Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[NH:8]2)=[C:4]([N:18]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:31][C:32]1[CH:42]=[CH:41][C:35]([O:36][CH2:37][C:38](Cl)=[O:39])=[CH:34][CH:33]=1>O1CCOCC1.CO.O1CCOCC1>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[NH:8]2)=[C:4]([N:18]2[CH2:24][CH2:23][CH2:22][N:21]([C:38](=[O:39])[CH2:37][O:36][C:35]3[CH:41]=[CH:42][C:32]([Cl:31])=[CH:33][CH:34]=3)[CH2:20][CH2:19]2)[N:3]=1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: Nc1nc(N2CCCNCC2)c2nc(-c3ccc(F)cc3)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Product: Nc1nc(N2CCCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(-c3ccc(F)cc3)[nH]c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a solution of 2-amino-6-(homopiperazin-1-yl)-8-(4-fluorophenyl)-9H-purine (0.2 mmol) in dioxane/methanol (1:1; 5 ml) was added potassium carbonate (55 mg, 0.4 mmol) and a solution of 4-chlorophenoxyacetyl chloride (60 mg, 0.24 mmol) in dioxane (1 ml). The resulting mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was purified by flash chromatography on silica (methanol/dichloromethane 1:40), yielding the pure title compound (60 mg, 60%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[C:14]([CH3:15])=[C:13]([F:16])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].OS(O)(=O)=O>>[Cl:5][C:6]1[C:14]([CH3:15])=[C:13]([F:16])[C:12]([N+:1]([O-:4])=[O:2])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: Cc1c(F)ccc(C(=O)O)c1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1c(F)c([N+](=O)[O-])cc(C(=O)O)c1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Aq HNO3 (65%, 0.39 mL) is added at 0° C. to a mixture of 2-chloro-3-methyl-4-fluoro-benzoic acid (880 mg, 4.7 mmol) and 8 mL conc H2SO4 and it is stirred for 2 h without further cooling. The mixture is poured into ice water and the precipitate is collected by filtration and dried.
Reaction SMILES: [K+].[C:2]([C:4]1[CH:13]=[C:12]([F:14])[C:7]2[N:8]=[C:9]([S-:11])[S:10][C:6]=2[C:5]=1[F:15])#[N:3].[K].S[C:18]1SC2C(N=1)=NC=C(C(OCC)=O)C=2>>[F:14][C:12]1[C:7]2[N:8]=[C:9]([S:11][CH3:18])[S:10][C:6]=2[C:5]([F:15])=[C:4]([C:2]#[N:3])[CH:13]=1
Reactant: N#Cc1cc(F)c2nc([S-])sc2c1F
Reactant: CCOC(=O)c1cnc2nc(S)sc2c1
Agent: [K+]
Agent: [K]
Product: CSc1nc2c(F)cc(C#N)c(F)c2s1

