Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH2:12]Br)[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:4].[CH2:14]([NH:21][CH2:22][CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:14]([N:21]1[CH2:22][CH2:23][N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:12][CH:2]1[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:4])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCCCCCOC(=O)C(Br)CBr
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 86.4 %

Procedure:
A solution of 48.5 g (154 mmoles) of n-hexyl 2,3-dibromopropionate (II, Z=O(CH2)5CH3) in 100 ml of dry benzene stirred at 40° C. is added dropwise to a warm solution (80° C.) of 37 g (154 mmoles) of N,N'-dibenzylethylenediamine and 55 ml of triethylamine in 100 ml benzene. The mixture was stirred for 3 hours at 80° C. After cooling and filtration of the triethylammonium chloride, the solution was evaporated off and the crude residue treated with diethyl ether and washed with water. The organic layer was dried (MgSO4), evaporated and chromatographed on a silica gel column using diethyl ether/petroleum ether (10:90, in vol.) as eluent, yielding 52.5 g (86.5%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]([Cl:15])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([OH:13])=[C:8]([Cl:14])[CH:7]=1.O[CH2:17][CH2:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1.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>O1CCCC1>[Cl:14][C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH:3]=[C:2]([Cl:1])[Cl:15])[CH:11]=[C:10]([Cl:12])[C:9]=1[O:13][CH2:17][CH2:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: OCCc1cccs1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCc2cccs2)c(Cl)c1
Temperature: 25 °C
Yield: 62.5 %

Procedure:
To a solution of 0.44 g of 4-(3,3-dichloro-2-propenyloxy)-2,6-dichlorophenol, 0.20 g of 2-(2-hydroxyethyl)thiophene and 0.40 g of triphenylphosphine dissolved in 10 ml of tetrahydrofuran was added dropwise a solution of 0.31 g of diisopropyl azodicarboxylate dissolved in 5 ml of tetrahydrofuran, while stirring at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was concentrated, to which 20 ml of diethyl ether was added, and the precipitate was filtered. The filtrate was concentrated, and the residue was subjected to silica gel chromatography, which afforded 0.38 g of 3,5-dichloro-4-(2-(2-thienyl)ethoxy)-1-(3,3-dichloro-2-propenyloxy)benzene (62% yield), nD25.6 1.5919.
Reaction SMILES: [C:1]1([C:11]([N:13]2[CH2:17][CH:16]([CH:18]([OH:20])[CH3:19])[CH:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[CH3:37]I>CS(C)=O.CCOCC>[C:1]1([C:11]([N:13]2[CH2:17][CH:16]([CH:18]([O:20][CH3:37])[CH3:19])[CH:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CI
Reactant: CC(O)C1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOCC
Product: COC(C)C1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1

Procedure:
A solution of 0.026 g (0.057 mmol) of 1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1-hydroxyethyl)pyrrolidine (diastereomer 2), 0.012 mg (0.23 mmol) of KOH and 0.0042 mL (0.068 mmol) of methyliodide in 1 mL of DMSO was stirred at rt for 30 min. The reaction mixture was diluted with ether and washed with sat'd NaHCO3 and NaCl solutions. The organic fraction was dried over Na2SO4, filtered and the filtrate was concentrated and purified by chromatography (silica, hexanes:ethylacetate:(2N NH3 in MeOH), 10:10:1) to give the title compound. 1H NMR (CDCl3) δ (key peaks) 7.88-7.91(m, 3H), 7.45-7.55 (m, 4H), 7.20 and 7.10 (d of d, 2H, J=5.5, 8.5 Hz), 7.00 and 6.95 (t, 2H, J=9.0 Hz), 3.40 and 3.24 (s, 3H) 1.25 and 1.02 (d, 3H, J=6.5 Hz), Mass Spectrum (ESI) m/e=475 (M+1).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C1C2NC3C(=CC=CC=3)SC=2C=CC=1.[CH3:19][SiH:20]([CH3:24])[O:21][CH2:22][CH3:23]>C(O)C>[NH2:4][CH2:1][CH2:2][CH2:3][Si:20]([CH3:24])([CH3:19])[O:21][CH2:22][CH3:23]
Reactant: CCO[SiH](C)C
Reactant: C=CCN
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CCO
Product: CCO[Si](C)(C)CCCN
Yield: 55 %

