Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])[CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:33](Cl)(=O)[O:34]C1C=CC([N+]([O-])=O)=CC=1.[CH:46]([NH2:49])([CH3:48])[CH3:47]>C(#N)C>[F:29][C:28]([F:31])([F:30])[C:23]([C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:33]([NH:49][CH:46]([CH3:48])[CH3:47])=[O:34])=[CH:3][CH:4]=2)=[O:9])[CH2:11][CH2:12]1)([OH:32])[C:24]([F:25])([F:26])[F:27]
Reactant: Nc1ccc(C(=O)N2CCN(Cc3cccc(C(O)(C(F)(F)F)C(F)(F)F)c3)CC2)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)N
Solvent: CC#N
Product: CC(C)NC(=O)Nc1ccc(C(=O)N2CCN(Cc3cccc(C(O)(C(F)(F)F)C(F)(F)F)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.1 %

Procedure:
(4-Aminophenyl)(4-(3-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)-piperazin-1-yl)methanone (131 mg, 0.28 mmol) was dissolved in acetonitrile (5 mL) and treated with 4-nitrophenyl carbonochloridate (57.8 mg, 0.29 mmol). This was stirred at room temperature for 1 hour before isopropylamine (0.121 mL, 1.42 mmol) was added. The reaction was stirred for a further 2 hours at room temperature, filtered and concentrated under vacuum. The mixture was purified by HPLC and then treated with strong cation exchange column chromatography to afford the title compound (17.0 mg).
Reaction SMILES: [CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][NH:11]1)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1>>[CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]1[C:19]([CH:16]1[CH2:18][CH2:17]1)=[O:20])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][N:11]1[C:19]([CH:16]1[CH2:18][CH2:17]1)=[O:20])/[CH:2]=[CH:3]/[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C(=C/c1ccccc1)\CC1CCCCN1
Reactant: O=C(Cl)C1CC1
Product: O=C(C1CC1)N1CCCC1C/C=C/c1ccccc1
Product: O=C(C1CC1)N1CCCCC1C/C=C/c1ccccc1

Procedure:
Stage a) The method is the same as that of Example 1.1, Stage a), the initial reactants being (E)-2-(cinnamyl)piperidine (Preparation 2A, Stage b) and cyclopropanecarboxylic acid chloride, yielding (E)-2-cinnamyl-1-cyclopropanecarbonylpiperidine (formula II; Ar=C6 H5, m=1, n=2, R=cyclopropyl). Yield: 95%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:7](=[O:21])[N:6]([CH3:22])[C:5]2([CH2:27][N+:28]([O-])=O)[C:23]([F:26])([F:25])[F:24].CO.O.[Cl-].[NH4+]>C1COCC1.[Fe]>[NH2:28][CH2:27][C:5]1([C:23]([F:25])([F:26])[F:24])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[N:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C:7](=[O:21])[N:6]1[CH3:22]
Reactant: COc1ccc(CN2C(=O)N(C)C(C[N+](=O)[O-])(C(F)(F)F)c3cc(Br)ccc32)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(CN2C(=O)N(C)C(CN)(C(F)(F)F)c3cc(Br)ccc32)cc1
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
6-Bromo-1-(4-methoxybenzyl)-3-methyl-4-(nitromethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (217.3 mg, 0.445 mmol) was dissolved in THF (0.9 mL), methanol (0.9 mL) and water (0.5 mL), and iron (497 mg, 8.9 mmol) and ammonium chloride (476 mg, 8.9 mmol) were sequentially added to the reaction solution at room temperature. The reaction solution was stirred at 90° C. for 2.5 hours and then cooled to room temperature and insoluble substances were removed by Celite filtration. After the solvent was evaporated under reduced pressure, to the residue, chloroform and saturated sodium hydrogen carbonate were added, and the mixture was stirred at room temperature. The organic layer was separated and washed with saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=1/4), whereby the objective 4-(aminomethyl)-6-bromo-1-(4-methoxybenzyl)-3-methyl-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (148.3 mg, 72.7%) was obtained as a white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[F:15][C:16]1[C:23]([F:24])=[C:22]([C:25]([F:28])([F:27])[F:26])[C:21]([F:29])=[C:20]([F:30])[C:17]=1[CH2:18]Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([NH:14][CH2:18][C:17]2[C:20]([F:30])=[C:21]([F:29])[C:22]([C:25]([F:26])([F:28])[F:27])=[C:23]([F:24])[C:16]=2[F:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: Fc1c(F)c(C(F)(F)F)c(F)c(F)c1CBr
Reactant: CC(=O)Oc1ccc(N)cc1C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)cc1C(=O)O
Yield: 53 %

Procedure:
According to the similar procedure in Synthesis Example 1, by using 2-ethanoyloxy-5-aminobenzoic acid (0.81 g, 4.10 mmole) which was prepared from Synthesis Example (14-3), DMF (15 ml), TEA (0.1 ml), tetrabutyl ammonium iodide (5 mg), and 2,3,5,6-tetrafluoro-4-trifluoromethylbenzyl bromide (1.02 ml, 6.15 mmole), 0.92 g (53.0% yield) of was obtained 2-ethanoyloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid as a white solid.:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][N:21]4[CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].O.[OH-].[Na+]>O1CCOCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][N:21]4[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CCn1ccc2c(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)Oc1ncc(-c2nc(-c3cccc4c3ccn4CCC(=O)O)no2)cc1Cl
Temperature: 25 °C

Procedure:
Ethyl 3-[4-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]propanoate (D62) (1.1 g, 2.418 mmol) was dissolved in a mixture of 1,4-dioxane (100 ml) and ethanol (100 ml). Water (50.0 ml) was added followed by 2N sodium hydroxide (2.418 ml, 4.84 mmol). The mixture was stirred at RT for one and a half hours to give a single product. Evaporated off most of the solvent, acidified with glacial acetic acid, added water (50 ml) and extracted product into EtOAc (200 ml). Washed with water (30 ml) and dried over MgSO4. The solvent was evaporated off until a white precipitate was formed. The solid was filtered off and washed with ether. Mass of title compound obtained was 780 mg. δH (400 MHz, d6-DMSO) 1.38 (6H, d), 2.81 (2H, t), 4.50 (2H, t), 5.41-5.51 (1H, m), 7.07 (1H, dd), 7.36 (1H, t), 7.59 (1H, d), 7.81 (1H, d), 7.94 (1H, dd), 8.58 (1H, d), 8.96 (1H, d), 12.40 (1H, broad s). MS (ES) C21H1935ClN4O4 requires 426; found 427 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][CH:6]([C:11]([O:13]C)=O)[C:7]([O:9]C)=O.Cl.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[NH:27])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]2[NH:28][C:7](=[O:9])[C:6]([O:5][C:4]3[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=3[O:2][CH3:1])=[C:11]([OH:13])[N:27]=2)=[CH:29][CH:30]=1
Reactant: COc1ccc(C(=N)N)cc1
Reactant: COC(=O)C(Oc1ccccc1OC)C(=O)OC
Agent: Cl
Product: COc1ccc(-c2nc(O)c(Oc3ccccc3OC)c(=O)[nH]2)cc1

Procedure:
