Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](O)[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][OH:17].[BrH:19]>C1CCCCC1>[Br:19][CH2:1][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][OH:17]
Reactant: OCCCCCCCCCCCCCCCCO
Reactant: Br
Solvent: C1CCCCC1
Product: OCCCCCCCCCCCCCCCCBr
Yield: 67 %

Procedure:
1,16-Hexadecanediol (13.75 g) was dissolved in 37 ml of cyclohexane, and 57% hydrobromic acid solution (37 ml) was added to this solution. The reaction mixture was refluxed for six hours while stirring. After the reaction, the mixture was extracted three times with diethyl ether. The organic layer was neutralized with saturated sodium hydrogen carbonate solution, washed with saline solution, dried over magnesium sulfate, and filtered, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel flash chromatography (hexane:ethyl acetate=7:3) gave 16-bromohexadecan-1-ol as white crystals at a 67% yield.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][C:4]([C:13]2[CH:18]=[CH:17][C:16](OC)=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:3]1.Cl>>[NH2:1][CH:2]1[CH2:6][CH2:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:3]1
Reactant: COc1ccc(C2(c3ccccc3)CCC(N)C2)cc1
Agent: Cl
Product: NC1CCC(c2ccccc2)(c2ccccc2)C1

Procedure:
1amino-3-(4methoxyphenyl)-3-phenylcyclopentane [PUT 104] Hydrochloride m.p. 230°-232° C.
Reaction SMILES: Cl.[C:2]([O-:5])(O)=O.[Na+].[CH2:7]1[CH2:17]CN2C(=NCCC2)C[CH2:8]1.[Na+].[Cl-].[CH2:20]1[CH2:24][O:23][CH2:22][CH2:21]1>C(#N)C.CO>[CH:24]12[O:23][CH:22]([CH2:21][CH2:20]1)[CH2:17][CH:7]([CH:2]=[O:5])[CH2:8]2
Reactant: C1CCOC1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: O=CC1CC2CCC(C1)O2
Reaction time: 1.5 h
Yield: 78 %

Procedure:
To a stirred solution of intermediate 158.3 (1.71 g, 11.09 mol) in acetonitrile (13.5 ml) was added 2M HCl (11.09 ml, 22.18 mmol). Stirring was continued for 1.5 h at RT and then carefully basified with 1M NaHCO3. The mixture was extracted with diethyl ether (4×). The organic phases were dried over Na2SO4, filtered and evaporated to dryness to get the crude aldehyde (the NMR showed a mixture of equatorial and axial configuration) witch was dissolved in THF (19 ml) and MeOH (19 ml). To the stirred solution was added DBU (0.092 ml, 0.610 mmol) and stirring was continued for 1 h. The reaction mixture was neutralized with 1M HCl, saturated with NaCl and extracted with EtOAc (6×). The organic phases were dried over Na2SO4, filtered and evaporated to dryness. Purification of the residue by normal phase column chromatography, eluting with a gradient of heptane-EtOAc 80:20 to 0:100, gave the title compound as a colorless oil (1.22 g, 8.70 mmol, 78%): 1H-NMR (600 MHz, DMSO-d6): δ 1.56-2.05 (m, 8H), 2.65 (m, 1H), 4.48 (m, 2H), 9.55 (s, 1H) (equatorial conformation was confirmed by ROESY NMR).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.[CH2:13](OC(OCC)OCC)C.OS(O)(=O)=O.[CH3:28][NH2:29]>C(O)C.Cl>[CH3:28][NH:29][CH:13]=[N:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2c[nH]cn2)cc1
Reactant: CCOC(OCC)OCC
Reactant: CN
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CNC=Nc1ccc(-c2c[nH]cn2)cc1
Temperature: 25 °C

