Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([OH:20])=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:20][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=2)=[C:15]([CH:19]=1)[C:16]([O:18][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1)=[O:17]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1ccc(Cl)cc1)c1cc(Br)ccc1OCc1ccc(Cl)cc1
Temperature: 55 °C
Reaction time: 18 h

Procedure:
1-(Bromomethyl)-4-chlorobenzene (592 mg, 2.88 mmol) was added in a single charge to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (250 mg, 1.15 mmol) and potassium carbonate (478 mg, 3.46 mmol) in acetone (40 ml) under nitrogen at 20° C. The reaction mixture was stirred at 55° C. for 18 h. The organic phase was evaporated and the residue was washed with water (25 ml), extracted with ethyl acetate (30×3 ml) and evaporated in vacuo to yield the title compound as an off-white solid. 320 mg.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([N:17]2[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]2)[NH:11][C:10]3=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[CH2:28]([N:30]([CH2:31][CH3:32])[C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:8]=2)[N:13]=[C:12]([N:17]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]2)[N:11]=1)[CH3:29]
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(N4CCCCC4)cc3c(=O)[nH]2)c1
Reactant: CCNCC
Product: CCN(CC)c1nc(-n2cc(C(=O)O)cn2)nc2ccc(N3CCCCC3)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(piperidin-1-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and diethylamine in step E. MS (ESI/CI): predicted mass C21H26N6O2, 394.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:25]=[CH:24][C:14]3[C:15]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[N:16][O:17][C:13]=3[CH:12]=2)=[C:6]([CH:9]=1)[CH2:7][NH2:8].FC(F)(F)C[O:29][C:30](=O)[NH:31][C:32]1[N:33]([C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)[N:34]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:36]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:37]([C:35]1[CH:36]=[C:32]([NH:31][C:30]([NH:8][CH2:7][C:6]2[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:10][C:11]2[CH:25]=[CH:24][C:14]3[C:15]([CH2:18][N:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)=[N:16][O:17][C:13]=3[CH:12]=2)=[O:29])[N:33]([C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)[N:34]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(F)(F)F)cc1
Reactant: NCc1cc(F)ccc1Oc1ccc2c(CN3CCCC3)noc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2cc(F)ccc2Oc2ccc3c(CN4CCCC4)noc3c2)cc1
Temperature: 85 °C
Yield: 33.5 %

Procedure:
5-Fluoro-2-(3-pyrrolidin-1-ylmethyl-benzo[d]isoxazol-6-yloxy)-benzylamine (6v) (50 mg, 0.15 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trifluoro-ethyl ester (b) (75 mg, 0.18 mmol) and diisopropylethylamine (0.038 mL, 0.22 mmol) were combined in DMF (1.5 mL) and heated at 85° C. for 3 hours. The reaction was cooled and concentrated in vacuo and purified by column chromatography (silica, 40 to 60% EtOAc/hexanes/0.25% Et3N) to provide 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[5-fluoro-2-(3-pyrrolidin-1-ylmethyl-benzo[d]isoxazol-6-yloxy)-benzyl]-urea (8v) (30 mg, 34% yield). 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J=8.6 Hz, 1H), 7.31 (d, J=7.0 Hz, 2H), 7.20 (d, J=7.8 Hz, 2H), 7.02-6.88 (m, 5H), 6.17 (s, 1H), 6.02 (s, 1H), 5.30 (t, J=8.6 Hz, 1H), 4.36 (d, J=5.5 Hz, 2H), 3.98 (s, 2H), 2.60 (s, 4H), 2.36 (s, 3H), 1.80 (s, 4H), 1.32 (s, 9H); MS (ESI+) m/z 597 (M+H) detected; HPLC (5 to 95%) 2.93 min.
Reaction SMILES: [O:1]([CH:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][N:11]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:48][CH2:49][C:50]1[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56]>ClCCl>[OH:58][C:51]1[C:50]([CH2:49][NH:48][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][C:10]([CH:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH3:9])=[N:11][CH:12]=2)=[C:55]([CH3:56])[CH:54]=[C:53]([CH3:57])[N:52]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(Oc1ccccc1)c1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccccc3)nc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.3 %

