Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=2[F:15])[CH2:5][C:4](=[O:16])[CH2:3]1.[C:17]1(C)[CH:22]=CC=[CH:19][CH:18]=1.[OH-].[K+]>C(O)C>[F:15][C:9]1[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=1[CH:6]1[CH2:7][C:2]2[N:1]=[CH:22][CH:17]=[C:18]([CH3:19])[C:3]=2[C:4](=[O:16])[CH2:5]1
Reactant: NC1CC(=O)CC(c2cc(F)ccc2F)C1
Reactant: Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccnc2c1C(=O)CC(c1cc(F)ccc1F)C2
Reaction time: 5 h

Procedure:
A mixture of 1-amino-5-(2,5-difluorophenyl)cyclohexan-3-one (3.7 g), 3-oxobutylaldehyde dimethyl acetal (5.5 g), toluene (120 ml) and ethanol (70 ml) was stirred at 115° C. with adding potassium hydroxide powder (0.77 g). The mixture was combined with potassium hydroxide powder (0.16 g) after 30 minutes and with potassium hydroxide powder (0.16 g) and 3-oxobutylaldehyde dimethyl acetal (0.44 g) after 1 hour and further with potassium hydroxide powder (0.16 g) after 1 hour and 30 minutes, and then stirred at the same temperature for 5 hours. After cooling, the solvent was distilled off under reduced pressure and ethyl acetate was added. The organic layer was washed successively with water and saturated brine, and dried over magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was subjected to a silica gel column (ethyl acetate-hexane), and the resultant crystal was recrystallized from ethyl acetate-hexane to obtain 7-(2,5-difluorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (2.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([C:22](=[O:24])[CH3:23])[CH:19]=[C:18]([CH2:25][O:26][CH3:27])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[CH3:28][Mg]Br>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([C:22]([OH:24])([CH3:28])[CH3:23])[CH:19]=[C:18]([CH2:25][O:26][CH3:27])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COCc1cc(C(C)=O)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COCc1cc(C(C)(C)O)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-(2-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-6-(methoxymethyl)pyrimidin-4-yl)ethanone (160 mg, 0.44 mmol) in tetrahydrofuran (20 mL) was added dropwise to an ice-cold solution of methylmagnesium bromide (3.11 mL, 4.35 mmol) in tetrahydrofuran (10 mL). The mixture was stirred on ice-bath for 30 minutes and quenched with ammonium chloride (sat, aq). The mixture was extracted with dichloromethane, the organic phase was passed through a phase separator containing 1 cm layer of magnesium sulfate and the eluate was concentrated in vacuum. The residue was purified preparative HPLC to give the title compound as a solid, 124 mg (74%).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[C:33](Br)[CH:34]=[CH:35][CH:36]=4)[N:31]=3)[CH2:26][CH2:25]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[C:43]1(OB(O)O)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:42])([F:41])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[C:33]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)[CH:34]=[CH:35][CH:36]=4)[N:31]=3)[CH2:26][CH2:25]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc4cccc(Br)c4n3)CC2)c2ccccc2-c2ccccc21
Reactant: OB(O)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc4cccc(-c5ccccc5)c4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
A reaction mixture of 0.2 g (0.314 mmol) of 9-{4-[4-(8-bromo-quinolin-2-yl)-piperazin-1-yl]-butyl}-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide, 0.033 g (0.267 mmol) of phenylboric acid, 0.018 g (0.016 mmol) of tetrakis triphenyl palladium and 0.2 ml of a 2 M sodium carbonate solution in 3 ml of toluene is refluxed for 20 hours under nitrogen. The solvent is distilled off. The residue is purified by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate=3:2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([Si:13](Cl)([CH3:15])[CH3:14])([CH3:12])([CH3:11])[CH3:10].N1C=CN=C1.O>CN(C)C=O>[Si:13]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc(Br)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 133.1 %

