8%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH:12]([NH:14]S(C(C)(C)C)=O)[CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.O1CCOCC1>CO>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH:12]([NH2:14])[CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(NS(=O)C(C)(C)C)C1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(N)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution 3-[1-(2-methyl-propane-2-sulfinylamino)-ethyl]-azetidine-1-carboxylic acid tert-butyl ester (crude from step 2, 264 mg, 0.87 mmol) in MeOH at 0° C. was added 4.0 M HCl in dioxane (0.28 mL, 1.13 mmol) dropwise. The reaction mixture was stirred at 0° C. for 1 h then quenched with saturated aqueous NaHCO3, diluted with water and extracted with CH2Cl2 (3×). The combined organics were dried over MgSO4 and concentrated to afford 3-(1-amino-ethyl)-azetidine-1-carboxylic acid tert-butyl ester as a thick colorless oil which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14](/[CH:18]=[CH:19]/[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[N+:8]([C:7]1[C:2]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14](/[CH:18]=[CH:19]/[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1cccc(/C=C/c2cccnc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccnc1Nc1cccc(/C=C/c2cccnc2)c1
Yield: 25.6 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (1.15 g), 3-[(E)-2-(3-aminophenyl)vinyl]pyridine (1.23 g) and potassium carbonate (1.1 g) in 1,4-dioxane (15 ml) was stirred under reflux for 22 hours. After cooling, insoluble materials were removed by filtration and the filtrate was concentrated. The residue was chromatographed on silica gel column (2% methanol in chloroform) to give 3-nitro-2-[3-[(E)-2-(3-pyridyl)vinyl]phenylamino]pyridine (510 mg) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH:13]([CH3:15])[O:12][C@H:11](O)[C:10]2=[O:17])[CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=1[N:50]1[CH:54]=[C:53]([CH3:55])[N:52]=[CH:51]1)[CH:45]=O>>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][C@H:13]([CH3:15])[O:12]/[C:11](=[CH:45]\[C:44]3[CH:47]=[CH:48][C:49]([N:50]4[CH:54]=[C:53]([CH3:55])[N:52]=[CH:51]4)=[C:42]([F:41])[CH:43]=3)/[C:10]2=[O:17])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cn(-c2ccc(C=O)cc2F)cn1
Reactant: CC1CN(Cc2cccc(Cl)n2)C(=O)[C@@H](O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=S(Cl)Cl
Product: Cc1cn(-c2ccc(/C=C3\O[C@@H](C)CN(Cc4cccc(Cl)n4)C3=O)cc2F)cn1

Procedure:
24.3 mg of the title compound was obtained from (S)-4-(6-chloropyridin-2-ylmethyl)-2-hydroxy-6-methylmorpholin-3-one, thionyl chloride, triphenylphosphine, and 3-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde in the same manner as in Example 15.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[N:21]=[CH:20][C:19]([CH2:22][N:23]2[CH:27]=[C:26]([CH2:28][C:29]([O:31]CC)=[O:30])[C:25]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:24]2)=[CH:18][CH:17]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[N:21]=[CH:20][C:19]([CH2:22][N:23]2[CH:27]=[C:26]([CH2:28][C:29]([OH:31])=[O:30])[C:25]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[N:24]2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)Cc1cn(Cc2ccc(OCCc3nc(-c4ccccc4)oc3C)nc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(Cn2cc(CC(=O)O)c(-c3ccccc3)n2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
After a mixture of ethyl [1-[6-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-3-pyridylmethyl]-3-phenyl-1H-pyrazol-4-yl]acetate (575 mg), 1N sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml), and ethanol (6 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (3 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain [1-[6-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-3-pyridylmethyl]-3-phenyl-1H-pyrazol-4-yl]acetic acid (466 mg, yield: 86%). This was recrystallized from ethanol-hexane. Melting point: 148–149° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].[CH3:10][N:11]([CH3:16])[C:12](=[O:15])[CH:13]=[CH2:14].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][C:19]=1[C:28]([F:31])([F:30])[F:29]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:14][CH2:13][C:12]([N:11]([CH3:16])[CH3:10])=[O:15])=[C:2]([NH:1][S:24]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([C:28]([F:31])([F:29])[F:30])[CH:20]=2)(=[O:26])=[O:25])[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: C=CC(=O)N(C)C
Reactant: Nc1cc(Cl)ccc1S
Product: CN(C)C(=O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Following General Procedure H, B, the title compound was prepared from 2-amino-4-chloro-benzenethiol, N,N-dimethyl-acrylamide, and 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride.
Reaction SMILES: [CH2:1](I)[CH3:2].CC(C)=O.[N:8]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:9].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:14]([N:13]1[CH2:2][CH2:1][N:10]([N:8]=[O:9])[CH2:11][CH2:12]1)[CH3:15]
Reactant: CCI
Reactant: O=NN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCN1CCN(N=O)CC1
Yield: 103.5 %

