Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[CH2:12]Br.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Br:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([Cl:10])[CH:8]=1)[C:3](=[O:14])[N:21]([CH2:20][C:19]1[CH:22]=[CH:23][C:16]([Cl:15])=[CH:17][CH:18]=1)[CH2:12]2
Reactant: COC(=O)c1c(Cl)cc(Br)cc1CBr
Reactant: NCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 39.8 %

Procedure:
A mixture of 4-bromo-2-bromomethyl-6-chloro-benzoic acid methyl ester (0.900 g, 2.65 mmol), 4-chloro-benzylamine (0.391 mL, 3.2 mmol), and K2CO3 (0.69 g, 5.0 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-bromo-7-chloro-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-1-one (0.391 g, 41%). GC-MS: m/z 371 (M)+, 336 (M−35)+.
Reaction SMILES: N[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([I:9])=[C:4]([CH3:10])[N:3]=1.N([O-])=[O:12].[Na+]>OS(O)(=O)=O.O>[CH3:8][C:7]1[C:2](=[O:12])[NH:3][C:4]([CH3:10])=[C:5]([I:9])[CH:6]=1
Reactant: O=N[O-]
Reactant: Cc1cc(I)c(C)nc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1[nH]c(=O)c(C)cc1I
Temperature: 0 °C
Yield: 96.9 %

Procedure:
2-Amino-3,6-dimethyl-5-iodopyridine (4.01 g, 16.2 mmol) was dissolved in 0.5 M H2SO4 (70 mL) and the resulting solution cooled to 0° C. with stirring. A solution of sodium nitrite (3.3 g, 48.0 mmol) in H2O (5 mL) was added dropwise over 10 min. at 0° C. with vigorous stirring. After 1.5 h the cooling bath was removed and the mixture warmed to r.t. over 1 h. The solid was vacuum filtered, washed with H2O (50 mL), the solids air dried and then dried under vacuum for 18 h, yielding 3.9 g (15.7 mmol, 97%) of white solid.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([CH2:9][NH2:10])=[O:8].C(=O)(O)[O-].[Na+].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([NH:10][CH2:9][C:7]([C:3]1[S:2][CH:6]=[CH:5][CH:4]=1)=[O:8])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCC(=O)c1cccs1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(NCC(=O)c1cccs1)c1ccccc1
Yield: 94 %

Procedure:
5 g of N-[(2-thienylcarbonyl)methyl]amine hydrochloride, 10 g of sodium bicarbonate and 3.9 g of benzoyl chloride are treated in the same manner as described in Preparation 1-(3). 6.4 g of N-benzoyl-N-[(2-thienylcarbonyl)methyl]amine are thereby obtained. Yield: 93.3%
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.C(OC([NH:25][C@@H:26]([CH3:30])[C:27](O)=O)=O)(C)(C)C.C1C=NC2N(O)N=NC=2C=1.CN(C)CCCN=C=NCC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:27]([C@@H:26]([NH2:25])[CH3:30])[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=3)[C:4]=2[CH:3]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1cccc(Nc2cc(F)ccc2N)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: COc1cccc(-n2c([C@H](C)N)nc3ccc(F)cc32)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Fluoro-N2-(3-methoxyphenyl)benzene-1,2-diamine (0.7 g, 2.99 mmol) was dissolved in DCM (10 mL), under an atmosphere of nitrogen and (S)-2-tert-butoxycarbonylaminopropionic acid (0.63 g, 3.29 mmol) and HOAt (0.45 g, 3.29 mmol) added. The mixture was cooled to 0° C. before N-(3-dimethylaminopropyl)-N′ ethylcarbodiimide (0.63 g, 3.29 mmol) was added portion wise. The reaction mixture was stirred at 0° C. for 1 h, before being allowed to reach RT. It was then diluted with DCM (40 mL) and washed with 10% citric acid and brine (20 mL). The organic fraction was dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in acetic acid (10 mL) and heated at 70° C. overnight. The resultant mixture was allowed to cool to RT and concentrated in vacuo to afford a dark brown gum. This was purified by column chromatography (SiO2, gradient 0-5% MeOH in DCM) to afford boc protected title compound as a red gum, which solidified on standing (0.78 g, 68%). This was dissolved in DCM (10 mL) and TFA (3 mL) added. The reaction mixture was stirred at RT for 1 h. The resultant mixture was concentrated in vacuo and the residue dissolved in DCM (40 mL) and stirred vigorously with saturated aqueous NaHCO3 for 10 minutes. The layers were separated and the organic fraction washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a red gum (0.4 g, 70%). LCMS (Method B): RT 1.90 min [M+H]+ 286.0
Reaction SMILES: [CH2:1](/[C:3](/[C:11]#[C:12][C:13]1([OH:28])[C:24]([CH3:26])([CH3:25])[CH2:23][C:16]2(OC(C)C(C)[O:17]2)[CH:15]=[C:14]1[CH3:27])=[CH:4]/[C:5]([NH:7][CH2:8][CH2:9][CH3:10])=[O:6])[CH3:2].Cl.O>CC(C)=O>[CH2:1](/[C:3](/[C:11]#[C:12][C:13]1([OH:28])[C:24]([CH3:26])([CH3:25])[CH2:23][C:16](=[O:17])[CH:15]=[C:14]1[CH3:27])=[CH:4]/[C:5]([NH:7][CH2:8][CH2:9][CH3:10])=[O:6])[CH3:2]
Reactant: CCCNC(=O)/C=C(\C#CC1(O)C(C)=CC2(CC1(C)C)OC(C)C(C)O2)CC
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CCCNC(=O)/C=C(\C#CC1(O)C(C)=CC(=O)CC1(C)C)CC
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 87.5 %