In analogy to Example 1, paragraph d), 7.63 g of dimethyl (o-methoxyphenoxy)malonate and 5.6 g of p-methoxy-benzamidine hydrochloride were condensed to give 2-(p-methoxyphenyl)-5-(o-methoxyphenoxy)-6-hydroxy-4(3H)-pyrimidinone. Reaction of this compound in analogy to Example 1, paragraph e), yielded 4,6-dichloro-2-(p-methoxyphenyl)-5-(o-methoxyphenoxy)-pyrimidine, m.p. 113°-114° C., from which in analogy to Example 1, paragraph f), there was obtained p-tert-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(p-methoxyphenyl)-4-pyrimidinyl]benzenesulfonamide, m.p. 221°-222° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][NH:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)(=[O:17])[CH2:13][C:14]([CH3:16])=O.[NH2:30]/[C:31](/[CH3:43])=[CH:32]\[C:33]([O:35][CH2:36][CH2:37][CH2:38][O:39][N+:40]([O-:42])=[O:41])=[O:34].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([NH:21][CH2:20][CH2:19][O:18][C:12]([C:13]1[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:32]([C:33]([O:35][CH2:36][CH2:37][CH2:38][O:39][N+:40]([O-:42])=[O:41])=[O:34])=[C:31]([CH3:43])[NH:30][C:14]=1[CH3:16])=[O:17])=[O:29]
Reactant: C/C(N)=C/C(=O)OCCCO[N+](=O)[O-]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)OCCNC(=O)c1ccccn1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CC1=C(C(=O)OCCCO[N+](=O)[O-])C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCCNC(=O)c2ccccn2)=C(C)N1
Yield: 59.8 %

Procedure:
A solution of 9.07 g (0.06 mole) of m-nitrobenzaldehyde, 15.00 g (0.06 mole) of 2-picolinoylaminoethyl acetoacetate, 12.24 g (0.06 mole) of 3-nitrooxypropyl 3-aminocrotonate and 1.74 g (0.012 mole) of piperidinium acetate in 200 ml of 2-propanol was refluxed for 4 hours. After the reaction, the solvent was evaporated, and the residue was purified by silica gel column chromatography [eluent; ethyl acetate hexane (1:3)] to give 20.45 g of the title compound.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[NH2:7][C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([CH:14]=1)[OH:13]>O1CCOCC1>[CH:1]([NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([OH:13])[CH:14]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)N=C=O
Reactant: Nc1cc(O)cc(O)c1
Solvent: C1COCCO1
Product: CC(C)NC(=O)Nc1cc(O)cc(O)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
52 ml (0.53 mole) of isopropyl isocyanate are added dropwise over a period of 20 minutes to a solution of 62.5 g (0.5 mole) of 5-aminoresorcinol in 1000 ml of dioxan, the internal temperature rising to 35° C. The whole is subsequently stirred for 5 hours at room temperature and then 1000 ml of petroleum ether are added whereupon the title compound is precipitated in the form of fine crystals.
Reaction SMILES: [C:1]1([C@H:11]([NH:13][CH2:14][CH:15]2[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH2:18][NH:17][CH2:16]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:34][C:35]1[CH:36]=[C:37]([CH:42]=[CH:43][C:44]=1[NH:45][C:46](OC1C=CC([N+]([O-])=O)=CC=1)=[O:47])[C:38]([O:40][CH3:41])=[O:39]>C1COCC1>[Cl:34][C:35]1[CH:36]=[C:37]([CH:42]=[CH:43][C:44]=1[NH:45][C:46]([N:17]1[CH2:18][CH2:19][CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]([CH2:14][NH:13][C@@H:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH3:12])[CH2:16]1)=[O:47])[C:38]([O:40][CH3:41])=[O:39]
Reactant: COC(=O)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1
Reactant: C[C@@H](NCC1CNCCC1c1ccccc1)c1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)N2CCC(c3ccccc3)C(CN[C@H](C)c3cccc4ccccc34)C2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 217 mg of the crude product of (1R)-1-(1-naphthyl)-N-[(4-phenylpiperidin-3-yl)methyl]ethaneamine and 0.175 mL of triethylamine in 4.0 mL of THF was added 243 mg of methyl 3-chloro-4-{[(4-nitrophenoxy)carbonyl]amino}benzoate. After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 214 mg of methyl 3-chloro-4-({[3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidin-1-yl]carbonyl}amino)benzoate.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[N:7][C:8]([Cl:12])=[N:9]2)=[CH:4][CH:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:7][C:8]([Cl:12])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1nc(Cl)c2ccc(Br)cc2n1