Procedure:
Into the same reactor as used in Example 1, 54.7 parts of allylamine, 1.0 part of phenothiazine and 0.0005 part as platinum atom of the same platinum complex as in Example 1 were charged, 100 parts of dimethylethoxysilane were added at 50° C. through the dropping funnel over 20 minutes, and the reaction was completed by elevating the temperature to 125° C. over 4 hours. After cooling, 5.5 parts of ethanol were added, and distillation was carried out to give 87.8 parts of γ-aminopropyldimethylethoxysilane boiling at 75° to 77° C./18 Torr. This corresponded to 55% yield based on the theoretical amount.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][C:4]([C:15]([O:17]C)=[O:16])=[CH:3]1.[OH-].[Na+]>C(O)C>[CH3:1][N:2]1[C:6]([C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][C:4]([C:15]([OH:17])=[O:16])=[CH:3]1
Reactant: COC(=O)c1cc(C(=O)c2ccccc2)n(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1cc(C(=O)O)cc1C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
The entire batch of methyl 1-methyl-5-benzoylpyrrole-3-carboxylate from Example 84 was combined with 200 ml. of ethanol and 100 ml. of 1N sodium hydroxide and refluxed for 2 hours. The ethanol was boiled away, the aqueous residue was cooled to room temperature, extracted with 25 ml. of ether and acidified with conc. hydrochloric acid to yield crystalline product (4 g., m.p. 210°-212° C.). A portion (1.5 g.) was recrystallized from acetone to yield purified 1-methyl-5-benzoylpyrrole-3-carboxylic acid (925 mg., m.p. 215°-216.5° C., m/e 229).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][N:11]=2.[Na].[CH3:22][SH:23].CN(C=O)C>O>[CH3:22][S:23][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][N:11]=2
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)cnc2s1
Reactant: CS
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cnccc1-c1nc2cc(C(F)(F)F)cnc2s1
Reaction time: 1 h
Yield: 87.8 %

Procedure:
A mixture of 0.20 g of 2-(3-fluoropyridin-4-yl)-6-(trifluoromethyl)thiazolo[5,4-b]pyridine, 47 mg of methylmercaptan sodium salt and 6 ml of DMF was stirred for 1 hour under ice cool. To this mixture was added 47 mg of methylmercaptan sodium salt, and the resultant mixture was stirred further for 1 hour under ice cool. To the reaction mixture was added water, and the resultant mixture was extracted with ethyl acetate twice. The combined organic layers were washed with water and saturated saline, dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, to obtain 0.19 g of 2-[3-(methylthio)pyridin-4-yl]-6-(trifluoromethyl)thiazolo[5,4-b]pyridine (hereinafter, referred to as the present compound 14).
Reaction SMILES: Cl[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[C:21]1[CH:29]=[C:28]2[C:24]([C:25]3[CH:33]=[N:32][CH:31]=[N:30][C:26]=3[NH:27]2)=[CH:23][CH:22]=1.C[C:35]#[N:36].O>CN(C=O)C.[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:35]([C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[C:21]1[CH:29]=[C:28]2[C:24]([C:25]3[CH:33]=[N:32][CH:31]=[N:30][C:26]=3[NH:27]2)=[CH:23][CH:22]=1)#[N:36]
Reactant: CC#N
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(Cl)c(-c2ccc3c(c2)[nH]c2ncncc23)c1
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1ccc2c(c1)[nH]c1ncncc12
Temperature: 175 °C

Procedure:
4-Chloro-3-(9H-pyrimido[4,5-b]indol-7-yl)-N-[3-(trifluoromethyl)phenyl]benzamide (60 mg TFA salt, 0.103 mmol), zinc cyanide (121 mg, 1.03 mmol), and tetrakis(triphenylphosphine)-palladium(0) (59 mg, 0.051 mmol) were stirred in DMF (3 mL) and the mixture was flushed with nitrogen. The mixture was heated in a microwave reactor at 175° C. for 1 h. LCMS showed 65% conversion to the desired product, M+H 458. The product was isolated by prep LCMS using a 30 mm×100 mm C18 column; 35% CH3CN—H2O (0.1% TFA), 1 min, to 55% at 6 min; 60 mL/min; detector set at m/z 458. The HPLC fractions were rotovaped to give 23 mg of the produce as a TFA salt. The product was purified by prep HPLC using a 19 mm×100 mm C18 column; 50% CH3CN—H2O (0.1% AcOH), 1 min, to 75% at 6 min; 30 mL/min; detector set at 254 nm; retention time, 3.9 min. Fractions containing pure product were combined and freeze-dried. yield 4 mg. 1H NMR (DMSO-d6) δ 12.88 (s, 1H, NH); 10.83 (s, 1H, amide NH); 9.61 (s, 1H, NH); 9.07 (s, 1H); 8.48 (d, 1H); 8.29 (d, 1H); 8.23 (s, 1H); 8.20 (d, 1H); 8.14 (dd, 1H); 8.06 (d, 1H); 7.89 (d, 1H); 7.68 (dd, 1H); 7.62 (t, 1H); 7.49 (d, 1H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5](=[O:13])[O:4][C:3]=1[CH:14]([OH:16])[CH3:15].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:13])[O:4][C:3]([CH:14]([OH:16])[CH3:15])=[C:2]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(O)c1oc(=O)c2ccc(F)cc2c1Br
Product: CC(O)c1oc(=O)c2ccc(F)cc2c1-c1ccccc1
Yield: 78.2 %

