Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([OH:32])=[C:10]2[C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][C@@H:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])=[N:15][N:14]=2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[F:42][C:43]([F:58])([S:54](F)(=[O:56])=[O:55])[C:44]([F:53])([F:52])[C:45]([F:51])([F:50])[C:46]([F:49])([F:48])[F:47]>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([O:32][S:54]([C:43]([F:42])([F:58])[C:44]([F:52])([F:53])[C:45]([F:50])([F:51])[C:46]([F:49])([F:48])[F:47])(=[O:56])=[O:55])=[C:10]2[C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][C@@H:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])=[N:15][N:14]=2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: COc1ccc2ccc(O)c(-c3nnc(O[C@H](C)c4ccccc4)c4ccccc34)c2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2ccc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(-c3nnc(O[C@H](C)c4ccccc4)c4ccccc34)c2c1
Temperature: 23 °C
Reaction time: 19 h
Yield: 83.3 %

Procedure:
A solution of 7-methoxy-1-[4-((R)-1-phenyl-ethoxy)-phthalazin-1-yl]-naphthalen-2-ol (1.0 g, 2.4 mmol) in diisopropylethylamine (0.94 ml, 7.1 mmol) and dichloromethane (35 ml) was treated with N,N-dimethylaminopyridine (DMAP, 50 mg, 0.41 mmol) at 0° C. Then perfluoro-1-butanesulfonyl fluoride (0.51 ml, 2.8 mmol) was added dropwise and the resulting solution was stirred for 19 hrs at 23° C. The resulting solution was quenched with sat. aqueous ammonium chloride solution. The organic layer was separated and the water layer was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (hexane/EtOAc 3:1) to give 1.4 g (2.0 mmol) of the title compound as an oil.
Reaction SMILES: [Cl: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][CH2:16][CH3:17].[CH2:18]([N:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH3:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Cl-:1].[CH2:18]([N+:25]1[CH:29]=[CH:28][N:27]([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][CH2:16][CH3:17])[C:26]=1[CH3:30])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1nccn1Cc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCl
Product: CCCCCCCCCCCCCCCCn1cc[n+](Cc2ccccc2)c1C
Product: [Cl-]
Reaction time: 4 h

Procedure:
The procedure of Example 1 was repeated with minor change. 427 g of 1-chlorohexadecane (Aldrich) and 280 g of 1-benzyl-2-methyl imidazole (Shikoku Chemicals Corp. 1B2MZ) were added into a 2000 ml three-neck round-bottom flask. The reaction temperature was set from 75 to 80° C. After four hours the milk-like solution transferred into a homogenous solution. The reaction was continued for four days. Then, the product was washed with ethyl acetate five times. After that, it was dried under vacuum for three days.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)O)[CH3:3].[ClH:14].S(Cl)([Cl:17])=O>C(Cl)(Cl)Cl>[ClH:17].[CH3:1][N:2]([CH2:4][CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[Cl:14])[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CN(C)CCC(O)c1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CN(C)CCC(Cl)c1ccccc1

Procedure:
A solution containing 442 g. of N,N,-dimethyl 3-phenyl-3-hydroxypropylamine in 5 l. of chloroform was saturated with dry gaseous hydrogen chloride. 400 ml. of thionyl chloride were then added to the chloroform solution at a rate sufficient to maintain reflux. The solution was refluxed an additional 5 hours. Evaporation of the chloroform and other volatile constituents in vacuo yielded N,N-dimethyl 3-phenyl-3-chloropropylamine hydrochloride which was collected by filtration, and the filter cake washed twice with 1500 ml. portions of acetone. The washed crystals weighed about 500 g. and melted at 181°-3° C. with decomposition. An additional 30 g. of compound were obtained from the acetone wash by standard crystallization procedures. The structure of the above compound was verified by NMR and titration.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[C:18](Br)=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[C:18]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[CH3:23])=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(Br)cccc3O2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3c(cccc3-c3ccccc3C)O2)cc1
Yield: 68.6 %

