Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[Cl:24][C:25]1[CH:26]=[C:27]([NH2:38])[CH:28]=[C:29]([N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)[CH:30]=1.FC(F)(F)C(O)=O.C(N(CC)C(C)C)(C)C.[C:55]([N:59]=C=O)([CH3:58])([CH3:57])[CH3:56]>CN(C=O)C>[C:55]([NH:59][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:38][C:27]4[CH:28]=[C:29]([N:31]5[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]5)[CH:30]=[C:25]([Cl:24])[CH:26]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:58])([CH3:57])[CH3:56]
Reactant: CC(C)(C)N=C=O
Reactant: CN1CCN(c2cc(N)cc(Cl)c2)CC1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2cc(Cl)cc(Nc3ncnc4[nH]c(C5=CCN(C(=O)NC(C)(C)C)CC5)cc34)c2)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (88.0 mg, 0.263 mmol), 3-chloro-5-(4-methylpiperazin-1-yl)-phenylamine (71.2 mg, 0.316 mmol), trifluoroacetic acid (243 μL, 3.16 mmol), and DMF (2 mL) was stirred in a sealed tube at 80° C. for 16 h. After cooling, N,N-diisopropylethylamine (550 μL, 3.16 mmol) was added, and the mixture turned into a dark clear solution. Into above solution was added tert-butyl isocyanate (36.0 μL, 0.316 mmol) and the solution was stirring at rt for 1 h. After that time, the mixture was concentrated in vacuo to obtain dark-brown oil that was submitted for MS-directed purification to obtain a light-brown oil. Further purification by HPLC gave the title compound as an off-white powder. 1H NMR (DMSO-d6, 400 MHz): δ=1.29 (s, 9H), 2.23 (s, 3H), 2.46 (t, 4H, J=4.6 Hz), 3.18 (t, 4H, J=4.8 Hz), 3.53 (t, 2H, J=5.4 Hz), 4.00 (brs, 2H), 5.79 (s, 1H), 6.43 (s, 1H), 6.63 (d, 1H, J=1.6 Hz), 6.78 (s 1H), 7.30 (s, 1H), 7.75 (d, 1H, J=1.6 Hz), 8.32 (s, 1H), 9.27 (s, 1H), 11.98 (s, 1H). MS (ES+): m/z 522.98/525.01(100/33) [MH+]. HPLC: tR=2.13 min (ZQ2000, polar—5 min).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:3]=1[CH2:4]O.C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:3]=1[CH2:4][Br:13]
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc(F)c(F)cc1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cc(Br)c(CBr)cc1F
Reaction time: 2 h
Yield: 120.7 %

Procedure:
To a solution of 2.4 g (10 mmol) of 2-bromo-4,5-difluorobenzoic acid [prepared according to the procedure of Braish et al., Syn. Comm., 3067-3074 (1992)] in 75 mL of tetrahydrofuran was added 2.43 g (15 mmol) of 1,1′-carbonyldiimidazole. The solution was heated under reflux for 3.5 h, cooled to ambient temperature and 0.38 g (10 mmol) of sodium borohydride in 15 mL of water was added. The reaction was stirred for 10 min and partitioned between ethyl acetate and 10% aqueous sodium bicarbonate solution. The organic layer was washed twice with warm water, brine, dried over magnesium sulfate, and concentrated in vacuo. Purification by flash chromatography (silica gel, 4:1 hexane:ethyl acetate) afforded 1.9 g of 2-bromo-4,5-difluorobenzyl alcohol. To a solution of 1.9 g (8.4 mmol) of 2-bromo-4,5-difluorobenzyl alcohol in 30 mL of dichloromethane at 0° C. was added 3.4 g (10 mmol) of carbon tetrabromide and 2.7 g (10 mmol) of triphenylphosphine. The reaction was stirred for 2 h at this temperature, the solvent was removed in vacuo and the residue stirred with 100 mL of diethyl ether. The solution was filtered, concentrated in vacuo, and purified by flash chromatography (silica gel, 20:1 hexane:ethyl acetate) to afford 2.9 g of 2-bromo-4,5-difluorobenzyl bromide contaminated with carbon tetrabromide which was used without further purification. Using the procedures outlined for the preparation of Intermediates 2-4, the benzyl bromide derivative was converted to the title compound. LC-MS 394 and 396 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:7]=1.Cl[C:15]([O:17][C:18]([CH2:21][CH3:22])([CH3:20])[CH3:19])=[O:16].O>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][N:2]([C:3]1[S:4][CH:5]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:7]=1)[C:15]([O:17][C:18]([CH2:21][CH3:22])([CH3:20])[CH3:19])=[O:16]
Reactant: CCC(C)(C)OC(=O)Cl
Reactant: CCOC(=O)Cc1csc(NC)n1
Agent: CCOC(=O)Cc1csc(=NC)[nH]1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)Cc1csc(N(C)C(=O)OC(C)(C)CC)n1