Procedure:
The title compound was made in a similar way of that of Intermediate B53 from 4-bromo-6-fluoro-3-(1-hydroxyethyl)-1H-isochromen-1-one (intermediate A7, 0.95 g, 3.31 mmol) and phenylboronic acid (0.605 g, 4.96 mmol) to afford title compound (0.736 g) which was used without any additional purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:33])=[C:8]2[C:14](Br)=[C:13]([C:16]3[CH:21]=[CH:20][C:19](Cl)=[CH:18][CH:17]=3)[N:12]([CH2:23][C:24]3[CH:32]=[CH:31][C:27]4[O:28][CH2:29][O:30][C:26]=4[CH:25]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C([O-])=O.[NH4+]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:33])=[C:8]2[CH:14]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]([CH2:23][C:24]3[CH:32]=[CH:31][C:27]4[O:28][CH2:29][O:30][C:26]=4[CH:25]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(-c1ccc(Cl)cc1)n2Cc1ccc2c(c1)OCO2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ncc2c(cc(-c3ccccc3)n2Cc2ccc3c(c2)OCO3)c1O
Yield: 79 %

Procedure:
To a mixture of 1-benzo[1,3]dioxol-5-ylmethyl-3-bromo-2-(4-chloro-phenyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (200 mg, 0.38 mmol)(from Example 35(e)) in EtOAc (4 mL) was added palladium/char coal (Pd/C)(10% wet, containing 50% water) (95 mg) and ammonium formate (HCO2NH4)(495 mg, 7.86 mmol). The mixture was refluxed for 2 h. After cooled, it was diluted with EtOAc and then filtered through a pad of celite. Filtrate was concentrated and the residue was purified by silica gel chromatography (eluting with 30%-60% EtOAc/hexanes) to give the title compound 125 mg. MS-(+)-ion: M+1=417.13.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4](Cl)=[O:5].[C:13]1([P:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([CH3:33])([CH3:32])[CH3:31])[O:20]CC)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(Cl)C>C(N(CC)CC)C>[C:13]1([P:19]([C:4](=[O:5])[C:3]2[C:2]([CH3:1])=[CH:10][C:9]([CH3:11])=[CH:8][C:7]=2[CH3:12])(=[O:20])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([CH3:32])([CH3:31])[CH3:33])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Reactant: CCOP(Oc1ccccc1C(C)(C)C)c1ccccc1
Agent: CCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(C(=O)P(=O)(Oc2ccccc2C(C)(C)C)c2ccccc2)c(C)c1
Yield: 87 %

Procedure:
69.7 g (0.382 mol) of 2,4,6-trimethylbenzoyl chloride and 0.9 g of triethylamine were heated under a nitrogen atmosphere to 115° C. and 57.8 g (0.191 mol) of monoethyl mono-2-tert-butylphenyl phenylphosphonite were added dropwise in one hour with stirring. Ethyl chloride was given off as a gas and was condensed in a downstream cold trap. The mixture was further stirred for 2 hours. In total, 11.7 g of ethyl chloride (95% of theory) condensed. After distilling off the excess acid chloride, the residue was distilled with the aid of a thin-film evaporator (bath temperature: 270° C.; 0.4 mbar). 70 g were obtained. The product was brought to crystallization from concentrated acetone solution, melting point: 76°-79° C. The yield was 87% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH2:17][CH2:18][CH2:19][CH2:20]Cl)[CH:3]=1.[CH2:22]([NH:25][CH2:26][CH2:27][CH3:28])[CH2:23][CH3:24]>C(Cl)Cl>[CH2:22]([N:25]([CH2:20][CH2:19][CH2:18][CH2:17][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:26][CH2:27][CH3:28])[CH2:23][CH3:24]
Reactant: ClCCCCc1cc(Cl)ccc1OCCc1ccccc1
Reactant: CCCNCCC
Solvent: ClCCl
Product: CCCN(CCC)CCCCc1cc(Cl)ccc1OCCc1ccccc1
Temperature: 120 °C
Reaction time: 38 h