Procedure:
Treatment of (±)-(4-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.0 g, 5.21 mmol), 2-methylphenyl boronic acid (1.06 g, 7.82 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.205 g, 0.261 mmol), and potassium carbonate (1.80 g, 13.04 mmol) generally according to the procedure described for Intermediate 37 provided 1.41 g (69%) of (±)-[4-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow oil. Rf=0.42 (silica, ethyl acetate:hexanes 1:4); Anal. calcd. for C23H22O4S: C, 70.03; H, 5.62. Found: C, 69.70; H, 5.45.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11](Cl)=[O:12].[CH2:14]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20][CH2:19]1)[CH2:15][CH2:16][CH3:17]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]([O:25][CH2:24][CH:21]1[CH2:22][CH2:23][N:18]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:19][CH2:20]1)=[O:12]
Reactant: CCCCN1CCC(CO)CC1
Reactant: O=C(Cl)c1c[nH]c2ccc(F)cc12
Product: CCCCN1CCC(COC(=O)c2c[nH]c3ccc(F)cc23)CC1
Yield: 30 %

Procedure:
5-Fluoroindole-3-carboxylic acid chloride was reacted with (1-n butyl-4-piperidyl)methanol (D6) using the method of Example 1a to afford (1-n butyl -4-piperidyl)methyl 5-fluoroindole-3-carboxylate as an orange oil (30%), following flash chromatography on silica gel eluting with 10% ethanol/chloroform.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH2:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)[CH3:28]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([CH2:27][CH3:28])=[CH:30][CH:31]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: CCc1ccc(C(=O)O)cc1
Agent: Cl
Product: CCc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCCCC3c3coc4cccc-4c3)CC2)cc1

Procedure:
The title compound, white solid (94 mg, 82%), MS (ISP) m/z=459.5 [(M+H)+], mp 192° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-ethyl-benzoic acid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:46]=[CH:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=3)=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C(CCCCCBr)c1ccc2ccccc2c1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc3ccccc3c2)CC1
Yield: 37.9 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (0.75 g) as starting compound, potassium carbonate (2.0 g) and 6-bromo-1-(2-naphthyl)-1-hexanone (0.80 g) were reacted and treated in the same manner as in Example 172 to give 0.40 g of 4-amino-5-chloro-N-((1-(6-(2-naphthyl)-6-oxohexyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [Na:1].C[C:3]1[C:4]([CH2:22][S:23]([C:25]2[NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[N:26]=2)=[O:24])=[N:5][CH:6]=[CH:7][C:8]=1[O:9]CC1COC2(CCOCC2)OC1.SC1NC2C=CC=CC=2N=1.[CH2:44]1[C:46]2([CH2:51][O:50][CH:49]([CH2:52]OC3C=CN=C(CO)C=3)[O:48][CH2:47]2)[CH2:45]1>>[Na:1].[CH2:45]1[C:46]2([CH2:51][O:50][CH:49]([CH2:52][O:9][C:8]3[CH:7]=[CH:6][N:5]=[C:4]([CH2:22][S:23]([C:25]4[NH:26][C:27]5[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=5[N:29]=4)=[O:24])[CH:3]=3)[O:48][CH2:47]2)[CH2:44]1
Reactant: Cc1c(OCC2COC3(CCOCC3)OC2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: OCc1cc(OCC2OCC3(CC3)CO2)ccn1
Agent: Sc1nc2ccccc2[nH]1
Agent: [Na]
Product: O=S(Cc1cc(OCC2OCC3(CC3)CO2)ccn1)c1nc2ccccc2[nH]1

Procedure:
The same procedure as in the steps (10d) to (10f) of Example 10 was repeated using 2-mercaptobenzimidazole (291 mg, 1.94 mmol) and (4-(5,7-dioxaspiro[2.5]oct-6-ylmethoxy)pyridin-2-yl)methanol (443 mg, 1.76 mmol) to obtain the title compound (300 mg) as a white solid. Note that, in the same process as in the step (10d), 2-mercaptobenzimidazole was added to the reaction mixture and further 2 equivalents of triethylamine was added. The mixture was stirred at room temperature for 2 days.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:13]#[C:14][C:15]([OH:17])=[O:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N+](=[CH2:22])=[N-]>C1COCC1.CCOCC>[CH3:22][O:16][C:15](=[O:17])[C:14]#[C:13][C:5]1[CH:4]=[C:3]([C:2]([F:18])([F:19])[F:1])[CH:8]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:6]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)C#Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C#Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The 3-[3,5-bis(trifluoromethyl)phenyl]-propynoic acid was dissolved in a mixture of THF and ether and treated with diazomethane until all acid was methylated. All solvent was removed and the resulting oil was purified by chromatography (10% ether/hexane) to give 30.5 g of 3-[3,5-bis(trifluoromethyl)phenyl]-propynoic acid methyl ester.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH2:2][CH3:3].[N+:11]([O-])([O-:13])=[O:12].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:11]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:1][CH2:2][CH3:3])[C:5]=1[OH:10])([O-:13])=[O:12]
Reactant: CCCc1ccccc1O
Reactant: O=[N+]([O-])[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CCCc1cccc([N+](=O)[O-])c1O
Reaction time: 24 h
Yield: 0 %

