Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](O)=[O:18])[CH2:15][C:8]=3[CH:7]=[C:6]([Br:26])[C:5]=2[NH:4][N:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[NH:60]1[CH2:65][CH2:64][CH:63]([N:66]2[C:74]3[C:69](=[N:70][CH:71]=[CH:72][CH:73]=3)[NH:68][C:67]2=[O:75])[CH2:62][CH2:61]1>CN(C)C=O>[Br:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:23])[F:24])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](=[O:18])[N:60]4[CH2:61][CH2:62][CH:63]([N:66]5[C:74]6[C:69](=[N:70][CH:71]=[CH:72][CH:73]=6)[NH:68][C:67]5=[O:75])[CH2:64][CH2:65]4)[CH2:15][C:8]=3[CH:7]=[C:6]([Br:26])[C:5]=2[NH:4][N:3]=1
Reactant: O=C(O)C[C@@H]1Cc2cc(Br)c3[nH]nc(Br)c3c2CN(CC(F)(F)F)C1=O
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C[C@@H]1Cc2cc(Br)c3[nH]nc(Br)c3c2CN(CC(F)(F)F)C1=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 34 %

Procedure:
(S)-2-(1,4-Dibromo-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (51 mg, 0.102 mmol) was dissolved in N,N-dimethylformamide (1.5 mL). N,N-Diisopropylethylamine (90 μl, 0.517 mmol) was added to the mixture followed by TBTU (36.1 mg, 0.112 mmol). 1-(Piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one dihydrochloride (36.5 mg, 0.125 mmol) was added to the mixture. Reaction stirred at room temperature for 2.5 hours. Reaction was quenched with 50% acetonitrile-water. Mixture was purified by reverse phase prep HPLC (acetonitrile-water-trifluoroacetic acid). Acetonitrile was removed from the fraction by roto-vap. Remaining aqueous was made basic with aqueous sodium bicarbonate. Material was extracted twice with ethyl acetate. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white solid in 34% yield. 1H NMR (500 MHz, DMSO-D6) δ ppm 13.92 (s, 1H) 11.56 (d, J=6.41 Hz, 1H) 7.90 (d, J=5.19 Hz, 1H 7.65 (dd, J=69.89, 7.93 Hz, 1H) 7.49 (s, 1H) 6.81-7.06 (m, 1H) 5.54-5.68 (m, 1H) 5.35-5.50 (m, 1H) 4.49-4.63 (m, 1H) 4.32-4.42 (m, 1H) 4.20-4.49 (m, 1H) 4.13-4.20 (m, 1H) 3.93-4.14 (m, 1H) 3.22 (d, J=16.17 Hz, 2H) 2.97-3.12 (m, 1H) 2.86-2.97 (m, 1H) 2.67-2.79 (m, 1H) 2.52-2.66 (m, 1H) 2.42-2.48 (m, J=17.09 Hz, 1H) 2.34-2.42 (m, 1H) 1.93-2.32 (m, 1H) 1.74-1.85 (m, 1H) 1.65-1.74 (m, 1H). High resolution MS m/e (M+H)+=698.0314.
Reaction SMILES: C[O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30]C1C=CC=CC=1>CO.[Pd]>[CH3:30][O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][OH:2]
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COCCOCCOCCOCCOCCOCCOCCOCCOCCO
Yield: 74 %