Procedure:
To 0.91 g of the crude 4-chloro-2-(4-chlorobutyl)-1-(2-phenylethoxy)benzene, was added 10 ml of di-n-propylamine and the resulting mixture was stirred at 120° C. for 38 hours. After diluting with methylene chloride, the mixture was successively washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, the obtained residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate:n-hexane =1:6) to give 1.07 g of N,N-di-n-propyl-4-[5-chloro-2-(2-phenylethoxy)phenyl]butylamine. To a solution of 1.07 g of N,N-di-n-propyl-4-[5-chloro-2-(2-phenylethoxy)phenyl]butylamine in 10 ml of ethanol, was added a solution of 123 mg of oxalic acid in 5 ml of ethanol. After evaporation of the solvent under reduced pressure, the obtained crystals were recrystallized from ethyl acetate to give 421 mg of N,N-di-n-propyl-4-[5-chloro-2-(2-phenylethoxy)phenyl]butylamine oxalate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([N:16]([C:20]2[CH:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[CH:22][C:21]=2[O:29][CH3:30])[CH2:17][CH2:18][CH3:19])[S:13][C:14]=1[CH3:15].[CH3:31][Li]>C(OCC)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([N:16]([C:20]2[CH:25]=[C:24]([C:26](=[O:27])[CH3:31])[CH:23]=[CH:22][C:21]=2[O:29][CH3:30])[CH2:17][CH2:18][CH3:19])[S:13][C:14]=1[CH3:15]
Reactant: [Li]C
Reactant: CCCN(c1nc(-c2ccc(OC)cc2Cl)c(C)s1)c1cc(C(=O)O)ccc1OC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCN(c1nc(-c2ccc(OC)cc2Cl)c(C)s1)c1cc(C(C)=O)ccc1OC
Reaction time: 2 h

Procedure:
At 0° C., under an inert atmosphere, 2 g of 4-(2-chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-carboxy-2-methoxyphenyl)-N-propylamino]thiazole are dissolved in 30 ml of diethyl ether. Methyllithium (3 equivalents) is slowly added to the ethereal solution. When the addition is complete, the reaction mixture is brought to room temperature. After 2 hours, it is diluted with ethyl acetate and then hydrolyzed. The organic phase is washed with water and then dried over sodium sulphate. After evaporation, the residue is purified on a silica gel. The expected product is obtained in the form of a powder; m.p.=50° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@H:12]2[C@@H:16]([OH:17])[CH2:15]N(C(OCC3C=CC=CC=3)=O)[CH2:13]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].N[C@H]1C[O:32]C[C@H]1O>>[CH2:1]([C:3]1[C:4]([NH:11][C@H:12]2[CH2:13][O:32][CH2:15][C@H:16]2[OH:17])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCc1cnc(CC)c(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2O)n1
Reactant: N[C@H]1COC[C@H]1O
Product: CCc1cnc(CC)c(N[C@H]2COC[C@H]2O)n1

Procedure:
Following the procedure for the preparation of benzyl(3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylate but substituting cis-(+/−)-4-aminotetrahydrofuran-3-ol and making non-critical variations provided the title compound as a light yellow amorphous solid. IR (diffuse reflectance) 3399, 3259, 3223, 3218, 3212, 2969, 2867, 2847, 1582, 1546, 1493, 1465, 1160, 1066, 920 cm−1; MS (EI) m/z 237 (M+); HRMS (FAB) calcd for C12H19N3O2+H1 238.1555, found 238.1558.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:16])[CH:3]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:16][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([C:18]([F:29])([F:28])[F:17])=[CH:20][CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: O=C1NCCn2c1cc1cc(F)cc(Br)c12
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: O=C1NCCn2c1cc1cc(F)cc(-c3ccc(C(F)(F)F)cc3)c12

Procedure:
The title compound, off-white solid (81 mg, 93%), MS (ISP) m/z=349.2 [(M+H)+], mp 346° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 1) (70.8 mg, 0.25 mmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([NH:17][C:18](=[O:30])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25](OCC)=[O:26])[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]=1[OH:11])=[O:5])[CH3:2].[C:31]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([N:17]2[C:18](=[O:30])[C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]2=[O:26])[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]=1[O:11][CH3:31])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccccc1C(=O)Nn1cc(C(=O)OCC)c(O)c1C(=O)OCC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)c1cn(N2C(=O)c3ccccc3C2=O)c(C(=O)OCC)c1OC
Temperature: 50 °C
Yield: 75.1 %

