Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][C:8]([OH:17])=[CH:9][CH:10]=3)[C:5](=[O:18])[C:4]=2[CH:3]=1.[N:19]1([CH2:25][CH2:26][Cl:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[ClH:28].[N:29]1([CH2:35][CH2:36][Cl:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.O>[OH-].[K+].C1(C)C(C)=CC=CC=1>[OH2:1].[ClH:27].[ClH:37].[N:19]1([CH2:25][CH2:26][O:1][C:2]2[CH:15]=[CH:14][C:13]3[C:12](=[O:16])[C:11]4[C:6](=[CH:7][C:8]([O:17][CH2:36][CH2:35][N:29]5[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)=[CH:9][CH:10]=4)[C:5](=[O:18])[C:4]=3[CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[N:19]1([CH2:25][CH2:26][O:1][C:2]2[CH:15]=[CH:14][C:13]3[C:12](=[O:16])[C:11]4[C:6](=[CH:7][C:8]([O:17][CH2:36][CH2:35][N:29]5[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)=[CH:9][CH:10]=4)[C:5](=[O:18])[C:4]=3[CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[ClH:28].[ClH:27]
Reactant: O=C1c2ccc(O)cc2C(=O)c2cc(O)ccc21
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C1c2ccc(OCCN3CCCCC3)cc2C(=O)c2cc(OCCN3CCCCC3)ccc21

Procedure:
With efficient stirring, 100 g (0.42 mole) of 2,7-dihydroxyanthraquinone is dissolved in 500-700 ml of about 10% potassium hydroxide solution. This solution is filtered and evaporated to dryness in a rotary evaporator. The reddish brown solid is dried in a vacuum oven at 100°C, ground to a fine powder, then redried at 100°C. To a stirred suspension of 30 g of the powdered diphenoxide, containing about 24 g (0.075 mole) of the dipotassium salt of 2,7-dihydroxyanthraquinone, in 200 ml of xylene is heated to reflux and a small amount of water collected. A solution of 2-piperidinoethyl chloride in 100 ml of xylene, prepared from 53.3 g (0.29 mole) of 2-piperidinoethyl chloride hydrochloride, is added and the resulting mixture heated to reflux for about 24 hours. The mixture is poured into about 500 ml of water, and the solid which separates at the xylene/water interface is removed by filtration, washed with hot water and dried. This major portion of the free base is recrystallized from a mixture of hot methanol and chloroform, then dissolved in chloroform and acidified to Congo Red with ethereal HCl and diluted with ether. The precipitate is suspended in boiling methanol (12-20 ml per gram) and a small volume of water is added to effect solution. This solution is filtered, reduced about 1/4 in volume, diluted with additional methanol and chilled. The recrystallized dihydrochloride is filtered and dried in a vacuum oven at 100°C to give 2,7-bis(2-piperidinoethoxy)anthraquinone dihydrochloride hemihydrate, M.P. 275°-277°C.
Reaction SMILES: [CH2:1]([O:5][N:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3].C([BH3-])#N.[Na+]>>[F:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][NH:6][O:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:13][CH:12]=1
Reactant: CC(C)CON=Cc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)CONCc1ccc(F)cc1
Yield: 65 %

Procedure:
Reduction of 4-fluorobenzaldehyde O-isobutyloxime with sodium cyanoborohydride as described in the preparation of compound 3-B gave the title hydroxylamine as a clear oil after chromatography (65% yield). 1HNMR 400 MHz (C6D6) δ (ppm): 0.87 (6H, d, J=6.75 Hz, CH3), 1.88 (1H, m, CH), 3.46 (2H, d, J=6.41 Hz, OCH2), 4.05 (2H, s, NCH2), 7.04 (2H, m, aromatics), 7.37 (2H, m, aromatics). Anal. calcd for C11H16FNO: C, 66.98; H, 8.17; N, 7.10. Found: C, 66.88; H, 7.97; N, 7.32.