Procedure:
4,7-Difluoro-2-(methylthio)benzo[d]thiazole-6-carbonitrile was synthesized as a yellow solid (1.0 g, 37%) using a procedure analogous to that described in Step 2 of Example 114, substituting 6-cyano-4,7-difluorobenzo[d]thiazole-2-thiolate potassium salt from the previous step for ethyl 2-mercaptothiazolo[4,5-b]pyridine-6-carboxylate potassium salt used in Example 114. 1H NMR (500 MHz, DMSO-d6) δ 8.04 (m, 1H), 2.88 (s, 3H); LCMS (ESI) m/z 243 (M+H)+.
Reaction SMILES: [CH:1]1(Br)[CH2:3][CH2:2]1.[Mg].[CH2:6]([N:8]([CH2:27][CH3:28])[C:9]([C:11]1[CH:26]=[CH:25][C:14]([C:15]([C:17]2[CH:18]=[C:19]([O:23][CH3:24])[CH:20]=[CH:21][CH:22]=2)=[O:16])=[CH:13][CH:12]=1)=[O:10])[CH3:7].[Cl-].[NH4+]>O1CCCC1>[CH:1]1([C:15]([C:14]2[CH:25]=[CH:26][C:11]([C:9](=[O:10])[N:8]([CH2:27][CH3:28])[CH2:6][CH3:7])=[CH:12][CH:13]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[OH:16])[CH2:3][CH2:2]1
Reactant: BrC1CC1
Reactant: CCN(CC)C(=O)c1ccc(C(=O)c2cccc(OC)c2)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(C(O)(c2cccc(OC)c2)C2CC2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
A solution of cyclopropyl bromide (0.31 ml) dissolved in tetrahydrofuran (1.5 ml) was added with magnesium (46.9 mg) and stirred at 60° C. for 1 hour to prepare a Grignard reagent. The Grignard reagent was added with a solution of 3-(4-diethylcarbamoylbenzoyl)anisole (150 mg) synthesized in accordance with the method described in WO97/10230, which was dissolved in tetrahydrofuran (1.5 ml), and then stirred at 60° C. for 2 hours. The reaction mixture was added with saturated aqueous ammonium chloride (4 ml) with ice cooling to terminate the reaction and then extracted twice with dichloromethane (4 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=2:1→1:1) to obtain 90.9 mg of the title compound. Yield: 53%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:29])[C:15]([O:18][C:19]1[CH:24]=[C:23]([F:25])[C:22]([Cl:26])=[CH:21][C:20]=1[CH:27]=O)([CH3:17])[CH3:16].N1CCCC1>CO>[CH3:12][O:13][C:14](=[O:29])[C:15]([O:18][C:19]1[CH:24]=[C:23]([F:25])[C:22]([Cl:26])=[CH:21][C:20]=1/[CH:27]=[C:6]1\[C:7](=[O:11])[NH:8][C:9]2[C:5]\1=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)([CH3:17])[CH3:16]
Reactant: COC(=O)C(C)(C)Oc1cc(F)c(Cl)cc1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNC1
Solvent: CO
Product: COC(=O)C(C)(C)Oc1cc(F)c(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C

Procedure:
To the mixture of 6-chloro-1,3-dihydro-indol-2-one (0.73 g, 4.4 mmol) and 2-(4-Chloro-5-fluoro-2-formyl-phenoxy)-2-methyl-propionic acid methyl ester (1 g, 3.65 mmol) in methanol (15 mL) was added pyrrolidine (0.26 g, 4.4 mmol) dropwise. Then the mixture was heated at 70° C. for 1 h. After cooled to room temperature, the mixture was concentrated to give the crude product which was used for the next step reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[C@@H:12]2[CH2:17][CH2:18][C@H:9]1[C@@H:10]([OH:20])[C@H:11]2[OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O[N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=C[C:26]=2[N:25]=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.Cl.N1CCC[C@H]1C#N>CN(C)C=O>[C:26]([C@@H:27]1[CH2:28][CH2:29][CH2:30][N:23]1[C:14]([C@@H:13]1[C@@H:12]2[CH2:17][CH2:18][C@@H:9]([C@@H:10]([OH:20])[C@H:11]2[OH:19])[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[O:16])#[N:25]
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)O)[C@@H]2CC[C@H]1[C@@H](O)[C@H]2O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N#C[C@@H]1CCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@H](C(=O)N2CCC[C@H]2C#N)[C@@H]2CC[C@H]1[C@@H](O)[C@H]2O
Reaction time: 3 h

Procedure:
To a solution of (1S,3S,4S,5S,6R)-2-(tert-butoxycarbonyl)-5,6-dihydroxy-2-azabicyclo[2.2.2]octane-3-carboxylic acid obtained in Example 1-3 (500 mg) 1-hydroxybenzotriazole hydrate (415 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (493 mg) in dimethylformamide (10 mL), were added diisopropylethylamine and (2S)-2-pyrrolidinecarbonitrile hydrochloride with cooling on an ice bath. The reaction mixture was stirred at that temperature for 3 hrs.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.[CH3:11][Mg]Br>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH3:11])=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
To a solution of 4-bromo-2-fluorobenzaldehyde (2.01 g, 9.9 mmol) in tetrahydrofuran (20 mL) was dropped methylmagnesium bromide (10 mmol, 1N in tetrahydrofuran) and the mixture was stirred at room temperature for 30 minutes. TLC showed all starting material was consumed, then the mixture was quenched with aqueous ammonium chloride (1N, 5 mL). To the mixture, water (50 mL) was added and extracted with dichloromethane (2*50 mL). The combined organic phase was separated, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20:1) to give the product 1-(4-bromo-2-fluorophenyl)ethanol as colorless oil (2.0 g, 92%). 1H NMR (300 MHz, CDCl3): δ 7.40-7.19 (m, 3H), 5.16 (q, J=6.3 Hz, 1H), 1.76 (s, 1H), 1.49 (d, J=6.3 Hz, 3H).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:18]C(=O)C)[C:13]=1OC(=O)C)C(Cl)=O)(=O)C.C([O:40]CCCN)CCCCCCCCCCCCCCCCC.C(N(CC)CC)C.[OH2:52]>O1CCCC1>[CH3:6][C:7]([CH2:11][C:12]([CH2:13][C:5]([OH:40])=[O:4])=[O:18])=[O:52]
Reactant: O
Reactant: CC(=O)Oc1cc(C(=O)Cl)cc(OC(C)=O)c1OC(C)=O
Reactant: CCCCCCCCCCCCCCCCCCOCCCN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)CC(=O)O
Reaction time: 4 h