Procedure:
Ethyl iodide (8.13 g, 0.052 mole) was added to acetone (80 ml) containing N-nitroso piperazine (6.0 g, 0.052 mole) (prepared as described in U.S. Pat. No. 2,907,767) and anhydrous potassium carbonate (7.3 g, 0.052 mole). The mixture was heated under reflux for 24 hours, cooled, treated with water (50 ml) evaporated to 1/2 volume and extracted with ether (3×150 ml). The combined extracts were dried (K2CO3) filtered and evaporated in vacuo to yield N-ethyl-N'-nitrosopiperazine (7.71 g, 98%), as a straw coloured oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@:9]45[CH2:22][C@H:10]4[CH2:11][C:12](=[O:21])[C@:13]5([CH2:15][CH2:16]3)[CH3:14])[CH2:7][CH2:6][C:5]=2[CH:4]=1.[BH4-].[Na+].C(O)(=O)C>CO>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@:9]45[CH2:22][C@H:10]4[CH2:11][C@@H:12]([OH:21])[C@:13]5([CH2:15][CH2:16]3)[CH3:14])[CH2:7][CH2:6][C:5]=2[CH:4]=1.[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@:9]45[CH2:22][C@H:10]4[CH2:11][C@H:12]([OH:21])[C@:13]5([CH2:15][CH2:16]3)[CH3:14])[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)C[C@@H]3C[C@]312
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)C[C@@H]3C[C@]312
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@H](O)C[C@@H]3C[C@]312
Reaction time: 8 h

Procedure:
400 mg of 3-methoxy-14α,15α-methylene-estra-1,3,5(10)-triene-17-one dissolved in 150 ml of methanol are mixed with 400 mg of sodium borohydride at 0° C. and set aside overnight at room temperature. The mixture is poured into cold aqueous acetic acid. The precipitate is dried and preparative layer chromatography on silica gel (mobile phase: benzene/acetone/methanol 45:5:1) yields 180 mg of 3-methoxy-14α,15α-methylene-estra-1,3,5(10)-triene-17α-ol and 220 mg of 3-methoxy-14α,15α-methylene-estra-1,3,5(10)-triene-17β-ol.
Reaction SMILES: [CH2:1]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Br-].[C:15]([CH2:18][CH2:19][CH2:20][CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:17])=[O:16]>C1COCC1>[CH2:1]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH:21][CH2:20][CH2:19][CH2:18][C:15]([OH:17])=[O:16])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCc1ccc(C=O)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCCCc1ccc(C=CCCCC(=O)O)cc1
Yield: 47.8 %

Procedure:
This compound was synthesized from p-pentylbenzaldehyde (3.52 g, 20 mmol, prepared from p-pentylbenzoyl chloride and lithium tri(t-butoxy)aluminum hydride) and 4-carboxybutyltriphenylphosphonium bromide (8.86 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Kugelrohr distillation (bp 147-151° C./0.05 torr) afforded the product (2.49 g, 48%). IR: 3400-2500, 1725 cm-1 ; 1H-NMR: 0.90 (t, 3 H), 1.28 (m, 6 H), 1.82 (m, 2 H), 1.37 (m, 4 H), 2.57 (t, 2 H), 5.55+6.10 (m, 1 H), 6.38 (m, 1 H), 7.10 (m, 4 H), 10.50 (bs, 1 H). Anal. Calcd. for C17H24O2 : C, 78.42, H, 9.29%; Found: C, 78.22, H, 9.27%. Z:E=35:65.
Reaction SMILES: CC(C1C=CC2CC[C@@H]3[C@@:15]([CH2:17][NH2:18])(C)CCC[C@@]3(C)C=2C=1)C.CN(C(O[N:30]1[N:38]=[N:37][C:32]2C=CC=C[C:31]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:46][CH2:47][N:48](C(C)C)C(C)C.O>CN(C=O)C>[N:18]1([C:32]2[N:37]=[N:38][NH:30][CH:31]=2)[CH2:17][CH2:15][NH:48][CH2:47][CH2:46]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)c1ccc2c(c1)[C@]1(C)CCC[C@@](C)(CN)[C@H]1CC2
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: c1[nH]nnc1N1CCNCC1
Reaction time: 8 h