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:7][P:8]([CH2:28][NH2:29])([CH2:10][CH:11]([C:16](=[O:27])[NH:17][C@H:18]([C:23](=[O:26])[NH:24][CH3:25])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])[CH3:6].[CH3:30][O:31][C:32]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:34]2[C:35]([O:37][C:38](=O)[C:33]=12)=[O:36]>>[CH2:5]([O:7][P:8]([CH2:28][N:29]1[C:35](=[O:36])[C:34]2=[C:40]([O:43][CH3:44])[CH:41]=[CH:42][C:32]([O:31][CH3:30])=[C:33]2[C:38]1=[O:37])([CH2:10][CH:11]([C:16](=[O:27])[NH:17][C@H:18]([C:23](=[O:26])[NH:24][CH3:25])[CH2:19][CH:20]([CH3:21])[CH3:22])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])[CH3:6]
Reactant: CCOP(=O)(CN)CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC
Reactant: COc1ccc(OC)c2c1C(=O)OC2=O
Solvent: CC(=O)O
Product: CCOP(=O)(CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC)CN1C(=O)c2c(OC)ccc(OC)c2C1=O
Yield: 50.1 %

Procedure:
In a manner analogous to that described in Example 3(A), from 0.5 g of (aminomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid ethyl ester acetate and 0.27 g of 3,6-dimethyoxyphthalic anhydride, there was obtained 0.325 g of [(3,6-dimethoxyphthalimido)methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid ethyl ester in the form of a pale yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]=[C:11]=[O:12].C([N:15](CC)CC)C.Cl>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]([NH2:15])=[O:12]
Reactant: O=C=Nc1c(Cl)cc(Cl)cc1Cl
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CC#N
Product: NC(=O)Nc1c(Cl)cc(Cl)cc1Cl
Reaction time: 1 h
Yield: 143.8 %

Procedure:
To a stirred mixture of CC-16313 (0.450 g, 1.22 mmol) and 2,4,6-trichlorophenyl isocyanate (0.271 g, 1.22 mmol) in acetonitrile (10 mL), was added triethylamine (0.34 mL, 2.44 mmol) at room temperature under nitrogen. After 1 h, 1N aq. HCl (10 mL) was added and the mixture was stirred for 10 min. The product was isolated by filtration, washed with 1N aq. HCl (20 mL), acetonitrile (20 mL) and dried overnight in vacuo to give 1-[2-(2,6-Dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-(2,4,6-trichloro-phenyl urea as a white solid (0.42 g, 69% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.22 min (99.7%); mp: 264-266° C.; 1H NMR (DMSO-d6) δ 1.91-2.06 (m, 1H, CH), 2.31-2.47 (m, 1H, CH), 2.60 (d, J=17.0 Hz, 1H, CH), 2.83-3.02 (m, 1H, CH), 4.21-4.54 (m, 4H, CH2, CH2), 5.11 (dd, J=4.9, 13.2 Hz, 1H, NCH), 7.01 (t, J=5.9 Hz, 1H, NH), 7.44 (d, J=7.9 Hz, 1H. Ar), 7.51 (s, 1H, Ar), 7.66-7.75 (m, 311, Ar), 8.24 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.48, 31.20, 43.02, 47.07, 51.56, 121.66, 122.87, 126.72, 128.09, 130.23, 131.24, 133.34, 134.87, 142.29, 144.84, 154.97, 167.95, 170.99, 172.86; LCMS: MH=495, 497; Anal Calcd for C21H17N4O4Cl3: C, 50.51; H, 3.45; N, 11.22; Cl, 22.01. Found: C, 50.28; H, 3.17; N, 11.13; Cl, 21.96.