Procedure:
To a solution of ethyl 2-(2-methylamino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-methylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (8 g.) in a mixture of pyridine (80 ml.) and methylene chloride (40 ml.) was dropwise added tert-pentyl chloroformate over 2 hours at -25° to -20° C. with stirring, and the mixture was stirred for 30 minutes at the same temperature. After the reaction, the reaction mixture was poured into water (200 ml.), the mixture was extracted with ethyl acetate (300 ml.), and then the organic layer was separated. The organic layer was washed with 2N hydrochloric acid, water, 5% sodium bicarbonate aqueous solution and water in turn. The organic layer was dried over magnesium sulfate and then concentrated to give oil of ethyl 2-[2-(N-methyl-N-tert-pentyloxycarbonylamino)1,3-thiazol-4-yl]acetate (14.5 g.).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:15]1[C:27]2[NH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C1O[CH2:50][CH2:49]OCCOCCOCCOCCOC1>[Cu].C(Cl)Cl.ClC1C=CC=CC=1Cl>[CH:3]1[C:4]2[N:26]([C:25]3[CH:20]=[CH:21][C:22]([C:50]4[CH:49]=[CH:27][C:15]([N:26]5[C:25]6[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=6[C:19]6[C:27]5=[CH:15][CH:16]=[CH:17][CH:18]=6)=[CH:16][CH:17]=4)=[CH:23][CH:24]=3)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:5]=2[CH:6]=[CH:7][CH:2]=1
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1Cl
Solvent: ClCCl
Product: c1ccc2c(c1)c1ccccc1n2-c1ccc(-c2ccc(-n3c4ccccc4c4ccccc43)cc2)cc1
Temperature: 180 °C
Reaction time: 8 h

Procedure:
4,4′-Diiodobiphenyl (10.001 g, 24.63 mmol), carbazole (9.078 g, 54.29 mmol), K2CO3 (20.087 g, 145.34 mmol), 18-crown-6 (0.100 g, 0.34 mmol), and copper powder (10.051 g, 158.16 mmol) were combined in reaction flask. To the flask, o-dichlorobenzene (50 mL) was added. The reaction was heated under inert N2 atmosphere at 180° C. overnight. TLC showed evidence of limited di-substitution product which necessitated the addition of K2CO3 (4.994 g, 36.13 mmol) and Cu powder (5.223 g, 82.19 mmol) to the reaction flask to promote di-substitution. The reaction was allowed to proceed overnight. Additional reagents had no noticeable effect on the reaction so the reaction was stopped. Insoluble material was removed by vacuum filtration and washed with several portions of THF. On standing, a crystalline product crashed out of the filtrate. Further crystallization was promoted by the addition of a large amount of methanol. The precipitate was vacuum filtered to isolate. TLC (hexanes: DCM=8:2) confirmed precipitate was product with minor impurity. Purification was accomplished by dissolving the precipitate in hot boiling THF followed by filtration to obtain a green insoluble impurity. The product began to precipitate on standing and cooling. The filtrate/product mixture was dried under vacuum until the product started crashing out of solution and methanol was added to promote full precipitation. The product was isolated by vacuum filtration and air dried (24 hours). A cream colored flaky product was obtained (7.660 g, 64.2%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(Cl)(Cl)(=O)=O.[CH3:17]O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:17])=[O:10])=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(Br)cc1
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)Cc1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-(4-bromophenyl)acetic acid (10 g, 0046 mol) in MeOH (100 mL) was added sulfuryl dichloride (8.3 g, 0.069 mol) dropwise. The reaction mixture was stirred overnight at 80° C., allowed to cool to rt and concentrated under reduced pressure to afford compound 68a as a colorless oil. Mass Spectrum (GCMS, ESI pos.): Calcd. for C9H9BrO2: 228.0 (M). found: 228.0.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:31])([CH2:27][CH2:28][C:29]#N)[CH3:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-:32].[K+].CCO.[OH2:37]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:31])([CH3:26])[CH2:27][CH2:28][C:29]([OH:37])=[O:32])=[CH:19]5)=[O:14])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O
Reactant: CC(C)(CCC#N)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(CCC(=O)O)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Temperature: 100 °C

