Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][O:41][CH2:42][CH3:43])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:42]([O:41][CH2:40][CH2:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:33][CH:34]=1)[CH3:43]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
Reactant: CCOCCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
To methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (5.0 g) was added toluene/ethanol/water (10/1/1, 188 ml) and then were added 4-(2-ethoxyethoxy)phenyl borate (4.1 g) and potassium carbonate (4.6 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (0.7 g), and the mixture was refluxed for 14 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=2/1) to give methyl 7-[4-(2-ethoxyethoxy)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (4.6 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16](=[O:18])[CH3:17])=[N:14][CH:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+]>C1COCC1.CO.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([CH:16]([OH:18])[CH3:17])=[N:14][CH:15]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 1-(5-(4-nitrophenyl)pyridin-2-yl)ethanone (100 mg, 0.4 mmol) in THF (2 mL) and methanol (2 mL) was added NaBH4 (3 mg, 0.8 mmol) at rt and the reaction was stirred at rt for about 5 min. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine solution (10 mL), organic layer was dried over Na2SO4 and concentrated under vacuum to obtain 1-(5-(4-nitrophenyl)pyridin-2-yl)ethanol as off white solid (100 mg, 100% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.88 (d, 1H), 8.31 (d, 2H), 8.19 (dd, 1H), 8.01 (d, 2H), 7.64 (d, 1H), 5.43 (d, 1H), 4.78 (t, 1H), and 1.38 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[C:31]([Cl:40])[C:32]=1[O:33][C:34]([F:39])([F:38])[CH:35]([F:37])[F:36])[NH2:29].C(N(CC)CC)C.Cl>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[CH:15][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH:29][C:28]3[CH:30]=[C:31]([Cl:40])[C:32]([O:33][C:34]([F:39])([F:38])[CH:35]([F:37])[F:36])=[C:26]([Cl:25])[CH:27]=3)=[O:20])=[CH:23][CH:24]=2)=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: Nc1cc(Cl)c(OC(F)(F)C(F)F)c(Cl)c1
Reactant: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Nc1cc(Cl)c(OC(F)(F)C(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3.5 mmol of 2-(4-((3-chloro-5-(trifluoromethyl)-2-pyridinyl)oxy)phenoxy)propionyl chloride in 15 ml of methylene chloride was added dropwise to an ice-cooled solution prepared from 1.22 g (3.5 mmol) of an 80 percent solution of 3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)aniline in DMF, 0.42 g (4.2 mmol) of triethylamine and 40 ml of methylene chloride. The reaction mixture was stirred at room temperature overnight and then poured into a dilute aqueous HCl solution. The organic layer was separated, washed with a saturated aqueous NaHCO3 solution, dried over MgSO4 and evaporated to dryness. The residual material, a gum, was purified by preparative scale liquid chromatography, eluting with an 86:14 hexane:acetone mixture. After removal of the solvent, there was left 1.02 g (47 percent of theoretical) of the above-named product as a light yellow glassy material. The structure of the product was confirmed by its IR and NMR spectrum (NMR Spectrum: (d6 -DMSO); 8.55 (br, m, 1H); 8.45 (br, 1H); 7.9 (s, 2H); 6.6-7.2 (m, 5H); 4.9 (q, 1H); 1.6 (d, 3H). (Compound 2)
Reaction SMILES: [H-].[Na+].[NH2:3][S:4]([CH2:7][CH2:8][CH:9]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[F:23])[C:10](OC)=[O:11])(=[O:6])=[O:5].CO>CCCCCC.O1CCCC1>[F:23][C:15]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=1[CH:9]1[CH2:8][CH2:7][S:4](=[O:6])(=[O:5])[NH:3][C:10]1=[O:11]
Reactant: COC(=O)C(CCS(N)(=O)=O)c1ccc([N+](=O)[O-])cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CO
Product: O=C1NS(=O)(=O)CCC1c1ccc([N+](=O)[O-])cc1F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 60% sodium hydride oil dispersion (520 mg, 13.0 mmol) is washed with hexane (3×5 ml) then dry tetrahydrofuran (30 ml) added. To this stirred ice cooled mixture is added a solution of methyl .alpha.-[2-(aminosulfonyl)ethyl]-2-fluoro-4-nitrobenzeneacetate (3.20 g, 10.0 mmol) in dry tetrahydrofuran (30 ml). After stirring for 3 hr, additional sodium hydride (300 mg, 7.5 mmol) is added. Methanol (5 ml) is added after an additional 20 hr and the reaction evaporated to dryness. The residue is partitioned between 5% methanol-chloroform (150 ml) and 1N.HCl (50 ml), and the brown solid filtered. This solid is chromatographed over silica gel (150 g) eluting with 50% acetone-hexane. Recrystallization from acetone-hexane gives the title compound as solid. mp 218-219°.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])=[C:2]=[O:3].[CH2:13]([C:15]1[N:16]=[C:17]([CH:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21]2)[NH:18][CH:19]=1)[CH3:14]>C1COCC1>[CH2:13]([C:15]1[N:16]=[C:17]([CH:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]2[C:2]([NH:1][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N+:10]([O-:12])=[O:11])=[O:3])[NH:18][CH:19]=1)[CH3:14]
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Reactant: CCc1c[nH]c(C2Cc3ccccc3N2)n1
Solvent: C1CCOC1
Product: CCc1c[nH]c(C2Cc3ccccc3N2C(=O)Nc2ccccc2[N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 45 %