Procedure:
A solution of nonaethylene glycol benzyl methyl ether from above (38 g) in methanol (200 ml) was shaken with 10% palladium on activated charcal (Aldrich, 1.0 g) under hydrogen (50 psi) on a Parr apparatus overnight. The catalyst was filtered off (Celite), and the filtrate was concentrated in vacuo to provide nonaethylene glycol monomethyl ether as an oil (23 g, 74%), 1H-NMR (CDCl3) δ: 3.67–3.47 (m, 36, 18 OCH2), 3.32 (s, 3, CH3).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]4[CH2:27][CH2:26][CH2:25][C:12]=4[N:13]=[C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C@@:17]4([CH3:24])[C:21](O)=[O:22])[N:15]=3)[CH:5]=2)[CH2:3][CH2:2]1.[F:28][C:29]1[N:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]4[CH2:27][CH2:26][CH2:25][C:12]=4[N:13]=[C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C@@:17]4([CH3:24])[C:21]([NH:35][C:32]4[CH:33]=[N:34][C:29]([F:28])=[CH:30][CH:31]=4)=[O:22])[N:15]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc(F)nc1
Reactant: C[C@@]1(C(=O)O)CCCN1c1nc2c(c(Nc3cc(C4CC4)[nH]n3)n1)CCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@]1(C(=O)Nc2ccc(F)nc2)CCCN1c1nc2c(c(Nc3cc(C4CC4)[nH]n3)n1)CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 3.6 %

Procedure:
To a solution of (S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methylpyrrolidine-2-carboxylic acid (1.1 g, 2.99 mmol) in DMF (12 mL) was added 6-fluoropyridin-3-amine (1.7 g, 15.18 mmol), diisopropylethylamine (0.578 g, 4.48 mmol) and HBTU (1.13 g, 2.99 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layer was washed with water (9×200 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave a crude product which was purified by reverse phase HPLC to afford 50 mg of (S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide. 1H NMR (400 MHz, CD3OD, TFA salt) δ (ppm): 0.70-0.80 (m, 2H), 0.89-0.99 (m, 2H), 1.77-1.83 (m, 1H), 1.80 (s, 3H), 2.16-2.30 (m, 5H), 2.38-2.43 (m, 1H), 2.77-2.83 (m, 2H), 2.98-3.05 (m, 2H), 3.78-3.82 (m, 1H), 3.88-3.98 (m, 1H), 6.02 (s, 1H), 6.99 (d, 1H), 7.82-7.90 (m, 1H), 8.18 (s, 1H). The other enantiomer was prepared using the (R) chiral starting material.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])=[CH:16][CH:15]=2)=[C:5]([C:11]([OH:13])=O)[N:6]([CH3:10])[C:7]=1[CH2:8][CH3:9])#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:34][C:35]1[NH:36][CH:37]=[N:38][N:39]=1>C(Cl)Cl.CN(C=O)C.N1C=CC=CC=1>[NH:38]1[CH:37]=[N:36][C:35]([NH:34][C:11]([C:5]2[N:6]([CH3:10])[C:7]([CH2:8][CH3:9])=[C:3]([C:1]#[N:2])[C:4]=2[C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])=[CH:18][CH:19]=2)=[O:13])=[N:39]1
Reactant: Nc1nnc[nH]1
Reactant: CCc1c(C#N)c(-c2ccc(-c3ccccc3C#N)cc2)c(C(=O)O)n1C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCc1c(C#N)c(-c2ccc(-c3ccccc3C#N)cc2)c(C(=O)Nc2nc[nH]n2)n1C
Temperature: 0 °C
Yield: 46 %

Procedure:
prepare a solution of 4-cyano-3-(2′-cyano-biphenyl-4-yl)-5-ethyl-1-methyl-1H-pyrrole-2-carboxylic acid (200 mg, 0.57 mmol, prepared in example A-75) in 5 mL of methylene chloride and stir under nitrogen. Add 2 drops of dry DMF and cool the mixture to 0° C. Next, add oxalyl chloride (1.10 mmol) dropwise over five minutes. Remove the icebath and stir the reaction for one hour. Add another 1.10 mmol of oxalyl chloride and continue stirring for one hour. Then concentrate the reaction mixture under vacuum to provide the crude acid chloride. Dissolve the crude acid chloride in 3.5 mL of dry pyridine and add 2-amino-1,3,4-triazole (5.9 mmol) and stir overnight at room temperature. Pour into 100 mL of ice-water and extract with methylene chloride (3×50 mL). Dry the combined organic layers over anhydrous Na2SO4, filter and evaporate. Chromatograph the residue over silica gel (100/0-3/1 toluene/EtOAc) to give the title compound (110 mg, 46% yield). MS(ES+, m/e)=422 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][CH2:11][C:10](=[O:13])[C:9]=2[CH:14]=1)=[O:4].[C:15]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O)([OH:17])=[O:16].Cl.O>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][CH:11](/[CH:21]=[C:20]3/[CH2:19][C:18](=[CH:25][CH:24]=[CH:23]/3)[C:15]([OH:17])=[O:16])[C:10](=[O:13])[C:9]=2[CH:14]=1)=[O:4]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: COC(=O)c1ccc2c(c1)C(=O)CO2
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(c1)C(=O)C(/C=C1\C=CC=C(C(=O)O)C1)O2