Procedure:
A mixture of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-(4-cyano-2-methylbutan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (0.060 g, 0.15 mmol) and KOH (0.081 g, 1.5 mmol) in 50% EtOH/water (2 mL) was heated in the microwave at 100° C. for 1 h. The solvent was evaporated under reduced pressure. The crude product was dissolved in DMSO (1 mL), filtered, and purified by reverse phase preparative HPLC to give 4-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-2-yl)-4-methylpentanoic acid. 1H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 10.79 (s, 1H), 8.44 (s, 1H), 7.56 (s, 1H), 7.15 (d, J=8.6 Hz, 1H), 7.03-6.90 (m, 4H), 6.05 (s, 1H), 6.02 (s, 2H), 1.97-1.87 (m, 4H), 1.41-1.38 (m, 2H), 1.30 (s, 6H), 1.04-1.02 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=4[CH:20]=[O:21])=[CH:17][C:11]=3[N:10]=2)=[CH:5][CH:4]=1.[CH2:30]([Mg]Cl)[CH3:31]>C1COCC1>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=4[CH:20]([OH:21])[CH2:30][CH3:31])=[CH:17][C:11]=3[N:10]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reactant: CC[Mg]Cl
Solvent: C1CCOC1
Product: CCC(O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reaction time: 0.25 h
Yield: 87.9 %

Procedure:
To a solution of 2-[2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazol-5-yl]-benzaldehyde (0.080 g, 0.224 mmol) in THF (6 mL) at −78° C. was added dropwise ethylmagnesium chloride (0.22 mL, 0.673 mmol, 1.0 M solution in THF). After stirring 15 min, the reaction mixture was quenched with brine. The mixture was concentrated, and the residue was purified by chromatography (silica, hexanes: EtOAc, 1:2) to afford the title compound as a off-white solid (0.084 g, 91%). 1H NMR (400 MHz, CD3OD) δ (ppm): 7.64-7.59 (m, 4H), 7.39 (td, 1H, J=8.4 Hz, J=1.6 Hz), 7.29 (td, 1H, J=8.0 Hz, J=1.2 Hz), 7.26-7.20 (m, 5H), 5.45 (s, 2H), 4.67 (t, 1H, J=6.6 Hz), 1.68-1.63 (m, 2H), 0.71 (t, 2H, J=7.6 Hz). Mass Spectrum (LCMS, ESI pos.) Calcd. For C24H22F3N2O2: 427.4 (M+H), Found 427.2.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O)(=[O:3])[CH3:2].[O:13]([C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH4-].[Na+].[C:29](O)(=[O:31])[CH3:30]>CO>[C:29]([N:22]([CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=1[O:4][C:1](=[O:3])[CH3:2])[C:21]1[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=1[O:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)O
Reactant: CC(=O)Oc1ccccc1C=O
Reactant: Nc1ccccc1Oc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)Oc1ccccc1CN(C(C)=O)c1ccccc1Oc1ccccc1
Temperature: 25 °C

Procedure:
In 30 ml of methanol were dissolved 1.74 g of 2-acetoxybenzaldehyde and 1.85 g of 2-phenoxyaniline, and after stirring at room temperature for an hour, 3.00 g of sodium borohydride was added, followed by stirring at the same temperature for 30 minutes. To the reaction solution was added dropwise an aqueous acetic acid solution (3.0 ml of acetic acid and 60 ml of water), and after stirring at room temperature for 10 minutes, the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure. A solution of the residue and 4 ml of triethylamine in 50 ml of methylene chloride was cooled to 0° C., and 2.00 ml of acetyl chloride was added dropwise with stirring, followed by stirring at room temperature for 20 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with 0.5 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure to give a crude N-acetyl-N-(2-acetyloxybenzyl)-2-phenoxyaniline.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[C:13]([F:19])[CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3].BrC[CH2:22][F:23].N(C[C@H]1OC(=O)N(C2C=CC(SC(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=C(F)C=2)C1)=[N+]=[N-]>>[N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH2:18][CH2:22][F:23])=[C:13]([F:19])[CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3]
Reactant: FCCBr
Reactant: CSc1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F
Agent: [N-]=[N+]=NC[C@@H]1CN(c2ccc(SC(c3ccccc3)(c3ccccc3)c3ccccc3)c(F)c2)C(=O)O1
Product: [N-]=[N+]=NC[C@@H]1CN(c2ccc(SCCF)c(F)c2)C(=O)O1