Procedure:
The raw materials S (1 eq) and amine D (1 eq) which are commercially purchased or synthesized are dissolved in DMF, and then HBTU and DIPEA are sequentially added in an ice bath. The resultant mixture is gradually warmed up to room temperature and stirred overnight. Water is added into the mixture in an ice bath, and the resulting mixture is extracted with dichloromethane. The dichloromethane layer is washed with saturated aqueous sodium chloride, dried, and evaporated to remove solvent. The residue is separated by column chromatography to obtain piperazinotriazole compounds as shown in formula I.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:3]=1.[NH2:20][CH2:21][CH:22]([OH:30])[CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[ClH:1].[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[CH:3]=[C:2]([NH:20][CH2:21][CH:22]([OH:30])[CH2:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:13][CH:14]=1
Reactant: NCC(O)CN1CCCCC1
Reactant: COc1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Product: COc1ccc(-c2cc(NCC(O)CN3CCCCC3)c3ccccc3n2)cc1
Product: Cl

Procedure:
The title compound, m.p. 269-272° C., and MS: m/e=392.3 (M+H+), was prepared from 4-chloro-2-(4-methoxy-phenyl)-quinoline and (RS)-1-amino-3-piperidin-1-yl-propan-2-ol.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.[CH:12]12[NH:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][CH:14]([CH2:20][OH:21])[CH2:13]2.C(=O)([O-])[O-].[K+].[K+].CO>C(#N)C.ClCCl>[Br:1][C:2]1[C:10]2[C:9]([N:19]3[CH:12]4[CH2:18][CH2:17][CH:16]3[CH2:15][CH:14]([CH2:20][OH:21])[CH2:13]4)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1
Reactant: OCC1CC2CCC(C1)N2
Reactant: Clc1ncnc2scc(Br)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Solvent: ClCCl
Product: OCC1CC2CCC(C1)N2c1ncnc2scc(Br)c12
Yield: 91.5 %

Procedure:
5-Bromo-4-chloro-thieno[2,3-d]pyrimidine (1.0 g, 4.0 mmol) in acetonitrile (25 mL) was treated with 8-azabicyclo[3.2.1]octan-3-ylmethanol (705 mg, 16 mmol) and potassium carbonate (2.208 g, 16 mmol) at reflux for 4 h. The reaction was then concentrated in vacuum to a gum and partitioned between ethyl acetate (100 mL) and water (50 mL). The ethyl acetate was separated, dried over sodium sulphate and concentrated in vacuum to give a yellow gum. The gum was columned on silica in a gradient of 2-8% methanol in dichloromethane on a 100 g column. The main first fraction was collected and concentrated in vacuum to a gum. The gum was triturated with diethyl ether (20 mL) and crystallized on standing for a few minutes. The diethyl ether was decanted off and the crystals dried in vacuum to yield 3 [8-(5-bromothieno[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-yl]methanol (1.297 g, 3.66 mmol, 91%). 1H NMR (CDCl3) δ: 1.42 (2H, dd, J=12 Hz, J′=4 Hz), 1.67 (2H, d, J=4 Hz), 1.82 (1H, br s), 1.98 (3H, br m), 2.48 (2H, quintet, J=4 Hz), 3.64 (2H, d, J=4 Hz), 4.7 (2H, br s), 7.32 (1H, s), 8.45 (1H, s).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](OCC)=O.O.[NH2:11][NH2:12].C(S[C:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[N:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C>C(O)CCC>[C:24]1([C:16]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:3]([C:2]([F:1])([F:8])[F:9])=[N:12][N:11]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: NN
Reactant: CCSC(=Nc1ccccc1)c1ccccc1
Solvent: CCCCO
Solvent: O
Product: FC(F)(F)c1nnc(-c2ccccc2)n1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 26 %