Procedure:
5-Methoxycarbonylbenzofuran-3-(2H)one (4.9 g) was dissolved in warm dioxan (50 ml). 3-Carboxybenzaldehyde (4.5 g) was then added followed by concentrated hydrochloric acid (10 ml). The mixture was heated on a steam bath for 15 minutes with formation of yellow crystals. After cooling and addition of an equal volume of water, the crystalline product was filtered off and recrystallised from dimethylformamide to give the title compound, m.p. 280° C.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C:7]1[C:8]([CH:16]=O)=[CH:9][C:10]2[O:14][CH2:13][O:12][C:11]=2[CH:15]=1)([CH3:4])[CH3:3].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=1.[CH:28]1[CH2:32][CH:31]=[CH:30][CH:29]=1>C(#N)C.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Sc+3]>[CH3:4][Si:2]([C:5]#[C:6][C:7]1[C:8]([CH:16]2[CH:31]3[CH2:32][CH:28]=[CH:29][CH:30]3[C:20]3[CH:21]=[C:22]([C:25](=[O:27])[CH3:26])[CH:23]=[CH:24][C:19]=3[NH:18]2)=[CH:9][C:10]2[O:14][CH2:13][O:12][C:11]=2[CH:15]=1)([CH3:1])[CH3:3]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: C1=CCC=C1
Reactant: C[Si](C)(C)C#Cc1cc2c(cc1C=O)OCO2
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CC#N
Product: CC(=O)c1ccc2c(c1)C1C=CCC1C(c1cc3c(cc1C#C[Si](C)(C)C)OCO3)N2
Temperature: 23 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A solution of the catalyst Sc(OTf)3 (0.032 g, 0.065 mmol, 10 mol %) in acetonitrile (0.2 mL) was added to the mixture of 6-trimethylsilanylethynyl-benzo[1,3]dioxole-5-carbaldehyde (0.160 g, 0.65 mmol), p-aminoacetophenone (0.0878 g, 0.65 mmol) and cyclopentadiene (0.214 g, 3.25 mmol) in acetonitrile (3 mL). The reaction was stirred at ambient temperature (˜23° C.) and the progress was monitored by thin layer chromatography. The reaction was complete after 2 hr. The reaction mixture was worked up by removal of solvent and other volatiles by evaporation under reduced pressure. The crude material was purified by preparative column chromatography using silica gel (SiO2) eluted with EtOAc/hexane (polar phase composition 8% EtOAc). The fractions containing pure product were evaporated in vacuo. The yield was 97%.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]#[N:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:13]I.[Cl-].[NH4+]>C1COCC1>[CH3:13][C:8]1([C:11]#[N:12])[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: CI
Reactant: N#CC1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C#N)CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 101.4 %