Procedure:
To 31 g (0.1M) of 3,4,5-triacetoxybenzoic acid chloride dissolved in 100 ml of tetrahydrofuran was added a solution of 33 g (0.1M) of octadecyloxypropylamine and 10 g (0.1M) of triethylamine dissolved in 50 ml of tetrahydrofuran as the reaction system was cooled with water. Further, the reaction proceeded at room temperature for 4 hours. Thereafter, 200 ml of water was added thereto, and the reaction product was extracted with ethyl acetate. The extract was washed with water and concentrated. Then, it was recrystallized from an ethanol-methanol (250 ml/50 ml) mixture. Thus, the intended triacetate was obtained. Yield 43.5 g (72%). This triacetate was dissolved in a mixed solution consisting of 100 ml of methanol and 50 ml of THF and thereto 2 g of sodium acetate was added. The reaction proceeded at 50° C. for 2 hours. Thereafter, the reaction mixture was neutralized with 24 ml of 1N hydrochloric acid and thereto 300 ml of water was added. Thereupon, crystals separated out. These were filtered off, and recrystallized from 140 ml of chloroform. Thus, 26 g (76%) of the intended compound was obtained. Melting Point 106°-107.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][C@@H:9]([C:11](=[O:29])[NH:12][CH2:13][CH2:14][C:15]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)[CH:18]=[N:17][CH:16]=2)[CH2:8][NH:7][CH2:6]1)=[O:4].[C:30]1([CH2:36][CH:37]=O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([BH3-])#N.[Na+]>CO>[CH2:37]([N:7]1[CH2:8][C@H:9]([C:11](=[O:29])[NH:12][CH2:13][CH2:14][C:15]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)[CH:18]=[N:17][CH:16]=2)[CH2:10][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1)[CH2:36][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)[C@@H]1CNC[C@H](C(=O)NCCc2cncn2Cc2ccc(C#N)cc2)C1
Reactant: O=CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H]1C[C@@H](C(=O)NCCc2cncn2Cc2ccc(C#N)cc2)CN(CCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
cis-3-Methoxycarbonyl-5-[N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl]piperidine (59.0 mg, 0.149 mmol) was dissolved in MeOH (2 mL). Phenylacetaldehyde (52.3 ul, 0.447 mmol) was added followed by sodium cyanoborohydride (28.1 mg, 0.447 mmol). The solution was stirred overnight at ambient temperature. The MeOH was removed under reduced pressure and chromatography (silica gel, 1-2% MeOH/CH2Cl2 /NH4OH) gave the title compound as a white solid. 1H NMR (CDCl3); δ7.62 (d, 2H, J=8 Hz), 7.50 (s, 1H), 7.08-7.37 (m, 7H), 6.88 (s, 1H), 6.46 (br s, 1H), 5.22 (s, 2H), 3.64 (s, 3H), 3.27-3.19 (m, 1H), 3.03-3.20 (m, 1H), 2.86-3.00 (m, 1H),2.73-2.85 (m, 3H), 2.44-2.70 (m, 5H), 2.26-2.41 (m, 2H), 1.98-2.10 (m, 2H), 1.80-1.95 (m, 1H). FAB MS 500 (M+1)
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:5][CH2:6][OH:7])[CH2:3][OH:4].[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1.C(OCC)(=O)C>C1COCC1.O>[Si:9]([O:7][CH2:6][CH2:5][C:2]([CH3:8])([CH3:1])[CH2:3][OH:4])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(CO)CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(CO)CCO[Si](C)(C)C(C)(C)C
Reaction time: 24 h
Yield: 69.8 %