Procedure:
To a solution of 6-(1-phenoxyethyl)nicotinic acid (100 mg, 0.41 mmol) in dichloromethane (20 mL) were added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg, 0.60 mmol), N-hydroxybenzotriazole (81 mg, 0.60 mmol) and triethylamine (122 mg, 1.20 mmol). The resultant reaction mixture was stirred for 30 minutes at room temperature. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (76 mg, 0.50 mmol) was added and the mixture was stirred at ambient temperature overnight. The mixture was washed with brine (20 mL), dried over sodium sulfate, filtered, concentrated. The residue was purified through pre-HPLC and the obtained solution was freeze-dried to afford N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-(1-phenoxyethyl)nicotinamide (50 mg, 32.2%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[N:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=1.[H-].[Na+].Cl[CH2:21][O:22][CH3:23].C(=O)(O)[O-].[Na+]>C(N(CC)C(C)C)(C)C>[Br:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:21][O:22][CH3:23])[C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[N:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=1
Reactant: COCCl
Reactant: COC(=O)c1cc(Br)cc(Nc2nccs2)n1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COCN(c1cc(Br)cc(C(=O)OC)n1)c1nccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 34.3 g of methyl 4-bromo-6-(1,3-thiazol-2-ylamino)pyridine-2-carboxylate and 440 ml of N,N-diisopropylethylamine was added 5.29 g of sodium hydride (60%, in oil) under an ice bath followed by stirring at the ambient temperature for 30 minutes. To the reaction mixture was added 9.9 ml of chloromethylmethyl ether followed by stirring at the ambient temperature for 4 hours. To the reaction mixture was added 4.52 g of sodium hydride (60%, in oil) and 8.3 ml of chloromethylmethyl ether, followed by further stirring for three hours. After warming to room temperature, to the reaction mixture was added saturated aqueous sodium bicarbonate. The precipitate was filtered off and washed with water. The filtrate was extracted with ethyl acetate and then the organic layer was washed with water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=9/1 to 3/1) to give the title compound as a pale yellow solid.
Reaction SMILES: [S:1]1[C:5]([C:6]2[N:10]3[CH2:11][CH2:12][NH:13][CH2:14][C:9]3=[N:8][N:7]=2)=[N:4][CH:3]=[N:2]1.C(N(CC)CC)C.[Cl:22][C:23]1[C:31]([F:32])=[C:30]([Cl:33])[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26].C([O-])(O)=O.[Na+]>ClCCl.CO.C(OCC)(=O)C>[Cl:22][C:23]1[C:31]([F:32])=[C:30]([Cl:33])[CH:29]=[CH:28][C:24]=1[C:25]([N:13]1[CH2:12][CH2:11][N:10]2[C:6]([C:5]3[S:1][N:2]=[CH:3][N:4]=3)=[N:7][N:8]=[C:9]2[CH2:14]1)=[O:26]
Reactant: c1nsc(-c2nnc3n2CCNC3)n1
Reactant: O=C(Cl)c1ccc(Cl)c(F)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Cl)c(F)c1Cl)N1CCn2c(nnc2-c2ncns2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-(1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (I115) (30 mg, 0.144 mmol) and triethylamine (0.030 mL, 0.216 mmol) in Dichloromethane (DCM) (2 mL) was stirred at room temperature. 2,4-Dichloro-3-fluorobenzoyl chloride (36.0 mg, 0.158 mmol) in DCM (0.5 ml) was added and stirring continued at room temperature. After 30 mins, 2 drops MeOH were added followed by sat. NaHCO3 solution (3 ml) and ethyl acetate (30 ml). The product was extracted into the ethyl acetate which was dried (Na2SO4) and concentrated. The product was purified by high pH MDAP to give desired product as a white solid after evaporation of the fractions.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[CH2:17]([N:24]=[C:25]=[S:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([NH:24][C:25](=[S:26])[NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: S=C=NCc1ccccc1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=S)NCc3ccccc3)c2)CC1
Yield: 89 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and benzyl isothiocyanate (92 μL, 0.688 mmol), 37.6 mg (89%) of the title compound were recovered.
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)C.[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:39]=[CH:38][C:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])=[CH:28][CH:27]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:39]=[CH:38][C:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:4]3[C:5](=[O:16])[C:6](=[O:15])[C:7]=3[NH:8][C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)=[CH:28][CH:27]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: NCCCCCCOc1ccc(OCCN2CCOCC2)cc1
Reactant: CCOc1c(Nc2cccnc2)c(=O)c1=O
Product: O=c1c(NCCCCCCOc2ccc(OCCN3CCOCC3)cc2)c(Nc2cccnc2)c1=O
Yield: 76 %