Procedure:
A 1.6M solution of Butyllithium in THF (14.6 mL, 23.3 mmol) was slowly added over 10 min to a solution of diisopropylamine (3.54 mL, 25.15 mmol) in 11 mL of anhydrous THF at −40° C. under nitrogen. The resulting mixture was stirred for 30 min at −40° C. and the solution of lithium diisopropylamide obtained was transferred dropwise over 15 min to a 0° C. solution of 1,4-Dioxa-spiro[4.5]decane-8-carbonitrile (3.00 g, 17.9 mmol) in 25 of anhydrous THF. The reaction mixture was stirred 15 min at 0° C. and methyl iodide (3.35 mL, 53.8 mmol) was added dropwise over 15 min. The resulting mixture was stirred 30 min at 0° C. then, 30 min at room temperature. A portion of 20 mL of saturated aqueous ammonium chloride was added. It was extracted with ether (3×150 mL). The organic portions were combined, dried over anhydrous Na2SO4 and concentrated. Drying under vacuum for 30 min afforded the desired 8-methyl-1,4-dioxa-spiro[4.5]decane-8-carbonitrile as a yellow solid (3.29 g, 101%).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=O.[NH:8]1[CH2:13][CH2:12][C:11]2([C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@@H:16]([NH:23][C:24](=[O:26])[CH3:25])[CH2:15][CH2:14]2)[CH2:10][CH2:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>ClCCl.C(O)(=O)C>[CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][N:8]1[CH2:13][CH2:12][C:11]2([C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@@H:16]([NH:23][C:24](=[O:26])[CH3:25])[CH2:15][CH2:14]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)CC=O
Reactant: CC(=O)N[C@H]1CCC2(CCNCC2)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N[C@H]1CCC2(CCN(CCC(C)(C)C)CC2)c2ccccc21
Reaction time: 5 h

Procedure:
A solution of 3,3-dimethylbutyraldehyde (13 mg, 0.13 mmol) and the spiro-piperidine (B5) (25 mg, 0.10 mmol) in dry dichloromethane (2 ml) was stirred at room temperature for 30 min, cooled with ice-bath, and treated with sodium triacetoxyborohydride (44 mg, 0.2 mml), followed by acetic acid (1 drop) and methanol (1 ml). The reaction mixture was stirred for another 5 hours and concentrated under a stream of nitrogen. The residue was dissolved in methanol (1 ml) and purified by reverse phase HPLC to give the title compound no. 17 as a TFA salt. LC-MS: m/e=343.30 (M+H). Rt=1.63 min. 1H-NMR (500 MHz, DMSO-d6): 9.28 (br.s, 1H), 8.18 (d, 1H), 7.35 (d, 1H), 7.30 (t, 1H), 7.19 (t, 1H), 7.16 (d, 1H), 4.92 (m, 1H), 3.45 (m, 2H), 3.14 (m, 4H), 2.19 (m, 2H), 2.05 (m, 1H), 1.87 (s, 3H), 1.82 (m, 2H), 1.73 (d, 1H), 1.60 (m, 3H), 0.93 (m, 9H).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])ON1C(=O)CC([CH2:18][CH:19]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)C1=O.[C:35](=O)([O-:37])[O-:36].[Na+].[Na+].O1CCOCC1>>[C:35]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)([O:37][CH2:18][CH:19]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:36]
Reactant: O=C(O)C1CCNCC1
Reactant: O=C([O-])[O-]
Reactant: O=C([O-])ON1C(=O)CC(CC2c3ccccc3-c3ccccc32)C1=O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Reaction time: 14 h
Yield: 95 %

Procedure:
To a solution of 10.0 g (77.4 mmol) of isonipecotic acid (Aldrich) in 1 N sodium carbonate/dioxane (1:1) at 0° C., was added 21.1 g (77.4 mmol) of 9-fluorenylmethylsuccinimidyl carbonate, portionwise. After 14 h, the dioxane was removed in vacuo, and the suspension diluted with 1200 mL of water. After extraction with 2 portions of ether (discarded), the aqueous solution was cooled in an ice bath and acidified to pH 3 with concentrated hydrochloric acid. The slurry was extracted twice with ethyl acetate and the combined organics washed with water, brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to 500 mL, diluted with 700 mL of hexane, and placed in a refrigerator overnight. The product was collected on a filter and dried in vacuo to give 25.8 g (95%) of N-FMOC-isonipecotic acid as a colorless solid.
Reaction SMILES: [CH:1]12[O:7][CH:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2.[N-:18]=[N+:19]=[N-:20].[Na+].[Cl-].[NH4+]>CO.O>[N:18]([C@H:1]1[C@H:6]([OH:7])[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:2]1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(OCc1ccccc1)N1CCC2OC2C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: [N-]=[N+]=N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1O
Temperature: 65 °C
Yield: 100.4 %