Procedure:
First, 1.8 g of ethyl trifluoroacetate and 50 mL of 1-butanol were put in a three-neck flask, and the air in the flask was replaced by nitrogen. After that, the mixture was stirred at 0° C. for 10 minutes, and 0.397 g of hydrazine monohydrate was dripped to the mixed solution. This mixed solution was stirred at 0° C. for 20 minutes, and then stirred at room temperature for 1 hour to be reacted. After the reaction, 3.0 g of N-[(ethylsulfanyl)phenylmethylidene]aniline was further added to the mixed solution, and the solution was heated and stirred at 120° C. for 5 hours to be reacted. The mixed solution after the reaction was cooled down to room temperature and filtered, so that filtrate was obtained. The obtained filtrate was concentrated to give a solid. This solid was washed with hexane, so that the triazole derivative HCF3ptz was prepared (yield: 26%). The synthesis scheme of Step 1 is shown by (a-2).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[N:15]=[C:14]([NH:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH3:18])[C:13]([NH2:26])=[CH:12][CH:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.Cl.[C:28](N)(=N)[CH3:29].C([O-])(O)=O.[Na+].CCOC(C)=O>CCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[N:15]=[C:14]4[N:16]([C@H:17]([C:19]5[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=5)[CH3:18])[C:28]([CH3:29])=[N:26][C:13]4=[CH:12][CH:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(=N)N
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)ccc1N)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(Nc3cc(C4CC4)[nH]n3)nc2n1[C@@H](C)c1ccc(F)cc1
Temperature: 25 °C
Yield: 43 %

Procedure:
A mixture of crude (S)—N6-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,3,6-triamine (Method 9; 0.120 g, 0.34 mmol) and acetamidine hydrochloride (0.052 g, 0.55 mmol) in EtOH (5 ml) was heated at reflux overnight. After cooling to 25° C., saturated NaHCO3 solution (10 ml) and EtOAc (30 ml) were added to the reaction mixture. The organic layer was separated, washed with brine (10 ml), dried over Na2SO4, concentrated, and purified by chromatography (EtOAc:MeOH=100:1) to give the title compound as an off-white solid (0.055 g, 43%). NMR (400 MHz, d6-Acetone) 11.14 (br s, 1H), 8.44 (br s, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.44 (m, 2H), 7.11 (m, 2H), 7.00 (br s, 1H), 6.00 (m, 2H), 2.12 (s, 3H), 2.11 (d, J=7.2 Hz, 3H), 0.89 (m, 2H), 0.65 (m, 2H). MS: Calcd.: 376. Found: [M+H]+ 377.
Reaction SMILES: [CH2:1]([OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH3:14].[OH-].[Na+].Cl[C:19]1[O:23][C:22]([C:24]([OH:26])=[O:25])=[CH:21][CH:20]=1.CN(C)P(=O)(N(C)C)N(C)C>C1(C)C=CC=CC=1.C(O)(=O)C>[CH2:1]([O:15][C:19]1[O:23][C:22]([C:24]([OH:26])=[O:25])=[CH:21][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH3:14]
Reactant: CC/C=C\CCCCCCCCCCO
Reactant: O=C(O)c1ccc(Cl)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC/C=C\CCCCCCCCCCOc1ccc(C(=O)O)o1
Reaction time: 3 h

Procedure:
8.8 g (0.0414 mole) of cis-11-tetradecen-1-ol was combined with 4.0 g (0.0829 mole) of sodium hydroxide (50% in oil) in 200 ml of dry toluene and heated to reflux with stirring for 3 hours. 6.1 g (0.414 mole) of 5-chloro-2furoic acid was added, followed by 25 ml of hexamethylphosphoric triamide (HMPA), and the reaction mixture refluxed with stirring for 20 hours, cooled, and acidified with acetic acid. The mixture was extracted into ether and the organic layer washed with water and with brine and evaporated to yield cis-5-(11-tetradecenyloxy)furan-2-carboxylic acid, M.P. 89°-90° C.