Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:18]=[C:19]([CH:21]([OH:26])[C:22]([F:25])([F:24])[F:23])[CH:20]=2)[C:11]([O:13]C(C)(C)C)=[O:12])=[N:6][CH:7]=1.Cl>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:18]=[C:19]([CH:21]([OH:26])[C:22]([F:25])([F:23])[F:24])[CH:20]=2)[C:11]([OH:13])=[O:12])=[N:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(C(O)C(F)(F)F)c2)nc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(O)C(F)(F)F)c2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 3-(5-methylpyridin-2-yl)-5-(2,2,2-trifluoro-1-hydroxyethyl)benzoate (3.25 g, 8.85 mmol) in dichloromethane (15 mL) was added hydrogen chloride (4.0 M in dioxane; 11.1 mL, 44.2 mmol). The reaction mixture was stirred at ambient temperature. After 18 h, the mixture was concentrated. Dichloromethane was added the suspension was filtered. The solid cake was washed with dihchloromethane and dried under reduced pressure to give the hydrochloride salt of the title compound. MS 312.1 (M+1).
Reaction SMILES: B(Br)(Br)Br.[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)=[CH:9][C:8]=1[F:21])#[N:6].O>ClCCl>[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:9][C:8]=1[F:21])#[N:6]
Reactant: COc1ccc(-c2ccc(C#N)c(F)c2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccc(O)cc2)cc1F
Reaction time: 20 h

Procedure:
A solution of boron tribromide (12.0 ml, 31.8 g, 0.13 mol) in dry dichloromethane (100 ml) was added dropwise to a stirred, cooled (-78° C.) solution of compound 4 (14.0 g, 0.06 mol) in dry dichloromethane (250 ml) under dry nitrogen. The stirred mixture was allowed to warm. to room temperature over 20 h (i.e., until glc analysis revealed absence of starting material). Water was added and a yellow precipitate was produced. The product was extracted into ether (twice), and the combined ethereal extracts were washed with water and dried (MgSO4). The solvent was removed in vacuo to afford a pale-yellow powder.
Reaction SMILES: CO[C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH2:18][O:19][CH3:20])[N:13]=[CH:12][N:11]=2)[CH:5]=1.ClC1N=CN=C(C2C=[C:31](C=CC=2)[C:32]([OH:34])=[O:33])C=1>COCCN>[C:4]([O:34][C:32](=[O:33])[CH2:31][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH2:18][O:19][CH3:20])[N:13]=[CH:12][N:11]=2)[CH:5]=1)=[O:21])([CH3:9])([CH3:5])[CH3:3]
Reactant: O=C(O)c1cccc(-c2cc(Cl)ncn2)c1
Reactant: COCCNc1cc(-c2cccc(C(=O)OC)c2)ncn1
Agent: COCCN
Product: COCCNc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ncn1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
The title compound was prepared from 3-[6-(2-methoxy-ethylamino)-pyrimidin-4-yl]-benzoic acid methyl ester [prepared by the following procedure: 3-(6-Chloro-pyrimidin-4-yl)-benzoic acid (1.0 g, 4.3 mmol) was heated in 2-methoxy-ethylamine (5 ml) to 80° C. for 1 h. The mixture was evaporated in vacuum and the residual oil was stirred in 1N HCl-MeOH (25 mL) for 18 h at 50° C. The crude product was purified by chromatography (silica gel, AcOEt-hexane 1:1) to give the methyl ester as light yellow solid (0.67 g).] (0.66 g, 2.3 mmol) by treatment with lithium tert-butyl acetate according to general procedure K (method b). Obtained as a light yellow oil (0.93 g, not pure).
Reaction SMILES: [CH3:1][Li].[C:3]1([CH:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH:11]=[CH:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl-].[NH4+]>C(OCC)C.O.[Cu]Br>[CH3:1][CH:10]1[CH:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:14][CH2:13][C:12](=[O:15])[CH2:11]1
Reactant: [Li]C
Reactant: O=C1C=CC(c2ccccc2)CC1
Agent: [Cu]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CC1CC(=O)CCC1c1ccccc1
Temperature: -20 °C
Yield: 37.4 %

