Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].[CH:4]1[CH:13]=[C:12]2[C:14]([O:16][C:17](=O)[C:10]3=[C:11]2[C:6](=[CH:7][C:8]([N+:19]([O-:21])=[O:20])=[CH:9]3)[CH:5]=1)=[O:15]>N1C=CC=CC=1.O>[OH:3][N:2]1[C:17](=[O:16])[C:10]2[CH:9]=[C:8]([N+:19]([O-:21])=[O:20])[CH:7]=[C:6]3[C:11]=2[C:12](=[CH:13][CH:4]=[CH:5]3)[C:14]1=[O:15]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])cc3cccc1c23
Reactant: NO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C1c2cccc3cc([N+](=O)[O-])cc(c23)C(=O)N1O
Yield: 99.2 %

Procedure:
Hydroxylamine hydrochloride (0.9 g, 13.0 mmol) was added to a suspension of 3-nitro-1,8-naphthalic anhydride (2.0 g, 8.2 mmol) in pyridine (30 mL). The mixture was refluxed for 3 hours and concentrated in vacuo to give a brown solid. The solid was suspended in water, stirred, filtered, and dried to give 2.1 g of the title compound, mp 277-279° C.
Reaction SMILES: O1CCCCC1[N:7]1[CH:15]=[C:14]2[C:9]([CH:10]=[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C4CCCCO4)[CH:18]=3)[CH:12]=[C:13]2[NH2:16])=[N:8]1.CCN(C(C)C)C(C)C.[CH:39]1([C:45](Cl)=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.[OH-].[Na+]>C(Cl)Cl>[OH:23][C:19]1[CH:18]=[C:17]([C:11]2[CH:12]=[C:13]3[C:14]([CH:15]=[N:7][NH:16]3)=[C:9]([NH:8][C:45]([CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[O:46])[CH:10]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1cc(-c2cccc(OC3CCCCO3)c2)cc2nn(C3CCCCO3)cc12
Reactant: O=C(Cl)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cc(-c2cccc(O)c2)cc2[nH]ncc12)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(Tetrahydro-2H-pyran-2-yl)-6-[3-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2H-indazol-4-amine (50 mg, 0.127 mmol) was dissolved in DCM (1 ml) and DIPEA (0.111 ml, 0.635 mmol) and cyclohexanecarbonyl chloride (45 mg, 0.254 mmol) were added. The reaction was stirred at RT for 1 h. 2 M Sodium hydroxide (aq) (2 ml) was added and the reaction stirred at RT for 1 h, before the organic layer was passed through a hydrophobic frit. The aqueous layer was washed several times with DCM, which was passed through a hydrophobic frit. The combined organic layers were evaporated under a stream of nitrogen. The residue was dissolved in MeOH (2 ml) and 4 M HCl in dioxane was added (2 ml). The reaction was stirred at RT for 1 h. The solvent was removed under a stream of nitrogen and the residue was dissolved in DMSO:MeOH (1:1, v/v) and purified by MDAP (Method B). The residue was dissolved in 1,4-dioxane:water and freeze dried to produce the title compound.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][NH:9][C:10](=O)[C:5]=2[NH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:14].C(=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([Cl:14])[C:5]=2[NH:4][CH:3]=1
Reactant: O=c1[nH]cnc2c(Br)c[nH]c12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ncnc2c(Br)c[nH]c12
Temperature: 115 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
A mixture of 7-bromo-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one (100 mg, 0.5 mmol) and 6 mL of POCl3 under argon was warmed at 115° C. After 3 hours, the mixture was cooled to room temperature and poured over 300 mL of ice, stirred, made basic with potassium carbonate and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo to provide 101 mg (93%) of the desired 7-bromo-4-chloro-5H-pyrrolo[3,2-d]pyrimidine as beige solid which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:16]([O-])=O)=[C:5]([CH:13]=[CH:14][CH:15]=1)[NH:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH3:12]>CO.[C].[Pd]>[CH3:1][O:2][C:3]1[C:4]([NH2:16])=[C:5]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH3:12])[CH:13]=[CH:14][CH:15]=1
Reactant: COCCCCNc1cccc(OC)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COCCCCNc1cccc(OC)c1N
Reaction time: 2 h
Yield: 103.5 %