Procedure:
Benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (6.78 g, 29.1 mmol), sodium azide (3.78 g, 2 equiv), and ammonium chloride (1.56 g, 1 equiv) were dissolved in methanol (100 mL) and water (20 mL). The mixture was heated at 65° C. for 18 h. The mixture was cooled to rt and methanol was removed under vacuum. The aqueous residue was extracted with ether (3×120 mL). The combined ether layers were washed with brine (30 mL) and dried over Na2SO4. Concentration afforded (3R,4R)-benzyl 3-azido-4-hydroxypiperidine-1-carboxylate (8.07 g, quant.) which was used for without further purification. LC-MS (3 min) tR=1.45 min., m/z 277 (M+1).
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]([CH2:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[C:8](/[CH:11]=[C:12]2\[NH:13][C:14](=[O:22])[N:15]([CH2:18][CH2:19][CH2:20][CH3:21])[C:16]\2=[O:17])=[CH:9][N:10]=1)[CH2:3][CH2:4][CH3:5].C([O-])([O-])=O.[K+].[K+].Cl.[CH3:41][C:42]1[S:43][CH:44]=[C:45]([CH2:47][Cl:48])[N:46]=1.Cl>CN(C=O)C.CCOCC>[ClH:48].[ClH:1].[CH2:2]([C:6]1[N:7]([CH2:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[C:8](/[CH:11]=[C:12]2\[N:13]([CH2:47][C:45]3[N:46]=[C:42]([CH3:41])[S:43][CH:44]=3)[C:14](=[O:22])[N:15]([CH2:18][CH2:19][CH2:20][CH3:21])[C:16]\2=[O:17])=[CH:9][N:10]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1ncc(/C=C2\NC(=O)N(CCCC)C2=O)n1Cc1ccc(C(=O)OC)cc1
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2Cc2csc(C)n2)n1Cc1ccc(C(=O)OC)cc1
Reaction time: 0.5 h

Procedure:
To a solution of methyl Z-4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate hydrochloride (0.474 g, 1.0 mmol) in DMF (5 mL) is added K2CO3 (2.0 g, 15 mmol). After stirring for 5 minutes 2-methyl-4-(chloromethyl)thiazole hydrochloride (0.184 g, 1.0 mmol) is added. An additional amount of DMF (10 mL) is added after stirring for 30 minutes. The mixture is stirred for 5 days and then filtered. The filtrate is concentrated in vacuo and dissolved in ether (50 mL). This solution is washed with water and dried over K2CO3 and charcoal. A viscous oil is obtained by evaporation of the solvents in vacuo which is dissolved in ether and treated with ethereal HCl and then evaporated in vacuo to afford a solid foam. Recrystallized from 2-propanol/ether. Anal. Calcd. for C29H35N5O4S. 2HCl.0.5 H2O: C, 55.14; H, 6.07; N, 11.08
Reaction SMILES: [CH3:1][NH2:2].O1CCCC1.O1CCCC1.N1(O[C:23](=[O:39])[CH2:24][C@H:25]2[O:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27][CH2:26]2)C2C=CC=CC=2N=N1>C(OCC)(=O)C>[CH3:1][NH:2][C:23](=[O:39])[CH2:24][C@H:25]1[O:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](CC(=O)On2nnc3ccccc32)OC1
Reactant: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)C[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
Methylamine/tetrahydrofuran solution (2.0 mol/l, 1 ml) was added to a tetrahydrofuran (5 ml) solution of the compound (378 mg, 1.00 mmol) obtained in Step 1 above and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution, and brine in that order and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [methanol:ethyl acetate=5:95 (v/v)] to give 135 mg (49%) of the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][CH2:19][CH:18]3[CH3:27])=[C:12]([O:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36].[OH-].[Na+].C(=O)([O-])O.[Na+]>CO.O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][CH2:19][CH:18]3[CH3:27])=[C:12]([O:28][S:29]([CH3:32])(=[O:30])=[O:31])[CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:33][CH2:34][C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)CCc1ccc(NCc2ccc(CN3c4ccccc4CCC3C)c(OS(C)(=O)=O)c2)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1CCc2ccccc2N1Cc1ccc(CNc2ccc(CCC(=O)O)c(F)c2)cc1OS(C)(=O)=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
To a solution of ethyl 3-[2-fluoro-4-({4-[(2-methyl-3,4-dihydroquinolin-1(2H)-yl)methyl]-3-[(methylsulfonyl)oxy]benzyl}amino)phenyl]propanoate (0.60 g, 1.07 mmol) in a mixture of methanol (3.0 mL) and tetrahydrofuran (6.0 mL) was added 1 N aqueous sodium hydroxide solution (2.14 mL, 2.14 mmol), and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with 10% aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (gradient cycle A) to give a colorless oil. The obtained oil was dissolved in ethyl acetate, and the solution was neutralized with saturated aqueous sodium hydrogencarbonate solution, washed with saturated brine and dried to give the title compound (0.25 g, yield 56%) as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1O)[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].S([O:20][CH3:21])(OC)(=O)=O.[C:22](=O)([O-])[O-].[K+].[K+].O>C(C(C)=O)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:20][CH3:21])[C:8]([O:10][CH3:22])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(C)c1cc(C(=O)O)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(OC)c(C(C)(C)C)c1
Yield: 97.8 %

