Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH:6]([C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1)[CH:7]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[C:26]([O:34][CH:35]([F:37])[F:36])[CH:25]=1)[C:8]1[CH:9]=[N:10][C:11]([N:14]([CH3:23])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)(OCC)=O.[Li+].[OH-].Cl>C1COCC1.CO.O>[F:37][CH:35]([F:36])[O:34][C:26]1[CH:25]=[C:24]([CH:7]([C:8]2[CH:9]=[N:10][C:11]([N:14]([CH3:23])[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)=[CH:12][CH:13]=2)[CH2:6][C:38]2[CH:39]=[CH:40][N:41]=[CH:42][CH:43]=2)[CH:29]=[CH:28][C:27]=1[O:30][CH:31]([F:33])[F:32]
Reactant: CCOC(=O)C(c1ccncc1)C(c1ccc(N(C)c2ccc(OC)cc2)nc1)c1ccc(OC(F)F)c(OC(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(N(C)c2ccc(C(Cc3ccncc3)c3ccc(OC(F)F)c(OC(F)F)c3)cn2)cc1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a solution of the crude ester from Step 3 above in a mixture of THF/MeOH/water (4.5 mL/1.5 mL/1.5 mL), was added 1.6 mL (3.24 mmol) of a 2 N solution of LiOH. The resulting solution was stirred at 65 ° C. for 3 h, cooled down to room temperature followed by the addition of 3.4 mL of a 1.0 N HCl solution. The resulting mixture was rotovaped down to evaporate MeOH and the aqueous residue was diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layer were washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (Gradient 70% Ethyl acetate/hexane to 100% ethyl acetate) to afford 67 mg (47%, 2 steps) of the title compound.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[C:5]([N:8]1[C:17]2[CH:16]=[CH:15][C:14]([NH2:18])=[CH:13][C:12]=2[C:11]2[N:19]([C:25]3[CH:33]=[CH:32][C:28]4[O:29][CH2:30][O:31][C:27]=4[CH:26]=3)[N:20]=[C:21]([C:22]([NH2:24])=[O:23])[C:10]=2[CH2:9]1)(=[O:7])[CH3:6].[Cl:34][C:35]1C=[CH:41][CH:40]=[CH:39][C:36]=1CCl>N1C=CC=CC=1>[C:5]([N:8]1[C:17]2[CH:16]=[CH:15][C:14]([NH:18][C:1](=[O:4])[C:2]3[CH:41]=[CH:40][CH:39]=[CH:36][C:35]=3[Cl:34])=[CH:13][C:12]=2[C:11]2[N:19]([C:25]3[CH:33]=[CH:32][C:28]4[O:29][CH2:30][O:31][C:27]=4[CH:26]=3)[N:20]=[C:21]([C:22]([NH2:24])=[O:23])[C:10]=2[CH2:9]1)(=[O:7])[CH3:6]
Reactant: CC(=O)O
Reactant: CC(=O)N1Cc2c(C(N)=O)nn(-c3ccc4c(c3)OCO4)c2-c2cc(N)ccc21
Reactant: ClCc1ccccc1Cl
Solvent: c1ccncc1
Product: CC(=O)N1Cc2c(C(N)=O)nn(-c3ccc4c(c3)OCO4)c2-c2cc(NC(=O)c3ccccc3Cl)ccc21
Reaction time: 4 h
Yield: 25 %

Procedure:
The title material from Example 17 (280 mg, 0.00072 mol) and 2-chlorobenzyl chloride (126 mg, 0.00072 mol, d=1.382 g/mol, 91 μL) were dissolved in pyridine (2 mL) and stirred for 4 hours. The pyridine was removed in vacuo and the resulting material was purified via HPLC to give the title compound. 95 mg (MW=529.93, 25% yield). LC/MS m/z=530.96 (m+1).
Reaction SMILES: [CH:1]1([C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH:3]=[CH:2]1.C1(C(OC)=O)CCC(C(OC)=O)CC=1.C(Cl)Cl>[Pd].C(O)C>[CH:4]1([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2][CH:1]([C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]1
Reactant: COC(=O)C1C=CC(C(=O)OC)CC1
Agent: [Pd]
Agent: COC(=O)C1=CCC(C(=O)OC)CC1
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)C1CCC(C(=O)OC)CC1