Procedure:
A solution of 2,2-dimethyl-1,4-butanediol (8.01 g, 67.8 mmol) in dry THF (80 mL) was treated with t-butyldimethylsilyl chloride (10.2 g, 67.8 mmol) and imidazole (4.60 g, 67.6 mmol). After 24 h at room temperature, work-up with ethyl acetate and water followed by drying the organics and concentration gave a crude product, which was purified by silica gel flash chromatography (being eluted with 5% ethyl acetate in hexane) to afford 11.0 g (Y: 70%) of 4-t-butyldimethylsilyloxy-2,2-dimethyl-1-butanol (XXVIIb) as a colorless oil; 1H-NMR (DMSO-d6) δ ppm: 4.43 (t, 1H) 3.61 (t, 2H) 3.05 (d, J=2.7 Hz, 2H) 1.38 (t, 2H) 0.83 (s, 9H) 0.78 (s, 6H) 0.00(s, 6H); HRMS Calcd for C12H29O2Si (MH+): 233.1937, found: 233.1930.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[CH:10]=[C:9]([I:11])[CH:8]=[C:7]([F:12])[CH:6]=1)[CH2:3][OH:4].C1COCC1.C([O-])(O)=O.[Na+].[C:23](Cl)(=[O:39])[O:24][CH2:25][CH:26]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2>C(OCC)(=O)C.O>[F:12][C:7]1[CH:6]=[C:5]([C@H:2]([NH:1][C:23](=[O:39])[O:24][CH2:25][CH:26]2[C:38]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:32]3[C:27]2=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:3][OH:4])[CH:10]=[C:9]([I:11])[CH:8]=1
Reactant: N[C@H](CO)c1cc(F)cc(I)c1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@H](CO)c1cc(F)cc(I)c1)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 75.4 %

Procedure:
To (S)-2-amino-2-(3-fluoro-5-iodophenyl)ethanol (4500 mg, 14.17 mmol) was added THF (Volume: 40 mL, Ratio: 2.67) and water (Volume: 15 mL, Ratio: 1.000), followed by NaHCO3 (4762 mg, 56.7 mmol). The mixture was stirred for 2 minutes then cooled to 0° C. in an ice bath. To the reaction was added (9H-fluoren-9-yl)methyl carbonochloridate (5499 mg, 21.26 mmol) and the reaction was stirred at 0° C. for 30 minutes, allowed to warm to room temperature and stirred for a further 60 minutes, before conducting LCMS. Ethyl acetate was added to the crude reaction mixture. The mixture was washed with water (2×), saturated salt solution, dried sodium sulfate, filtered and concentrated to residue. The crude product was purified by silica gel chromatography using a 300 g column (solid load) eluting from 0-60% ethyl acetate in heptane. The desired fractions were concentrated to constant mass to give as white solid 5375 mg of the desired product as free base used as is, (73% yield). LCMS (m/z): 504.1 (MH+), 1.05 min. 1H NMR (<cd3od>) d: 7.78 (d, J=7.4 Hz, 2H), 7.64 (d, J=7.2 Hz, 2H), 7.53 (s, 1H), 7.33-7.43 (m, 3H), 7.25-7.33 (m, 2H), 7.07 (d, J=9.2 Hz, 1H), 4.64 (t, J=5.9 Hz, 1H), 4.31-4.46 (m, 2H), 4.21 (t, J=6.3 Hz, 1H), 3.66 (d, J=3.1 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH:5](O)[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:2].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[O:21]=[C:19]1[C:18]2[C:17](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16](=[O:26])[N:20]1[CH:5]([CH2:4][O:3][CH2:1][CH3:2])[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOCC(O)CNC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOCC(CNC(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At RT, 3.73 g of rac-tert-butyl (3-ethoxy-2-hydroxypropyl)carbamate (17 mmol, 1 equivalent), 2.50 g of phthalimide (17 mmol, 1 equivalent) and 6.69 g of triphenylphosphine (25.52 mmol, 1.5 equivalents) were initially charged in 70 ml of dry THF. 5.06 ml of diisopropyl azodicarboxylate (25.5 mmol, 1.5 equivalents) were added dropwise, and the mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure. The crude product was diluted with methanol, acetonitrile and water to 90 ml and purified by preparative HPLC (column material: Sunfire C18 5 μm 75×30 mm; flow rate 56 ml/min; mobile phase: 45% Milli-Q-water/50% acetonitrile/5% 1% aqueous formic acid; injection volume: 0.5 ml; detection wavelength: 210 nm). This gave 4.88 g of the title compound (82% of theory).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])[C@H:3]1[C:13]([OH:15])=[O:14].[C:17]([C@@H:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)#[N:18]>>[CH3:16][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])[C@H:3]1[C:13]([O:15][C@H:19]([C:17]#[N:18])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:21]=1)=[O:14]
Reactant: CC(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Product: CC(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Yield: 69.6 %