Procedure:
2-n-propylphenol (5.00 g, 36.8 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (3.43 g, 40.5 mmol). The addition of sulfuric acid (45 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(3.2 mg, 48%). 1H NMR (CD3COCD3): d 7.99 (d, 1H), 7.46 dd, 1H) 6.90 (t, 1H), 2.70 (t, 2H), 1.70 (m, 2H), 1.00 (t, 3H).
Reaction SMILES: [CH2:1]([C:3]1([CH3:22])[CH:8]([CH3:9])[CH:7]([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][C:5]([CH2:20][CH3:21])([CH3:19])[NH:4]1)[CH3:2].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>S1(=O)(=O)CCCC1.C1(C)C=CC=CC=1>[CH2:23]([N:4]1[C:5]([CH2:20][CH3:21])([CH3:19])[CH2:6][CH:7]([NH:10][C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:8]([CH3:9])[C:3]1([CH2:1][CH3:2])[CH3:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CCC1(C)CC(NC(=O)c2ccccc2)C(C)C(C)(CC)N1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: Cc1ccccc1
Product: CCC1(C)CC(NC(=O)c2ccccc2)C(C)C(C)(CC)N1Cc1ccccc1
Temperature: 25 °C

Procedure:
20 g of 2,6-diethyl-2,3,6-trimethyl-4-benzamidopiperidine (compound no. 9), 12.5 g of benzylbromide, 1 g of potassium iodide and 20 g of potassium carbonate are stirred in 200 ml of tetrahydrothiophene dioxide (sulpholane) at 110° C. for 4 days. Thereafter the reaction mixture is diluted with 200 ml of toluene, cooled to room temperature and purified by filtration. The filtrate is washed four times with about 200 ml of water, the toluene phase is dried over sodium sulfate and evaporated under vacuum. Crystallization of the residue from acetic acid ethyl ester yields 1-benzyl-2,6-diethyl-2,3,6-trimethyl-4-benzamidopiperidine (compound no. 48); m.p. 234°-236° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][O:6][C:7]1[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.O>[CH2:23]([NH:30][C:13]([C:12]1[C:7]([O:6][CH2:5][C:4]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:2]([Cl:1])[CH:3]=2)=[N:8][C:9]([S:16][CH3:17])=[N:10][CH:11]=1)=[O:15])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(COc2nc(SC)ncc2C(=O)O)cc1Cl
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(COc2nc(SC)ncc2C(=O)NCc2ccccc2)cc1Cl
Yield: 21.6 %

Procedure:
4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)pyrimidine-5-carboxylic acid (2.2 g, 6.47 mmol), benzylamine (1.0 g, 9.34 mmol) and HATU (2.95 g, 7.76 mmol) were dissolved in 60 mL of THF, DIEA (N,N-diiso-propylethylamine, 3.36 mL, 19.41 mmol) was added dropwise, reacted at room temperature for 8 h. To the reaction solution was added 100 mL of water and then extracted with dichloromethane (50 mL×3), dried with anhydrous sodium sulfate, dried by rotation, the solid was separated with silica gel column (dichloromethane:methanol=100:1) to obtain a white solid N-benzyl-4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)pyrimidine-5-carboxamide 600 mg, 22% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]([OH:22])[CH3:21])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)[S:5][CH:6]=1.[CH2:23]([NH2:27])[CH:24]([CH3:26])[CH3:25].C1C[O:31][CH2:30]C1.C1CCN2C(=NCCC2)CC1>CS(C)=O.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[CH2:23]([NH:27][C:30]([C:2]1[CH:3]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([OH:22])[CH3:21])[CH:15]=3)[N:8]=2)[S:5][CH:6]=1)=[O:31])[CH:24]([CH3:26])[CH3:25]
Reactant: C1CCOC1
Reactant: CC(O)c1cccc(Nc2nccc(-c3cc(Br)cs3)n2)c1
Reactant: CC(C)CN
Agent: [Mo]
Agent: [C-]#[O+]
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)CNC(=O)c1csc(-c2ccnc(Nc3cccc(C(C)O)c3)n2)c1
Temperature: 150 °C
Yield: 25 %