Procedure:
A mixture of 393C (0.84 g, 2 mmol) and K2CO3 (1.0 g, 7.25 mmol) in acetone (5 ml) was heated at 50° C. for 30 min, then cooled to rt. Dimethyl sulfate (0.29 ml, 3.0 mmol) was added, the resulting mixture was heated at 40° C. until starting material consumed, quenched with brine and extracted with EtOAc. The organic layer was dried and concentrated, the residue was purified by silica gel flash column chromatography to afford 393D (0.58 g, 74% for 3 steps from 393B) (0%-5% EtOAc—CH2Cl2).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:22]=[CH:21][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1>CO.[Pd]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([S:9]([NH:8][CH2:7][C:6]2[CH:21]=[CH:22][C:3]([N:2]([CH3:23])[CH3:1])=[CH:4][CH:5]=2)(=[O:10])=[O:11])=[CH:17][CH:16]=1
Reactant: CN(C)c1ccc(CNS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: CO
Product: CN(C)c1ccc(CNS(=O)(=O)c2ccc(N)cc2)cc1
Reaction time: 8 h

Procedure:
To a solution of N-(4-dimethylamino-benzyl)-4-nitro-benzenesulfonamide (472 mg, 1.409 mmol), prepared as described in D.1, in MeOH (10 ml) under nitrogen was added Pd/C 10% (74.92 mg, 0.007 mmol). The system was purged with hydrogen and let stirred overnight under an atmosphere of hydrogen. After filtration through a celite plug, the solvent is removed under reduced pressure to yield the title compound, which is used as such for the next step.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:30]=2)O1.Br[C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH:43]=[N:42][N:41]=[N:40]2)=[CH:35][CH:34]=1>>[N:39]1([C:36]2[CH:37]=[CH:38][C:33]([C:9]3[CH:10]=[CH:11][C:12]4[O:16][C:15]([CH:17]5[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:21][CH2:22]5)=[N:14][C:13]=4[CH:30]=3)=[CH:34][CH:35]=2)[CH:43]=[N:42][N:41]=[N:40]1
Reactant: Brc1ccc(-n2cnnn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3o2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(-n5cnnn5)cc4)ccc3o2)CC1
Yield: 40.7 %

Procedure:
Following the General Procedure-1, the titled compound (80 mg) was prepared from Intermediate 8 (200 mg, 0.47 mmol) and 1-(4-bromophenyl)-1H-tetrazole (100 mg, 0.44 mmol) as a brown solid. M.P.: 207-211° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 9.02 (s, 1H), 7.91 (d, J 1.2, 1H), 7.82-7.79 (m, 4H), 7.62-7.55 (m, 2H), 4.16 (d, J 10.6, 2H), 3.21-3.12 (m, 1H), 3.00 (t, J 12.3, 2H), 2.20-2.14 (m, 2H), 2.00-1.88 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]([O:16][C@H:17]2[CH2:25][CH2:24][C@H:23]3[C@@H:19]([CH2:20][NH:21][CH2:22]3)[C@@H:18]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH2:14][OH:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:35](Cl)(=[O:39])[CH:36]([CH3:38])[CH3:37].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([O:16][C@H:17]2[CH2:25][CH2:24][C@H:23]3[C@@H:19]([CH2:20][N:21]([C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH2:22]3)[C@@H:18]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH2:14][OH:15])[CH:4]=[C:3]([C:2]([F:33])([F:1])[F:34])[CH:8]=1
Reactant: Cc1ccccc1[C@H]1[C@@H]2CNC[C@H]2CC[C@@H]1O[C@H](CO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1[C@H]1[C@@H]2CN(C(=O)C(C)C)C[C@H]2CC[C@@H]1O[C@H](CO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the compound from EXAMPLE 2 in CH2Cl2 was added isobutyric chloride, triethylamine and a catalytic amount of DMAP. The mixture was stirred at room temperature for 2 hr. The solvent was removed and the residue was heated with 10 mL 2 N NaOH in 40 mL methanol at 50° C. for 1 hr. Methanol was removed under vacuum. The residue was diluted with water and the aqueous was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and the solvent was removed. The residue was purified by preparative TLC (80:20 EtOAc:hexane), 0.07 mg. M++1: 558.16.