Procedure:
3-Methoxy-N-(4-methoxybutyl)-2-nitroaniline (230 mg) was dissolved in methanol (30 ml), palladium-carbon (5%, 90 mg) was added, and the mixture was stirred for 2 hr under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the object product (210 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:21]([O-])=O)=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=3[O-:19])[C:6]=2[CH:20]=1>C(O)(=O)C.[C].[Pd]>[NH2:1][C:2]1[C:3]([NH2:21])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=3[O-:19])[C:6]=2[CH:20]=1
Reactant: CC1(C)CN(c2cccc[n+]2[O-])c2cc(N)c([N+](=O)[O-])cc2O1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1(C)CN(c2cccc[n+]2[O-])c2cc(N)c(N)cc2O1

Procedure:
To a solution of 549 mg 2-(6-amino-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-4-yl)pyridine N-oxide in 30 ml acetic acid, was added a catalytic amount of 10% palladium-carbon powder, and catalytic hydrogenation was performed at ordinary temperature and pressure. The catalyst was filtered off from the reaction mixture, and the solvent was distilled off from the filtrate, thus giving crude 2-(6,7-diamino-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazin-4-yl)pyridine N-oxide. This product was immediately used for the succeeding reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:37])[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[C:28]4[CH:27]=[CH:26][N:25]=[C:24]([NH:29]C(=O)OC(C)(C)C)[C:23]=4[CH:22]=[CH:21]3)=[CH:16][CH:15]=2)=[O:12])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[NH2:29][C:24]1[C:23]2[CH:22]=[CH:21][N:20]([C:17]3[CH:16]=[CH:15][C:14]([NH:13][C:11](=[O:12])[CH2:10][C:9]([NH:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[O:37])=[CH:19][CH:18]=3)[C:28]=2[CH:27]=[CH:26][N:25]=1
Reactant: CC(C)(C)OC(=O)Nc1nccc2c1ccn2-c1ccc(NC(=O)CC(=O)Nc2ccc(F)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nccc2c1ccn2-c1ccc(NC(=O)CC(=O)Nc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.4 %