Procedure:
A 5 mL Personal Chemistry™ microwave vial was charged with 1-{3-[4-(4-Bromo-thiophen-2-yl)-pyrimidin-2-ylamino]-phenyl}-ethanol (149.3 mg, 0.40 mmol, prepared according to Method 22), isobutylamine (120 uL, 1.20 mmol), molybdenum hexacarbonyl (109.2 mg, 0.41 mmol), THF (2 mL), 20 mg (0.02 mmol) of Hermann's Palladacycle [trans-di-mu-acetatobis[2-9di-O-tolylphpsphino)benzyl]dipalladium(II)], and DBU (180 uL, 1.20 mmol). The reaction mixture was heated to 150° C. in a microwave reactor for 15 min. The crude reaction mixture was diluted with DMSO (2 mL), filtered through a plug of silica gel, then purified by mass-triggered reverse-phase HPLC, (C-18; eluting with a 5-95% gradient consisting of 0.1% formic acid in water: 0.1% formic acid in ACN). Lyophilization of the purified fraction provided 39.5 mg (25% yield) of 5-{2-[3-(1-Hydroxy-ethyl)-phenylamino]-pyrimidin-4-yl}-thiophene-3-carboxylic acid isobutyl-amide as a white powder. 1H NMR (d6-DMSO) δ 9.49 (br. s, 1H), 8.34 (d, J=5.0 Hz, 1H), 8.20 (t, J=6.0 Hz, 1H), 8.16 (dd, J=6.0, 0.5 Hz, 1H), 7.67 (br.s, 1H), 7.49 (dd, J=5.0, 1.2 Hz, 1H), 7.15 (d, J=5.0 Hz, 1H), 7.09 (t, J=7.5 Hz, 1H), 6.80 (d, J=7.5 Hz, 1H), 4.97 (br.d, J=3.5 Hz, 1H), 4.55 (qrt, J=5.5 Hz, 1H), 2.91 (t, J=6.5 Hz, 2H), 1.67 (m, 1H), 1.19 (d, J=6.0 Hz, 3H), 0.74 (d, J=7.0 Hz, 6H); HPLC/MS m/z: 397 [MH]+.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[C@H:18]([CH2:19][CH2:20][C:21](=[O:25])[CH:22]=2)[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C:12](=[O:26])[CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].C(Cl)(Cl)(Cl)[Cl:51]>C(#N)C.ClCCl>[Cl:51][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[C@H:18]([CH2:19][CH2:20][C:21](=[O:25])[CH:22]=2)[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C:12](=[O:26])[CH2:11][CH2:10]1
Reactant: C[C@]12CC[C@H]3[C@@H]([C@H](CCCCCO)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reactant: ClC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: ClCCl
Product: C[C@]12CC[C@H]3[C@@H]([C@H](CCCCCCl)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O

Procedure:
The same product is obtained from 8.05 g of 7α-(5-hydroxypentyl)-estr-4-ene-3,17-dione (Example 1b) by a 3.5-hour reaction with 8.66 g of triphenylphosphine in 85 ml of carbon tetrachloride and 30 ml of acetonitrile at room temperature. The reaction mixture is diluted with dichloromethane, shaken out with saturated bicarbonate solution and with saturated common salt solution, dried with sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel with dichloromethane and ethyl acetate, whereby 4.08 g of 7α-(5-chloropentyl)-estr-4-ene-3,17-dione is obtained, [α]D22 =+68°(c=0.5% in chloroform)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13](F)=[CH:12][CH:11]=2)[CH:6]=1.N[C:19]1([C:31]#[N:32])[CH:24]=[CH:23][C:22](C2C=CC=CC=2)=[CH:21][CH2:20]1.COC1C(CC(OC)=O)CC(OC)O1>>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([C:22]3[CH:23]=[CH:24][C:19]([C:31]#[N:32])=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1ccn(-c2ccc(F)cc2)c1
Reactant: N#CC1(N)C=CC(c2ccccc2)=CC1
Agent: COC(=O)CC1CC(OC)OC1OC
Product: COC(=O)Cc1ccn(-c2ccc(-c3ccc(C#N)cc3)cc2)c1
Yield: 60 %