Procedure:
A solution of dimethyl cyclohex-2-ene-1,4-dicarboxylate and dimethyl cyclohex-1-ene-1,4-dicarboxylate is hydrogenated under balloon pressure at room temperature over Pd/C catalyst. If methylene chloride is used as the solvent, primarily the g-ene tautomer is reduced, whereas most of the 1-ene tautomer remains unreacted. If ethanol is used as the solvent both tautomers are reduced.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH2:10]([CH2:14][CH:15]=[O:16])[CH2:11][CH:12]=O.[CH2:17]([C:24](O)=O)[C:18](CC(O)=O)=O.C([O-])(=O)C.[Na+]>Cl.O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:7]2[CH:10]3[CH2:11][CH2:12][CH2:24][CH:17]2[CH2:18][C:15](=[O:16])[CH2:14]3)=[CH:4][CH:3]=1
Reactant: O=C(O)CC(=O)CC(=O)O
Reactant: O=CCCCC=O
Reactant: NCc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C1CC2CCCC(C1)N2Cc1ccc(F)cc1

Procedure:
A solution of 4-fluorobenzylamine (25 g) in dilute hydrochloric acid (5N, 40 ml) was added to glutaric dialdehyde (50%, 48 ml) in water (800 ml) with stirring. A solution of 1,3-acetonedicarboxylic acid (29.2 g) and sodium acetate (16.4 g) in water (200 ml) was then added and the mixture stirred for 24 hours at room temperature. A further quantity of dilute hydrochloric acid (10 ml) was then added and the mixture stirred for a further 48 hours.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.[Br:9]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([CH2:8][Br:9])=[N:6][CH:7]=1
Reactant: Cc1ncc(Br)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ncc(Br)cn1
Temperature: 60 °C
Reaction time: 3 h
Yield: 11 %

Procedure:
A mixture of 5-bromo-2-methylpyrimidine (119) (1.34 g, 7.75 mmol), N-bromosuccinimide (1.40 g, 7.87 mmol) and AIBN (0.13 g, 0.79 mmol) in CCl4 (15 mL) was stirred at 60° C. for 3 h. The resulting mixture was filtered, the filter cake was washed with Et2O (100 mL), and the combined filtrates were concentrated under reduced pressure. Column chromatography of the residue, eluting with 2:1 EtOAc:hexanes, gave 5-bromo-2-(bromomethyl)pyrimidine (120) (0.214 g, 11%) as a white solid: mp 55-57° C.; 1H NMR (CDCl3) δ 8.79 (s, 2H), 4.57 (s, 2H). Anal. (C5H4Br2N2) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[Br:11]N1C(=O)CCC1=O>>[Br:11][C:4]1[C:5]([OH:10])=[C:6]([CH:9]=[C:2]([CH3:1])[CH:3]=1)[CH:7]=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(O)c(C=O)c1
Product: Cc1cc(Br)c(O)c(C=O)c1
Yield: 76.1 %

Procedure:
Proceeding as in Reference 9, but substituting 5-methyl salicylaldehyde (3 g, 22 mmol) and N-bromosuccinimide (4.7 g, 26.4 mmol), gave 3-bromo-2-hydroxy-5-methylbenzaldehyde (3.6 g).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C:37](=O)[C:36]([C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1)([CH3:42])[CH2:35][CH2:34]2.[Cl-].[NH4+]>C(OCC)C.CCCCCC>[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C:37](=[CH:2][O:3][CH3:4])[C:36]([C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1)([CH3:42])[CH:35]=[CH:34]2
Reactant: COc1ccc(C2(C)CCc3cc(OC)ccc3C2=O)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: COC=C1c2ccc(OC)cc2C=CC1(C)c1ccc(OC)cc1