Procedure:
A mixture of 1.59 gm of 4-(4-aminophenyl)-1-H-imidazole and 2.22 gm of triethylorthoformate was heated for 30 minutes at 100° C. in the presence of a catalytic amount of 96% H2SO4. A 33% solution of methylamine in ethanol (9.5 gm) was then added dropwise to the cooled reaction mixture. The solution was stirred at room temperature for twenty hours and then evaporated to dryness. The residue obtained was dissolved in 10% hydrochloric acid, and the acid solution was washed with ethyl acetate and then adjusted to pH 10 with 10% NaOH. The product which separated was extracted with ethyl acetate to yield, after evaporation of the solvent, 0.45 gm of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])=[O:9].Cl[S:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:19]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:29][CH:30]=1)(=[O:21])=[O:20])=[O:9]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1C(=O)c1ccc(Cl)cc1Cl
Product: O=C(O)c1ccc(S(=O)(=O)Nc2ccccc2C(=O)c2ccc(Cl)cc2Cl)cc1

Procedure:
The title compound was prepared from (2-amino-phenyl)-(2,4-dichloro-phenyl)-methanone [Synthesis, (1980) 677-688] and 4-chlorosulfonyl-benzoic acid according to the method described in Example 1.1/c. MS (EI) 451 (MH+).
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16](Br)=[C:15]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[N:14]=1)=[O:12])([C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[NH:32]1[CH2:35][CH:34]([OH:36])[CH2:33]1>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[CH3:1][C:2]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:32]2[CH2:35][CH:34]([OH:36])[CH2:33]2)=[C:15]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[N:14]=1)=[O:12])([C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH3:3]
Reactant: OC1CNC1
Reactant: Cc1nc(C(C)(C)NC(=O)c2ccc(Br)c(OCC3CC3)n2)no1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(N3CC(O)C3)c(OCC3CC3)n2)no1
Temperature: 100 °C
Yield: 54.3 %

Procedure:
5-Bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (150 mg, 380 μmol) was dissolved in toluene (6.0 mL) to give a colorless solution. This solution was degassed under an Argon stream for 5 minutes. Cesium carbonate (371 mg, 1.14 mmol), Pd2(dba)3CHCl3 (39.3 mg, 38.0 μmol), [rac]-BINAP (47.3 mg, 75.9 μmol) and 3-azetidinol hydrochloride (1:1) (CAN 18621-18-6; 49.9 mg, 455 μmol) were added and the mixture was heated for 18 hours in a microwave oven to 100° C. After cooling to room temperature the mixture was diluted with ethyl acetate (5 mL) and water (3 mL), filtered through Celite® and the filter pad was washed with water (10 mL) and ethyl acetate (30 mL). Phases were separated and the aqueous phase was extracted with ethyl acetate (20 mL). Organic phases were combined, dried with Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel. 20 g, 0% to 100% ethyl acetate in heptane) to give the title compound (80 mg, 54%) as yellow solid; NMR complies.
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)[C:10]#[N:11])[CH:5]=[CH:4]1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].O>C1COCC1>[CH3:27][S:28]([O:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)[C:10]#[N:11])[CH:5]=[CH:4]1)(=[O:30])=[O:29]
Reactant: Cc1ccc(C(C#N)=C2C=CC(=NO)C=C2)cc1C
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C(C#N)=C2C=CC(=NOS(C)(=O)=O)C=C2)cc1C
Temperature: 0 °C
Yield: 70.8 %

Procedure:
10 g (40 mmol) of (4-Hydroxyimino-cyclohexa-2,5-dienylidene)-(3,4-dimethylphenyl)-acetonitrile are dissolved in 160 ml of THF and cooled in an ice bath. After adding 8.4 ml (60 mmol) of triethylamine to the solution, 3.4 ml (44 mmol) of methanesulfonyl chloride are added dropwise, keeping the temperature below 5° C. The reaction mixture is stirred in the ice bath for 30 min. The reaction mixture is poured into 150 ml of water, and extracted with ethyl acetate. The organic phase is washed with hydrochloric acid solution, water, and sodium chloride solution. The organic phase is dried over MgSO4, the solvent is distilled off, and the residue is purified by recrystallization from toluene. 9.3 g (71%) of (4-methylsulfonyloxyiminocyclohexa-2,5-dienylidene)-(3,4-dimethylphenyl)-acetonitrile are obtained in the form of yellow crystals having a melting point of 131-133° C. (dec.).
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[C:18]([O:24][CH3:25])=[CH:19][CH:20]=[C:21](C=1)[NH2:22]>CC(O)C>[CH3:25][O:24][C:18]1[CH:19]=[CH:20][C:21]([NH:22][C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=3[CH:5]=[CH:4][N:3]=2)=[N:16][CH:17]=1
Reactant: COc1ccc(N)cc1N
Reactant: COC(=O)c1cccc2c(Cl)nccc12
Solvent: CC(C)O
Product: COC(=O)c1cccc2c(Nc3ccc(OC)cn3)nccc12
Temperature: 90 °C
Yield: 60.1 %