Procedure:
(2Z)-3-Ethyl-5-(8-hydroxy-2,3,7,9,9-pentamethyl-1,4-dioxaspiro[4.5]dec-6-en-8-yl)-N-propylpent-2-en-4-ynamide (280 mg, 0.72 mmol) was dissolved in acetone (4 ml) under argon in a round-bottom flask, and 10% strength hydrochloric acid was added. The resulting reaction solution was stirred at room temperature for 50 minutes, and water was then added. After removing acetone under reduced pressure, the aqueous phase was extracted repeatedly with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By final column chromatography purification of the resulting crude product (ethyl acetate/heptane gradient), it was possible to obtain (2Z)-3-ethyl-5-(1-hydroxy-2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl)-N-propylpent-2-en-4-ynamide (200 mg, 88% of theory) in the form of a colorless solid. 1H-NMR (400 MHz, CDCl3 δ, ppm) 6.08 (br. t, 1H, NH), 6.00 (s, 1H), 5.87 (s, 1H), 3.54 (br. s, 1H, OH), 3.27 (m, 2H), 2.53 (d, 1H), 2.42 (d, 1H), 2.27 (q, 2H), 2.17 (s, 3H), 1.56 (sext, 2H), 1.22 (s, 3H), 1.13 (s, 3H), 1.11 (t, 3H), 0.93 (t, 3H).
Reaction SMILES: C(S[CH:14]([OH:26])[CH:15]=[CH:16][C:17]1[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=1[Cl:25])CCCCCCCCCCC.S(=O)(=O)(O)[OH:28].O1CCOCC1>CO.O>[OH:26][CH2:14][C:15](=[O:28])[CH2:16][C:17]1[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=1[Cl:25]
Reactant: O=S(=O)(O)O
Reactant: CCCCCCCCCCCCSC(O)C=Cc1c(Cl)cc(Cl)cc1Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: O=C(CO)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 28 °C
Reaction time: 18 h
Yield: 16.6 %

Procedure:
To an emulsion of dodecylsulfanyl-3-(2,4,6-trichloro-phenyl)-prop-2-en-1-ol (0.82 g; 1.9 mmol), prepared as described in example P61 in methanol (3 ml) was added dropwise 30% sulfuric acid (1.5 ml; 5.6 mmol). The temperature increased from 23° C. until 28° C. The mixture was heated at 60° C. for 5 h. Dioxane (2 ml) was added and reaction was stirred at 60° C. for 18 h. The biphasic mixture was transferred in a sealed microwave vial and heated at 80° C. for 10 min and at 100° C. for 10 min. The mixture obtained was poured in water and was extracted once with ethyl acetate. Organic layer was washed three times with water, dried over sodium sulfate and evaporated. The crude oil obtained was subject to flash chromatography (eluant: c-hexane/ethyl acetate 4:1). 80 mg (18% of theory) of 1-hydroxy-3-(2,4,6-trichloro-phenyl)-propan-2-one was obtained as a light yellow solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][C@@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.[C:18](=O)([O:29]C1C=CC([N+]([O-])=O)=CC=1)[O:19][CH2:20][C:21]1[O:25][N:24]=[C:23]([C:26](=[O:28])[NH2:27])[CH:22]=1.CN1CCOCC1.O>ClCCl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][C@@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:19][CH2:20][C:21]2[O:25][N:24]=[C:23]([C:26](=[O:28])[NH2:27])[CH:22]=2)=[O:29])[CH2:14]1
Reactant: NC(=O)c1cc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)on1
Reactant: c1ccc2cc(OC[C@@H]3CCNC3)ccc2c1
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: NC(=O)c1cc(COC(=O)N2CC[C@@H](COc3ccc4ccccc4c3)C2)on1
Temperature: 25 °C
Reaction time: 20 h
Yield: 38.5 %