Reaction SMILES: Cl.[F:2][C:3]([CH3:7])([CH3:6])[CH2:4][NH2:5].C(N(CC)CC)C.Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[N:19]=[CH:18][C:17]=1[N+:26]([O-:28])=[O:27].O>C(Cl)Cl>[F:2][C:3]([CH3:7])([CH3:6])[CH2:4][NH:5][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[N:19]=[CH:18][C:17]=1[N+:26]([O-:28])=[O:27]
Reactant: CC(C)(F)CN
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(F)CNc1c([N+](=O)[O-])cnc2cccnc12
Reaction time: 48 h
Yield: 100.8 %

Procedure:
2-Fluoro-2-methylpropan-1-amine hydrochloride (4.02 g, 31.4 mmol) was dissolved in 80 mL of dry CH2Cl2. Triethylamine (13.1 mL, 94.2 mmol) and 4-chloro-3-nitro[1,5]naphthyridine (6.56 g, 31.4 mmol) were then added and the reaction was stirred under N2 for 2 days. The reaction mixture was then concentrated under reduced pressure to give a dark-yellow solid. The solid was treated with 200 mL of H2O and the mixture was heated to reflux with rapid stirring. The mixture was cooled and the yellow solid was isolated by filtration. The material was washed with H2O and the dried under vacuum to give N-(2-fluoro-2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine (8.36 g) as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:31](=[O:41])[N:32]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])=[N:4][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][C:9]=2[C:19]([N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)=[O:20])[C:6]=1[CH3:7].[OH-].[Na+]>CCO.C1COCC1>[Cl:1][C:2]1[C:3]([C:31](=[O:41])[N:32]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])=[N:4][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=2[C:19]([N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)=[O:20])[C:6]=1[CH3:7]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)OCC)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)O)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Temperature: 40 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of ethyl 4-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (930 mg, 1.61 mmol) in EtOH (5.0 mL) and THF (5.0 mL) was added 2N NaOH (4.0 mL, 8.03 mmol). The resulting reaction mixture was stirred at 40° C. for 1 h, cooled to room temperature and quenched with 6N HCl. The solution was extracted with CHCl3 (3×), and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (885 mg, 99%), which was used without further purification. 1H NMR (DMSO-d6, 2:1 mixture of amide rotamers) δ 8.32 (s, 0.5H), 8.14 (dd, J=8.36, 1.98 Hz, 1H), 8.07-7.98 (m, 1H), 7.83-7.72 (m, 1H), 7.28-7.06 (m, 3H), 7.03-6.93 (m, 0.5H), 4.86-4.68 (m, 0.5H), 4.65-4.47 (m, 1H), 4.42-4.24 (m, 0.5H), 3.88-3.70 (m, 0.5H), 3.66-3.34 (m, 3.5H), 3.23-3.06 (m, 1H), 3.04-2.94 (m, 1H), 2.87-2.70 (m, 2H), 2.26 (s, 2H), 2.21 (s, 1H), 1.47-1.34 (m, 0.5H), 1.33-1.06 (m, 5.5H), 1.01-0.91 (m, 2H), 0.88-0.82 (m, 3H), 0.70-0.62 (m, 3H); MS(ESI+) m/z 551.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.C(OC([N:24]1[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][C@@H:25]1[C:33](O)=[O:34])=O)(C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C1COCC1.C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:30]([N:27]1[CH2:28][CH2:29][NH:24][C@@H:25]([C:33]([N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][N:7]=3)[CH2:14][CH2:13]2)=[O:34])[CH2:26]1)([CH3:32])[CH3:31]
Reactant: CC(C)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N1CCN[C@@H](C(=O)N2CCN(c3ccc(C(F)(F)F)cn3)CC2)C1
Reaction time: 4 h
Yield: 35.3 %

Procedure:
1-[5-(Trifluoromethyl)pyridin-2-yl]piperazine (170 mg) and (2R)-1-(tert-butoxycarbonyl)-4-isopropylpiperazine-2-carboxylic acid (200 mg) were dissolved in dry THF (10 ml) followed by addition of N′N-di-isopropylethylamine (0.15 ml) and O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-TetramethylUronium Hexafluorophosphate (307 mg) and the reaction was stirred for 4 hours. The solvent was evaporated under reduced pressure, redissolved in DCM (50 ml) and washed with saturated aqueous NaHCO3 (20 ml). The organic layer was separated on a phase separation cartridge and evaporated. Purification by chromatography (3-10% MeOH:DCM) afforded the crude product (231 mg) as a foam which was then dissolved in TFA/DCM (1:1, 10 ml) and stirred for 30 minutes. The solvents were removed under reduced pressure, the residue taken up in 1M aqueous NaOH (30 ml) and extracted with DCM (2×30 ml). The organic layer was separated on a phase separation cartridge and evaporated. Purification by chromatography (5-25% MeOH:DCM) afforded the title compound (100 mg) as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17].[C:19](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:19]
Reactant: O=C(Nc1ccc(F)cc1F)c1ccccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccccc1C(=O)Nc1ccc(F)cc1F
Temperature: 25 °C

Procedure:
To a solution of compound 3a (0.50 g, 2 mmole) in anhydrous acetone (10 mL) were added potassium carbonate (0.69 g, 5 mmole) and iodomethane (0.28 mL, 4.4 mmol) and refluxed 8 hr. After cooled to room temperature, the reaction mixture was filtered through Celite and concentrated. The residue was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, then concentrated and recrystallized with hot methanol.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[O:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][O:11][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(C2CN(Cc3ccccc3)C(=O)CO2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(C2CN(Cc3ccccc3)CCO2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
In a 500 mL round-bottomed flask, 4-benzyl-6-(3-methoxyphenyl)morpholin-3-one (2.3 g, 7.74 mmol) was combined with THF (75 ml) to give a light yellow solution. The reaction was cooled to 0° C. LiAlH4 (9.67 ml of 2M solution in THF, 19.3 mmol) was added by dropwise addition. The resulting reaction mixture was allowed to warm to room temperature and then stirred at this temperature overnight. Reaction was complete as determined by LCMS. The crude reaction mixture was cooled to 0° C. and quenched carefully by sequential addition of H2O (0.75 mL), 2M NaOH (1.5 mL) and then H2O (1.5 mL). Additional THF was added during the addition of NaOH because mixture got too thick for stirring. The mixture was stirred for 1 h and filtered through Celite. The filtercake was washed several times with ethyl acetate. The combined filtrate and washes were concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 80 g, 1.5% to 2% MeOH in dichloromethane) to yield 4-benzyl-2-(3-methoxy-phenyl)-morpholine (1.32 g, 60%) as an oil. (M+H)+=284 m/e. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.14 (dd, J=11.37, 10.36 Hz, 1H) 2.31 (td, J=11.43, 3.41 Hz, 1H) 2.77 (dd, J=11.37, 1.77 Hz, 1H) 2.94 (dt, J=11.62, 2.02 Hz, 1H) 3.57 (s, 2H) 3.83 (s, 3H) 3.84-3.92 (m, 1H) 3.98-4.09 (m, 1H) 4.58 (dd, J=10.11, 2.27 Hz, 1H) 6.84 (ddd, J=8.21, 2.53, 1.14 Hz, 1H) 6.91-7.00 (m, 2H) 7.21-7.42 (m, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.[H-].[Na+].Br[C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Br:17])[CH:16]=1.O>CN(C)C=O>[Br:17][C:15]1[CH:14]=[N:13][CH:12]=[C:11]([O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:16]=1
Reactant: Brc1cncc(Br)c1
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cncc(Oc2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
To a solution of 3-pyridinol (4.32 g, 45 mmol) in dimethylformamide (50 mL) was added sodium hydride (1.35 g of a 80% suspension in mineral oil, 45 mmol). The mixture was stirred for 1 h at room temperature and 3,5-dibromopyridine (5.92 g, 25 mmol) was added. The mixture was heated for 20 h at 130° C., then cooled to room temperature and poured into water (300 mL). The aqueous phase was extracted with diethyl ether (3×100 mL) and the organic phase was washed with water (2×100 mL) and brine (100 mL), then dried (MgSO4), filtered and concentrated by rotary evaporation. The crude product was purified by column chromatography, eluting with ethyl acetate/cyclohexane (30/70, v/v). Selected fractions containing the product were concentrated via rotary evaporation to give 3.5 g (56%) of a yellow oil.