Procedure:
Methyl 1-chloroisoquinoline-5-carboxylate (0.5 g, 2.26 mmol) obtained in Step (1) above was dissolved in 2-propanol (5 mL), and added with 5-amino-p-methoxyaniline (0.33 g, 2.74 mmol) at room temperature. The reaction solution was sealed and stirred for 4 hours or more at 90° C. The reaction mixture was cooled to room temperature, and the solvent was distilled under reduced pressure. The concentrated solid was added with diethyl ether, the solid thus obtained was filtered under reduced pressure. The resulting solid was dried with warm wind in an oven (40° C.) for 3 hours or more to obtain the title compound (0.42 g, 61%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][NH2:16]>CN(C=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([NH:16][CH3:15])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: CN
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: CNc1ccc(C(=O)OC)cc1[N+](=O)[O-]

Procedure:
4-Methylamino-3-nitro-benzoic acid methyl ester (822 mg) was prepared by following General Procedure A using methyl 4-chloro-3-nitrobenzoate (1.0 g) and methylamine (2 M in THF, 6.95 mL, 13.9) in DMF (5 mL). The crude product was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([F:11])[CH:3]=1.Cl[C:13]1[N:18]=[C:17]([NH:19][CH2:20][C:21]2[C:22]([N:27]([CH3:32])[S:28]([CH3:31])(=[O:30])=[O:29])=[N:23][CH:24]=[CH:25][CH:26]=2)[C:16]([C:33]([F:36])([F:35])[F:34])=[CH:15][N:14]=1.FC(F)(F)[C:39]([OH:41])=[O:40].CS(C)=O>CC(O)C>[CH:39]([OH:41])=[O:40].[F:11][C:4]1[CH:3]=[C:2]([NH:1][C:13]2[N:18]=[C:17]([NH:19][CH2:20][C:21]3[C:22]([N:27]([CH3:32])[S:28]([CH3:31])(=[O:30])=[O:29])=[N:23][CH:24]=[CH:25][CH:26]=3)[C:16]([C:33]([F:34])([F:36])[F:35])=[CH:15][N:14]=2)[CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: O=C(O)C(F)(F)F
Reactant: CN(c1ncccc1CNc1nc(Cl)ncc1C(F)(F)F)S(C)(=O)=O
Reactant: NC(=O)c1ccc(N)cc1F
Solvent: CC(C)O
Solvent: CS(C)=O
Product: CN(c1ncccc1CNc1nc(Nc2ccc(C(N)=O)c(F)c2)ncc1C(F)(F)F)S(C)(=O)=O
Product: O=CO
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 4-amino-2-fluorobenzamide (1.5 eq., 189 μM) in 2-propanol (1.0, mL) was treated with C9 (1 equiv., 130 uM) followed by trifluoroacetic acid (2.7 equiv., 341 μM) and stirred in a sealed vial at 100° C. for about 20 hours. The mixture was then cooled to 25° C., treated with DMSO, filtered, and purified on a Shimadzu using a reverse phase Symmetry C-8 column and eluting with 20-80% B for 10 min at 40 ml/min (A: 0.1% formic acid in water, B: 0.1% formic acid in acetonitrile to provide the formic acid salt of 13 as a cream colored solid. Yield: 17.5 mg, 27%. LC-MS M+1=514. NMR (d6-DMSO) δ: 3.13 (6H, s), 4.81 (2H, s), 7.30-7.40 (6H, m), 7.41-7.73 (2H, m), 8.3 (1H, s), 8.41 (1H, s), 9.96 (1H, s). FAK IC50: <0.000595 μM (Table 1, Example 320)
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([CH2:8][NH:9][C:10](=[O:40])[CH2:11][CH2:12][NH:13][C:14](=[O:39])[CH2:15][NH:16][C:17](=[O:38])[CH2:18][C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:3]1.C(O[BH-](O[C:51](=O)[CH3:52])OC(=O)C)(=O)C.[Na+].O1C[CH2:58][CH2:57][CH2:56]1>CC(CC)C=O.C(OCC)(=O)C>[CH3:56][CH:57]([CH2:51][CH3:52])[CH2:58][N:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([CH2:8][NH:9][C:10](=[O:40])[CH2:11][CH2:12][NH:13][C:14](=[O:39])[CH2:15][NH:16][C:17](=[O:38])[CH2:18][C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:3]1
Reactant: O=C(CCNC(=O)CNC(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1)NC[C@H]1CCCNC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: C1CCOC1
Agent: CCC(C)C=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCC(C)CN1CCC[C@H](CNC(=O)CCNC(=O)CNC(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reaction time: 2 h