Procedure:
1-Isocyanato-2-nitro-benzene (0.002 mol) was added to a solution of intermediate (15) (0.016 mol) in THF (10 ml). The mixture was stirred at room temperature under argon for 5 hours. The mixture was diluted with hexanes, filtered, and allowed to dry, yielding 0.34 g of 2-(4-ethyl-1H-imidazol-2-yl)-2,3-dihydro-N-(2-nitrophenyl)-1H-indole-1-carboxamide (compound 77, mp. 208–209° C.).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:33])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][C:5]2=[N:31][OH:32].Cl.CC(C)=[O:37]>>[OH:8][C:7]([CH3:14])([CH2:6][C:5](=[N:31][OH:32])[C:4]1[C:9](=[O:37])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:33])[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:29][CH:30]=1
Reactant: Cc1c(C)c2c(c(C)c1O)C(=NO)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Reactant: CC(C)=O
Agent: Cl
Product: CC1=C(C)C(=O)C(C(CC(C)(O)COc2ccc(CC3SC(=O)NC3=O)cc2)=NO)=C(C)C1=O

Procedure:
The procedure of Example 1 was repeated, but using 2 g of 5-[4-(6-hydroxy-4-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine, 15 ml of acetone and 5 ml of an aqueous solution of ferric chloride acidified with hydrochloric acid (a mixture of about 65% by weight of FeCl3.6H2O and about 35% by weight of concentrated hydrochloric acid), to afford 0.74 g of the title compound as a yellow powder softening at 80°-85° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.Br[CH:33]=[C:34]([C:36]1[S:37][CH:38]=[CH:39][N:40]=1)[CH3:35]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:33]=[C:34](/[C:36]3[S:37][CH:38]=[CH:39][N:40]=3)\[CH3:35])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: CC(=CBr)c1nccs1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1nccs1
Temperature: 85 °C

Procedure:
8-Chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (110 mg, 0.5 mmol) was dissolved in DMF (3 mL) and potassium phosphate (212.4 mg, 1 mmol), copper(I) iodide (9.5 mg, 0.05 mmol) and L-proline (11.51 mg, 0.1 mmol) was added in to it. Then 2-(1-bromoprop-1-en-2-yl)thiazole (122.4 mg, 0.6 mmol) was dissolved in DMF (2 mL) and added dropwise. Nitrogen was purged for 2 min and the reaction mixture was heated at 85° C. overnight (prolonged heating was required some cases). DMF was evaporated and water was added. The precipitate obtained was filtered and purified by silica gel chromatography (100-200 mesh) using 0-3% MeOH:DCM as eluent. The compound was further purified through reverse phase purification. Yield: 9 mg. 1H NMR (CD3OD, oxalate salt) δ (ppm): 7.90 (d, 1H), 7.65 (d, 2H), 7.55 (s, 1H), 7.22 (s, 2H), 4.55 (m, 2H), 3.70 (m, 2H), 3.18 (m, 2H), 3.10 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([F:13])=[C:11]([F:14])[C:10]([Br:15])=[C:9]([F:16])[C:8]=1[F:17].[C:18](=[O:20])=[O:19].Cl>O1CCCC1.O>[Br:15][C:10]1[C:11]([F:14])=[C:12]([F:13])[C:7]([C:18]([OH:20])=[O:19])=[C:8]([F:17])[C:9]=1[F:16]
Reactant: Fc1c(F)c(Br)c(F)c(F)c1Br
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1c(F)c(F)c(Br)c(F)c1F
Temperature: -70 °C
Yield: 81.5 %