Procedure:
According to the procedure described in Example 14(a) for the preparation of 2-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]-acetic acid methyl ester, 4-amino-4-cyano-biphenyl (commercially available from TCI) and methyl 2-(2,5-dimethoxy-tetrahydrofuran-3-yl)acetate were condensed in 6 hours at 80° C. to give a crude product. Successive flash column chromatography with EtOAc/CH2Cl2Cl2 /hex gave in 60% yield 2-[1-(4'-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-acetic acid methyl ester as an amorphous solid. 1 1H NMR: δ 7.75 (d, 2H, J=8.8 Hz), 7.69 (d, 2H, J=8.8 Hz), 7.64 (d, 2H, J=8.5 Hz), 7.48 (d, 2H, J=8.8 Hz), 7.10-7.09 (m, 2H), 6.33 (t, 1H, J=2.2 Hz), 3.73 (s, 3H), 3.58 (s, 2H). Anal. Calculated for C20H16N2O2 : C, 75.93; H, 5.10; N, 8.86. Found: C, 75.86; H, 5.14; N, 8.90.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C)C=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:21]=[C:22]([C:24](O)=[O:25])[N:23]=2)=[CH:15][CH:14]=1.[CH3:37][NH:38][O:39][CH3:40].Cl.N1C=CC=CC=1>C(#N)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]([C:27]3[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:31][CH:32]=3)[CH:21]=[C:22]([C:24]([N:38]([O:39][CH3:40])[CH3:37])=[O:25])[N:23]=2)=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)c1ccc(-n2cc(C(=O)O)nc2-c2ccc(Cl)cc2)cc1
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cn(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(Cl)cc2)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Oxalyl chloride (0.34 g, 2.65 mmole) in 5 ml acetonitrile was added to 16 ml acetonitrile containing dimethylformamide (0.25 g, 3.46 mmole) cooled to 0° C. After 15 minutes, 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-4-carboxylic acid from step 1 (1.0 g, 2.65 mmole) was added with 20 ml acetonitrile. After warming to room temperature N,0-dimethylhydroxylamine HCl (0.28 g, 2.92 mmole) and pyridine (0.42 g, 5.31 mmole) were added and the mixture was stirred at room temperature for three days. The reaction mixture was concentrated to give an oily solid. The amide was purified by silica gel chromatography: Anal. Calc'd. C19H15N3O4SCl (419.89); C, 54.35; H. 4.32; N, 10 10.01. Found: C, 53.96; H, 4.30; N, 9.68.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[NH2:23]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:24]=[C:25]([Cl:27])[CH:26]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: COCC1COc2cc3ncnc(Cl)c3cc2O1
Product: COCC1COc2cc3ncnc(Nc4cc(Cl)cc(Cl)c4)c3cc2O1
Yield: 85 %

Procedure:
The titled compound (20 mg, 80%, m.p. 269-274° C.) was prepared in a similar manner as in Example 8, except for employing 4-chloro-7-methoxymethyl-[1,4]dioxano[2,3-g]quinazoline (17 mg, 0.06 mmol) and 3,5-dichloroaniline (21 mg, 0.12 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:14]([CH2:16][NH2:17])[OH:15].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:15][CH2:14][CH2:16][NH:17][C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: NCCO
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cc1cccc([N+](=O)[O-])c1)NCCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.7 %

Procedure:
To a solution of 3-nitrophenylacetic acid (3.21 g, 17.7 mmol), ethanolamine (2.8 g, 46 mmol), and triethylamine (3.0 mL, 22 mmol) in anhydrous DMF (110 mL) was added a solution of benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP, 9.37 g, 18.0 mmol) in anhydrous DMF (80 mL). After stirring 16 hours at ambient temperature (under nitrogen), the reaction mixture was concentrated in vacuo, dissolved in DCM and filtered. The filtrate was washed with 10% aqueous citric acid, saturated aqueous NaHCO3, pH 7 buffer, and brine, dried over Na2SO4 and filtered. The evaporated filtrate was then purified by flash chromatography (10% methanol in DCM) giving the title compound (1.02 g, 26%) as a light yellow solid. 1H NMR (300 MHz, CDCl3/CD3OD) δ 8.18 (m, 1H), 8.11 (ddd, 1H, J=8.1 Hz, 2.4 Hz, 1.1 Hz), 7.72 (m, 1H), 7.60 (t, 1H, J=7.8 Hz), 3.62 (s, 2H), 3.44 (t, 2H, J=5.9 Hz), 3.16 (t, 2H, J=5.9 Hz).