Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[OH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][CH2:29][C:30]1[N:31]=[N:32][N:33]([CH3:35])[N:34]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[OH:21])[CH2:29][C:30]3[N:31]=[N:32][N:33]([CH3:35])[N:34]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Reactant: Cn1nnc(CNc2ccccc2O)n1
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2nnn(C)n2)c2ccccc2O)[C@H]1O
Yield: 21 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using the epoxide compound (370 mg, 1.32 mmol) obtained in step 1 of example 2 and N-(2-hydroxyphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=1:2), to give desired compound (140 mg, yield: 21%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([OH:9])=O.S(Cl)(Cl)=O.Cl.[NH2:18][N:19]1[CH2:25][C:23](=[O:24])[NH:22][C:20]1=[O:21]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([NH:18][N:19]1[CH2:25][C:23](=[O:24])[NH:22][C:20]1=[O:21])=[O:9]
Reactant: O=C(O)C=Cc1cccc(F)c1
Reactant: NN1CC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(C=Cc1cccc(F)c1)NN1CC(=O)NC1=O
Reaction time: 8 h

Procedure:
To 99.5 g (0.6 mole) of m-fluorocinnamic acid was added dropwise thionyl chloride (600 ml) followed by heating at reflux for 2 hours. The excess thionyl chloride was removed in vacuo and the residue remaining flushed with dry benzene. The reaction residue was chilled on an ice bath followed by the rapid addition of 1-aminohydantoin hydrochloride (91 g, 0.6 mole). To the cold reaction mixture was added dropwise pyridine (600 ml). After the addition was complete the cold reaction mixture was heated on a steam bath for 3 hours then poured into 6 l. of HCl/ice. Upon standing at room temperature overnight the acidic reaction mixture was filtered and washed with water to give 116 g (73.5%) which after recrystallization from CH3NO2 melted at 294°-296°.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]1([O:9][N:10]=[C:11]([C:15]2[N:16]=[C:17]([NH:20][CH:21]=[O:22])[S:18][CH:19]=2)[C:12]([OH:14])=O)[CH2:8][CH2:7]1.[NH2:23][C@@H:24]1[C:57](=[O:58])[N:26]2[C:27]([C:41]([O:43][CH:44]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:42])=[C:28]([CH2:31][S:32]/[CH:33]=[CH:34]\[C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)[CH2:29][S:30][C@H:25]12.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.O1CCCC1.CN(C)C=O>[CH:6]1([O:9][N:10]=[C:11]([C:15]2[N:16]=[C:17]([NH:20][CH:21]=[O:22])[S:18][CH:19]=2)[C:12]([NH:23][C@@H:24]2[C:57](=[O:58])[N:26]3[C:27]([C:41]([O:43][CH:44]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)=[O:42])=[C:28]([CH2:31][S:32]/[CH:33]=[CH:34]\[C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)[CH2:29][S:30][C@H:25]23)=[O:14])[CH2:7][CH2:8]1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CS/C=C\c3cccnc3)CS[C@H]12
Reactant: O=CNc1nc(C(=NOC2CC2)C(=O)O)cs1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=CNc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CS/C=C\c4cccnc4)CS[C@H]23)cs1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 54.5 %

Procedure:
Phosphorus oxychloride (0.256 ml) was added to a solution of N,N-dimethylformamide (0.212 ml) in ethyl acetate (0.6 ml) under ice-cooling and the mixture was stirred at the same temperature for 10 minutes. To the mixture was added tetrahydrofuran (13 ml) and the mixture was stirred under ice-cooling for additional 10 minutes. To the mixture was added 2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (540 mg) and the mixture was stirred for 30 minutes under ice-cooling to give an activated acid solution. On the other hand, benzhydryl 7β-amino-3-[(Z)-2-(3-pyridyl)vinylthiomethyl]-3-cephem-4-carboxylate (1.03 g) was dissolved in a solution of bis(trimethylsilyl)acetamide (20 ml) in tetrahydrofuran (15 ml). To the solution was added the activated acid solution obtained above at -30° C. and the mixture was stirred for 30 minutes at -20° C. to -10° C. The mixture was poured into a mixture of ice-water (50 ml) and ethyl acetate (70 ml) and adjusted to pH 7 with saturated aqueous solution of sodium bicarbonate. The organic layer was separated, washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether to give benzhydryl 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[(Z)-2-(3-pyridyl)vinylthiomethyl]-3-cephem-4-carboxylate (syn isomer) (820 mg).
Reaction SMILES: [P:1]([O:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([F:27])[CH:26]=1)[N:23]=[CH:22][C:21]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)=[O:29])=[C:20]2[OH:39])([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2]>C(O)(C(F)(F)F)=O.ClCCl>[P:1]([OH:3])([OH:8])([O:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([F:27])[CH:26]=1)[N:23]=[CH:22][C:21]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)=[O:29])=[C:20]2[OH:39])=[O:2]
Reactant: CC(C)(C)OP(=O)(OCCCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(CCCOP(=O)(O)O)cc2c1O
Yield: 84.8 %