Procedure:
To a solution of 200 mg of N-(2-{3-((3S)-3-piperidylmethyl)amino-3-oxopropyl}amino-2-oxoethyl)-3,3,3-triphenylpropanamide monohydrochloride in 10 ml of tetrahydrofuran, 0.10 ml of 2-methylbutanal and 230 mg of sodium triacetoxyborohydride were successively added at room temperature, followed by 2 hours' stirring at the same temperature. The reaction liquid was diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate solution and saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resultant residue was purified by means of silica gel column chromatography (eluting solvent: chloroform/methanol=19/1-4/1), to provide 158 mg of the title compound as a colorless solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5](OC)=[O:6].[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[C:21](=O)[O:20][C:19](=O)[N:18](C)[C:17]=2[CH:25]=1.O>CN(C=O)C>[Br:12][C:13]1[CH:25]=[C:17]2[C:16]([C:21]([OH:20])=[C:4]([C:3]([O:10][CH3:11])=[O:9])[C:5](=[O:6])[N:18]2[CH3:19])=[CH:15][CH:14]=1
Reactant: Cn1c(=O)oc(=O)c2ccc(Br)cc21
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(O)c2ccc(Br)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
To a 50 mL RBF was added sodium hydride (0.15 g, 3.7 mmol) and N,N-dimethylformamide (50 mL, 3.1 mmol) under nitrogen. The mixture was cooled with an ice-water bath for 10 min, and then dimethyl malonate (6.4 mL, 56 mmol) was added over 3 min. A mixture of 7-bromo-1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (0.80 g, 3.1 mmol) in DMF (5.0 mL) was added, and then the reaction was placed in oil bath at 120° C. for 3 hours. The reaction was cooled to room temperature, and water (25 mL) was added to the mixture. A white solid was collected by filtration and washed with water (100 mL), followed by ether (100 mL). The white solid was placed in vacuum oven at 50° C. for 6 h to afford the desired product as a white solid (0.65 g, 67%).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]#N)[CH:8]=[CH:9][CH:10]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([C:26]3[CH:31]=C[C:29]([N+:32]([O-])=[O:33])=[CH:28][CH:27]=3)[O:25][CH2:24][CH2:23][O:22]2)=[CH:17][CH:16]=1.O>CO>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2([C:26]3[CH:27]=[CH:28][C:29]4[C:12]([CH:31]=3)=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH3:3])[CH:6]=3)[O:33][N:32]=4)[O:22][CH2:23][CH2:24][O:25]2)=[CH:19][CH:20]=1
Reactant: COc1cccc(CC#N)c1
Reactant: O=[N+]([O-])c1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cccc(-c2onc3ccc(C4(c5ccc(Cl)cc5)OCCO4)cc23)c1
Yield: 90 %