Procedure:
Under a nitrogen atmosphere, a stirred mixture of 2.9 grams (0.020 mole) of copper(I) bromide in 10 mL of diethyl ether was cooled to -20° C., and 50 mL (0.070 mole) of 1.4M methyllithium in diethyl ether was added slowly. Upon completion of addition, a solution of 4.6 grams (0.027 mole) of 4-phenyl-2-cyclohexenone in 5 mL of diethyl ether was added dropwise at a rate to maintain the reaction mixture temperature below -20° C. Upon completion of addition, a solution of 4.2 grams (0.080 mole) of ammonium chloride in 20 mL of water was added. Upon completion of addition, the reaction mixture was stirred as it warmed to ambient temperature. The reaction mixture was then diluted with 200 mL of diethyl ether and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished commencing with 10% diethyl ether in petroleum ether and finishing with 15% diethyl ether in petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 1.9 grams of 3-methyl-4-phenylcyclohexanone as a liquid. The NMR spectrum was consistent with the proposed structure, and it indicated that the product was predominantly the trans isomer. The reaction-was repeated on a larger scale. The 3-methyl-4-phenylcyclohexanone isolated from the larger reaction was a solid, mp 71.5°-72.5° C. The NMR spectrum of a sample from the larger reaction was also consistent with the proposed structure.
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH:16]=[CH:17][C@@H:18]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].[OH:23]O>O>[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][CH:13]5[C:14]([CH:16]=[CH:17][C@:18]2([OH:23])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15]
Reactant: COc1ccc2c3c1O[C@H]1C(=O)C=C[C@H]4[C@@H](C2)N(C)CC[C@]314
Reactant: OO
Solvent: O
Product: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(O)[C@@H](C2)N(C)CC[C@]314

Procedure:
In the first method of this invention, codeinone is reacted with hydrogen peroxide in water in the presence of an acid at about 15° to about 70° C. for a period of time depending on the scale of the reaction to afford 14-hydroxycodeinone in good yield. 14-Hydroxycodeinone so produced is hydrogenated in the same reaction media with a catalyst to afford oxycodone in good yield. Preferably the temperature is between about 40° to about 50° C. and the acid is formic acid.
Reaction SMILES: [N:1]1([CH2:10][CH:11]([OH:26])[CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3Cl)[CH2:15][CH2:14]2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:27]C(O)C>>[N:1]1([CH2:10][CH:11]([OH:26])[CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:27])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: OC(CN1CCN(c2ccccc2Cl)CC1)Cn1cnc2ccccc21
Reactant: CC(C)O
Product: Cc1ccc(N2CCN(CC(O)Cn3cnc4ccccc43)CC2)cc1

Procedure:
1-Benzoimidazol-1-yl-3-{4-chloro-phenyl)-phenyl-methyl!-piperazin-1 -yl}-propan-2ol; -1-Benzoimidazol-1-yl-3-[4-(2-chloro-phenyl)-piperazin-1-yl]-propan-2-ol;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][F:22])[CH:14]=1)[C:5]2=O.O.[NH2:25][NH2:26]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][F:22])[CH:14]=3)=[CH:7][NH:26][N:25]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: NN
Reactant: O=c1c(-c2cccc(OCCF)c2)coc2cc(O)c(Cl)cc12
Solvent: O
Solvent: CCO
Product: Oc1cc(O)c(-c2n[nH]cc2-c2cccc(OCCF)c2)cc1Cl