Procedure:
A mixture of 300.0 g (1.7 mol) of 3-bromophenol, 392.1 g (2.6 mol) of tert-butylchlorodimethylsilane and 295.1 g (4.3 mol) of imidazole in 1 L of N,N-dimethylformamide was stirred at room temperature under nitrogen for 18 hours. The reaction mixture was poured into cold water and extracted with diethyl ether. The ether extracts were washed with water and brine, dried over sodium sulfate, and the solvent was evaporated under vacuum to give 650 g of crude 3-bromophenyl tert-butyldimethylsilyl ether as an orange oil. NMR (CDCl3, 200 MHz) δ: 0.2 (s, 6H); 0.95 (s, 9H); 6.8 (m, 1H); 7.0-7.1 (m, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.O=[CH:23][CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:23][CH2:24][CH:25]2[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:29][CH2:30]2)[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Reactant: Cn1c(OC2CCNCC2)nc(-c2ccncn2)cc1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cn1c(OC2CCN(CCC3CCN(C(=O)OC(C)(C)C)CC3)CC2)nc(-c2ccncn2)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a mixture of 1-methyl-2-(piperidin-4-yloxy)-1H-[4,4′]bipyrimidinyl-6-one (290 mg, 1.0 mmol), tert-butyl 4-(2-oxo-ethyl)piperidine-1-carboxylate (300 mg 1.3 mmol) and acetic acid (one drop) in 1,2-dichloroethane (5.0 ml) was added sodium triacetoxyborohydride (530 mg, 2.5 mmol). The mixture was stirred at room temperature overnight. The mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by NH-silica gel column chromatography (eluent; hexane/ethyl acetate=30/70) to afford tert-butyl 4-{2-[4-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yloxy)piperidin-1-yl]ethyl}piperidine-1-carboxylate as a colorless solid (340 mg, 0.67 mmol, 67%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=1.[O:29]=[C:30]1[NH:34][C@H:33]([CH2:35][O:36][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:32][O:31]1>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:34]4[C@H:33]([CH2:35][O:36][C:37](=[O:44])[C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH2:32][O:31][C:30]4=[O:29])=[CH:3][C:4]=3[S:25]([CH3:28])(=[O:27])=[O:26])=[O:9])[CH2:11][CH2:12]2)=[O:24])=[CH:18][CH:19]=1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Product: CS(=O)(=O)c1cc(N2C(=O)OC[C@H]2COC(=O)c2ccccc2)ccc1C(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Yield: 48.5 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 1 and using 4-bromo-2-methylsulfonylbenzoic acid (2.8 g) and (4-chlorophenyl)piperidin-4-ylmethanone (2.6 g), (4-bromo-2-methanesulfonylphenyl)[4-(4-chlorobenzoyl)piperidin-1-yl]methanone (4.8 g) was obtained. By reaction and treatment in the same manner as in Preparation Example 12 and using (4-bromo-2-methanesulfonylphenyl)[4-(4-chlorobenzoyl)piperidin-1-yl]methanone (1.5 g) and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (796 mg), the title compound (938 mg) was obtained.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:38])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:27]([C:29]1[O:30][C:31]([O:34][C:35](=[O:37])[CH3:36])=[CH:32][CH:33]=1)=[O:28])[C:23]([OH:25])=[O:24].[CH2:39]1CCN2C(=NCCC2)CC1.S(OC)(OC)(=O)=O>C(OCC)(=O)C.Cl>[O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:38])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:27]([C:29]1[O:30][C:31]([O:34][C:35](=[O:37])[CH3:36])=[CH:32][CH:33]=1)=[O:28])[C:23]([O:25][CH3:39])=[O:24]
Reactant: CC(=O)Oc1ccc(C(=O)O[C@]2(C(=O)O)[C@H](C)CC3C4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]45O[C@H]5C[C@@]32C)o1
Reactant: C1CCC2=NCCCN2CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)[C@@]1(OC(=O)c2ccc(OC(C)=O)o2)[C@H](C)CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@@]21C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Step 1 (721 mg) is dissolved in ethyl acetate (25 mL). DBU (242 mg) is added, followed by dimethyl sulfate (201 mg) and the reaction is stirred at room temperature for 2 hours, then diluted with 0.2 M HCl. The organic phase is washed with water and brine, then dried over magnesium sulfate and evaporated. Purification by flash chromatography on silica gel eluting with hexanes-ethyl acetate (2:1) affords 5-acetoxyfuran-2-carboxylic acid (6S,9S,10S,11S,13S,16R,17R)-9,11-epoxy-6-fluoro-17-methoxycarbonyl-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl ester. Selected NMR signals (CDCl3) δ 0.96 (3H, d), 0.98 (3H, s), 1.40 (3H, s), 2.18 (3H, s), 2.76 (3H, s).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([CH3:18])=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[O:12][CH2:11]2)=[CH2:7])CCC.C1C(=O)N([Br:26])C(=O)C1.Br>O.C1COCC1>[Br:26][CH2:5][C:6]([C:8]1[C:9]([CH3:18])=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[O:12][CH2:11]2)=[O:7]
Reactant: C=C(OCCCC)c1ccc2c(c1C)COC2=O
Reactant: O=C1CCC(=O)N1Br
Agent: Br
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)CBr)ccc2c1COC2=O
Temperature: 19 °C
Reaction time: 1 h

