Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([N:18]1[CH2:22][C:21](=O)[C@H:20]([CH2:24][NH:25][C:26]([C:28]2[S:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[O:27])[CH2:19]1)=[O:17].C1COCC1.[CH3:39][NH2:40].[OH-].[Na+]>O.CC(O)=O>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([N:18]1[CH2:22][CH:21]([NH:40][CH3:39])[C@H:20]([CH2:24][NH:25][C:26]([C:28]2[S:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[O:27])[CH2:19]1)=[O:17]
Reactant: O=C(NC[C@@H]1CN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)CC1=O)c1ccc(Cl)s1
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CNC1CN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@H]1CNC(=O)c1ccc(Cl)s1
Temperature: 22 °C
Reaction time: 1.5 h

Procedure:
A solution of the (R)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-oxo-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide (120 mg, example 81.3) and 12 ml of THF saturated with methylamine was treated at 5° C. with 3.5 ml of AcOH until pH=6 and the mixture was warmed to 22° C. After 1.5 h, the mixture was treated with 24 mg of Na(CN)BH3 and stirring was continued for 2.5 h. The mixture was diluted with 5 ml of water, the pH was adjusted to 14 using 3 N NaOH and the solution was extracted with THF. The organic layer was dried and evaporated to give (R)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-methylamino-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. Colorless foam. MS 504.0 ([M+H]+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[C:32]([F:36])=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:37](O)=[O:38])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(N(CC)CC)C>[F:36][C:32]1[C:24]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:21]([C:19]([N:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[C@H:12]3[CH2:11][C@@H:10]([C:37]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[O:38])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13]3)=[O:20])=[N:22][C:23]=2[CH:35]=[CH:34][CH:33]=1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2cccc(F)c21
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2cccc(F)c21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[7-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (207 mg), morpholine (87 μl), HOBt (40 mg) and triethylamine (210 μl) were dissolved in DMF (10 ml), WSC.HCl (180 mg) was added, and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9)-ethyl acetate was concentrated under reduced pressure to give the object product (160 mg).
Reaction SMILES: [CH:1]1([C@@H:4]2[CH2:9][CH2:8][NH:7][CH2:6][C@H:5]2[NH:10][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[CH2:3][CH2:2]1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH2:19]([N:7]1[CH2:8][CH2:9][C@@H:4]([CH:1]2[CH2:2][CH2:3]2)[C@H:5]([NH:10][P:11](=[O:18])([O:12][CH2:13][CH3:14])[O:15][CH2:16][CH3:17])[CH2:6]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOP(=O)(N[C@@H]1CNCC[C@H]1C1CC1)OCC
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOP(=O)(N[C@@H]1CN(Cc2ccccc2)CC[C@H]1C1CC1)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
A mixture of diethyl trans-4-cyclopropylpiperidin-3-ylphosphoramidate (1.24 g, 4.49 mmol), benzaldehyde (0.68 mL, 6.73 mmol) and acetic acid (0.51 mL, 8.98 mmol) in methanol (20 mL) was stirred at 0° C. for 30 minutes. NaCNBH3 (0.42 g, 6.73 mmol) was added at 0° C. The resulting solution was warmed to room temperature and stirred at room temperature for 1 hour. The solvent was removed in vacuo, and saturated sodium bicarbonate (20 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate) and concentrated in vacuo to give diethyl trans-1-benzyl-4-cyclopropylpiperidin-3-ylphosphoramidate (1.64 g, 100%), which was used directly in the next step without purification.
Reaction SMILES: [C:1]1([CH2:7][C:8]([N:10]=[C:11]=[S:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:42]=[CH:41][C:17]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]([N:28]3[CH2:33][CH2:32][CH:31]([N:34]4[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]4)[CH2:30][CH2:29]3)=[O:27])[CH:20]=2)=[C:16]([F:43])[CH:15]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(O)C>[F:43][C:16]1[CH:15]=[C:14]([NH:13][C:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[S:12])[CH:42]=[CH:41][C:17]=1[O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]([N:28]2[CH2:29][CH2:30][CH:31]([N:34]3[CH2:35][CH2:36][CH:37]([OH:40])[CH2:38][CH2:39]3)[CH2:32][CH2:33]2)=[O:27])[CH:20]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC(O)CC4)CC3)c2)c(F)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC(O)CC4)CC3)c2)c(F)c1
Reaction time: 1 h
Yield: 57 %