Procedure:
Sodium hydroxide (16.4 g) and (3-methoxyphenyl)acetonitrile (20.6 ml) were added at room temperature to a solution of interm. (5-a) (25 g) in methanol (100 ml) and the mixture was stirred at room temperature overnight. Water was added, the precipitate was filtered off, washed with cold methanol and dried. The product was used without further purification, yielding 30 g (90%) of 5-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-3-(3-methoxyphenyl)-2,1-benzisoxazole (interm. 5-b).
Reaction SMILES: [Mg].Br[C:3]1[CH:13]=[CH:12][C:6]2[O:7][C:8]([CH2:10][CH3:11])=[CH:9][C:5]=2[CH:4]=1.CI.[C:16](=[O:18])=[O:17].Cl>CCOCC>[C:16]([C:3]1[CH:13]=[CH:12][C:6]2[O:7][C:8]([CH2:10][CH3:11])=[CH:9][C:5]=2[CH:4]=1)([OH:18])=[O:17]
Reactant: CCc1cc2cc(Br)ccc2o1
Reactant: O=C=O
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: CI
Product: CCc1cc2cc(C(=O)O)ccc2o1
Reaction time: 0.08 h

Procedure:
Magnesium (1.50 g) was stirred in ether (30 ml) at room temperature. Thereto was dropwise added a solution of 5-bromo-2-ethylbenzo[b]furan (8.30 g) and methyl iodide (0.55 g) in ether (30 ml) over 30 min. Then, the mixture was refluxed for 50 min and cooled in an ice water bath. In a different container, pulverized dry ice was stirred in ether and the Grignard reagent prepared above was transferred over about 5 min. 2N Hydrochloric acid was added to the reaction mixture to acidify the solution, and the ether layer was separated. The solution was basified with a 5% aqueous solution of sodium hydroxide and the separated aqueous layer was acidified with 2N hydrochloric acid. After extraction with ether, the extract was dried over sodium sulfate and concentrated to give the objective compound (2.48 g).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.B(Br)(Br)Br>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:12]1([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[OH:2])[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: COc1ccccc1B(O)O
Reactant: c1cn[nH]c1
Agent: [Cu+2]
Agent: BrB(Br)Br
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: Oc1ccccc1-n1cccn1

Procedure:
2-Methoxyphenylboronic acid (2 eq.) and pyrazole (1 eq.) are coupled with copper(II) acetate catalysis as described in Tetrahedron Lett. 39:2941-44, 1998 and the product is demethylated by treatment with boron tribromide in dichloromethane (see, for example, Synth. Commun. 27(20):3581-90, 1997) to yield 2-(pyrazol-1-yl)phenol. This phenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to give the title epoxide.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][C:18]4[C:21]([C:32]([F:35])([F:34])[F:33])=[N:22][N:23]([C:24]5[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=5)[C:17]=4[C:16]3=[O:36])=[CH:11][CH:10]=2)[CH2:8][CH2:7]1.CCN(CC)CC.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[CH3:44][S:45]([N:3]1[CH2:4][CH2:5][N:1]=[C:2]1[C:6]1([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][C:18]4[C:21]([C:32]([F:33])([F:34])[F:35])=[N:22][N:23]([C:24]5[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=5)[C:17]=4[C:16]3=[O:36])=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)(=[O:47])=[O:46]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(C4(C5=NCCN5)CC4)cc2)CC3)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(C4(C5=NCCN5S(C)(=O)=O)CC4)cc2)CC3)cc1
Reaction time: 12 h