Procedure:
A solution of 95 mg of compound of Example 267 (F-2 wherein X=CH2 and Y=F) in 1 mL of 1:1 TFA-dichloromethane is stirred for 30 min, then added dropwise to 50 mL of rapidly stirred 2:1 ether-hexane. The solid is filtered off, washed with hexane, and dried under vacuum to provide 65 mg of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]O)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[O-]S([O-])=O.[Na+].[Na+].[BrH:24]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C1(C)C=CC=CC=1>[CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][Br:24])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(CCO)cc1
Reactant: Br
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=S([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCCCCCCCc1ccc(CCBr)cc1
Temperature: 100 °C

Procedure:
2-(4-octylphenyl)ethanol (5) (46.9 g) is added within 10 min to an aqueous solution containing 3.05 g Na2SO3, 252.9 g 48% HBr and 3.2 g tricaprylmethylammonium chloride. The reaction mixture is heated to 100° C. for 18 to 22 hours with stirring. The resulting 2-phase mixture is cooled to room temperature, diluted with toluene (150 ml) and the aqueous phase is then removed. The organic phase is washed twice with a volume of 100 ml of a 9% NaHCO3 solution. The organic phase is treated with basic aluminium oxide, then filtered. The filter residue is washed with toluene (50 ml) and evaporated to yield compound (19) as a clear pale yellow oil. The resulting Compound (19) has the same physico-chemical characteristics as indicated in Example 14.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([F:15])[C@@H:12]([OH:16])[C@H:11]1[C:17](=[O:28])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[F:27])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:29](I)[CH:30]=[CH2:31]>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([F:15])[C@@H:12]([O:16][CH2:31][CH:30]=[CH2:29])[C@H:11]1[C:17](=[O:28])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[F:27])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: C=CCI
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)[C@@H](O)[C@H]1C(=O)NCc1cccc(Cl)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCO[C@H]1[C@@H](C(=O)NCc2cccc(Cl)c2F)N(C(=O)OC(C)(C)C)C[C@@H]1F
Reaction time: 0.5 h