Reaction SMILES: I[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1)([O-:23])=[O:22]>C1COCC1.CCOC(C)=O>[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=2)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: FC(F)(F)c1ccc(CCI)cc1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(SCCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.5 %

Procedure:
To a solution of 1-(2-iodo-ethyl)-4-trifluoromethyl-benzene (7.51 g, 25.0 mmol), triethylamine (3.84 mL, 27.5 mmol) in THF (100 mL) was added p-nitrothiophenol (4.85 g, 25.0 mmol). The reaction was stirred at room temperature for two days, diluted with EtOAc, washed with water, saturated NaHCO3, H2O, brine and dried over anhydrous sodium sulfate. The compound was purified on silica gel (hexane-EtOAc) to give 7.24 g of a yellow solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:11]2[C@H:12]3[C@H:21]([CH2:22][CH2:23][C@:8]2([CH2:9][CH3:10])[C:7](=[O:25])[CH2:6]1)[C@@H:20]1[C:15](=[CH:16][C:17](=[O:24])[CH2:18][CH2:19]1)[CH2:14][CH2:13]3)(=[O:3])[CH3:2].[CH3:26]OC(OC)(C)C.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.CO>[C:1]([O:4][C@@H:5]1[C@H:11]2[C@H:12]3[C@H:21]([CH2:22][CH2:23][C@:8]2([CH2:9][CH3:10])[C:7](=[O:25])[CH2:6]1)[C@@H:20]1[C:15]([CH:16]=[C:17]([O:24][CH3:26])[CH2:18][CH2:19]1)=[CH:14][CH2:13]3)(=[O:3])[CH3:2]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC[C@]12CC[C@H]3[C@@H](CC=C4C=C(OC)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
60.0 g of 15α-acetoxy-18-methyl-4-estrene-3,17-dione in 500 ml of dimethylformamide is stirred with 500 ml of 2,2-dimethoxypropane, 20 ml of methanol and 6.0 g of pyridinium tosylate at 110° C. under argon. After 3.5 hours, 9.0 g of solid sodium bicarbonate is added, the reaction mixture is stirred into 10 liters of ice/water, the precipitated product is suctioned off, washed repeatedly with water, and dried under vacuum at 70° C. The crude product is suspended in 375 ml of methanol and stirred under reflux for 15 minutes. After gradual cooling down to room temperature, the colorless crystallized product is suctioned off and washed with cold methanol. Yield: 56 g of 15α-acetoxy-3-methoxy-18-methyl-3,5-estradien-17-one. Melting point 190° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]1[S:12][CH:13]([CH2:16][C:17](O)=[O:18])[CH2:14][N:15]=1)=[CH:7]2.[NH4+].O[N:33]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]1[S:12][CH:13]([CH2:16][C:17]([NH2:33])=[O:18])[CH2:14][N:15]=1)=[CH:7]2
Reactant: On1nnc2ccccc21
Reactant: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(N)=O)S3)[nH]c12
Temperature: 25 °C
Yield: 74.8 %

Procedure:
To a solution of [2-(7-methyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (300 mg) in N,N-dimethylformamide (12 mL) were added 1-hydroxybenzotriazole ammonium salt (154 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (194 mg) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 2 days. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:methanol=100:0 to 90:10, volume ratio) to give pale-yellow crystals. The obtained crystals were recrystallized from methanol-ethyl acetate to give the title compound (224 mg, yield 75%) as colorless crystals.