Procedure:
n-Butyllithium (42 ml, 2.4M in hexane) was slowly added to a solution of 30.78 g 1,4-dibromo-2,3,5,6-tetrafluorobenzene in 200 ml tetrahydrofuran cooled to -70° C. under nitrogen. Solid carbon dioxide (about 12 g) was then added to the stirred mixture which was then allowed gradually to warm to 0° C. at which point 16 ml 6M hydrochloric acid and 16 ml water were added. The reaction mixture was concentrated and the residue extracted with methylene dichloride. The extract was washed with concentrated sodium chloride solution, dried (magnesium sulfate) and concentrated to dryness to give 22.23 g (81.5%) 4-bromo-2,3,5,6-tetrafluorobenzoic acid, m.p. 128°-135° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([CH:14]([CH3:16])[CH3:15])=[CH:7][C:6]=1[CH:17]([CH3:19])[CH3:18])=O.[NH2:20][C:21]([NH2:23])=[S:22]>CCO>[CH:17]([C:6]1[CH:7]=[C:8]([CH:14]([CH3:16])[CH3:15])[CH:9]=[C:10]([CH:11]([CH3:13])[CH3:12])[C:5]=1[C:3]1[N:20]=[C:21]([NH2:23])[S:22][CH:2]=1)([CH3:19])[CH3:18]
Reactant: CC(C)c1cc(C(C)C)c(C(=O)CBr)c(C(C)C)c1
Reactant: NC(N)=S
Solvent: CCO
Product: CC(C)c1cc(C(C)C)c(-c2csc(N)n2)c(C(C)C)c1
Yield: 25.5 %

Procedure:
A mixture of 2-bromo-1-(2,4,6-triisopropylphenyl)ethanone (13.9 g, 42.7 mmol) and thiourea (3.24 g, 42.6 mmol) in 95% EtOH (60.9 mL) was heated at reflux overnight. The solution was concentrated and added with water (100 mL), saturated aqueous Na2CO3 (10 mL), and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure, which was purified by column chromatography on silica gel (33% EtOAc in hexanes as eluant) to give 4-(2,4,6-triisopropylphenyl)thiazol-2-amine (3.28 g) as white solids in 25% yield: 1H NMR (500 MHz, CDCl3) δ 7.03 (s, 2 H), 6.22 (s, 1 H), 4.75 (s, 2 H), 2.89 (m, 1 H), 2.68 (m, 2 H), 1.27-1.14 (m, 18H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[C:5]2[NH2:12].Cl.Cl[CH2:15][CH2:16][N:17]([CH2:19][CH2:20]Cl)[CH3:18].O.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[C:5]2[N:12]1[CH2:20][CH2:19][N:17]([CH3:18])[CH2:16][CH2:15]1
Reactant: Cn1nc(N)c2cc(Br)ccc21
Reactant: CN(CCCl)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CCN(c2nn(C)c3ccc(Br)cc23)CC1
Temperature: 100 °C

Procedure:
A vessel was charged with 5-bromo-1-methyl-1H-indazol-3-amine (250 mg, 1.10 mmol), 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (230 mg, 1.21 mmol), H2O (250 μL), K2CO3 (500 mg, 3.63 mmol), and DMF (2.5 mL). The vessel was sealed and heated to 100° C. for 18 h. The reaction was poured into EtOAc and washed with 5% w/v aq LiCl (3×), dried (Na2SO4), filtered, and concentrated. The residue was treated with DCM and purification by flash column chromatography on silica gel (hexanes/ethyl acetate to remove side products; then DCM/MeOH eluent to elute product) provided 5-bromo-1-methyl-3-(4-methylpiperazin-1-yl)-1H-indazole. LCMS-ESI+: calc'd for C13H17BrN4: 309.1, 311.1 (M+H+); Found: 309.2, 311.2 (M+H+).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[S:11][C:10]=1[C:20]([NH2:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]([CH3:26])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:1]([N:8]1[C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[S:11][C:10]=2[C:20](=[O:21])[NH:22][C:24]1([CH3:26])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1NCc1ccccc1
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)NC(=O)c2sc(-c3ccncc3)cc2N1Cc1ccccc1
Temperature: 70 °C
Reaction time: 72 h
Yield: 60 %