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridin-3-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 1A and 6-[4-(2-morpholin-4-yl-ethoxy)-phenoxy]-hexylamine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([Cl:13])[CH:7]=1)[CH3:5].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][Br:15])=[C:8]([Cl:13])[CH:7]=1)[CH3:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(C)c1ccc(C)c(Cl)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(C)c1ccc(CBr)c(Cl)c1

Procedure:
Fifty (50) g of methyl-2-(3-chloro-4-methylphenyl)propionate, 42 g of N-bromosuccinimide and 600 ml of carbon tetrachloride were mixed together to form a mixed liquid which was then incorporated with a catalytic amount of benzoyl peroxide and refluxed under agitation for one hour. After the end of the reaction, the reaction mixture was filtered to remove insolubles and obtain a filtrate which was then freed of the solvent at a reduced pressure. The residue obtained was introduced into a silica gel-packed column to be adsorbed thereon and then eluted with isopropyl ether-hexane (1:10) to obtain an eluate. The thus obtained eluate was freed of the solvent thereby to obtain 31 g of methyl-2-(4-bromomethyl-3-chlorophenyl)propionate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([OH:14])[C:10]([F:13])([F:12])[F:11].[Cl:15][C:16]1[CH:21]=[C:20](Cl)[N:19]=[C:18]([NH2:23])[N:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([O:14][C:20]1[CH:21]=[C:16]([Cl:15])[N:17]=[C:18]([NH2:23])[N:19]=1)[C:10]([F:11])([F:12])[F:13]
Reactant: O[C@H](c1ccc(Cl)cc1Br)C(F)(F)F
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Nc1nc(Cl)cc(O[C@H](c2ccc(Cl)cc2Br)C(F)(F)F)n1
Temperature: 80 °C

Procedure:
To a solution of (R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethanol (Intermediate 43) (400 mg, 1.4 mmol) in dioxane (25 mL) was added 4,6-dichloropyrimidin-2-amine (1.1 g, 7 mmol) and Cs2CO3 (1.3 g, 4 mmol). The mixture was heated for 24 h at 80° C. The reaction was then cooled to RT and filtered. The solvent was removed in vacuo, then CH2Cl2 and heptane was added. The solvent volume was reduced until a solid precipitated out. The solid was filtered and the procedure repeated several times to provide (R)-4-(1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)-6-chloropyrimidin-2-amine as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][Cl:27].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O>[ClH:27].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])[C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Yield: 92.8 %

Procedure:
A mixture of 30.1 g of cis-(+)-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one, 18.7 g of 2-(dimethylamino)ethyl chloride hydrochloride, 33.0 g of potassium carbonate and 240 ml of ethyl acetate is refluxed for 30 minutes under stirring. Then, 5 ml of water are added to the mixture, and the aqueous mixture is further refluxed for 6 hours under stirring. After cooling the reaction mixture, said mixture is washed with water. The ethyl acetate layer is separated and washed with water. The ethyl acetate layer is then evaporated under reduced pressure to remove ethyl acetate. The residue is dissolved in ethanol. After cooling the solution, said solution is acidified with 10% HCl/ethanol and then stirred at a temperature below 10° C. for 5 hours. The crystalline precipitates are collected by filtration, washed with ethanol and then dried. 37.9 g of cis-(+)-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride are thereby obtained. Yield: 92.7%
Reaction SMILES: [ClH:1].[F:2][C:3]1[N:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6]>CO.[Pd]>[ClH:1].[F:2][C:3]1[C:4]([CH2:5][NH2:6])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: N#Cc1cccnc1F
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1cccnc1F
Reaction time: 6 h
Yield: 82 %

Procedure:
Add concentrated HCl (0.46 mL) to a suspension 2-fluoro-nicotinonitrile (0.34 g, 2.8 mmol) and 5% Pd/C (0.5 g) in methanol (10 mL) at RT. Stir suspension under an atmosphere of hydrogen at 1 atm. For 6 hours. Filter reaction mixture and concentrate the filtrate. Add ether to the residue, bubble HCl gas through the suspension, filter precipitate, and dry to give the title compound (0.37 g, 82%). MS (ES) 127.1 (M+1)+. 1H NMR (400 MHz, DMSO) δ: 8.65 (brs, 3H), 8.24 (m, 1H), 8.16 (m, 1H), 7.41 (m, 1H), 4.06 (m, 2H).
Reaction SMILES: C[O:2][C:3]1[CH2:4][C:5]2[CH2:6][CH2:7][C@@H:8]3[C@@H:17]([C:18]=2[CH2:19][CH:20]=1)[CH2:16][CH2:15][C@@:13]1([CH3:14])[C@@H:9]3[CH2:10][CH2:11][C@H:12]1[CH2:21][OH:22].C(O)(=O)C(O)=O>CO.O1CCCC1.O>[OH:22][CH2:21][C@@H:12]1[CH2:11][CH2:10][C@@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C:18]1[CH2:19][CH2:20][C:3](=[O:2])[CH2:4][C:5]=1[CH2:6][CH2:7]3
Reactant: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(C)[C@H](CO)CC[C@H]32)C1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@H]1CC[C@H]2CO)CC(=O)CC4
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.9 %