Procedure:
A suspension of (methoxymethyl)triphenylphosphonium chloride (25.7 g) in diethyl ether (400 ml) was stirred under an argon atmosphere and cooled in an ice-bath while a solution of n-butyl-lithium in hexane (1.6M, 46 ml) was added slowly over 10 minutes. The reaction mixture was then stirred at that temperature for 1 hour. A solution of 6-methoxy-2-(4-methoxyphenyl)-2-methyltetralone (8.9 g ) in diethyl ether 150 ml) was added to the reaction, and it was then stirred at room temperature for 16 h, saturated ammonium chloride solution (300 ml) was added to the reaction mixture and the organic layer was separated. The aqueous layer was extracted twice with diethyl ether (200 ml). The organic extracts were combined, dried and evaporated to dryness. The resulting gum was subjected to flash column chromatography on silica (K60) using toluene as eluting solvent to give 6-methoxy-1-methoxymethylene-2-(4-methoxyphenyl)-2-methylnaphthalene as a colourless oil.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH:2]=[CH2:3]>C(O)(=O)C.C(O)C.C(OCC)(=O)C.[Fe]>[CH2:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCc1cccc([N+](=O)[O-])c1C(=O)OC
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C=CCc1cccc(N)c1C(=O)OC
Temperature: 25 °C

Procedure:
To a stirred suspension of Step 1 intermediate (4.2 g, 19.98 mmol) in a mixture of 50% aqueous acetic acid (100 ml) and ethanol (100 ml) was added iron powder (5.3 g, 99.9 g atom) and the mixture was refluxed for 3 h. The mixture was cooled to room temperature and filtered through a celite bed. The filtrate was concentrated and the residue obtained was diluted with ethyl acetate and washed with water (2×50 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated to give 3.2 g of the product as a brown oil; 1H NMR (δ ppm, CDCl3, 300 MHz): 7.15-7.07 (m, 1H); 6.62-6.55 (m, 2H); 5.99-5.82 (m, 1H); 5.05-4.95 (m, 2H); 3.86 (s, 3H); 3.53 (d, J=6.0, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8](=[O:13])[NH:9][CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:17][C:18]1[CH:28]=[CH:27][C:21]2[N:22]=[C:23]([S:25][CH3:26])[S:24][C:20]=2[CH:19]=1.O>CN(C=O)C>[CH3:26][S:25][C:23]1[S:24][C:20]2[CH:19]=[C:18]([CH2:17][N:9]3[CH:10]=[CH:11][N:12]=[C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[C:8]3=[O:13])[CH:28]=[CH:27][C:21]=2[N:22]=1
Reactant: O=c1[nH]ccnc1N1CCOCC1
Reactant: CSc1nc2ccc(CCl)cc2s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc2ccc(Cn3ccnc(N4CCOCC4)c3=O)cc2s1
Reaction time: 0.33 h
Yield: 95.4 %

Procedure:
To a stirred solution of 3-morpholinopyrazin-2(1H)-one (317 mg, 1.75 mmol) in DMF (8 mL) at 0° C. was added NaH (60% in mineral oil, 105 mg, 2.63 mmol). After stirring for 20 min, a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (400 mg, 1.75 mmol) in DMF (2 mL) was added dropwise, and the mixture was stirred at rt for 2 h. The mixture was poured into water and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-morpholinopyrazin-2(1H)-one as a light yellow solid (625 mg, 95.4%). 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J=8.4 Hz, 1H), 7.71 (s, 1H), 7.36 (d, J=6.6 Hz, 1H), 6.92 (d, J=4.2 Hz, 1H), 6.71 (d, J=4.2 Hz, 1H), 5.10 (s, 2H), 3.81 (s, 8H), 2.80 (s, 3H). LCMS (ESI) m/z 375 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([NH:23][CH3:24])=[CH:19][C:18]=4[O:25][CH3:26])=[N:11][C:10]=3[N:9]([CH3:27])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([N:23]([CH3:24])[S:29]([CH3:28])(=[O:31])=[O:30])=[CH:19][C:18]=4[O:25][CH3:26])=[N:11][C:10]=3[N:9]([CH3:27])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: CNc1ccc(-c2nc3c(c(C4CCCCC4)nn3C)c(=O)[nH]2)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1cc(N(C)S(C)(=O)=O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.3 %