Procedure:
After adding a solution of 2-phenylacetyl isothiocyanate in toluene (0.2 M, 4.0 ml) to a solution of 4-(4-amino-2-fluorophenoxy)-2-{[4-(4-hydroxypiperidin-1-yl)piperidin-1-yl]carbonylamino}pyridine (164 mg) and (+)-10-camphorsulfonic acid (85 mg) in ethanol (4.0 ml) at room temperature, the mixture was stirred for 1 hour. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine in that order and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=98:2 to 95:5) to provide the title compound (127 mg, 57%) as white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([NH2:25])[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.C(N(C(C)C)C(C)C)C.[C:35](Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH:8]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)[NH:25][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of C-(3-chloropyrazin-2-yl)-C-(2-phenylquinolin-7-yl)-methylamine (231.4 mg, 0.6672 mmol), DMAP (4 mg, 0.033 mmol), and (iPr)2EtN (174 μL, 129 mg, 1 mmol) in dry CH2Cl2 (5 mL), cooled to 0° C., pivaloyl chloride (90 μL, 89 mg, 0.734 mmol) was added under N2 atmosphere, the cooling bath was removed, and the reaction mixture was allowed to stir at ambient temperature for 16 h. The reaction was quenched with H2O and extracted with CH2Cl2 (3×20 mL). The combined CH2Cl2 layers were washed with (1×30 mL each) 0.25M citric acid (pH 2-3), H2O, NaHCO3 sat. aq. sol., and brine, dried over anhydrous MgSO4, and filtered. Sample was purified by filtration through a plug of silica gel, eluting with EtOAc:CH2Cl2 10:1→5:1 (300 mL). Filtrate was concentrated in vacuo, yielding the title compound, as a yellow solid, containing approximately 10% of bis-acetylated material; 1H NMR (CDCl3, 400 MHz) δ 1.23 (s, 9H), 6.75 (d, J=7.6 Hz, 1H), 7.43-7.48 (m, 1H), 7.49-7.55 (m, 2H), 7.60 (d, br, J=7.6 Hz, —NH), 7.72-7.77 (m, 1H), 7.81-7.89 (m, 2H), 7.90 (s, 1H), 8.07-8.14 (m, 2H), 8.20 (d, J=8.8 Hz, 1H), 8.38 (d, J=2.8 Hz, 1H), 8.59 (d, J=2.0 Hz, 1H); MS (ES+): m/z 430.9/432.9 (100/37) [MH+]; HPLC: tR=3.5 min (OpenLynx, polar—5 min).
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([S:19][CH3:20])[N:4]=1.[CH3:21][OH:22]>>[CH3:20][S:19][C:5]1[N:4]=[C:3]([O:22][CH3:21])[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=1
Reactant: CSc1nc(Cl)cc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: CO
Agent: [Na]
Product: COc1cc(-c2ccc(C(F)(F)F)cc2)nc(SC)n1

Procedure:
A solution of 0.38 g sodium in 50 ml methanol are added to 4.6 g of the compound from example 4 in 75 ml methanol at room temperature. After stirring over night the mixture is evaporated, re-dissolved in dichloro-methane and filtered to give 4.1 g of the title product (m.p. 82-84° C.).
Reaction SMILES: [CH2:1]([N:8](C)[S:9]([CH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18](CC1C=CC=CC=1)[CH:17]=[C:16]2[CH2:29][C@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[CH3:35])(=[O:11])=[O:10])C1C=CC=CC=1.N.[Na].[Cl-].[NH4+]>O1CCCC1.O>[CH3:1][NH:8][S:9]([CH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH2:29][C@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[CH3:35])(=[O:10])=[O:11]
Reactant: CN1CCC[C@@H]1Cc1cn(Cc2ccccc2)c2ccc(CS(=O)(=O)N(C)Cc3ccccc3)cc12
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CNS(=O)(=O)Cc1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1
Temperature: 25 °C
Yield: 56.1 %

Procedure:
A solution of (R)-N-Benzyl-1-[1-benzyl-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl]-N-methylmethanesulfonamide (from step (f), 2.04 g) in tetrahydrofuran (2 ml) was added dropwise to liquid ammonia (10 ml) at −40° C. under a nitrogen atmosphere. Sodium (approximately 500 mg) was then added portionwise to the colourless solution, until a permanent dark blue coloured solution was obtained. The blue solution was stirred for a further 30 min at −40° C. before saturated ammonium chloride solution (5 ml) was added and the grey slurry warmed to ambient temperature over an 8 hr period. The white slurry was then diluted with water (10 ml), filtered and dried in vacuo at 50° C. to give the title compound (733 mg, 56%) as a white solid. m.p. 209-213° C.
Reaction SMILES: [ClH:1].O[CH:3]([C:22]1[C:23]([NH:28][C:29](=[O:34])C(C)(C)C)=[N:24][CH:25]=[CH:26][CH:27]=1)[CH:4]([CH:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)C(OC)=O>O>[ClH:1].[ClH:1].[NH:12]1[CH2:11][CH2:10][CH:9]([C:4]2[C:29](=[O:34])[NH:28][C:23]3[C:22]([CH:3]=2)=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:14][CH2:13]1
Reactant: COC(=O)C(C1CCN(C(=O)OC(C)(C)C)CC1)C(O)c1cccnc1NC(=O)C(C)(C)C
Agent: Cl
Solvent: O
Product: O=c1[nH]c2ncccc2cc1C1CCNCC1
Reaction time: 25 h
Yield: 33 %