Procedure:
To a 1 L 3-neck flask equipped with overhead stirrer was added crude 5-(1-butoxy-vinyl)-4-methyl-3H-isobenzofuran-1-one (55.8 g) and THF (315 mL). The solution was cooled to <5° C. after which water (79 mL) was added and the solution was maintained at <5° C. NBS (41.6 g) was then added portionwise while maintaining Tmax=19° C. The solution was then warmed to RT for 30 minutes. HBr (48%, 0.241 mL) was added and the reaction was aged at RT for approximately 1 h after which 236 mL water was then added to the batch. A water bath is used to maintain temp at 20° C. Another 315 mL of water was added (solvent composition 1:2 THF:water) and the slurry was cooled to 15° C. The resulting solids were filtered and washed with cold 1:2 THF:water (15° C.): 150 mL displacement wash followed by 100 mL slurry wash. The solids were dried under vacuum at RT to provide 5-(2-bromo-acetyl)-4-methyl-3H-isobenzofuran-1-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([F:12])([F:11])[F:10].C([Li])(CC)C.C1CCCCC1.[CH3:24][Si:25](Cl)([CH3:27])[CH3:26]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Si:25]([CH3:27])([CH3:26])[CH3:24])=[C:4]([F:8])[C:3]=1[C:9]([F:12])([F:10])[F:11]
Reactant: C[Si](C)(C)Cl
Reactant: Fc1cccc(Cl)c1C(F)(F)F
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: C[Si](C)(C)c1ccc(Cl)c(C(F)(F)F)c1F
Temperature: -70 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
1-Chloro-3-fluoro-2-(trifluoromethyl)benzene (10 g, 50 mmol) was dissolved in tetrahydrofuran (100 ml), cooled to −70° C. under argon, and treated with a 1.4M solution of sec-butyl lithium in cyclohexane (37.5 ml, 52.5 mmol). Stirring was continued for 2 hrs and then trimethylsilyl chloride (6.7 ml, 52.5 mmol) was added and stirring continued, still at −70° C., for a further 1 hr. The mixture was allowed to warm to room temperature and the tetrahydrofuran was then removed in vacuo. The residue was partitioned between diethyl ether and water and then the organic layer was separated and washed with 2N aqueous hydrogen chloride. The organic phase was separated and concentrated to give the crude product which was purified by flash silica-gel column chromatography, eluting with hexane, to give pure [4-chloro-2-fluoro-3-(trifluoromethyl)phenyl](trimethyl)silane as a clear oil (10.35 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]2[CH:26]([C:27](O)=[O:28])[CH2:25][CH:24]=[CH:23][CH2:22]2)[O:10][C:9]1([CH3:31])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:53]([NH2:57])([CH3:56])([CH3:55])[CH3:54]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:11]([CH2:20][CH:21]2[CH:26]([C:27](=[O:28])[NH:57][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:25][CH:24]=[CH:23][CH2:22]2)[O:10][C:9]1([CH3:31])[CH3:30])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N1C(Cc2ccccc2)C(CC2CC=CCC2C(=O)O)OC1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)NC(=O)C1CC=CCC1CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Temperature: 25 °C
Yield: 9512.6 %