Procedure:
tert-Butyl 1-(4-(3-(4-fluorophenylamino)-3-oxopropanamido)phenyl)-1H-pyrrolo[3,2-c]pyridin-4-ylcarbamate (37 mg, 0.074 mmol) was treated with 4 N HCl in dioxane (2 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between saturated NaHCO3 (2 mL) and EtOAc (2 mL). The EtOAc phase was separated, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 10-15% MeOH-CHCl3 gradient elution) to afford the title compound (7.0 mg, 23%) as a white solid. 1H NMR (DMSO-d6) δ 10.58 (s, 1H), 10.38 (s, 1H), 8.01 (br s, 2H), 7.84 (d, 2H, J=9.0 Hz), 7.69-7.62 (m, 3H), 7.60 (d, 1H, J=7.4 Hz), 7.52 (d, 2H, J=9.0 Hz), 7.20-7.13 (m, 3H), 6.91 (d, 1H, J=8.2 Hz), 3.52 (s, 2H); LCMS (ESI+) m/z 404 (M+H)+; HPLC tR=2.98 min.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8](=[N:10]O)[CH3:9])=[CH:6][CH:5]=[C:4]([F:12])[N:3]=1.[OH-].[Na+]>FC(F)(F)C(O)=O.[Zn]>[F:1][C:2]1[C:7]([CH:8]([NH2:10])[CH3:9])=[CH:6][CH:5]=[C:4]([F:12])[N:3]=1
Reactant: CC(=NO)c1ccc(F)nc1F
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: O=C(O)C(F)(F)F
Product: CC(N)c1ccc(F)nc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
Zinc (9.29 g) was added in three portions to a solution of 1-(2,6-difluoropyridin-3-yl)ethanone oxime (2.44 g) in trifluoroacetic acid (100 mL), and the reaction solution was stirred at room temperature for two hours. The reaction solution was made basic (pH 14) with 5 N sodium hydroxide and filtered through celite, and the celite was washed with chloroform. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 1.61 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[CH3:12][O-].[Na+]>CO.[Cl-].C1([N+](C)(C)C)C=CC=CC=1.CN(C=O)C>[CH3:12][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: Oc1cccc2cnccc12
Reactant: C[O-]
Agent: C[N+](C)(C)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cccc2cnccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of 5-hydroxyisoquinoline (10 g, 69 mmol) in MeOH (100 ml) was added a solution of sodium methoxide in methanol (30% by weight, 13.8 ml, 72.4 mmol) followed by phenyltrimethylammonium chloride (12.4 g, 72.4 mmol). The reaction mixture was stirred at room temperature for 2 h, after which time it was filtered and the filtrate evaporated under reduced pressure to afford an oil which was dissolved in DMF (50 ml ). The reaction mixture was refluxed for 2 h after which time the reaction mixture was evaporated under reduced pressure. The resulting oil was partitioned between CH2Cl2 and 1N aqueous NaOH, the organic layer was washed twice with 1N aqueous NaOH, dried over MgSO4 and evaporated under reduced pressure. The crude product was purified on silica gel eluting with EtOAc/hexane (1/1, v/v) to afford the subtitle compound as a yellow oil (6.11 g, 56%). 1H NMR (CDCl3) δ: 4.05 (3H, s), 7.00 (1H, d), 7.55 (2H, m), 8.02 (1H, d), 8.55 (1H, d), 9.22 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([OH:15])[CH2:13][CH2:12][C@H:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].Cl>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([O:15][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:13][CH2:12][C@H:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)[C@H]1CC[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1CC[C@@H](OS(C)(=O)=O)[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Ethyl (1S,3R,4R)-3-(tert-butoxycarbonylamino)-4-hydroxycyclohexane-1-carboxylate (53.5 g) and triethylamine (130 ml) were dissolved in dichloromethane (500 ml), and methanesulfonyl chloride (42 ml) was added dropwise while cooling the solution to −10° C. to −15° C. After stirring for 20 minutes at the same temperature, the mixture was heated to room temperature over 30 minutes and further stirred for 2 hours. The reaction mixture was cooled to 0° C., 0.5N hydrochloric acid (800 ml) was added dropwise, and the mixture was extracted with dichloromethane. The resultant organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crude ethyl (1S,3R,4R)-3-(tert-butoxycarbonylamino)-4-(methanesulfonyloxy)cyclohexane-1-carboxylate.
Reaction SMILES: C[CH:2]([O:13][CH:14](C)C1C=C([N+]([O-])=O)C=CC=1C)[C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[CH3:12].O.[S-2].[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(O)C.O>[CH3:14][O:13][CH2:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[CH3:12])[NH2:9]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(C)OC(C)c1cc([N+](=O)[O-])ccc1C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CCO
Product: COCc1cc(N)ccc1C
Yield: 184.2 %

Procedure:
Methyl-2-methyl-5-nitrobenzyl ether (11.5 g) was dissolved in 125 ml of absolute ethanol. To this was added a solution of sodium sulfide monohydrate (48.3 g) and sodium bicarbonate (16.7 g) in 75 ml of water. The resulting mixture was refluxed until tlc indicated all the starting material was gone. The mixture was then concentrated in vacuo to an oily solid. Methylene chloride was added and the mixture filtered. The methylene chloride layer was separated and dried. After removal of the drying agent, the solvent was concentrated in vacuo to give 9.3 g of a mobile orange liquid.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH3:7][SiH:8]([CH3:10])[Cl:9]>>[CH2:1]([Si:8]([CH3:10])([CH3:7])[Cl:9])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCC=C
Reactant: C[SiH](C)Cl
Product: C=CCCCC[Si](C)(C)Cl
Reaction time: 48 h
Yield: 68 %

Procedure:
5-Hexenyldimethylchlorosilane was prepared by combining 1,5-hexadiene (164 g) and 0.05 g of platinum complex ##STR3## in a flask equipped with a condenser, addition-funnel and a thermometer. Dimethylchlorosilane (92 g) was added at such a rate that the pot temperature did not rise above 40° C. The mixture was allowed to stand at room temperature for 48 hours. The product was isolated in 68% yield by distillation under reduced pressure (bp 39°-40° C./2.2 mm Hg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](C(C)C)[C:5]([Cl:11])=[CH:4][C:3]=1[CH3:12]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:11])=[CH:4][C:3]=1[CH3:12]
Reactant: Cc1cc(Cl)c(C(C)C)cc1Cl
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)ccc1Cl