Procedure:
Concentrated hydrochloric acid (25 mL, 305 mmol) was added with stirring to a mixture of tert-butyl 4-(1-hydroxy-3-methoxy-3-oxo-1-(2-pivalamidopyridin-3-yl)propan-2-yl)piperidine-1-carboxylate (14.0 g, 30.2 mmol) and water (75 mL). Reaction was heated to reflux and held for 25 hours. Mixture was concentrated in vacuo. Residue was crystallized from ethanol. Title compound was obtained as white solid in 33% yield. (M+H)+=230.2.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH:10]=[C:9]([C:12]([O:14]CC)=[O:13])[CH2:8][CH2:7]1)=O)C.[BrH:17]>>[BrH:17].[NH:6]1[CH2:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH2:10][CH2:11]1
Reactant: CCOC(=O)C1=CCN(C(=O)OCC)CC1
Agent: Br
Product: O=C(O)C1=CCNCC1

Procedure:
To 104.4 g of ethyl 1-ethoxycarbonyl-1,2,3,6-tetrahydropyridine-4-carboxylate, 1500 g of 47% hydrobromic acid was added, and the mixture was heated under reflux for 100 hours. The reaction mixture was concentrated under reduced pressure to yield crude 1,2,3,6-tetrahydropyridine-4-carboxylic acid hydrobromide. The obtained crude 1,2,3,6-tetrahydropyridine-4-carboxylic acid hydrobromide was dissolved in a mixed solution of 0.48 l of dioxane and 0.48 l of a 2M aqueous solution of sodium hydroxide, and 105.2 g of tert-butyl bicarbonate were added thereto. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and 1.4 l of a 1M aqueous solution of potassium hydrogensulfate was poured thereinto. The precipitated crystals of 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-4-carboxylic acid was obtained in an amount of 100.5 g by filtration.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([OH:13])=O)=[CH:8][C:9]=1[Br:10])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH2:55][CH2:56][C:57]1[CH:58]=[C:59]([OH:63])[CH:60]=[CH:61][CH:62]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:13])[NH:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([OH:63])[CH:58]=2)=[CH:8][C:9]=1[Br:10])=[O:4]
Reactant: COC(=O)c1sc(C(=O)O)cc1Br
Reactant: NCc1cccc(O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1Br
Temperature: 25 °C
Reaction time: 15 h
Yield: 58.5 %

Procedure:
To a solution of 3-Bromo-thiophene-2,5-dicarboxylic acid 2-methyl ester (204 mg, 0.76 mmol) in anhydrous DMF (7 mL) was added triethylamine (0.32 mL, 2.28 mmol), HBTU (0.43 g, 1.14 mmol), HOBT (123 mg, 0.91 mmol), and 3-Aminomethyl-phenol (110 mg, 0.91 mmol). The mixture was stirred at room temperature 15 h, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-50% EtOAc in hexane to afford the desired product (0.1647 g, 59% yield).
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=O)[CH3:14])=[C:8]([OH:16])[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].CC1C=CC(S(O)(=O)=O)=CC=1>>[CH3:14][C:13]1[O:16][C:8]2[CH:7]=[C:6]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH:11]=[CH:10][C:9]=2[N:12]=1
Reactant: CCCC(=O)c1ccc(NC(C)=O)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCC(=O)c1ccc2nc(C)oc2c1
Temperature: 160 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
To a suspension of N-(4-butyryl-2-hydroxyphenyl)acetamide (0.81 g, 3.7 mmol) in xylenes (3 mL) was added p-TsOH (0.7 g, 3.7 mmol, 1.0 eq) at room temperature then the mixture was heated to 160° C. and stirred overnight. The solvent was removed under reduced pressure then saturated aqueous NaHCO3 was added and the biphasic mixture was extracted by CH2Cl2 (4×20 mL). The solvent was concentrated to give a crude product which was purified by flash column chromatography (0-25% EtOAc in hexanes) to afford the title compound as a light yellow solid (262 mg, 1.3 mmol, 35%).
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[Li+].[Br-:22].[BH4-].[Na+]>C(OCC)(=O)C.C1C=CC=CC=1>[CH3:1][C@@:2]12[C:18](=[O:19])[C@H:17]([Br:22])[CH2:16][C@H:15]1[C@@H:14]1[CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([OH:20])[CH:8]=[CH:7][C:6]=3[C@H:5]1[CH2:4][CH2:3]2
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: [Br-]
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](Br)C2=O