Procedure:
The product from Example 144 (0.017 g, 0.034 mmol) from was dissolved in CH2Cl2 (0.3 mL). Et3N (0.1 mL, 0.07 mmol) and MsCl (0.07 mL, 0.09 mmol) were added at rt under N2. The reaction was stirred for 12 h, concentrated to dryness, and purified via flash chromatography (silica, 100% EtOAc then 0.5% Et3N:10% MeOH:CH2Cl2) to afford the title compound. LC/MS (ESI+) 574.4 (M+H)+, tR=2.84 min (10–90% CH3CN/H2O in a 4-min run). 1H NMR ((CD3)2CO, 300 MHz) δ 7.50 (d, J=9.1 Hz, 2H), 7.33 (m, 4H), 6.98 (d, J=9.1 Hz, 2H), 4.16 (t, J=6.6 Hz, 2H), 3.83 (m, 7H), 3.16 (t, J=6.4 Hz, 2H), 2.42 (s, 3H), 1.47 (m, 2H), 1.18 (m, 2H) ppm.
Reaction SMILES: C(O[C:5]1[C:22]2[C@@H:21]3[C@@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16]([O:23]C(=O)C)=[CH:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:27][C:28](=[O:30])[CH3:29])[CH:6]=1)(=O)C.C([O:34][C:35](=[O:37])[CH3:36])(=O)C.[C:38]([O-:41])(=[O:40])[CH3:39].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C(O)(=O)C>[C:38]([O:41][C:5]1[C:22]2[C@@H:21]3[C@@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:23])[C@@H:15]([O:34][C:35](=[O:37])[CH3:36])[CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:27][C:28](=[O:30])[CH3:29])[CH:6]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)OC1=CC[C@H]2[C@H]3CCc4cc(OC(C)=O)cc(OC(C)=O)c4[C@H]3CC[C@]12C
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)O
Product: CC(=O)Oc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(=O)[C@@H](OC(C)=O)C[C@H]3[C@H]1CC2

Procedure:
Two grams of rac.-1,3,17-triacetoxy-8α-estra-1,3,5(10),16-tetraene is agitated in 40 ml. of glacial acetic acid and 2 ml. of acetic anhydride with 5.5 g. of lead tetraacetate for 15 hours at room temperature. The mixture is evaporated in a forced circulation evaporator. The residue is taken up in ethyl acetate and washed neutral with saturated sodium chloride solution. By preparative thin-layer chromatography, minor amounts of starting material are separated. After elution with acetone, the mixture is afteracetylated with acetic anhydride and pyridine. After working up the reaction mixture and recrsytallization from methylene chloride/isopropyl ether, 700 mg. of rac.-1,3,16β-triacetoxy-8α-estra-1,3,5(10)-trien-17-one is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([C:11]#[N:12])[CH:3]=1.[CH:13]1([C:16]2[C:17]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:18][CH:19]=[C:20]([CH:22]3[CH2:24][CH2:23]3)[CH:21]=2)[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:28]2[CH2:29][CH2:30][N:25]([C:17]3[C:16]([CH:13]4[CH2:14][CH2:15]4)=[CH:21][C:20]([CH:22]4[CH2:24][CH2:23]4)=[CH:19][N:18]=3)[CH2:26][CH2:27]2)=[O:8])=[C:4]([CH:3]=1)[C:11]#[N:12]
Reactant: N#Cc1cc(Br)ccc1C(=O)O
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Product: N#Cc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 92.8 %

Procedure:
Using 4-bromo-2-cyanobenzoic acid (3.39 g) described in Preparation Example 76 and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine (4.02 g) described in Preparation Example 88 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (6.28 g) was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:15][CH2:14][C:13](=[O:16])[NH:12][C:11]=3[CH:17]=2)=[CH:3][CH:2]=1.Cl>CO.CCOCC.[Pt](=O)=O>[NH:1]1[CH2:2][CH2:3][CH:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:15][CH2:14][C:13](=[O:16])[NH:12][C:11]=3[CH:17]=2)[CH2:5][CH2:6]1
Reactant: O=C1COc2ccc(-c3ccncc3)cc2N1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=C1COc2ccc(C3CCNCC3)cc2N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.8 %

Procedure:
A solution of 6-(4-pyridyl)-4H-benzo[1,4]oxazin-3-one (0.57 g, 2.52 mmol), in methanol (15 mL) was treated with platinum (IV) oxide (50 mg, 0.22 mmol) and 1M HCl in ether (2.7 mL) and stirred at room temperature under an atmosphere of hydrogen for 24 h. The reaction mixture was filtered through celite and the filtrate evaporated in vacuo to give the title compound (0.59 g, 87%) as a pale yellow solid.