Procedure:
In the next step, the obtained 2,5-dichloro-4-t-alkyltoluene or 2,5-dichloro-4-isopropyltoluene is brought into contact with toluene, thereby subjecting to transalkylation, disconnecting the t-alkyl group or the isopropyl group from the mother compound to obtain 2,5-dichlorotoluene.
Reaction SMILES: [C:1]1([CH:7]2[NH:11][N:10]=[CH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N>CO.[Ni]>[C:1]1([CH:7]([NH2:11])[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1=NNC(c2ccccc2)C1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCC(N)c1ccccc1

Procedure:
73 g (0.5 mol) of 5-phenyl-2-pyrazoline are hydrogenated in 400 ml of methanol saturated with ammonia with 10 g of freshly prepared Raney nickel for 5 hours at 80° C./100 atmospheres. The Raney nickel is filtered off on a suction filter containing a layer of kieselguhr. The solvent is removed from the filtrate in a rotary evaporator and the residue is distilled in a simple distillation apparatus and then through a 25 cm Vigreux column. This gives 66 g=88% of theory of a colourless oil with a boiling point under 0.0004 mm of 73° C. (literature: boiling point under 21 mm, 138°-141° C.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][NH2:20])[CH3:16].C(N(CC)CC)C>ClCCl>[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][NH:20][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH3:16]
Reactant: CCOC(CN)OCC
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(CNc1c([N+](=O)[O-])cnc2ccccc12)OCC
Yield: 97.3 %

Procedure:
The general method described in Step 1 of Example 1 was used to react 4-chloro-3-nitroquinoline (20.9 g, 100 mmol), aminoacetaldehyde diethyl acetal (14.4 g, 110 mmol), and triethylamine (12.6 g, 125 mmol) in dichloromethane for 15 hours to provide (2,2-diethoxyethyl)-(3-nitroquinolin-4-yl)amine (29.7 g) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[CH:17]1([CH2:22][C:23](O)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH:17]1([CH2:22][C:23]([N:12]2[CH2:11][CH2:10][N:9]([C:4]3[C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:14][CH2:13]2)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(O)CC1CCCC1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(CC1CCCC1)N1CCN(c2ncccc2C(F)(F)F)CC1
Yield: 43 %

Procedure:
Coupling of 1-(3-(trifluoromethyl)pyridin-2-yl)piperazine (271 mg, 1.17 mmol) with 2-cyclopentylacetic acid (100 mg, 0.78 mmol) was carried out according to a similar procedure described for example 19A using N,N-dimethylformamide (1 mL) as solvent and benzotriazole-1 yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (700 mg, 1.56 mmol) as coupling agent. 1-(cyclopentylacetyl)-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine was obtained in 43% yield (114 mg) as colorless oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:35])[CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(OC(=O)C)C>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:35])[CH2:16][CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:29][CH:30]=3)[CH2:23][CH2:24]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)CCCN2CCN(c3ccc(C(F)(F)F)cc3)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1)NC1CCNCC1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
Trifluororoacetic acid (1 mL) is added to a solution of 4-{4-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-butyrylamino}-piperidine-1-carboxylic acid tert-butyl ester (660 mg; 1.32 mmol, prepared in accordance with Example 74) in dichloromethane (4 mL) and the resulting mixture is stirred at room temperature. After 3 hours reaction time, the excess acid is neutralized by the addition of potassium carbonate, the mixture is filtered and the filtrate is concentrated under reduced pressure. The residue obtained is diluted in ethylacetate (20 mL) and the organic phase is extracted with water (2×10 mL). The combined aqueous phases are extracted with dichloromethane (10 mL) and diethylether (10 mL). The combined organic layers are dried over magnesium sulfate and the solvents removed under reduced pressure to afford the desired product (417 mg; 1.05 mmol).
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.C1(C)C=CC(NN)=CC=1.[O:16]=[CH:17][C@@H:18]([C@H:20]([C@@H:22]([C@@H:24]([CH2:26][OH:27])[OH:25])[OH:23])[OH:21])[OH:19].[O:28]=[CH:29][C:30]([C@H:32]([C@@H:34]([C@@H:36]([CH2:38][OH:39])[OH:37])[OH:35])[OH:33])=O.C1(C)C=CC(NN=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)=CC=1>O>[C@@H:26]1([O:27][C@H:30]([C@H:32]([C@@H:34]([C@@H:36]([CH2:38][OH:39])[OH:37])[OH:35])[OH:33])[CH:29]=[O:28])[O:19][C@H:18]([CH2:17][OH:16])[C@@H:20]([OH:21])[C@H:22]([OH:23])[C@H:24]1[OH:25]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=CC(=O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CC(=O)[O-]
Agent: Cc1ccc(NN)cc1
Agent: Cc1ccc(NN=C[C@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@H](O)[C@H](O)CO)cc1
Solvent: O
Product: O=C[C@H](O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 70 °C