Reactant: C1COCCN1
Solvent: ClCCl
Product: Clc1nc(N2CCOCC2)c2ccc(Br)cc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
To an ice cold solution of 7-bromo-2,4-dichloro-quinazoline (7 g, 0.0255 mol) in dichloromethane (150 mL), morpholine (4.43 mL, 0.0509 mol) was slowly added and the reaction was continued at 0° C. for 30 minutes. The solvent was evaporated to dryness to provide the crude compound. The crude product was purified using column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to provide the title compound (7 g, 84%). 1H NMR (300 MHz, CDCl3): δ 8.17 (d, J=7.5 Hz, 1H), 8.04 (d, J=7.5 Hz, 1H), 7.63 (d, J=8.1 Hz, 1H), 3.72-3.74 (m, 8H): LC-MS (ESI): Calculated mass: 327.0; Observed mass [M+H]+: 329.8. (RT: 0.45 min).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15](N)[CH:16]([CH3:18])[CH3:17].N(CCO)(CCO)CCO>C1(C)C=CC=CC=1>[CH2:15]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH:16]([CH3:18])[CH3:17]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)CN
Solvent: OCCN(CCO)CCO
Solvent: Cc1ccccc1
Product: CC(C)Cc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
4-chloro-3-nitro-quinoline is reacted with isobutyl amine in the presence of triethanolamine (TEA) at between −10 and +15° C. in toluene, while excluding moisture. Afer washing and phase separation, the organic solution is ready for the next step.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.[N+:18]([C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].C(N(CC)CC)C>ClCCl>[N+:18]([C:21]1[CH:22]=[C:23]([S:27]([O:1][C@@H:2]2[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]2)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2cccc([N+](=O)[O-])c2)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Under an atmosphere of argon, (2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (10 g, 39.5 mmol, Eq: 1.00) was combined with dichloromethane (75 ml) to give a colorless solution. Then at 0° C., 3-nitrobenzene-1-sulfonyl chloride (9.58 g, 41.9 mmol, Eq: 1.06) was added. Also at 0° C., triethylamine (12.0 g, 16.5 ml, 119 mmol, Eq: 3.00) was added dropwise to the reaction mixture. The reaction was stirred for 1.5 h at 0° C. and then for 2 days at room temperature. The reaction mixture was diluted in dichloromethane (200 ml) and then extracted with 2×50 ml HC10.5N, 70 ml satd. NaHCO3 solution and 50 ml satd. NaCl solution. The organic layer was stirred over Na2SO4, filtered and concentrated under reduced pressure. The title compound was obtained as a brown gum (17.25 g, quant., MS (m/e)=431.3 [M+H+]. The product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]([CH3:17])[C:9]1[C:14]([F:15])=[CH:13][NH:12][C:11](=[O:16])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24].CCN(CC)CC>C(Cl)Cl>[CH2:1]([N:8]([CH3:17])[C:9]1[C:14]([F:15])=[CH:13][N:12]([C:23]([C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)=[O:24])[C:11](=[O:16])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccs1
Reactant: CN(Cc1ccccc1)c1nc(=O)[nH]cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1ccccc1)c1nc(=O)n(C(=O)c2cccs2)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 6.3 %

Procedure:
To a round-bottomed flask charged with 4-(benzyl(methyl)amino)-5-fluoropyrimidin-2(1H)-one (250 mg, 1.06 mmol) in CH2Cl2 (11 mL) and 2-thiophene carbonyl chloride (172 mg, 1.1 mmol, 1.1 eq) was added Et3N (237 mg, 2.35 mmol) at 0° C. under N2. The reaction mixture was warmed to room temperature after complete addition and stirred at for 12 h. The reaction mixture was diluted with CH2Cl2 (25 mL), washed with satd aq NaCl solution (10 mL), dried over Na2SO4 and evaporated to dryness in vacuo at room temperature. The crude product was purified by reverse phase chromatography to yield the product as a white solid (23 mg, 6%): mp 101.3-102.4° C.; 1H NMR (methanol-d4) δ 8.10 (d, J=6.3 Hz, 1H), 8.00 (d, J=3.8 Hz, 1H), 7.91 (d, J=4.9 Hz, 1H), 7.38-7.20 (m, 6H), 4.88 (s, 2H), 3.22 (d, J=3.2 Hz, 3H); ESIMS m/z 344 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]3[CH:15]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[NH:17][C:13]=3[CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1.Br[CH2:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]3[CH:15]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[N:17]([CH2:35][CH2:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:13]=3[CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: BrCCCc1ccccc1
Reactant: COC(=O)c1cc2c(-c3cccc(OC)c3)nccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1cc2c(-c3cccc(OC)c3)nccc2n1CCCc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
Methyl 4-(3-methoxyphenyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (50 mg, 0.177 mmole) and K2CO3 (49.0 mg, 0.354 mmole) were combined in a screw cap vial. To this was added 1,4-dioxane (0.75 mL) and 1-bromo-3-phenylpropane (0.035 mL, 0.230 mmole). The vial was capped then heated to 100° C. After stirring overnight the mixture was cooled to RT and diluted with EtOAc. The mixture was filtered through Celite washing with EtOAc. The filtrate was concentrated. Flash column (Biotage-SNAP-10 g SiO2, 30% EtOAc/hexanes) gave the title compound (68 mg, 96%) as a pale yellow oil. 1H NMR (399 MHz, CDCl3): δ 8.46 (d, J=6.0 Hz, 1 H); 7.58 (d, J=1.0 Hz, 1 H); 7.55-7.50 (m, 2 H); 7.48-7.39 (m, 1 H); 7.32-7.27 (m, 2H); 7.23-7.17 (m, 3 H); 7.09 (dd, J=6.0, 1.0 Hz, 1 H); 7.02 (ddd, J=8.2, 2.7, 1.1 Hz, 1 H); 4.65-4.57 (m, 2 H); 3.91 (m, 6 H); 2.76-2.68 (m, 2 H); 2.21-2.13 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]([C:4]1C(O)=[CH:6][CH:7]=[CH:8][C:9]=1[OH:10])=O.[C:12](=O)([O-])[O-:13].[K+].[K+].[CH3:18][O:19][CH:20](Br)[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]>CC(C)=O>[CH3:12][O:13][C:26]1[CH:27]=[CH:28][C:23]([C:21]([C:20]2[O:19][C:18]3[CH:1]=[CH:2][CH:4]=[C:9]([OH:10])[C:8]=3[C:7]=2[CH3:6])=[O:22])=[CH:24][CH:25]=1
Reactant: COC(Br)C(=O)c1ccccc1
Reactant: CC(=O)c1c(O)cccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(=O)c2oc3cccc(O)c3c2C)cc1
Yield: 65.8 %

Procedure:
A mixture of 2,6-dihydroxyacetophenone (5.35 gm; 35.0 mmoles), potassium carbonate (4.83 gm; 35.0 mmoles), and p methoxyphenacylbromide (8.05 gm; 35.0 mmoles) in acetone (150 mL) was refluxed for a period of 22 hours. The reaction mixture was cooled, filtered through Celite, and concentrated in vacuo. The residue was dissolved in methylene chloride and washed with IN sodium hydroxide. The aqueous phase was then acidified with 20% citric acid. The solid was filtered, washed with water, and air dried to yield 6.5 gm (65%) of 2-(p-methoxybenzoyl)-3-methyl-4-hydroxybenzofuran, mp. 192°-195° C.