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-3-[3-(2-fluoro-ethoxy)-phenyl]-7-hydroxy-chromen-4-one (0.2 g, 0.6 mmol), hydrazine hydrate (2.5 ml), ethanol (10 ml). The quenched solution was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give an oil which was purified by column chromatography to give 4-Chloro-6-{4-[3-(2-fluoro-ethoxy)-phenyl]-1H-pyrazol-3-yl}-benzene-1,3-diol as an off white solid (0.12 g, 57.3%); Rf 0.5 cf SM 0.85 ethyl acetate/hexane (80/20).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([CH:37]=[CH:38][CH:39]=1)[O:10][C@H:11]1[CH2:15][CH2:14][N:13]([C:16]([CH3:36])([CH3:35])[CH2:17][CH2:18][C:19]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]([NH2:22])=[O:21])[CH2:12]1>ClCCl>[OH:6][C:7]1[CH:8]=[C:9]([CH:37]=[CH:38][CH:39]=1)[O:10][C@H:11]1[CH2:15][CH2:14][N:13]([C:16]([CH3:36])([CH3:35])[CH2:17][CH2:18][C:19]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:20]([NH2:22])=[O:21])[CH2:12]1
Reactant: COc1cccc(O[C@H]2CCN(C(C)(C)CCC(C(N)=O)(c3ccccc3)c3ccccc3)C2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(CCC(C(N)=O)(c1ccccc1)c1ccccc1)N1CC[C@H](Oc2cccc(O)c2)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
Boron tribromide (1M in dichloromethane, 20.7 mL, 20.7 mmol) was added to an ice-cooled solution of the product of example 6 (2.45 g, 5.18 mmol) in dichloromethane (25 mL) and the mixture was stirred at 0° C. for 20 minutes. The reaction was then quenched with 0.88 ammonia solution and stirred at room temperature for 20 minutes. The reaction mixture was extracted with dichloromethane (3×25 mL) and the combined organic solution was dried over sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with pentane:ethyl acetate/methanol/0.88 ammonia (90:10:1), 50:50 to 33:66, afforded the title compound as a white foam in 60% yield, 1.42 g.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([O:13]C)=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[NH2:15][C@H:16]([C:18]([NH:20][C@H:21]([C:23]([OH:25])=[O:24])[CH3:22])=[O:19])[CH3:17].[OH-].[Na+]>>[NH2:1][C@H:2]([C:11]([NH:15][C@H:16]([C:18]([NH:20][C@H:21]([C:23]([OH:25])=[O:24])[CH3:22])=[O:19])[CH3:17])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: C[C@H](N)C(=O)N[C@@H](C)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O

Procedure:
0.2 ml of aqueous solution containing 2 mM Mal-Tyr-OMe, 50 mM H-Ala-Ala-OH, 25 mM NaOH and 0.3 M α-chymotrypsin are deep-frozen. Subsequently the reaction mixture is kept at -25° C. until the Mal-Tyr-OMe is consumed. Following thawing, the yield is determined analytically by RP-HPLC and amounts to 94% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[NH:17][C:16]2=O)=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].P(Cl)(Cl)([Cl:32])=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:27])([F:28])[C:23]([F:26])([F:25])[F:24])[N:17]=[C:16]2[Cl:32])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)OC(=O)c1cc(-n2c(Cl)nc(C(F)(F)C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
using isopropyl 2-chloro-5-[3,6-dihydro-2,6-dioxo-4-pentafluoroethyl-1(2H)-pyrimidinyl]-4-fluorobenzoate with phosphorus oxychloride and pyridine within 1 hour at room temperature there is obtained isopropyl 2-chloro-5-[2-chloro-6-oxo-4-pentafluoroethyl-1(6H)-pyrimidinyl]4-fluorobenzoate, 1H-NMR (CDCl3, 60 MHz): 7.90 ppm (d,1H), 7.48 ppm (d,1H), 6.96 ppm (s,1H), 5.30 ppm (m,1H), 1.40 ppm (d,6H);
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([S:17]([OH:20])(=[O:19])=[O:18])[CH:16]=1)[C:8]([O:10]C(C)C)=[O:9])([OH:4])(=[O:3])=[O:2].[CH2:21]([CH:23]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24]O)[CH3:22]>C(O)(C)C>[S:1]([C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([S:17]([OH:20])(=[O:18])=[O:19])[CH:16]=1)[C:8]([O:10][CH2:24][CH:23]([CH2:21][CH3:22])[CH2:26][CH2:27][CH2:28][CH3:29])=[O:9])([OH:4])(=[O:2])=[O:3]
Reactant: CC(C)OC(=O)c1cc(S(=O)(=O)O)cc(S(=O)(=O)O)c1
Reactant: CCCCC(CC)CO
Solvent: CC(C)O
Product: CCCCC(CC)COC(=O)c1cc(S(=O)(=O)O)cc(S(=O)(=O)O)c1
Reaction time: 3 h