Procedure:
To a 3 ml pyridine solution of 91.8 mg (0.25 mmol) of the compound obtained in Example 47, 23.2 μl (0.3 mmol) of methanesulfonyl chloride was added, and the mixture was stirred at room temperature for 20 hours. Then, an aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/1˜only ethyl acetate) to obtain 97.2 mg (87%) of the captioned compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][C:26]4[CH2:27][NH:28][CH:29]([CH3:33])[CH2:30][C:31]=4[N:32]=3)=[O:23])[CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.C[I:35].[C:36](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[I-:35].[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:17][CH2:18][N:19]([C:22]([C:24]3[S:25][C:26]4[CH2:27][NH:28][C:29]([CH3:36])([CH3:33])[CH2:30][C:31]=4[NH+:32]=3)=[O:23])[CH2:20][CH2:21]1)(=[O:14])=[O:15])[CH:7]=[CH:6]2
Reactant: CI
Reactant: CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)sc2CN1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2[nH+]c(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)sc2CN1
Product: [I-]
Temperature: 80 °C
Reaction time: 8 h

Procedure:
In N,N-dimethylformamide (20 ml), 1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine hydrochloride (200 mg) was dissolved, followed by the addition of methyl iodide (0.05 ml) and potassium carbonate (79.0 mg). The resulting mixture was stirred overnight at 80° C. The reaction mixture was concentrated under reduced pressure. Water was added to the residue and the precipitate so formed was collected by filtration. The precipitate was dissolved in a 1:1 mixed solution of dichloromethane and methanol. Ethyl acetate was added to the resulting solution and the precipitate thus formed was collected by filtration, whereby the title compound (144 mg, 56%) was obtained.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][CH:20]=O)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:23][O:24][NH2:25]>>[CH3:23][O:24][N:25]=[CH:20][CH2:19][CH2:18][C:9]1[O:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1
Reactant: O=CCCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: CON
Agent: Cl
Product: CON=CCCc1nc(-c2ccccc2)c(-c2ccccc2)o1

Procedure:
The process described in Method A was followed. 3-(4,5-Diphenyl-1,3-oxazol-2-yl)propanal (554 mg, 2.0 mmol, see Pridgen L. N. et al in Tetrahedron Lett., 25(27), 2835 (1984)) and methoxyamine hydrochloride (222 mg, 2.66 mmol) were used to obtain the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14].[OH-].[Na+].ClC1C=CC=C(C(OO)=[O:25])C=1>CN(C)C=O.O>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][C:11]([OH:25])=[CH:12][C:7]=1[CH3:6]
Reactant: COc1ccccc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc(O)cc1C
Reaction time: 2 h

Procedure:
4-Methoxy-3-methylphenol was prepared according to the procedures described in Higgins et al., “An Assessment of the Reaction Energetics for Cytochrome P450-Mediated Reactions,” Arch. Biochem. Biophys. (2001); 385: 220-30. Specifically, phosphorus oxychloride (5.1 ml, 0.057 mol) was added dropwise to a solution of o-methylanisole (5.33 ml, 0.043 mol) in dimethylformamide (6 g) under nitrogen. After addition, the mixture was heated and refluxed for 4 hours, cooled, and then added to 100 ml of water. To the solution, 10% NaOH was added and the solution was extracted with 4×100 ml of ether. The ether layers were washed with water and then brine solution, dried over magnesium sulfate, and evaporated under reduced pressure. The dark oil that remained (5.0 g, 77%) was purified by column chromatography (silica gel: 90% hexane, 10% ethyl acetate). The purified oil (1.78 g, 28%) was dissolved in dichloromethane (100 ml) and then 3.03 g (0.018 mol) 3-chloroperbenzoic acid was added. The mixture was refluxed under nitrogen for ˜5 hours, cooled, and evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with aqueous saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate and evaporated under reduced pressured. The dark oil that remained was dissolved in 7 ml of methanol and 5.5 ml of 10% aqueous potassium hydroxide solution was added. The solution was stirred for ˜2 hours, water was added, and the solution was extracted with ether. The ether layers were combined and washed with saturated sodium bicarbonate solution and then with water. The ether was dried over magnesium sulfate and evaporated under reduced pressure. The oil that remained (1.21 g, 74%) was recrystallized twice with hexane to give 4-methoxy-3-methyl-phenol as long white needles.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH:11]=O)=[CH:4][CH:3]=1.[CH3:13]CCCCC>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH:11]=[CH2:13])=[CH:4][CH:3]=1
Reactant: CCCCCC
Reactant: O=C[C@H]1C[C@@H]1c1ccc(Br)cc1
Product: C=C[C@H]1C[C@@H]1c1ccc(Br)cc1