Procedure:
0.21 g (0.92 mmol) of (R)-3-(naphth-2-yloxymethyl)-pyrrolidine is dissolved in 3.80 ml of dichloromethane and then 0.31 g (1.01 mmol) of 3-carbamoylisoxazol-5-ylmethyl 4-nitrophenyl carbonate and 0.15 ml (1.38 mmol) of N-methylmorpholine are added. The mixture is stirred at ambient temperature for 20 hours and then water is added to the reaction medium. After extraction of the aqueous phase with dichloromethane, the organic phases are successively washed three times with a 1M aqueous sodium hydroxide solution and then twice with a saturated aqueous ammonium chloride solution. After having dried the organic phases over sodium sulphate, they are filtered and the filtrate is evaporated to dryness. 0.14 g of the desired product is thus obtained in the form of a white solid after purification on a column of silica gel, elution being carried out with a dichloromethane/methanol mixture, and then taken up in isopropyl ether.
Reaction SMILES: Cl[C:2]([CH3:10])([CH2:4][CH2:5][C:6](Cl)([CH3:8])[CH3:7])[CH3:3].[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:11][C:12]1[C:13]([OH:18])=[CH:14][C:15]2[C:2]([CH3:10])([CH3:3])[CH2:4][CH2:5][C:6]([CH3:8])([CH3:7])[C:16]=2[CH:17]=1
Reactant: Cc1ccccc1O
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc2c(cc1O)C(C)(C)CCC2(C)C
Temperature: 25 °C

Procedure:
50.8 g (0.27 mol) of 2,5-dichloro-2,5-dimethylhexane, 30 g (0.27 mol) of 2-methylphenol and 500 ml of dichloromethane were introduced into a three-necked flask. 14.8 g (0.11 mol) of aluminum chloride were added in small amounts at 0° C. and the entire contents were stirred at room temperature for twelve hours. The reaction medium was poured into ice-cold water, extracted with dichloromethane, the organic phase decanted off, washed with sodium bicarbonate, dried over magnesium sulfate and evaporated.
Reaction SMILES: C([C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[C:10](=[N:26][N:27]([CH2:30][CH3:31])[C:28]=3[CH3:29])[C:11]([N:19](C([O-])=O)C([O-])=O)=[N:12][C:13]=2[C:14]=1C(C)(C)C)(C)(C)C.[O:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1.C(C1C=CC2C3C(=NN(CCC)C=3C)C(N(C([O-])=O)C([O-])=O)=NC=2C=1C(C)(C)C)(C)(C)C>>[NH2:19][C:11]1[C:10]2=[N:26][N:27]([CH2:30][CH3:31])[C:28]([CH2:29][C:35]3([OH:38])[CH2:36][CH2:37][O:32][CH2:33][CH2:34]3)=[C:9]2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C1CCOCC1
Reactant: CCn1nc2c(N(C(=O)[O-])C(=O)[O-])nc3c(C(C)(C)C)c(C(C)(C)C)ccc3c2c1C
Agent: CCCn1nc2c(N(C(=O)[O-])C(=O)[O-])nc3c(C(C)(C)C)c(C(C)(C)C)ccc3c2c1C
Product: CCn1nc2c(N)nc3ccccc3c2c1CC1(O)CCOCC1