Procedure:
Using the procedure of Step D of Example 1, 900 mg of the product of Step C and 900 mg of (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain 1.8 g of raw product which was chromatographed over silica gel. Elution with a 9-1 cyclohexane-ethyl acetate mixture yielded 1.2 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[Z-2-(isopropoxycarbonyl)-ethenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+54°±2° (c=0.4% in benzene).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH:13]=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:31].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH:13]=[N:12][C:7]=3[C:8]([NH2:31])=[N:9][C:10]=2[CH:11]=1
Reactant: CC(C)Cn1cnc2cnc3cc(Br)ccc3c21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: CC#N
Product: CC(C)Cn1cnc2c(N)nc3cc(Br)ccc3c21

Procedure:
The method described in Part J of Example 365 was used to oxidize and aminate 7-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (18.7 g, 58.4 mmol). 3-Chloroperoxybenzoic acid (22.1 g of 50% pure material, 129 mmol) was added in five portions during the oxidation step, and the amination with ammonium hydroxide (146 mL) and p-toluenesulfonyl chloride (16.6 g, 87.6 mmol) proceeded overnight. The crude product was obtained as an oil, which was treated with acetonitrile to form a precipitate. The precipitate was isolated by filtration, washed with a small amount of acetonitrile, and recrystallized from acetonitrile to provide 4 g of 7-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine as off-white needeles, mp 218-220° C.
Reaction SMILES: C[C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][CH:5]([C:12]([OH:14])=O)[CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8].[C:19]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:39]1[CH:51]=[CH:50][C:49]2C3C(=CC=CC=3)[CH2:42][C:41]=2[CH:40]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH:15]1[C:16]2[CH2:42][C:41]3[C:40](=[CH:39][CH:51]=[CH:50][CH:49]=3)[C:17]=2[CH:18]=[CH:2][C:3]=1[O:4][CH:5]1[CH2:6][CH:7]([C:9]([O:11][CH3:19])=[O:10])[NH:8][C:12]1=[O:14]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccccc1OC(C[C@H](N)C(=O)O)C(=O)O
Reactant: Oc1ccc2c(c1)Cc1ccccc1-2
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: COC(=O)C1CC(Oc2ccc3c(c2)Cc2ccccc2-3)C(=O)N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.2 %

Procedure:
A mixture of the compound prepared as described in Example 4 (0.462 g), triphenylphosphine (0.864 g), and 2-hydroxyfluorene (0.600 g) in tetrahydrofuran (4.2 ml) was cooled to approximately 1°-2° C., and treated with a solution of diethylazodicarboxylate (0.573 g) in tetrahydrofuran (1.7 ml) over a five minute period. After the addition was complete, the reaction was allowed to warm to room temperature. After about 24 hours, the resulting suspension was filtered, and the insolubles washed with tetrahydrofuran (5 ml) to give 0.526 g of methyl 3-(2-fluorenoxy)-2-pyrrolidone-5-carboxylate. This material was dried in a vacuum oven at 60° C. for approximately 24 hours.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:12]=[N:13][C:14]=2[C:15]2[N:19]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[O:17][N:16]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(Cl)Cl.[NH3:26]>C(O)C>[NH2:26][C:2]1[C:3]2[N:4]([CH:12]=[N:13][C:14]=2[C:15]2[N:19]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[O:17][N:16]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Clc1nc2ccccc2n2cnc(-c3noc(C4CC4)n3)c12
Reactant: N
Solvent: ClCCl
Solvent: CCO
Product: Nc1nc2ccccc2n2cnc(-c3noc(C4CC4)n3)c12