Procedure:
The product from Example 30A was subjected to the conditions outlined in Example 26E, followed by chromatography (100% hexane) to provide the title compound.
Reaction SMILES: [CH2:1]=O.[CH:3]1([NH:6][C@H:7]2[CH2:12][CH2:11][C@H:10]3[C@H:13]4[C@H:23]([CH2:24][CH2:25][C@:8]23[CH3:9])[C@:21]2([CH3:22])[C:16]([C:17]([F:28])([F:27])[C@@H:18]([OH:26])[CH2:19][CH2:20]2)=[CH:15][CH2:14]4)[CH2:5][CH2:4]1.[OH-].[Na+]>C(O)=O>[F:28][C:17]1([F:27])[C@@H:18]([OH:26])[CH2:19][CH2:20][C@@:21]2([CH3:22])[C:16]1=[CH:15][CH2:14][C@@H:13]1[C@@H:23]2[CH2:24][CH2:25][C@@:8]2([CH3:9])[C@H:10]1[CH2:11][CH2:12][C@@H:7]2[N:6]([CH:3]1[CH2:5][CH2:4]1)[CH3:1]
Reactant: C=O
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C(F)(F)[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2NC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CN(C1CC1)[C@H]1CC[C@H]2[C@@H]3CC=C4C(F)(F)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
To a mixture of 10 ml of formic acid and 5 ml of formaldehyde is added 1.4 g of 17β-(cyclopropylamino)-4,4-difluoroandrost-5-en-3β-ol. The mixture is heated at reflux for 5 hours, the volume is then reduced to 7.5 ml in vacuo, and 10 ml of 50% (w/w) aqueous sodium hydroxide is added. The aqueous layer is separated and extracted with ethyl acetate and the combined organic solutions are dried over magnesium sulfate. The solvent is then removed in vacuo and the residual product is purified by flash chromatography to give 4,4-difluoro-17β-[N-methyl(cyclopropylamino)]androst-5-en-3β-ol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[C:5]([N:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][CH2:17][CH2:18][C:19]#[N:20])[CH3:8])=[O:6].[N:25]([Sn](CCCC)(CCCC)CCCC)=[N+:26]=[N-:27].C([Al](CC)CC)C.Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[C:5]([N:7]([CH3:8])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][CH2:17][CH2:18][C:19]1[NH:27][N:26]=[N:25][N:20]=1)=[O:6]
Reactant: CN(C(=O)c1ccc(Cl)c(Br)c1)c1ccccc1OCCCC#N
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: CC[Al](CC)CC
Agent: Cl
Solvent: Cc1ccccc1
Product: CN(C(=O)c1ccc(Cl)c(Br)c1)c1ccccc1OCCCc1nnn[nH]1
Temperature: 80 °C
Yield: 87.4 %

Procedure:
A mixture of 3-bromo-4-chloro-N-[2-(3-cyano-propoxy)-phenyl]-N-methyl-benzamide (2.0 g, 4.9 mmol), azidotributyltin (4.03 mL, 14.7 mmol) and triethylaluminum (7.74 mL, 14.7 mmol, 25% in toluene) in toluene (25 mL) was heated at 80° C. for 5 hrs. The mixture was allowed to cool to room temperature and was acidified with 1N HCl. The mixture was extracted with DCM. The organic layer was washed with water and brine, and was dried. The filtrate was concentrated in vacuo and the residue purified by silica gel column chromatography (eluent: 3% MeOH in DCM) to afford 3-bromo-4-chloro-N-methyl-N-{2-[3-(1H-tetrazol-5-yl)-propoxy]-phenyl}-benzamide (1.93 g). MS [M+H]+: 451.9; tR=2.26 min. (method 1)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[NH2:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1.C(N(CC)CC)C.CN(C)P(N(C)C)(N(C)C)=O>O>[OH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=1
Reactant: OCCCCCCCCCCCBr
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1ccc(NCCCCCCCCCCCO)cc1