Procedure:
Di(tert-butyl)2-ethyl-1-methyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate was reacted with tetrahydro-4H-pyran-4-one according to the method of Example 2 using di(tert-butyl)2-ethyl-1-methyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate in lieu of di(tert-butyl)1-methyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate. The crude product was recrystallized acetonitrile provide 0.349 g 4-[(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-ol as off-white crystals, mp 253-255° C.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH2:5]([S:19][CH2:20][CH:21]1[O:23][CH2:22]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C(O)C>[OH:2][CH2:1][CH2:3][NH:4][CH2:22][CH:21]([OH:23])[CH2:20][S:19][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCSCC1CO1
Reactant: NCCO
Solvent: CCO
Product: CCCCCCCCCCCCCCSCC(O)CNCCO
Temperature: 80 °C
Yield: 90.9 %

Procedure:
A 300-ml flask equipped with a stirrer and dropping funnel was charged with 61.1 g (1 mol) of ethanolamine and 61 g of ethanol. While stirring the contents at 80° C., a solution of 14.3 g (50 mmol) of 1-tetradecylthio-2,3-epoxypropane in 30 g ethanol was added dropwise over 3 hours. After completion of the dropping, the resultant reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from hexane, thereby obtaining 15.8 g (yield: 91%) of the title compound (IIe-1).
Reaction SMILES: CC(C[C@H](NC([C@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](N[C:84]([C@@H:86]([NH2:92])[CH2:87][CH2:88][C:89]([OH:91])=[O:90])=[O:85])CC1NC=NC=1)=O)CC1C2C(=CC=CC=2)NC=1)=O)CO)=O)CC1NC=NC=1)=O)CC1C=CC(O)=CC=1)=O)C(N[C@H](C(N1[C@H](C(NCC(O)=O)=O)CCC1)=O)CCCN=C(N)N)=O)C.C[OH:94].ClCl.CC1C=C(C2C=CC(N)=C(C)C=2)C=CC=1N.II>CC(O)=O>[NH2:92][C@H:86]([C:84]([OH:85])=[O:94])[CH2:87][CH2:88][C:89](=[O:90])[OH:91]
Reactant: CO
Reactant: CC(C)C[C@H](NC(=O)[C@@H](Cc1ccc(O)cc1)NC(=O)[C@H](Cc1cnc[nH]1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1cnc[nH]1)NC(=O)[C@@H](N)CCC(=O)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1CCC[C@H]1C(=O)NCC(=O)O
Agent: Cc1cc(-c2ccc(N)c(C)c2)ccc1N
Agent: ClCl
Agent: II
Solvent: CC(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
A stirred mixture of pGlu--His--Trp--Ser--Tyr--Gly--OH (XXXVIII) (16.6 gm) and 1-hydroxybenzotriazole (3 gm) in dry DMF (250 ml) was treated with DCI (4.5 gm) at 0°C and after 3 hours, the dihydrofluoride salt of Leu--Arg--Pro--Gly--NH2 (LXVI) (10.5 gm) and Et3N (3.1 ml) in dry DMF were added and stirring was continued at room temperature for a further 36 hous. The reaction mixture was evaporated in vacuo and the residue was treated with H2O (200 ml). The insoluble DCI-urea was removed and the filtrate was evaporated in vacuo to afford 38 g of crude LHRH. A portion of this (6.47 gm) in 1% AcOH (250 ml) was passed over Bio-Rad AG1-8 (OAc) (1×15 cm) and the filtrate was evaporated in vacuo. The residue, in H2O (15 ml), was chromatographed over CMC (4.5 × 27 cm) and eluted in a stepwise manner with NH4OAc buffers of pH 6.9: (0.005, 0.01, 0.025, 0.075 and 0.1 M). The pooled LHRH fractions, located in the 0.075 M eluate by the Pauly reaction, were lyophilized. The LHRH (3 gm) was further purified by gel filtration over Bio-Gel P-2 (400 gm) (110 cm × 2.5 cm) with 1.3% AcOH. Individual fractions (5 ml) were collected at a flow rate of about 5 ml.min and the pure LHRH was located in fractions 21-31 by the Pauly reaction and by tlc. Fractions showing one spot on tlc were pooled and lyophilized to constant weight affording 2.85 gm. (59%) of pure pGlu--His--Trp--Ser--Tyr--Gly--Leu--Arg--Pro--Gly--NH2 (XXII) (LHRH): [α]D22 -33.9 (c, 0.66, MeOH); [α]D22 -46.6 (c, 0.73, 1% AcOH); Rf1 0.64 and Rf3 0.37, single spot with Pauly, chlorine-tolidine and I2 reagents. Amino acid analysis gave Glu 1.08; His 0.99; Trp 0.87; Ser 0.85; Tyr 0.98; Gly 2.07; Leu 1.04; Arg 1.02; Pro 0.97; NH3 1.08.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:15])=O>CN(C=O)C>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:15])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Temperature: 78 °C