Procedure:
This compound was prepared analogously to the synthesis of 5-(S)-azidomethyl-3-[4′-methylthio-3′-fluorophenyl]oxazolidine-2-one from 1-bromo-2-fluoroethane (0.109 ml, 1.47 mmol) and 5-(S)-azidomethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]-oxazolidine-2-one (0.500 g, 0.979 mmol). Yield 0.280 g (91%). MS (m/z): [M+H]+=315.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:26]=[C:27]=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[CH3:29][N:30]([CH3:45])[CH2:31][CH2:32][CH2:33][N:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][OH:44])[CH:35]=[O:36].C(Cl)(Cl)Cl>ClCCl>[CH3:45][N:30]([CH3:29])[CH2:31][CH2:32][CH2:33][N:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][O:44][C:27](=[O:28])[NH:26][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:35]=[O:36]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: CN(C)CCCN(C=O)c1ccccc1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCc1ccccc1N(C=O)CCCN(C)C
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Triethylamine (0.65 ml) and octadecyl isocyanate (1.47 ml) were added to a solution of N-[3-(dimethylamino)propyl]-[2-(hydroxymethyl)phenyl]formamide (1.01 g) in dichloromethane (10 ml). After being stirred for 19 hours at room temperature, the reaction mixture, with chloroform added thereto, was washed with water, dried over sodium sulfate anhydride, and then concentrated. The residue was purified by silica gel column chromatography (silica gel 40 g, chloroform:methanol=50:1-10:1), thereby yielding 1.36 g of the aimed compound as white wax.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:18]([OH: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.[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>C1(C)C=CC=CC=1>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([O-:30])=[O:29])=[CH:31][CH:32]=1)([O-:23])=[O:22].[CH3:1][C@@:2]12[C@@H:18]([OH: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: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Solvent: Cc1ccccc1
Product: O=C([O-])c1ccc([N+](=O)[O-])cc1