Procedure:
A solution of 16 g. of 11-bromoundecanol, 9.9 g. of ethyl 4-aminobenzoate, and 6.0 g. of triethylamine in 50 ml. of hexamethylphosphoramide is stirred at 70° C. under argon for 128 hours. The resulting solution is cooled, diluted with water, and filtered. Recrystallization of the solid from acetonitrile affords ethyl 4-(11-hydroxyundecylamino)benzoate as a white, crystalline solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:23][C:24]1[C:32]([OH:33])=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[CH:27][NH:28]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:23][C:24]1[C:32]([O:33][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[CH:27][NH:28]2
Reactant: Oc1ccc2[nH]ccc2c1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3F)ncnc2cc1OCC1CCN(C)CC1
Temperature: 95 °C
Reaction time: 3 h
Yield: 26.6 %

Procedure:
A solution of 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (213 mg, 0.662 mmol), (prepared as described for the starting material in Example 10), and 4-fluoro-5-hydroxyindole (120 mg, 0.794 mmol), (prepared as described for the starting material in Example 242), in DMF (3 ml) containing potassium carbonate (137 mg, 0.994 mmol) was stirred at 95° C. for 3 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried (MgSO4) and evaporated. The residue was triturated in cold ether. The solid was filtered and dried under vacuum to give 4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (77 mg, 26%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][C@@H:15]([C:28]2[N:29]=[N:30][N:31]([C:33]([CH3:37])([CH3:36])[CH2:34]O)[CH:32]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][N:17]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.F.F.F.C(N(CC)C(C)C)(C)C.[F:59]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F>CC#N>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][C@@H:15]([C:28]2[N:29]=[N:30][N:31]([C:33]([CH3:37])([CH3:36])[CH2:34][F:59])[CH:32]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:25])[F:26])=[CH:18][N:17]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(C)(C)c1ccc(CC(=O)N[C@H](c2ccc(OCC(F)(F)F)cn2)c2cn(C(C)(C)CO)nn2)cc1
Agent: F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)c1ccc(CC(=O)N[C@H](c2ccc(OCC(F)(F)F)cn2)c2cn(C(C)(C)CF)nn2)cc1
Temperature: 45 °C
Reaction time: 2 h
Yield: 14.4 %

Procedure:
To a solution of 0.02 g (0.04 mmol) 2-(4-tert-butylphenyl)-N-{(S)-[1-(2-hydroxy-1,1-dimethylethyl)-1H-1,2,3-triazol-4-yl][5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}acetamide in 0.20 ml CH3CN at rt was added 0.02 ml (0.13 mmol) DIEA, 0.009 ml (0.05 mmol) N,N-diisopropylethylamine trihydrofluoride, and 0.007 ml (0.04 mmol) perfluoro-1-butanesulfonyl fluoride (PBSF). After 2 h at room temperature, 0.007 ml (0.04 mmol) PBSF was added to the reaction mixture and the reaction was heated to 45° C. After 18 h at 45° C., the reaction temperature was increased to 60° C. After 4 h at 60° C., add 0.009 ml (0.05 mmol) N,N,-diisopropylethylamine trihydrofluoride and 0.007 ml (0.04 mmol) PBSF and continue heating. After 24 h, the reaction is still incomplete. At this point, the reaction mixture was quenched with water, filtered through a plug of silica and concentrated in vacuo. Purification by preparative HPLC (5->95% CH3CN/H2O over 15 min, 0.05% added TFA, C18) afforded 0.003 g (16%) 2-(4-tert-butylphenyl)-N-{(S)-[1-(2-fluoro-1,1-dimethylethyl)-1H-1,2,3-triazol-4-yl][5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}acetamide. ES-MS [M+1]+=522.3. 1H NMR (CDCl3, 400 MHz) 8.24 (d, 1H, J=2.65 Hz); 7.57 (s, 1H); 7.40-7.30 (m, 3H); 7.31-7.22 (m, 3H); 4.57-4.46 (d, 1H, J=47.2 Hz); 4.41 (q, 2H, J=8.06 Hz); 3.63 (s, 2H); 1.63 (s, 6H); 1.32 (s, 9H).