Procedure:
To a solution of NaH (60% in mineral oil, 8.6 mg, 0.215 mmol) in DMF (5 mL) cooled with an ice-bath and under argon was added (2S,3S,4S)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (70 mg, 0.179 mmol). The reaction mixture was stirred for 20 min before addition of allyl iodide (0.025 mL, 0.269 mmol) at 0° C. The reaction mixture was stirred for 30 min then quenched by addition of water and extracted with EtOAc (×2). The organic extracts were combined, washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 3:2). MS (UPLC): 431.4/433.1 [M+H]+, 475.5/577.5 [M+HCOO]−; tR (HPLC conditions f): 2.29 min.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([O:20][CH2:21][C:22]([OH:24])=O)[S:18][CH:19]=2)=[CH:11][CH:10]=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[C:17]([O:20][CH2:21][C:22]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:24])[S:18][CH:19]=2)=[CH:13][CH:14]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)COc1nc(-c2ccc(F)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1nc(-c2ccc(F)cc2)cs1)Nc1ccccc1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-yloxy]-acetic acid trifluoroacetic acid salt and 50.7 mg (0.54 mmol) of aniline. Yield: 7.6 mg.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]1[C:13]2([CH2:18][CH2:17][C:16](=[N:19]S(C(C)(C)C)=O)[CH2:15][CH2:14]2)OCC1.Cl>C1COCC1>[NH2:9][C:13]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:14][CH2:15][C:16](=[O:19])[CH2:17][CH2:18]1
Reactant: CC(C)(C)S(=O)N=C1CCC2(CC1)OCCO2
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: NC1(c2ccccc2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of phenyl magnesium bromide (Aldrich, 1.0 N in THF, 5.7 mL, 5.70 mmol) was added into the solution of 2-methyl-propane-2-sulfinic acid (1,4-dioxa-spiro[4.5]dec-8-ylidene)-amide (as prepared in the previous step, 1.23 g, 4.75 mmol) in THF (10 mL) at 0° C. After addition, the reaction was slowly warmed to room temperature over 2 hours. 1N HCl (5 mL) was added, and the reaction was stirred overnight. The reaction was quenched with saturated sodium bicarbonate. The solvent was removed in vacuo and the residue was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to afford the title compound as colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:16])([CH3:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:5]=[C:4]([N:17]2[CH2:23][CH:22]3[CH2:24][CH2:25][CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[N:3]=1.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>CC(C)=O>[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:2]2[N:7]=[C:6]([NH:8][C:9]([CH3:15])([CH3:16])[CH2:10][C:11]([CH3:12])([CH3:14])[CH3:13])[N:5]=[C:4]([N:17]3[CH2:23][CH:22]4[CH2:24][CH2:25][CH:19]([CH2:20][CH2:21]4)[CH2:18]3)[N:3]=2)=[CH:29][CH:28]=1
Reactant: CC(C)(C)CC(C)(C)Nc1nc(Cl)nc(N2CC3CCC(CC3)C2)n1
Reactant: Nc1ccc(F)cc1
Solvent: CC(C)=O
Product: CC(C)(C)CC(C)(C)Nc1nc(Nc2ccc(F)cc2)nc(N2CC3CCC(CC3)C2)n1

Procedure:
Eight grams (0.022 mole) of 3-[4-chloro-6-(1,1,3,3-tetramethylbutylamino)-s-triazin-2-yl]-3-azabicyclo[3.2.2]nonane and 21 ml. (0.22 mole) of p-fluoroaniline is placed in a glass liner in a bomb and then heated in an oil bath maintained at 190°-205° C. for about 40 hours. After cooling, the indigo contents of the bomb are rinsed with chloroform and water into a flask and 50 ml. of 10 N NaOH is added. The solution is then evaporated in vacuo and the aqueous solution remaining is extracted with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulfate, filtered through Magnesol® and the Magnesol® washed with chloroform. Removal of solvent in vacuo, addition of toluene and re-evaporation in vacuo several times gives an orange solid which on slurrying with acetone gives white crystals. Recrystallization from acetone gives 7.1 g. of colorless crystals m.p. 173.5°-174.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]([OH:14])[CH3:13])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[C:17](Cl)(=[O:22])[CH2:18][CH:19]([CH3:21])[CH3:20]>N1C=CC=CC=1>[C:17]([O:14][CH:12]([CH3:13])[CH2:11][O:10][C:9]1[CH:15]=[CH:16][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=1)(=[O:22])[CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: CCOC(=O)c1ccc(OCC(C)O)cc1
Reactant: CC(C)CC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(OCC(C)OC(=O)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.3 %

Procedure:
Cooling in an ice bath 1.1g (5 mmol) of 1-(p-ethoxycarbonyl-phenoxy)-propan- 2-ol was dissolved in 10 ml of pyridine, and 0.6 g of isovaleroyl chloride was added dropwise to this solution. The mixture was stirred at room temperature for an additional 3 hours. The reaction mixture was treated in the same way as in Example 7, and purified by column chromatography using silica gel to afford 1.6g of 1-(p-ethoxycarbonyl-phenoxy)-propan-2-ol isovalerate (compound No. 5) in a yield of 90% as a colorless oily substance having an nD32 of 1.4885. Infrared absorption: 1715, 1605, 1260, 1160, 1103, 848 (cm -1).
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH2:15])[O:7][CH2:6]1)[CH2:2][CH3:3].CO[CH:21]1[CH2:25][CH2:24][CH:23](OC)O1.[OH-].[Na+]>C(O)(=O)C>[CH2:16]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N:15]2[CH:21]=[CH:25][CH:24]=[CH:23]2)[O:7][CH2:6]1)[CH2:17][CH3:18]
Reactant: COC1CCC(OC)O1
Reactant: CCCN(CCC)C1COc2cccc(N)c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCCN(CCC)C1COc2cccc(-n3cccc3)c2C1