Reaction SMILES: [CH:1]1([C:6]([OH:30])([C:17]#[C:18][C:19]2[CH:24]=[C:23]([F:25])[C:22]([CH2:26][OH:27])=[CH:21][C:20]=2[O:28][CH3:29])[CH2:7][C:8]2[O:13]C(C)(C)[O:11][C:10](=O)[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(O)(C#CC2C(OC)=CN=C(CC)C=2)CC2OC(C)(C)OC(=O)C=2)CCCC1>>[CH:1]1([C:6]2([CH2:17][CH2:18][C:19]3[CH:24]=[C:23]([F:25])[C:22]([CH2:26][OH:27])=[CH:21][C:20]=3[O:28][CH3:29])[O:30][C:10](=[O:11])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(CO)c(F)cc1C#CC(O)(CC1=CC(=O)OC(C)(C)O1)C1CCCC1
Agent: CCc1cc(C#CC(O)(CC2=CC(=O)OC(C)(C)O2)C2CCCC2)c(OC)cn1
Product: COc1cc(CO)c(F)cc1CCC1(C2CCCC2)CC(=O)CC(=O)O1

Procedure:
The desired product was prepared analogously to example A(2), where 6-[2-cyclopentyl-4-(5-fluoro-4-hydroxymethyl-2-methoxy-phenyl)-2-hydroxy-but-3-ynyl]-2,2 dimethyl-[1,3]dioxin-4-one (1.28 g, 3.03 mmol) was substituted in place 6-[2-Cyclopentyl-4-(2-ethyl-5-methoxy-pyridin-4-yl)-2-hydroxy-but-3-ynyl]-2,2-dimethyl-[1,3]dioxin-4-one. Yield: 1.4 g, 38%. 1H NMR (400 MHz, CDCl3) δ: 1.37–1.49 (1 H, m) 1.53–1.97 (9 H, m) 2.53–2.6 (1 H, m) 2.64–2.7 (1 H, m) 2.75 (2 H, s) 3.41 (2 H, s) 3.79 (3 H, s) 4.71 (2 H, s) 6.79 (1 H, d, J=9.85 HZ) 6.87 (1 H, d, J=5.81 Hz). MS (ESI): 363 (M−H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@H:24]1[C@@H:28]([NH2:29])[CH2:27]OC1)[N:17]=[CH:16]2.CCN(C(C)C)[CH:33]([CH3:35])[CH3:34].[C:39](Cl)(=[O:42])[CH:40]=[CH2:41]>ClCCl>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@@H:24]1[CH2:35][CH2:33][CH2:34][CH2:27][C@@H:28]1[NH:29][C:39](=[O:42])[CH:40]=[CH2:41])[N:17]=[CH:16]2
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4COC[C@@H]4N)ncc3c2)c1Cl
Reactant: C=CC(=O)Cl
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)N[C@H]1CCCC[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of (3S,4R)—N3-(6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)tetrahydrofuran-3,4-diamine (0.94 g, 2.1 mmol) in dichloromethane (25 mL) at 0° C. was added DIEA (0.37 mL, 2.1 mmol) and acryloyl chloride (0.17 mL, 2.1 mmol) and the reaction was stirred for 3 h. LC-MS indicated complete consumption of SM. The reaction mixture was purified by silica gel chromatography to yield N-((1S,2R)-2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)cyclohexyl)acrylamide (Compound 27) (0.8 g, 76%). MS (ES+) C23H22Cl2N4O4 requires: 488, found: 489
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:28])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH3:27].I[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]C.[C:39](=O)([O-])O.[Na+]>CN(C=O)C>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:28])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:39])[CH2:27][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CNCCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Reactant: CCCCCCCCCI
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCN(C)CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Temperature: 100 °C
Reaction time: 4 h

Procedure:
526 mg of 11β-fluoro-3-hydroxy-7α-[5-(methylamino)-pentyl]oestra-1,3,5(10)-trien-17-one and 127 mg of iodononane are dissolved in 5 ml of anhydrous DMF and stirred at a bath temperature of 100° C. for 4 h. For work-up, the mixture is added to half-saturated sodium hydrogencarbonate solution, extracted 3 times with methylene chloride, dried over magnesium sulphate and concentrated in vacuo. Preparative column chromatography yields 85 mg of 11β-fluoro-3-hydroxy-7α-{5-[methyl-nonyl-amino]pentyl}oestra-1,3,5(10)-trien-17-one as a foam.