Procedure:
A stirred solution of 4-chloro-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-imidazo[1,5-a]quinoxaline (0.15 g) in 10 ml of a 1:1 mixture of CH2Cl2 and ethanol was saturated with ammonia. The reaction was monitored by t.l.c. (silica gel/CH2Cl2 -acetone 4:1) and ammonia was bubbled through the solution in between. When the reaction was completed, the solvent was evaporated in vacuo and the residue was triturated with 10 ml of water. The precipitate was filtered off, rinsed with water and dried to give 0.12 g of the title compound as white needles, m.p. 305°-310° C. (Compound 3).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>O=[Pt]=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:20]=[C:21]([C:29]([F:30])([F:31])[F:32])[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=3)[CH2:17][CH2:18]2)(=[O:11])=[O:12])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)cc1
Reactant: [H][H]
Agent: O=[Pt]=O
Product: Nc1ccc(S(=O)(=O)N2CCN(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)cc1

Procedure:
In the manner given in Example 5B, 1-[(p-nitrophenyl)sulfonyl]-4-[3,5-di(trifluoromethyl)-phenyl]piperazine is reduced with hydrogen over PtO2 to give 1-[(p-aminophenyl)sulfonyl]-4-[3,5-di(trifluoromethyl)phenyl]piperazine.
Reaction SMILES: Cl[C:2]([O-:4])=[O:3].[NH2:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][NH2:11]>C1(C)C=CC=CC=1.CCCCCC>[C:2](=[O:3])([OH:4])[NH2:5].[NH2:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][NH2:11]
Reactant: O=C([O-])Cl
Agent: NCCNCCN
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: NC(=O)O

Procedure:
A 988 g (1:04 mole) portion of polyisobutyl-24 chloroformate prepared according to the procedure outlined in Example 2, which had been diluted to 1800 ml with toluene was combined with 1800 ml of a solution containing 870 ml (8.05 moles) of diethylenetriamine in toluene using a Kenics static mixer (11 inches×3/8 inch); the reaction mixture was discharged into a 5 liter receiver. The reaction mixture was stripped, and then diluted with 8 1 hexane. A lower layer containing excess diethylene triamine was removed. The upper layer was washed twice with 3 l 5% aqueous sodium hydroxide; phase separation was assisted by the addition of salt, NaCl (to give brine in situ). After a final wash with basic brine, the organic layer was dried (over Na2SO4 ), filtered and stripped to give the above-identified product as a viscous yellow liquid (AV=64).
Reaction SMILES: [ClH:1].[CH:2]1[C:15]2[CH:14]=[C:13]([CH2:16][NH:17][C@@:18]([CH3:24])([C@@H:21]([OH:23])C)[CH2:19][OH:20])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C1C2C=[C:36]([CH:39]=[O:40])C3C(=CC=CC=3)C=2C=CC=1.Cl.NC(COCC)(CO)CO>>[ClH:1].[CH2:39]([O:40][CH2:24][C:18]([NH:17][CH2:16][C:13]1[C:12]2[C:7]([C:6]3[CH:5]=[CH:4][CH:3]=[CH:2][C:15]=3[CH:14]=1)=[CH:8][CH:9]=[CH:10][CH:11]=2)([CH2:21][OH:23])[CH2:19][OH:20])[CH3:36]
Reactant: C[C@H](O)[C@@](C)(CO)NCc1cc2ccccc2c2ccccc12
Reactant: O=Cc1cc2ccccc2c2ccccc12
Agent: CCOCC(N)(CO)CO
Agent: Cl
Product: CCOCC(CO)(CO)NCc1cc2ccccc2c2ccccc12

Procedure:
Using the reductive amination procedure outlined for 7G, phenanthrene-9-carbaldehyde (Aldrich) and 2-amino-2-ethoxymethyl-1,3-propanediol hydrochloride.1/4H2O (8B) gave 2-ethoxymethyl-2-(((9-phenanthrenyl)methyl)amino)-1,3-propanediol hydrochloride mp 173°-175°, (EtOH/Et2O), (C, H, Cl, N).