Procedure:
3-Dipropylamino-5-aminochroman (Example 14; 0.60 g, 2.42 mmol) was dissolved in acetic acid (10 ml) and 2,5-dimethoxytetrahydrofuran (0.40 g, 3.0 mmol) was added. The solution was refluxed for 1 hour. The solution was neutralized with NaOH (aq.) and extracted with toluene. The organic phase was dried with sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel by elution with ethyl acetate/hexane 1:9 to give the title compound. 13C-NMR: 111.75 21.89 24.81 52.69 53.15 67.94 108.93 115.67 118.22 118.44 121.87 127.22 141.47 155.27
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[S:18])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:22][CH2:23][C:24](=O)[CH2:25]Cl>O1CCOCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:18][CH:25]=[C:24]([CH2:23][Cl:22])[N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Solvent: C1COCCO1
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3nc(CCl)cs3)c2[C@@H]2CCN12
Yield: 8.8 %

Procedure:
A yellow suspension of 7.91 g (0.0248 mol) of (S)-8-chloro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-thiocarboxamide in 160 ml of dioxan was treated with 3.46 g (0.0273 mol) of 1,3-dichloro-2-propanone. The suspension was boiled at reflux for 24 hrs. The suspension obtained was cooled and filtered. The solution was completely freed from the solvents. The crude product was chromatographed over silica gel with cyclohexane/ethyl acetate 1:2 as the eluent and recrystallized from hot acetonitrile. There was obtained 0.85 g (8.7%) of (S)-8-chloro-1-(4-chloromethyl-thiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one as white crystals; m.p. 221-223 and [α]D20 =-163.0° (MeOH, c=1%).
Reaction SMILES: C([Li])CCC.[CH3:6][C@:7]12[CH2:23][CH2:22][C@H:21]3[C@@H:12]([CH2:13][CH2:14][C:15]4[CH:16]=[C:17]([OH:24])[CH:18]=[CH:19][C:20]=43)[C@@H:11]1[CH2:10][CH:9]=[CH:8]2>C1COCC1>[CH3:6][C@:7]12[CH2:23][CH2:22][C:21]3[C:20]4[CH:19]=[CH:18][C:17]([OH:24])=[CH:16][C:15]=4[CH:14]=[CH:13][C:12]=3[C@@H:11]1[CH2:10][CH:9]=[CH:8]2
Reactant: C[C@@]12C=CC[C@H]1[C@@H]1CCc3cc(O)ccc3[C@H]1CC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@@]12C=CC[C@H]1c1ccc3cc(O)ccc3c1CC2
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a cooled (ice water bath) solution of crude estra-1,3,5(10)6,8-pentaen-3-ol 17-(p-toluenesuffonyl)hydrozone (7, 1.0887 g, ≤2463 mmol) in anh. THF (25 ml) under argon was added n-butyllithium (2.5 M in hexane, 3.9 ml, 9.8 mmol) dropwise with stirring over 2 min. See FIG. 159. Stirring was continued 3 days, during which the reaction was allowed to gradually warm to room temperature. 50 ml of 1 hydrochloric acid-ice were added and the mixture was extracted three times with 25 ml portions of ether. The combined organic extracts were washed with 50 ml of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed 10 ml of ether and the combined filtrates were concentrated under reduced pressure. Flash chromatography (20% ethyl acetate/hexanes on silica gel) and recrystallization from aqueous ethanol with charcoal decolorization gave tan platelets (245.8 mg, 0.9819 mmol, 40%), m.p. 162-163° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])/[CH:10]=[CH:11]/[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH2:29][N:30]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:31][Si](C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.CCOC(C)=O.COCN(CC1C=CC=CC=1)C[Si](C)(C)C.FC(F)(F)C(O)=O>[CH2:36]([N:30]1[CH2:31][C@@H:11]([C:12]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[C:13]=2[C:14]([O:16][CH3:17])=[O:15])[C@H:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:26])[CH2:29]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: COC(=O)c1c(/C=C/C(=O)OCc2ccccc2)cccc1C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c([C@@H]2CN(Cc3ccccc3)C[C@H]2C(=O)OCc2ccccc2)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.5 %