Reaction SMILES: Cl.C[O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].[CH3:11][O:12][C@@H:13]1[C@@H:17]([O:18][N+:19]([O-:21])=[O:20])[CH2:16][C@H:15]([C:22](O)=[O:23])[CH2:14]1.C(N(CC)CC)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[CH3:11][O:12][C@@H:13]1[C@@H:17]([O:18][N+:19]([O-:21])=[O:20])[CH2:16][C@H:15]([C:22]([NH:6][C@H:5]([C:4]([OH:3])=[O:10])[CH:7]([CH3:9])[CH3:8])=[O:23])[CH2:14]1
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: CO[C@H]1C[C@@H](C(=O)O)C[C@@H]1O[N+](=O)[O-]
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CO[C@H]1C[C@@H](C(=O)N[C@H](C(=O)O)C(C)C)C[C@@H]1O[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of L-valine methyl ester hydrochloride (633 mg, 3.78 mmol), (1R,3S,4S)-3-methoxy-4-(nitrooxy)cyclopentanecarboxylic acid (755 mg, 3.78 mmol), and triethylamine (1.05 mL, 7.55 mmol) in dichloromethane (30 mL) was added PyBOP (2.95 g, 5.67 mmol). After stirring at rt overnight, the mixture was washed saturated NaHCO3 (3×50 mL) and brine (50 mL), dried over MgSO4, and concentrated. The residue was purified by flash chromatography (RediSepRf 80 g) using 0-40% EtOAc/hexane gradient, affording the title compound (1.04 g, yield 86%): 1H NMR (500 MHz, CDCl3) δ 6.50 (d, J=8.6, 1H), 5.40 (d, J=6.0, 1H), 4.55 (dd, J=4.7, 8.8, 1H), 3.92 (m, 1H), 3.77 (s, 3H), 3.47 (s, 3H), 2.96-2.91 (m, 1H), 2.52-2.46 (m, 1H), 2.38-2.32 (m, 1H), 2.24-2.17 (m, 2H), 2.07-2.01 (m, 1H), 0.97 (d, J=6.9, 3H), 0.92 (d, J=6.9, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: CCNCC
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCN(CC)C(=O)c1ccc(C(=O)NCc2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, diethylamine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.59 minutes; C20H20Cl2N4O2 (419.31); mass spectrum: (M+H)+=419.2.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](=[O:29])[NH:22][CH2:23][C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:17][C:16]=3[C:30]3[C:31]([C:38]([OH:40])=[O:39])=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:5][CH:4]=1)#[N:2].Cl.O1C=C[N:44]=C1NC.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](=[O:29])[NH:22][CH2:23][C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:17][C:16]=3[C:30]3[C:31]([C:38]([OH:40])=[O:39])=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:5][CH:4]=1)(=[NH:44])[NH2:2]
Reactant: CNc1ncco1
Reactant: CCn1cc(Cc2ccc(C(=O)NCc3ncco3)cc2-c2ccc(OC)cc2C(=O)O)c2ccc(C#N)cc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCn1cc(Cc2ccc(C(=O)NCc3ncco3)cc2-c2ccc(OC)cc2C(=O)O)c2ccc(C(=N)N)cc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 91 %

Procedure:
Part A. 2′-(6-cyano-1-ethyl-1H-indol-3-ylmethyl)-4-methoxy-5′-[(oxazol-2-ylmethyl)-carbamoyl]-biphenyl-2-carboxylic acid: A mixture of the compound of Example 15, Part F (75 mg, 0.138 mmol), oxazol-2-yl-methylamine hydrochloride (28 mg, 0.208 mmol) NMM (0.012 mL, 1.10 mmol) and BOP reagent (76 mg, 0.172 mmol) in DMF (1 mL) was stirred at rt over 3 days. Reaction was worked up and product isolated as described for Example 15, Part G to provide the amide (78.3 mg, 91%). LC/MS m/z 625.3 (M+H)+.