Procedure:
16α-Bromoestrone was prepared by bromination of the enol acetate of estrone and then epimerized with LiBr (as described by Fishman et al., J. Org. Chem. 23, 1190 (1958) and Mueller et al., supra, which are hereby incorporated by reference). The resulting mixture of 16α- and 16β-bromoestrone was reduced with NaBH4. All four of the possible bromohydrins were isolated from the reaction mixture by chromatography on silica gel in 5 percent ethyl acetate in benzene. The second compound eluted from the column (60 percent of the reaction mixture) melted at 176° to 178° C., where-upon a new crystalline structure formed (melting point, 255° to 256° C.). It was identified as 16β-bromoestradiol by reaction with KOH to form estrone (cis-bromohydrin); epimerization with LiBr to form 16α-bromoestradiol (compared to an authentic sample); and its mass spectrum. 16α-Iodoestradiol (melting point, 190° to 191° C.) was synthesized from 16β-bromoestradiol by exchange with NaI. Its nuclear magnetic resonance (NMR) and mass spectra were consistent with the predicted structure.
Reaction SMILES: [C:1]1([C:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([CH:19]=[C:20]([C:22]([O:24]CC)=[O:23])[N:21]=4)[CH:18]=3)[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)(OC(NC1N=C(C2C=CC3N(C=C(C(O)=O)N=3)C=2)C=CC=1)=O)C>>[C:33]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([CH:19]=[C:20]([C:22]([OH:24])=[O:23])[N:21]=4)[CH:18]=3)[N:10]=[CH:9]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCOC(=O)c1cn2cc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2n1
Agent: CC(C)(C)OC(=O)Nc1cccc(-c2ccc3nc(C(=O)O)cn3c2)n1
Product: O=C(O)c1cn2cc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2n1
Yield: 73.3 %

Procedure:
500 mg of ethyl 6-(1-triphenylmethyl-1H-imidazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylate are saponified under conditions similar to those described for the preparation of Intermediate 11 (step 11.3) to give 346 mg of 6-(1-triphenylmethyl-1H-imidazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylic acid.
Reaction SMILES: C([O:8][C:9](=[O:56])[CH2:10][CH:11]([NH:36][C:37](=[O:55])[CH:38]([P:47]([O:52]CC)([O:49]CC)=[O:48])[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:12]([NH:14][CH:15]([C:26]([O:28]CC1C=CC=CC=1)=[O:27])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)=[O:13])C1C=CC=CC=1.C[Si](Br)(C)C>C(Cl)Cl.CO.[Pd]>[C:26]([CH:15]([NH:14][C:12](=[O:13])[CH:11]([NH:36][C:37](=[O:55])[CH:38]([P:47]([OH:52])([OH:49])=[O:48])[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:10][C:9]([OH:56])=[O:8])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)([OH:28])=[O:27]
Reactant: CCOP(=O)(OCC)C(CCc1ccccc1)C(=O)NC(CC(=O)OCc1ccccc1)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: ClCCl
Product: O=C(O)CC(NC(=O)C(CCc1ccccc1)P(=O)(O)O)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)O
Reaction time: 40 h

Procedure:
The more polar peptide phosphonate of Example 159 (54 mg, 69 μmol) was dissolved in dry CH2Cl2 (2 mL) followed by the addition of TMSBr (73 μL, 552 μmol). The resulting pale yellow solution was stirred for 40 h. The volatile materials were evaporated in vacuum at room temperature and the obtained residue was suspended in a water/methanol mixture (20:1) and vigorously stirred for 2 h after which it was lyophilized to give the crude phosphonic acid intermediate. This crude product was taken up in methanol (5 mL) and treated with Pd/C powder (10%, 25 mg). The mixture was stirred under an H2 atmosphere (45 PSI) for 12 h and then the catalyst was removed by filtration through a celite pad. The resulting mixture was concentrated to give the crude title compound which was purified by HPLC.
Reaction SMILES: O.CO.CCN([C:9]1[CH:14]=[CH:13][C:12]2[CH:15]=[C:16](C3SC4C(=CC=CC=4)N=3)[C:17]([O:19][C:11]=2[CH:10]=1)=[O:18])CC.C1C=CC(C(O)=O)=C(C2C3C=CC(O)=CC=3OC3C=2C=CC(C=3)=O)C=1>ClCCl.C(O)C>[O:19]1[C:11]2[C:12](=[CH:13][CH:14]=[CH:9][CH:10]=2)[CH:15]=[CH:16][C:17]1=[O:18]
Reactant: CCN(CC)c1ccc2cc(-c3nc4ccccc4s3)c(=O)oc2c1
Agent: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: O=c1ccc2ccccc2o1