Procedure:
To a solution of (E)-methyl 2-(3-(benzyloxy)-3-oxoprop-1-enyl)-6-(trifluoromethyl)benzoate (5.83 g, 16.0 mmol) in 60 mL of CH2Cl2 was added N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (4.0 g, 16.8 mmol) and trifluoroacetic acid (0.25 mL, 3.2 mmol). The solution was allowed to stir at ambient temperature for 18 h. Starting material still remained by TLC analysis and so additional N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (0.25 g, 1.05 mmol) and trifluoroacetic acid (0.05 mL, 0.65 mmol) were added and the reaction was stirred at 40° C. for an additional 2 h. The reaction was allowed to cool and was diluted with EtOAc, washed with sat'd aq NaHCO3 and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography (4:1 hexane/EtOAc) to afford 7.6 g (95%) of the title compound as an oil. LRMS (ES)+: 498.32 (M+H)+.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.CC1(C)C(C)(C)OB([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37]C)=[O:36])=[CH:30][CH:29]=2)O1.C([O-])([O-])=O.[Na+].[Na+].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].O>[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([CH2:34][C:35]([OH:37])=[O:36])=[CH:32][CH:33]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: COC(=O)Cc1ccc(CB2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)Cc1ccc(Cc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 90 °C
Reaction time: 72 h
Yield: 53.7 %

Procedure:
A 10-mL sealed tube, with stirrer bar, was charged with 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.100 g, 0.33 mol), methyl 2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate (0.096 g, 0.33 mmol), Pd(dppf)Cl2 (0.027 g, 0.033 mmol), and powdered Na2CO3 (0.141 g, 1.33 mmol). Dioxane (3 mL) and water (1.5 mL) were added. The resulting mixture was stirred under Ar at 90° C. for 3 d. until the starting chloride was consumed. After cooling to room temperature, the reaction mixture was adsorbed onto silica (4 g). Purification by chromatography on silica using dichloromethane/methanol (10:0 to 8:2) as eluent afforded the title compound (0.067 g, 53%) as a light brown solid. MW=377.86. 1H NMR (DMSO-d6, 500 MHz) δ 12.24 (br s, 1H), 8.09-8.07 (m, 1H), 8.00-7.97 (m, 1H), 7.70 (s, 1H), 7.51-7.42 (m, 2H), 7.25-7.16 (m, 2H), 7.15-7.09 (m, 2H), 3.97 (s, 2H), 3.51 (s, 2H), 2.94 (t, J=7.5 Hz, 2H), 2.84 (t, J=7.5 Hz, 2H), 2.09-2.01 (m, 2H); ESI MS m/z 378 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1.Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([NH:36][C@H:37]([CH3:40])[CH2:38][OH:39])(=[O:35])=[O:34]>>[F:1][C:2]1[CH:7]=[C:6]([C:27]2[C:28]([S:33]([NH:36][C@H:37]([CH3:40])[CH2:38][OH:39])(=[O:35])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc4[nH]ccc4c3)c(F)c2)OC1(C)C
Reactant: C[C@H](CO)NS(=O)(=O)c1ccccc1Br
Product: C[C@H](CO)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc3[nH]ccc3c2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine and (R)-2-bromo-N-(1-hydroxypropan-2-yl)benzenesulfonamide. MS (ESI): mass calcd. for C22H20FN3O3S, 425.12; m/z found, 426.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.65 (s, 1H), 8.30-8.19 (m, 2H), 7.93-7.84 (m, 1H), 7.69-7.61 (m, 1H), 7.61-7.53 (m, 1H), 7.44-7.31 (m, 4H), 7.27 (d, J=7.8, 1H), 6.56-7.47 (m, 1H), 6.07 (d, J=6.5, 1H), 3.57 (t, J=7.0, 1H), 3.49-3.32 (m, 2H), 2.41 (s, 1H), 1.04 (d, J=6.4, 3H).