Procedure:
4-Nitrobenzoic acid, thionyl chloride and DMF were placed in a 3-liter 4-necked glass flask and heated for 2 hours at 78° C. under reflux. The end of the reaction was monitored by the clarity of the reaction mixture. There was a clear solution at the end of the reaction. Thionyl chloride was removed under reduced pressure. Dichloroethane (1 liter) was added, and evaporation was carried out to yield 4-nitrobenzoyl chloride in the form of a solid. The solid was dissolved in dichloroethane (1 liter). Dichloroethane (10 liters) was introduced into a 20-liter glass flask and cooled to 0° C. Aluminium chloride was added at 0-5° C. The 4-nitrobenzoyl chloride prepared above, dissolved in dichloroethane, was then added dropwise at 0-5° C. Phenoxypropionic acid was added in portions to the reaction composition at 0.5° C., and stirring was carried out overnight at 25° C. The TLC was checked and the reaction composition was quenched in a mixture of hexane (8 liters) and ice-water (15 liters). The composition was stirred and the solids were filtered off. The product was washed with hexane and dried.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][CH:26]=3)[O:22][C:23]=1[CH3:24])[CH:13]([CH3:33])[CH2:12]2)([OH:8])[C:4]([F:7])([F:6])[F:5]>C1(C)C=CC=CC=1.O=[Mn]=O>[CH3:24][C:23]1[O:22][C:21]([C:25]2[CH:26]=[CH:27][C:28]([CH:31]=[O:32])=[CH:29][CH:30]=2)=[N:20][C:19]=1[CH2:18][N:14]1[C:15]2[C:11](=[CH:10][C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:1])([F:34])[F:35])=[CH:17][CH:16]=2)[CH:12]=[C:13]1[CH3:33]
Reactant: Cc1oc(-c2ccc(CO)cc2)nc1CN1c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2CC1C
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccc(C=O)cc2)nc1Cn1c(C)cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Temperature: 80 °C
Reaction time: 20 h
Yield: 50.4 %

Procedure:
A solution of 100 mg (0.2 mmol) of 1,1,1,3,3,3-hexafluoro-2-{1-[2-(4-hydroxymethyl-phenyl)-5-methyl-oxazol-4-ylmethyl]-2-methyl-2,3-dihydro-1H-indol-5-yl}-propan-2-ol in 2 ml of toluene was treated with 87 mg (1.0 mmol) of MnO2 and stirred at 80° C. during 20 hours. Filtration, evaporation of the solvent and chromatography on silica gel with heptane/EtOAc 4:1 gave 50 mg (50%) of 4-{5-methyl-4-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-indol-1-ylmethyl]-oxazol-2-yl}-benzaldehyde, pink solid, MS: 497 (MH+).
Reaction SMILES: P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C.[CH3:18][NH:19][C:20]1[CH:32]=[CH:31][C:23]([O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=1.[C:33]([O:37][C:38]([N:40]([CH2:42][C:43]([OH:45])=O)[CH3:41])=[O:39])([CH3:36])([CH3:35])[CH3:34]>CN(C)C=O>[C:33]([O:37][C:38]([N:40]([CH2:42][C:43]([N:19]([C:20]1[CH:32]=[CH:31][C:23]([O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=1)[CH3:18])=[O:45])[CH3:41])=[O:39])([CH3:34])([CH3:35])[CH3:36]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CCOC(=O)COc1ccc(NC)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccc(N(C)C(=O)CN(C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 48.5 %