Procedure:
A mixture of 3-(benzylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (0.124 g, 0.400 mmol), acetone (3.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred for 3 days at 70° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate (100 mL, 50 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. This oil was purified by column chromatography (Combiflash, 40 g silica gel, dichloromethane to ethyl acetate), then triturated with ethyl acetate/hexanes (1:1), and the precipitate was collected by filtration to afford the title compound (0.0841 g, 60%) as a yellow solid:
Reaction SMILES: [F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([O:21]C2CCCCO2)=[CH:13][C:12]=1[CH2:11][CH2:10]3.C(O)(=O)C(O)=O>CO.O>[F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([OH:21])=[CH:13][C:12]=1[CH2:11][CH2:10]3
Reactant: C[C@]12CC[C@@H]3c4ccc(OC5CCCCO5)cc4CC[C@H]3[C@@H]1CCC2=C(F)F
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=C(F)F
Yield: 47.1 %

Procedure:
1.3 g of crude 17-difluoromethylene-3-(tetrahydro-pyran-2-yl-oxy)-estra-1,3,5(10)-triene in 30 ml of methanol and 3 ml of water are suspended with 1.3 g of oxalic acid for 1 hour at a bath temperature of 100° C. Then, it is added to water, extracted three times with dichloromethane, washed neutral, dried on sodium sulfate and evaporated to dryness in a vacuum. 1.0 g of crude 17-difluoromethylene-estra-1,3,5(10)-trien-3-ol, which is chromatographed on silica gel with hexane/ethyl acetate, is obtained. 480 mg of pure 17-difluoromethylene-estra-1,3,5(10)-trien-3-ol is obtained as colorless crystals with a melting point of 154-156° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:19])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl.[CH3:23]S(C)=O>>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]([C@@H:11]2[CH2:23][C@H:12]2[C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)=[O:19])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)/C=C/c2cnn(C)c2)CC1
Reactant: CS(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCN(C(=O)[C@@H]2C[C@H]2c2cnn(C)c2)CC1
Temperature: 50 °C
Yield: 9 %

Procedure:
45A (380 mg, 1.45 mmol) dissolved in 5 mL of anhydrous DMSO was added to a suspension containing (CH3)3S(I)O (3188 mg, 14.48 mmol) prereacted with NaH (579 mg, 14.48 mmol) in 15 mL of anhydrous DMSO. The reaction mixture was heated at 50° C. in an oil bath overnight. The reaction mixture was concentrated under high vacuum to remove as much DMSO as possible, the resulting crude material was then dissolved in EtOAc and washed with a small amount of H2O. The aq. phase was extracted with EtOAc (2×50 ml). The organic phases were combined dried over MgSO4 then filtered on a thin pad of silica gel (1 cm). The silica gel was washed with more EtOAc and the resulting solution was concentrated under reduced pressure then purified on a 40 g silica column on the Companion machine using 0 to 20% MeOH in EtOAc gradient (with two 10 plateau at 10% MeOH then at 20% MeOH). The desired fractions were combined and concentrated under reduced pressure. These fractions were found to still contain some starting material. These samples were combined and repurified on preparative reverse phase chromatography (LCMS) using the long high pH 35-55% gradient on the XBridge Prep C18 OBD, 30×150, 5 um column. The pure fractions were combined and concentrated under reduced pressure. The resulting residue was placed under high vacuum overnight. The yellow liquid was dissolved in 1 ml of distilled H2O and 300 μL of HCl 2N was added to the solution which was then filtered and freeze dried to yield 46.4 mg 45B (9% yield) as a yellow solid HCl salt. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.46-1.60 (m, 1H) 2.28-2.48 (m, 2H) 2.99-3.30 (m, 4H) 3.52-3.64 (m, 3H) 4.04 (s, 3H) 4.54-4.78 (m, 2H) 8.01 (s, 1H) 8.03 (s, 1H). ES[M+H]+=277.2, HRMS[M+H]+ calc. for C15H24N4O+H=277.20229, [M+H]+ obs.=277.20211.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][C:5]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)=[C:4]([N+:26]([O-:28])=[O:27])[CH:3]=1.C(O)(C(F)(F)F)=O.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1[C:48]([C:49](O)=[O:50])=[C:47]([CH3:52])[NH:46][N:45]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:49]([C:48]3[C:44]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[O:37][CH3:36])=[N:45][NH:46][C:47]=3[CH3:52])=[O:50])[CH2:10][CH2:9]2)=[CH:6][C:5]([NH:14][C:15](=[O:25])[C:16]2[CH:17]=[CH:18][C:19]([N:22]([CH3:23])[CH3:24])=[CH:20][CH:21]=2)=[C:4]([N+:26]([O-:28])=[O:27])[CH:3]=1
Reactant: COc1ccccc1-c1n[nH]c(C)c1C(=O)O
Reactant: CN(C)c1ccc(C(=O)Nc2cc(N3CCNCC3)c(Cl)cc2[N+](=O)[O-])cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-c1n[nH]c(C)c1C(=O)N1CCN(c2cc(NC(=O)c3ccc(N(C)C)cc3)c([N+](=O)[O-])cc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33 %