Procedure:
An ice-cooled, stirred solution of 4-benzyl-5-(6-carboxy-cyclohex-3-enylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (3.0 g) in dichloromethane (70 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloide (1.61 g), 1-hydroxybenzotriazole and tert-butylamine (1.12 g). The reaction mixture was allowed to stir and warm to ambient temperature during 16 hours. The reaction mixture was then washed sequentially with 2M aqueous hydrochloric acid, 10% aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried (anhydrous magnesium sulfate) and evaporated to give 4-benzyl-5-(6-tert-butylcarbamoyl-cyclohex-3-enylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (322 g, 95%)
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[N:10]=[C:9]([NH:15][S:16]([CH:19]([CH:24]([CH3:26])[CH3:25])[C:20]([O:22][CH3:23])=[O:21])(=[O:18])=[O:17])[N:8]=1.N1C=CC=CC=1>ClCCl>[CH3:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[N:10]=[C:9]([N:15]([C:1](=[O:3])[CH3:2])[S:16]([CH:19]([CH:24]([CH3:26])[CH3:25])[C:20]([O:22][CH3:23])=[O:21])(=[O:18])=[O:17])[N:8]=1
Reactant: COC(=O)C(C(C)C)S(=O)(=O)Nc1nc(OC)cc(OC)n1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(C(C)C)S(=O)(=O)N(C(C)=O)c1nc(OC)cc(OC)n1
Reaction time: 2 h

Procedure:
Acetyl chloride (0.35 g) was added to a stirred, cooled mixture of the product of Example 1 (1.5 g) and pyridine (0.39 g) in dichloromethane (20 ml). Stirring was continued for 2 hours and the mixture was allowed to stand overnight. The organic solution was washed with water (twice), dried over magnesium sulfate and run down under vacuum. The residue was triturated with ether to yield a white solid, 0.38 g (23%), mp 100°-101.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH3:27][C:28]1[C:32]([C:33](O)=[O:34])=[C:31]([CH3:36])[O:30][N:29]=1>>[CH3:27][C:28]1[C:32]([C:33]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][N:12]([C:8]4[CH:7]=[CH:6][CH:5]=[C:4]5[C:9]=4[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]5)[CH2:17][CH2:16]3)[CH:21]=2)=[O:34])=[C:31]([CH3:36])[O:30][N:29]=1
Reactant: Cc1noc(C)c1C(=O)O
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)c5c(C)noc5C)c4)CC3)cccc2n1
Yield: 56 %

Procedure:
The title compound was prepared in 56% yield according to the general procedure for the preparation of the amides (Method C) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 3,5-dimethyl-4-isoxazolecarboxylic acid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH3:14]O>>[NH2:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5]([O:7][CH3:14])=[O:6]
Reactant: COc1ccc(N)c(C(=O)O)c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(OC)ccc1N
Temperature: 60 °C

Procedure:
Hydrogen chloride gas was bubbled through a solution of 2-amino-5-methoxybenzoic acid (5.0 g, 30 mmol) in MeOH (200 mL) for 30 minutes. The solution was heated at 60° C. overnight. The reaction was cooled and the solvent removed in vacuo. The residue was dissolved in water, basified with 5M NaOH and extracted twice with ether. The ether extracts were washed with 5M NaOH and water, dried (MgSO4), filtered and concentrated in vacuo to give i-e (4.25 g, 78%): MS m/z=182 (M+H).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[Br:15][C:16]1[CH:17]=[CH:18][C:19](I)=[N:20][CH:21]=1.CCOC(C)=O>CN(C=O)C>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([O:12][CH:10]2[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]2)=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: Brc1ccc(I)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(Br)cn2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 59.4 %

Procedure:
1-Boc-3-hydroxyazetidine (4.0 g, 23 mmol) was dissolved in DMF (30 mL) and cooled to 0° C. To this was added NaH (60% suspension, 0.83 g, 34 mmol) and it was stirred for 15 min. Finally, a solution of 5-bromo-2-iodopyridine (6.5 g, 23 mmol) in DMF (20 mL) was added to it and the reaction mixture was stirred at 70° C. for 5 h. It was, then, cooled to room temperature and diluted using EtOAc (200 mL). The organic layer was washed with water (150 mL×2), brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (10% EtOAc in hexane) to provide Va-2-I (4.5 g, 59% yield). LCMS: m/z; 329.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.S(OC)(OC)(=O)=O.[O:28]1[CH2:32]CC[CH2:29]1.[OH-].[K+]>O>[CH3:29][O:28][CH3:32].[CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2
Reactant: C1CCOC1
Agent: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COC
Reaction time: 1 h