Procedure:
Into a one-liter, four-necked round bottom flask equipped with a thermometer, distillation head, and a glass stirrer with TEFLON paddle were charged 177 grams of 2-propyl 3,5-disulfobenzoate solution in isopropyl alcohol and 200 grams of 2-ethylhexanol. The solution was vacuum distilled to a pot temperature of 105° C. and then held at this temperature for an additional three hours. The resultant 2-ethylhexyl 3,5-disulfobenzoate was a brown viscous oil with an acid value of 165.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([C:13]#[N:14])=[C:6](Cl)[C:5]=1[N+:16]([O-:18])=[O:17])[CH3:2].[NH3:21].C(COC)OC>C(O)C>[CH2:1]([N:3]([CH2:19][CH3:20])[C:4]1[C:5]([N+:16]([O-:18])=[O:17])=[C:6]([NH2:21])[C:7]([C:13]#[N:14])=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2]
Reactant: CCN(CC)c1c([N+](=O)[O-])cc(C#N)c(Cl)c1[N+](=O)[O-]
Reactant: N
Solvent: COCCOC
Solvent: CCO
Product: CCN(CC)c1c([N+](=O)[O-])cc(C#N)c(N)c1[N+](=O)[O-]
Reaction time: 72 h

Procedure:
A solution of 4.33 g. (0.0144 mole) of N,N-diethyl-3-chloro-2,6-dinitro-4-cyanoaniline, 6.40 g. (0.0288 mole) of a 7.66% solution of ammonia in absolute ethanol, and 15 ml. of dimethoxyethane was sealed in a Pyrex reaction tube and alloed to stand at room temperature for 72 hours. The contents were distilled to dryness at reduced pressure and extracted with 100 ml. of boiling chloroform. The filtered chloroform extract was evaporated to dryness and the residual orange solid taken up in hot 95% ethanol. Upon cooling, the product crystallized and was isolated by filtration to give 1.51 g. (37.3%) or an orange, crystalline solid melting at 142°-145°C. Recrystallization from 95% ethanol gave the desired product, m.p. 145.5°-146.5°C.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH2:3][OH:4].[N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[C:13]=[S:14]>>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:2]([NH:1][C:13]([NH:12][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[S:14])[CH2:3][OH:4]
Reactant: FC(F)(F)c1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Reactant: NC(CO)c1ccccc1Cl
Product: OCC(NC(=S)Nc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1)c1ccccc1Cl

Procedure:
The title compound was prepared with 2-amino-2-(2-chlorophenyl)ethanol and 3-(4-isothiocyanatophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole and isolated as a white solid (1.48 g, quantitative): 1H NMR (300 MHz, CDCl3) δ 8.07 (s, 1H), 7.77-7.55 (m, 2H), 7.41-7.23 (m, 3H), 7.21 (d, J=8.5 Hz, 2H), 6.81 (dd, J=8.7, 2.6 Hz, 2H), 6.65 (d, J=6.8 Hz, 6H), 5.40 (s, 1H), 3.39 (qd, J=11.6, 4.9 Hz, 2H); ESIMS m/z 518 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH2:11][CH2:12][CH2:13][C:14]([O:16]C)=O)=[CH:4][C:3]=1[CH3:18].[OH-].[Na+]>CO>[F:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:5]([CH2:11][CH2:12][CH2:13][C:14]2=[O:16])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: COC(=O)CCCc1cc(C)c(F)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(F)cc([N+](=O)[O-])c2c1C(=O)CCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound obtained in (3) above (7.1 gm) was dissolved in 20 ml of methanol. To the solution was added 10 ml of 15% aqueous solution of sodium hydroxide and the mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated, acidified with concentrated hydrochloric acid, and extracted with chloroform. The chloroform layer was washed with water and saturated brine in this order and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was slowly added to 50 ml of polyphosphoric acid heated to 110° C. and stirred for 4.5 hours. After the addition of 100 ml of ice-water, the reaction product was extracted with ethyl acetate, washed with water, saturated sodium bicarbonate and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was subjected to silica gel column chromatography using a hexane-ethyl acetate (1:1) mixed solvent as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 1.7 gm of the title compound.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]([F:32])([F:31])[C:15]1[CH:16]=[C:17]([S:21]([N:24]2[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]2)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1.O[N:34]1[C:42](=[O:43])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]1=[O:44].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[F:32][C:14]([F:13])([F:31])[C:15]1[CH:16]=[C:17]([S:21]([N:24]2[CH2:25][CH2:26][CH:27]([O:30][N:34]3[C:42](=[O:43])[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:35]3=[O:44])[CH2:28][CH2:29]2)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N1CCC(O)CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.8 %