Procedure:
Preparation C11, Step 1: 3-tert-butyl-4-hydroxybenzoic acid (1.00 g, 5.15 mmol, 1 eq), dimethyl sulfate (1.07 mL, 11.3 mmol, 2.2 eq) and potassium carbonate (2.85 g, 20.6 mmol, 4 eq) were refluxed in methyl ethyl ketone (20 mL) for 3 hours. Worked up by adding H2O (20 mL) then stripped off the methyl ethyl ketone. The aqueous was extracted 3 times with diethyl ether (25 mL). The organic layers were combined, dried (sodium sulfate) and stripped to give methyl 3-tert-butyl-4-methoxybenzoate (1.12 g) of an amber oil Yield=97%. LCMS detects (M+H)+=223.23.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:27])[C@:4]1([O:24]C=O)[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.C(=O)(O)[O-].[K+]>CO.O>[Cl:1][CH2:2][C:3](=[O:27])[C@:4]1([OH:24])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(OC=O)C(=O)CCl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
At room temperature, 1.6 g of 21-chloro-17-formyloxy-4-pregnene-3,20-dione is stirred in a mixture of 60 ml of methanol and 9 ml of water with 500 mg of potassium bicarbonate. After one hour, the reaction mixture is stirred into ice water. The thus-precipitated product is suctioned off, washed with water, and dried over sodium sulfate, yielding 1.3 g of 21-chloro-17-hydroxy-4-pregnene-3,20-dione; mp 239.4° C.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[O:20]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC(C)([O-:37])C.[K+]>>[O:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:37][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[O:11])=[CH:6][CH:5]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Reactant: CC(C)(C)[O-]
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: [K+]
Product: O=C(C(=O)c1ccc(Oc2ccccc2Oc2ccccc2)cc1)c1ccccc1

Procedure:
Equimolar amounts of 4-nitrobenzil and 4-phenoxyphenol are reacted in the presence of potassium t-butoxide under conditions described in Example 56 paragraph (d) to form 4-(phenoxyphenoxy)benzil. A polyquinoxaline terminated by aromatic groups which are susceptible to aromatic electrophilic substitution is synthesized by the reaction of p-BOB from Example 56, -(phenoxyphenoxy)benzil and 3,3',4,4'-tetraaminobiphenyl in m-cresol The resulting polyquinoxaline polymer is isolated.