Procedure:
Into a mixture of 1 g of estrone, 0.5 ml of dimethyl sulfate and 5 ml of tetrahydrofuran, 6 ml of 10% aqueous solution of potassium hydroxide was added over a period of one hour. The reaction temperature was maintained at 15° - 20°C during the addition. The resulting mixture was stirred for one hour to complete the etherification. Then, 6 ml of water was added, and tetrahydrofuran was distilled under atmospheric pressure. The crystals which formed during the distillation were filtered from the cooled reaction mixture, washed with water and dried to obtain 1.048 g of the 100% purity methyl ether of estrone in a 99.7% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12](O)[CH3:13].C1C=CC=CC=1>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)Cc1ccc(Cl)cc1
Reaction time: 6 h
Yield: 97 %

Procedure:
To p-chlorophenylacetic acid (85.30 g, 0.50 mole) was added ethanol (92 g, 2.0 mole), benzene (78.11 g) and conc. sulfuric acid (2.5 g, 0.025 mole) and the azeotropic dehydration reaction was performed for 6 hours. After completion of the reaction, water (200 ml) was added to the reaction mixture, while it was cool and the solution was extracted with diethyl ether. The ether layer was dried with anhydrous sodium sulfate, diethyl ether was distilled off under reduced pressure and the resulting residue was distilled under reduced pressure to give 96.30 g (96.9%) of the title compound as a colorless liquid, b.p. 105°-106° C./2.5 mmHg (lit. 130° C./13 mmHg).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[N:5][C:6]3[C:11]([N:12]=2)=[CH:10][C:9](Br)=[CH:8][CH:7]=3)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:22]([O:24][CH2:25][CH3:26])=[CH2:23])CCC>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:25]([O:24][C:22]([C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[N:5][C:6]3[C:11]([N:12]=2)=[CH:10][C:9]([C:22]([O:24][CH2:25][CH3:26])=[CH2:23])=[CH:8][CH:7]=3)[CH:3]=1)=[CH2:23])[CH3:26]
Reactant: Brc1ccc2nc3cc(Br)ccc3nc2c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: C=C(OCC)c1ccc2nc3cc(C(=C)OCC)ccc3nc2c1
Yield: 88.1 %

Procedure:
To a solution of 2,7-dibromophenazine (13-2) (1.52 g, 4.50 mmol) in dry dioxane (75 mL) under N2 was added tributyl(1-ethoxyvinyl)stannane (3.34 ml, 9.89 mmol) and Pd(dppf)Cl2 (0.316 g, 0.450 mmol). The resultant mixture was heated at 100° C. for 4 hrs in a sealed tube. The crude reaction mixture was filtered through CELITE™ 545, and the volatiles were removed in vacuo. The crude brown solid was triturated with isohexanes and filtered to give 2,7-bis(1-ethoxyvinyl)phenazine as a brown solid (1.27 g, 88% yield). 1H NMR (CDCl3): δ 8.55-8.53 (2H, m), 8.19-8.15 (2H, m), 8.11-8.07 (2H, m), 4.98 (2H, d, J=3 Hz), 4.49 (2H, d, J=3 Hz), 4.03 (4H, q, J=7 Hz), 1.50 (6H, t, J=7 Hz) ppm. LC-MS (ESI): m/z 322.1 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:28])[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[C:12]([O:26][CH3:27])[CH:11]=2)=[CH:6][CH:7]=1.[N:29]#[C:30]Br.[OH-].[Na+]>ClCCl.CO>[I:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[C:12]([O:26][CH3:27])[CH:11]=3)[C:30]([NH2:29])=[N:28][C:4]=2[CH:3]=1
Reactant: COc1ccc(COc2ccc(CNc3ccc(I)cc3N)cc2OC)cc1
Reactant: N#CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(COc2ccc(Cn3c(N)nc4cc(I)ccc43)cc2OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.5 %

Procedure:
To a stirred suspension of 4-iodo-N1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)benzene-1,2-diamine (8.32 g, 16.97 mmol) in dichloromethane (100 mL) and methanol (50 mL) was added cyanogen bromide solution (5.0 M in acetonitrile, 17.0 mL, 85.00 mmol). The resulting brown reaction mixture was allowed to stir at room temperature. After 16 h, the mixture was treated with 1 N sodium hydroxide solution (250 mL) and was allowed to stir at room temperature. After 15 min, a precipitate formed. The solids were isolated by filtration, washed with water, and dried to afford 4.42 g (51%) of 5-iodo-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-2-amine as a tan solid.