Procedure:
Inversion of the configuration of the 17-position of oestradiol was achieved using a Misunobu reaction. The complex formed by triphenylphosphine and DEAD was reacted with the 3-O-benzyl-17-□-estradiol BLE99051 and p-nitrobenzoic acid at 80° C. in toluene to give the 3-O-benzyl-17-□-p-nitrobenzoate-estradiol BLE99053. Hydrolysis of the ester moiety of BLE99053 using potassium carbonate afforded cleanly the 3-O-benzyl-17-□-estradiol BLE99056 in a 84.5% yield.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[OH:34])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1.Cl[C:45]1[N:50]=[CH:49][CH:48]=[CH:47][N:46]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[O:34][C:45]1[N:50]=[CH:49][CH:48]=[CH:47][N:46]=1)[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:13]=1
Reactant: Clc1ncccn1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2O)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2Oc2ncccn2)nc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (200 mg) is dissolved in N,N-dimethylformamide (3 ml), and thereto are added 2-chloropyrimidine (45 mg) and potassium carbonate (55 mg), and the mixture is stirred at 85° C. overnight. The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=41:9→13:7) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(pyrimidin-2-yloxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (120 mg). MS (m/z): 704 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:17]2[C:18]([CH3:26])=[N:19][N:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=23)[S:12][C:13]=1[C:14]([NH2:16])=O.O.[NH2:28]N.COC(OC)[N:33]([CH3:35])C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:17]2[C:18]([CH3:26])=[N:19][N:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=23)[S:12][C:13]=1[C:14]1[N:33]=[CH:35][NH:28][N:16]=1
Reactant: Cc1nn2ccccc2c1-c1nc(-c2ccc(F)cc2F)c(C(N)=O)s1
Reactant: COC(OC)N(C)C
Reactant: NN
Solvent: O
Product: Cc1nn2ccccc2c1-c1nc(-c2ccc(F)cc2F)c(-c2nc[nH]n2)s1
Temperature: 100 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A suspension of 4-(2,4-difluorophenyl)-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-1,3-thiazole-5-carboxamide (180 mg, 0.442 mmol, 0.5 equiv DMF adduct) obtained above in 1,1-Dimethoxy-N,N-dimethylmethanamine (3 mL) was stirred for 1 h at 100° C. and then the mixture was concentrated under reduced pressure. The residue was dissolved in AcOH (3 mL) and then was added hydrazine monohydrate (108 μL, 2.21 mmol). The resulting mixture was stirred for 1 h at 100° C. and then concentrated under reduced pressure. To the residue, were added a 1:1 mixture of EtOAc and THF (20 mL) and saturated aqueous solution of sodium bicarbonate (15 mL) and then the organic layer was separated, which was washed with brine (5 mL) and dried over anhydrous sodium sulfate. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was crystallized from THF (3 mL) and hexane (6 mL) to obtain title compound (147 mg, 84%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:17][CH3:18])=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.O1CCCC1.C([Li])CCC.[CH2:29]([O:31][C:32]([CH:34]1[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][CH2:35]1)=[O:33])[CH3:30].Cl>C1(C)C=CC=CC=1>[CH2:29]([O:31][C:32]([CH:34]1[CH2:39][CH2:38][C:37]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH2:17][CH3:18])=[N:7][N:8]3[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:4][CH:3]=2)([OH:40])[CH2:36][CH2:35]1)=[O:33])[CH3:30]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: CCc1nn(C2CCCCC2)c2cc(Br)ccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCC(O)(c2ccc3c(CC)nn(C4CCCCC4)c3c2)CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
To a solution of 6bromo-1-cyclohexyl-3-ethyl-1H-indazole (12.7 g, 41.3 mmol) in toluene (64 mL) was added tetrahydrofuran (6.70 mL, 82.6 mmol). The solution was cooled to -78° C. and n-butyllithium (17.3 mL of a 2.5M solution in hexanes, 43.4 mmol) was added dropwise. The solution was stirred 10 minutes and added to a solution of 4-oxo-cyclohexanecarboxylic acid ethyl ester (8.80 g, 51.7 mmol) in toluene (127 mL) at -78° C. The reaction mixture was stirred for 15 minutes and poured into 1N aqueous hydrochloric acid (200 mL). The layers were separated and the aqueous layer was reextracted with toluene (60 mL). The organic extracts were combined and dried over magnesium sulfate, filtered, and concentrated to an oil which was purified by filtration through a pad of silica gel eluting with 4:1 hexanes/ethyl acetate. The product-rich fractions were concentrated to yield 4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-hydroxy-cyclohexanecarboxylic acid ethyl ester (13.5 g, 82%) as a mixture of diastereoisomers. Upon standing, one of the diastereoisomers crystallized and was isolated by trituration with hexanes. 1H NMR (400 MHz, CDCl3) δ 1.25-1.40 (m, 4), 1.27 (t, 3, J=7.1), 1.35 (t, 3, J=7.7), 1.65-2.07 (m, 15), 2.37-2.44 (m, 1), 2.96 (q, 2, J=7.7), 4.15 (q, 2, J=7.1), 4.30-4.38 (m, 1), 7.13 (d, 1, J=8.5), 7.58 (s, 1), 7.63 (d, 1, J=8.5). 13C NMR (100 MHz, CDCl3) δ 14.16, 14.26, 20.69, 24.60, 25.39, 25.91, 32.54, 38.22, 42.57, 57.59, 60.34, 72.80, 104.49, 116.80, 120.28, 121.26, 139.84, 146.09, 146.93, 175.63. Analysis calculated for C24H34N2O3 : C, 72.33; H, 8.60; N, 7.03. Found: C, 72.11; H, 8.55; N, 6.92.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=O)=O.[C-:28]#[N:29].[K+]>CN(C=O)C.O>[C:28]([CH2:6][CH2:7][CH2:8][C:9]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:29]
Reactant: CCOC(=O)c1cccc(OCc2ccccc2)c1CCCOS(C)(=O)=O
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccc(OCc2ccccc2)c1CCCC#N
Temperature: 100 °C
Yield: 51.2 %

Procedure:
A mixture of ethyl 2-(3-methanesulfonyloxypropyl)-3-benzyloxybenzoate (19.42 g, 31.7 mmol) and potassium cyanide (2.28 g, 35 mmol) in DMF (50 ml) was heated at 100° C. for 8 hr. The mixture was cooled, diluted with water (250 ml), and extracted three times with ethyl acetate. The ethyl acetate extracts were dried with brine, and concentrated in vacuo. The crude product was chromatographed on silica gel using methylene chloride as the eluent to give the product as an oil (5.25 g, 53%).