Procedure:
To a solution of N-(4-chloro-2-nitro-5-(piperazin-1-yl)phenyl)-4-(dimethylamino)benzamide, 2 TFA (Preparation D, 35 mg, 0.055 mmol) in DMF (2 ml) was added 3-(2-methoxyphenyl)-5-methyl-1H-pyrazole-4-carboxylic acid (Preparation O, 15.44 mg, 0.066 mmol), HATU (25.3 mg, 0.066 mmol), followed by DIEA (0.048 ml, 0.277 mmol). The reaction was stirred at r.t. for 10 mins. Purified by prep-HPLC to afford 14 mg (33%) of the title compound. HPLC/MS (Method SZ6): (ES+) m/z (M+H)+=618; Rt=2.98 min.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]([O:17]C(C)(C)C)=[O:16].Cl(O)(=O)(=O)=O>C(#N)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]([OH:17])=[O:16]
Reactant: Cn1c(=O)c(C(=O)OC(C)(C)C)c(O)c2cc(I)ccc21
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC#N
Product: Cn1c(=O)c(C(=O)O)c(O)c2cc(I)ccc21
Reaction time: 0.01 h

Procedure:
To a solution of tert-butyl 4-hydroxy-6-iodo-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (4.1 g, 10 mmol) and Acetonitrile (20 ml), cooled in an ice bath, was added 70% perchloric acid (0.2 ml) and the mixture was stirred 30 sec. A yellow solid was filtered. Yield=0.5 g.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C@H:15]([C:16]([F:19])([F:18])[F:17])[C@@H:14]3[C@@H:20]([N:23]=[N+]=[N-])[CH2:21][CH2:22][N:13]3[C:12]2=[O:26])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H][H]>CCO.[Pt](=O)=O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C@H:15]([C:16]([F:18])([F:19])[F:17])[C@@H:14]3[C@@H:20]([NH2:23])[CH2:21][CH2:22][N:13]3[C:12]2=[O:26])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(N2C(=O)N3CC[C@H](N=[N+]=[N-])[C@H]3[C@H]2C(F)(F)F)ccc(C#N)c1Cl
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: Cc1c(N2C(=O)N3CC[C@H](N)[C@H]3[C@H]2C(F)(F)F)ccc(C#N)c1Cl
Yield: 42.8 %

Procedure:
To 69B (15.0 mg, 0.0391 mmol) in EtOH (1 mL) was added platinum (IV) oxide (5 mg) and hydrogen was bubbled through the system for 10 min. The hydrogen outlet was removed and the system was stirred under a hydrogen atmosphere. After 2h, the reaction was filtered through celite and concentrated. The resulting residue was purified via preparative HPLC (YMC ODS C-18, 21×100 mm, eluting with 50-100% solvent B (A=90% H2O—10% MeOH and B=10% H2O—90% MeOH) over 10 min; Flow rate at 40 mL/min; UV detection at 220 nm) to provide the title compound (6.00 mg) as a clear film. MS: m/z 419 [M+HCO3]−