Procedure:
A solution of diethyl azodicarboxylate (1.10 g, 6.32 mmol) in tetrahydrofuran (5 ml) was added dropwise to a mixture of 1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-ol (0.94 g, 3.04 mmol), 2-hydroxyisoindoline-1,3-dione (0.50 g, 3.07 mmol) and triphenylphosphine (1.65 g, 6.30 mmol) in tetrahydrofuran (10 ml) at 0° C. The reaction mixture was stirred at room temperature for 17 hours and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether: 25/75) to give 2-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yloxy)isoindoline-1,3-dione (1.02 g, 74%) as a white solid: LCMS: 455 [M+1]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])=[O:11])=[CH:5][CH:4]=1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:30](OCC)(=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])=[O:11])=[C:7]([CH3:30])[CH:8]=1
Reactant: CCOC(C)=O
Reactant: CCCN(CCC)CCCCNC(=O)Nc1ccc(C#N)cc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCN(CCC)CCCCNC(=O)Nc1ccc(CN)cc1C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The compound (466.4 mg) obtained in Example 12-1 was dissolved in anhydrous THF (14 ml) and the whole was cooled with ice. Lithium aluminum hydride (223.1 mg) was added thereto and the whole was stirred at room temperature for 2.5 hours. After the reaction has been stopped by addition of ethyl acetate, an aqueous potassium sodium tartrate solution was added thereto and the whole was stirred, followed by extraction with chloroform. The extract was washed with a saturated saline solution and dried with magnesium sulfate. The solvent was distilled off and the residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (195 mg) as a yellow oily substance.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:8]1.[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32]Cl)[CH3:28]>CN(C)C=O>[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:8]1)[CH3:28]
Reactant: O=C(Cc1c[nH]c2ccccc12)OCc1ccccc1
Reactant: CCN(CC)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCCn1cc(CC(=O)OCc2ccccc2)c2ccccc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
At a temperature of about +50° C., 6.2 g (44.9 mMol) of potassium carbonate were added to a solution of 4.0 g (15.1 mMol) of phenylmethyl 1H-indole-3-acetate in 40 ml of dimethylformamide and then at the same temperature a solution of 3.0 g (20.0 mMol) of 3-(diethylamino)propylchloride in 5 ml of dimethylformamid were added dropwise. The mixture was stirred for a further hour at 50° C. and overnight at ambient temperature, heated up to 100° C. again and once more 1.0 g of 3-(diethylamino)propylchloride were added. After stirring for 5 hours at ambient temperature, the mixture was stirred into 300 ml of ice water and extracted exhaustively with diisopropylether. The combined organic extracts were washed with saturated saline solution, dried over magnesium sulphate, clarified with activated charcoal and evaporated down under reduced pressure. A colourless oil was obtained in a yield of 5.37 g (94% of theory) and was used in the following step without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([N:20]([CH2:28][C:29]4[N:34]=[CH:33][C:32]5[O:35][CH2:36][CH2:37][O:38][C:31]=5[CH:30]=4)[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]3)[C:6]=2[N:39]=1.[C:40](=[O:47])([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[NH2:41].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:43]([O:42][C:40]([NH:41][C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][CH:17]([N:20]([CH2:28][C:29]4[N:34]=[CH:33][C:32]5[O:35][CH2:36][CH2:37][O:38][C:31]=5[CH:30]=4)[C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:26])[CH3:24])[CH2:18][CH2:19]3)[C:6]=2[N:39]=1)=[O:47])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(N)=O
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)cnc3ccc(Cl)nc32)CC1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc2ncc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 85 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
To a solution of 0.11 g of tert-butyl (1-(2-(6-chloro-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamate in 3 mL of dioxane, 25 mg of tert-butyl carbamate and 82 mg of cesium carbonate were added. Thereto were added 2.5 mg of tris(dibenzylideneacetate)dipalladium(0) and 3.1 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene under an argon atmosphere. The mixture was stirred at 80 to 90° C. for 2 hours under an argon atmosphere. The insoluble substance was filtered off, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using an eluent of chloroform:methanol=20:1 to obtain 78 mg of tert-butyl (1-(2-(6-((tert-butoxycarbonyl)amino)-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamate as a light brown oily substance.