Procedure:
A solution of (14β,17α)-3-methoxyestra-2,5(10)-diene-17-methanol (Example 1, step iii; 0.30 g) in a mixture of methanol (3 ml) and tetrahydrofuran (2.1 ml) was treated with a solution of oxalic acid (0.105 g) in water (1.8 ml). After 1.5 h stirring at room temperature, the reaction mixture was poured into water and the product was extracted into ethyl acetate. The combined organic phases were washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography afforded (14β,17α)-17-(hydroxymethyl)estr-5(10)-en-3-one (0.20 g), 1H NMR δ 3.77 (m, 1H), 3.52 (t, 1H, J=9.0 Hz), 2.74 (m, 2H), 1.09 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][NH:6][C:7](=[O:12])[C:8]([F:11])([F:10])[F:9].[C:16]([C:18]([OH:25])([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])#[CH:17]>>[F:9][C:8]([F:11])([F:10])[C:7]([NH:6][CH2:5][C:4]1[CH:13]=[CH:14][CH:15]=[C:2]([C:17]#[C:16][C:18]([OH:25])([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH:3]=1)=[O:12]
Reactant: O=C(NCc1cccc(Br)c1)C(F)(F)F
Reactant: C#CC(O)(CCC)CCC
Product: CCCC(O)(C#Cc1cccc(CNC(=O)C(F)(F)F)c1)CCC

Procedure:
N-(3-Bromobenzyl)-2,2,2-trifluoroacetamide was coupled with 4-ethynylheptan-4-ol following the procedure described in Example 140 to give 2,2,2-trifluoro-N-(3-(3-hydroxy-3-propylhex-1-ynyl)benzyl)acetamide as a yellow oil. Yield (0.462 g, 38%): 1H NMR (400 MHz, DMSO-d6) δ 9.97 (t, J=5.6 Hz, 1H), 7.32 (t, J=7.8 Hz, 1H), 7.27-7.22 (m, 3H), 5.15 (bs, 1H), 4.35 (d, J=6.0 Hz, 2H), 1.60-1.41 (m, 8H), 0.89 (t, J=7.2 Hz, 6H).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O-:19])(=[O:18])[CH3:17].[K+].Cl>C(OC(=O)C)(=O)C>[O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[CH:17][C:16]([OH:19])=[O:18])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: O=C(O)C=Cc1ccc(Oc2ccccc2)cc1
Temperature: 180 °C
Yield: 53.6 %

Procedure:
4-Phenoxybenzaldehyde (10.0 g) and potassium acetate (9.8 g) were suspended in acetic anhydride (9.5 ml), followed by reflux at 180° C. for 5 hours. After the reaction, the pH of the reaction mixture was adjusted to a value of 2 with hydrochloric acid and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous NaCl solution, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=2/1) to obtain the title compound (6.5 g, 54%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:19](=O)[CH2:18][CH2:17][C@@:16]2([CH3:21])[CH:3]1[C@@H:4]([CH2:24][OH:25])[C@@H:5]([OH:23])[C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[OH:22].[ClH:27].Cl.[NH:29]1[CH2:34][CH2:33][CH:32]([O:35][NH2:36])[CH2:31][CH2:30]1>N1C=CC=CC=1>[ClH:27].[NH:29]1[CH2:34][CH2:33][CH:32]([O:35]/[N:36]=[C:19]2/[C:2]([CH3:26])([CH3:1])[CH:3]3[C@:16]([CH3:21])([CH2:17][CH2:18]/2)[C@@H:15]2[C@H:6]([C@H:7]4[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C@@H:10]([OH:22])[CH2:9][CH2:8]4)[C@H:5]([OH:23])[C@@H:4]3[CH2:24][OH:25])[CH2:31][CH2:30]1
Reactant: CC1(C)C(=O)CC[C@@]2(C)C1[C@@H](CO)[C@@H](O)[C@H]1[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]12
Reactant: NOC1CCNCC1
Agent: Cl
Solvent: c1ccncc1
Product: CC1(C)/C(=N/OC2CCNCC2)CC[C@@]2(C)C1[C@@H](CO)[C@@H](O)[C@H]1[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 96 h