Procedure:
To a vigorously stirred 200 mL suspension 0.282 micrometer carboxylate-modified latex (Interfacial Dynamics Corp., Portland, Oreg.; 2.10% solids in 50% v/v distilled water/methanol) is added a solution of 50 mg of coumarin 6 and 50 mg of Compound 1 dissolved in a homogeneous mixture of 9 mL of dichloromethane and 16 mL of absolute ethanol. The addition of the dye and purification of the product is carried out as described in EXAMPLE 3. Visual analysis of a dilute aqueous suspension of the product by fluorescence microscopy using standard fluorescein excitation and emission filters shows uniformly dyed particles that are highly monodisperse. Spectral analysis of the product, exciting at 430 nm shows the major emission peak to be centered at 512 nm. There is a smaller emission peak centered at 520 nm from the coumarin 6, indicating substantial, but not complete energy transfer.
Reaction SMILES: C(I)C.CI.[CH2:6]([N:8]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)C>>[CH3:6][N:8]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2
Reactant: CCn1c(=O)c2ccccc2c2ccccc21
Solvent: CCI
Solvent: CI
Product: Cn1c(=O)c2ccccc2c2ccccc21

Procedure:
By the use of ethyl iodide rather than methyl iodide, 5-ethyl-6 (5H)phenanthridone was prepared in 97% yield (m.p. 87°-90°).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:28])=[C:22]([CH:24]=[CH:25][C:26]=1[Cl:27])[NH2:23])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:31]1[CH2:35][CH2:34][CH:33](OC)O1>C(O)(=O)C>[Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:28])=[C:22]([N:23]2[CH:31]=[CH:35][CH:34]=[CH:33]2)[CH:24]=[CH:25][C:26]=1[Cl:27])([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1CCC(OC)O1
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc(N)c1Cl)(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2)c1Cl)(c1ccccc1)c1ccccc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
To a solution of 3-(tert-butyldiphenylsilyloxymethyl)-2,4-dichloroaniline (6.08 g) in acetic acid (15 ml) was added 2,5-dimethoxytetrahydrofuran (1.87 g). The mixture was stirred at 90° C. for 1 hour and evaporated under reduced pressure. The residue was purified by a silica gel column chromatography eluted with n-hexane-ethyl acetate to give 1-[3-(tert-butyldiphenylsilyloxymethyl)-2,4-dichlorophenyl]pyrrole (5.82 g) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][P:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([O:23][CH3:24])[CH:15]=1)(=[O:12])[O:7][CH2:8][CH2:9][O:10][CH3:11].[H][H]>CO.[Pd]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][P:6](=[O:12])([O:7][CH2:8][CH2:9][O:10][CH3:11])[O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:15][C:16]=1[O:23][CH3:24]
Reactant: [H][H]
Reactant: COCCOP(=O)(Cc1ccc([N+](=O)[O-])c(OC)c1)OCCOC
Agent: [Pd]
Solvent: CO
Product: COCCOP(=O)(Cc1ccc(N)c(OC)c1)OCCOC
Yield: 96.8 %

Procedure:
A mixture of bis(2-methoxyethyl)(4-nitro-3-methoxybenzyl)phosphonate (Compound 217D, 4.5 g, 12.4 mmol) and 5% Pd/C (2 g, wet) in MeOH (100 mL) was hydrogenated under 50 psi hydrogen pressure at 50° C. for 18 h. The reaction mixture was filtered and the filtrate was concentrated to give the desired product (4 g, 97%). 1H NMR (DMSO-d6, 400 MHz): δ=3.11 (d, J=21.2 Hz, 2 H), 3.34 (s, 6 H), 3.49 (m, 4 H), 3.81 (s, 3 H), 4.05 (m, 4 H), 6.12 (d, J=8.4 Hz, 2 H), 6.20 (dd, J=8.4 Hz, 1 H), 6.78 (s, 1 H).