Procedure:
0.12 ml (0.72 mmol) of diethyl cyanophosphate and 0.20 ml (1.43 mmol) of triethylamine were added, whilst ice-cooling, to a solution of 160 mg (0.65 mmol) of ethyl 4-methylaminophenoxyacetate (prepared as an intermediate in Preparation 18) and 135 mg (0.72 mmol) of t-butoxycarbonylsarcosine in 2 ml of dimethylformamide, and the mixture was stirred at room temperature for 14 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was diluted with ethyl acetate. The resulting organic mixture was washed with a 5% w/v aqueous solution of citric acid, with a 5% w/v aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The reaction mixture was then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by preparative thin layer chromatography, using a 30:1 by volume mixture of methylene chloride and methanol as the developing solvent, to give 120 mg of ethyl 4-[N-(N-t-butoxycarbonylsarcosyl)-N-methylamino]phenoxyacetate as an oil. In a similar manner to that described in Preparation 15, 200 mg (0.55 mmol) of this compound were hydrolyzed to give 170 mg of the title compound as an amorphous substance.
Reaction SMILES: Cl.[CH2:2]1[N:7]2[C:8]3[C:13]([NH:14][C:15](=[O:16])[CH:6]2[CH2:5][NH:4][CH2:3]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[N:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26]Cl)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl>C(O)C.CC(C)=O.C(N(CC)CC)C>[N:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][N:4]2[CH2:3][CH2:2][N:7]3[C:8]4[C:13]([NH:14][C:15](=[O:16])[CH:6]3[CH2:5]2)=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:19][CH:18]=1
Reactant: ClCCCCc1ccncc1
Reactant: O=C1Nc2ccccc2N2CCNCC12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1Nc2ccccc2N2CCN(CCCCc3ccncc3)CC12

Procedure:
A solution of 6.2 g. (0.03 mole) of 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one, hydrochloride, 7 g. (0.04 mole) of 4-(4-pyridyl)-1-chlorobutane, 10 g. of potassium carbonate, 5 g. of potassium iodide and 0.5 ml. of triethylamine was stirred and refluxed in 200 ml. of acetone for 48 hours, cooled and filtered. The solvent was removed and the residue was dissolved in methylene chloride. This solution was washed with water and brine, dried over magnesium sulfate and filtered. The solvent was removed and the residue was chromatographed on 500 g. of Silicar, CC-7. Fractions eluted with 10% methanol in ethyl acetate afforded 3.2 g. of free base. 3 G. of the above free base was dissolved in ethanol and treated with dry hydrogen chloride saturated ether. The product hydrochloride was filtered and recrystallized from methanol to give 3.2 g. of the title compound as the dihydrochloride salt, m.p. 281°-283° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]4[C:20]([C:38]([NH2:40])=[O:39])=[N:21][CH:22]=[C:23]([N:25]5[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](N(CC)C)=[O:33])[CH2:26]5)[N:24]=4)=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Br:50][CH2:51][CH2:52][CH2:53]C(Cl)=O>CN(C=O)C.CCOC(C)=O>[Br:50][CH2:51][CH2:52][CH2:53][C:32]([NH:31][C@@H:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:23]2[N:24]=[C:19]([NH:18][C:15]3[CH:14]=[CH:13][C:12]([CH:9]4[CH2:10][CH2:11][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[CH2:7][CH2:8]4)=[CH:17][CH:16]=3)[C:20]([C:38]([NH2:40])=[O:39])=[N:21][CH:22]=2)[CH2:26]1)=[O:33]
Reactant: O=C(Cl)CCCBr
Reactant: CCN(C)C(=O)N[C@@H]1CCCN(c2cnc(C(N)=O)c(Nc3ccc(C4CCN(C5CCCC5)CC4)cc3)n2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1ncc(N2CCC[C@@H](NC(=O)CCCBr)C2)nc1Nc1ccc(C2CCN(C3CCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(R)-5-(3-Aminopiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide (436) (50 mg, 0.1 mmol) was dissolved in 4 mL DMF. To it were added DIEA (180 μL, 1.0 mmol) and then 4-bromobutyryl chloride (56 mg, 0.3 mmol). The mixture was stirred at RT for 1.5 hours, diluted with 60 mL EtOAc, washed with water ×3, dried, concentrated in vacuo to afford crude (R)-5-(3-(4-bromobutanamido)piperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide (448). It was dissolved in 3 mL dry DMF and the solution was stirred at RT. To it was added NaH (60%, 30 mg), and the mixture was stirred for 1 hour. It was quenched with 0.5 mL TFA, and directly subjected to reverse phase preparative HPLC using 5 mM HCl (aq) and nest MeCN to isolate the title compound, (R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(2-oxopyrrolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide (449), as HCl salt (7 mg). LC-MS (ESI): m/z (M+1) 532.6. UV: λ=267, 275, 305, 335, 373 nm.