Procedure:
4,4-Dimethyl-6α-hydroxymethyl-7α,17β-dihydroxyandrostan-3-one (Preparation 10, 40 mg) and 4-piperidyloxyamine dihydrochloride (Preparation 16, 52 mg) were dissolved in pyridine (1.0 ml) and stirred at RT for 4 days. After evaporation of the solvent, the resulting solid was triturated with DCM/AcOEt 1/1 to give, after filtration, the title compound (40 mg, 86%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:18][CH:17]=3)([CH3:15])[CH2:11][O:12]2)=[CH:7][CH:6]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(Cl)Cl>CO>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:6]3[CH:5]=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:16][CH2:17][CH:29]4[CH2:30][CH2:31][NH:26][CH2:27][CH2:28]4)=[CH:8][CH:7]=3)[C:10]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:20][CH:21]=3)([CH3:15])[CH2:11][O:12]2)=[CH:7][CH:6]=1
Reactant: C1CCNCC1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2)cc1
Solvent: ClCCl
Solvent: CO
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2ccc(OCCCCC3CCNCC3)cc2)cc1
Yield: 150.5 %

Procedure:
To (3RS,4RS)-4-[4-(4-chlorobutyloxy)phenyl]-(7-(methoxymethoxy)-3-(4-(methoxymethoxy)phenyl)-3-methylchroman (393 mg, 0.75 mmol) was added piperidine (738 mg, 7.5 mmol) and the mixture was refluxed for 12 h. After cooling, the mixture was extracted with ethyl acetate, dried over MgSO4, and filtered. The filtrate was evaporated under reduced pressure, and the concentrate thus obtained was subjected to silica gel columnchromatography (CH2Cl2:methanol=20:1) to give 325 mg (yield: 75%) of a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[N:5]=[C:4]([N:12]2[CH2:17][C@@H:16]3[CH2:18][C@H:13]2[CH2:14][O:15]3)[CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=2)O1.C([O-])(=O)C.[K+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[C@H:16]12[CH2:18][C@H:13]([N:12]([C:4]3[N:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[N:7]=[C:2]([C:27]4[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=4)[CH:3]=3)[CH2:17]1)[CH2:14][O:15]2
Reactant: CS(=O)(=O)c1nc(Cl)cc(N2C[C@@H]3C[C@H]2CO3)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CS(=O)(=O)c1nc(-c2cnc(N)nc2)cc(N2C[C@@H]3C[C@H]2CO3)n1
Temperature: 140 °C
Yield: 52.7 %

Procedure:
To a microwave vial charged with (1S,4S)-5-(6-chloro-2-(methylsulfonyl)pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]-heptane (600 mg, 2.07 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (641 mg, 2.90 mmol), potassium acetate (284 mg, 2.90 mmol) and sodium carbonate (307 mg, 2.90 mmol) in acetonitrile/water (1 (5:1, 6.0 mL) was added PdCl2{PtBu2(Ph-p-NMe2)}2 (147 mg, 0.21 mmol) under nitrogen. The vial was sealed and heated by microwave irradiation at 140° C. for 40 min. The reaction mixture was concentrated in vacuo, and resulting residue was purified by flash column chromatography (5% methanol in dichloromethane) to provide 6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(methylsulfonyl)-[4,5′-bipyrimidin]-2′-amine (380 mg, 52.7% yield). LCMS (ESI): [MH]+=349.0.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:9].CN([CH:13]=[O:14])C>>[O:14]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:9])[C:13]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Product: BrCCCCCOc1ccccc1
Reaction time: 4 h
Yield: 40 %

Procedure:
To a well-stirred suspension of sodium hydride (15.3 g, 0.32 mol; 50% oil dispersion) in dry DMF (500 ml) containing (25 g, 0.26 mol), was added dropwise 1,5-dibromopentane (122.3 g, 0.53 mol). After the addition was complete, the reaction mixture was stirred at 60°-70° C. for 4 hours. Most of the DMF was next removed under reduced pressure, and the residue was dissolved in ethyl acetate (250 ml). The organic extract was washed successively with a 5% sodium hydroxide solution, water and brine. After drying the organics over anhydrous magnesium sulfate, all volatiles were removed. The residual yellow liquid was then distilled under reduced pressure, and the pure product was collected at 118°-125° C./1 mm as a clear colorless liquid (26 g, 40% yield).