Procedure:
This oligosaccharide (5 μmol), sodium acetate (10 μmol) and p-tolylhydrazine hydrochloride (30 μmol) were dissolved in 0.15 mL water in a small vial (Pierce reacti-vial, 0.2 mL capacity, with Tuf-bond Teflon-silicone cap seals). The vial was sealed under argon and warmed on a heating block to 70° C. for 6 hours; the solution became yellow over time and gave a yellow crystalline precipitate, which increased upon cooling to room temperature overnight. The water-insoluble material was the cleavage product, glucose p-tolylosazone (D-arabino-hexos-2-ulose p-tolylosazone). The water soluble fraction contained 2-O-β-D-glucopyranosyl-D-glucose p-tolylhydrazone, and small amounts of D-glucose and the starting oligosaccharide.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH3:11][Si:12]([CH3:15])(O)O.N(CCO)(CCO)CCO>C(O)CCCO>[C:1]([O:10][SiH:12]([CH3:15])[CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: C[Si](C)(O)O
Reactant: O=C(O)c1ccccc1O
Solvent: OCCCCO
Solvent: OCCN(CCO)CCO
Product: C[SiH](C)OC(=O)c1ccccc1O

Procedure:
Capillisil is available from Exsymol S.A.M. of Monaco and is a 20% solution of dimethylsilanediol salicylate in butylene glycol with triethanolamine. It is obtained by mild hydrolysis of dimethylsilyl salicylate.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[N:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19])=[N+:12]=[N-:13]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([CH:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9])=[O:19])=[N+:12]=[N-:13]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: [N-]=[N+]=NCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(C(=O)CCCCN=[N+]=[N-])C(=O)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (4.45 g, 30.9 mmol) and 4-dimethylaminopyridine (7.55 g, 61.8 mmol) in 100 ml of CH2Cl2 was added the solution of crude 5-azidovaleric chloride in 10 ml of CH2Cl2 at 0° C. The mixture was stirred at 0° C. for 1 hr and at room temperature for 1 hr. The solution was washed with 1N aqueous HCl (100 ml), brine (250 ml) and dried over Na2SO4. After evaporation of solvent, 5-(5-azidopentanoyl)-2,2-dimethyl-1,3-dioxane-4,6-dione was obtained as a light pink oil (8.17 g, 98%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].O[CH2:14][CH:15]([CH2:17]O)O.N.C>S(=O)(=O)(O)O.O.II>[CH3:12][O:11][C:10]1[C:2]2[N:1]=[CH:17][CH:15]=[CH:14][C:3]=2[C:4]([C:5]([OH:7])=[O:6])=[CH:8][CH:9]=1
Reactant: OCC(O)CO
Reactant: COc1ccc(C(=O)O)cc1N
Agent: II
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1ccc(C(=O)O)c2cccnc12
Yield: 69.3 %

Procedure:
A of 3-amino-4-methoxybenzoic acid (5.0 g), glycerol (4.16 g), and iodine (135 mg) in concentrated sulphuric acid (5 ml) was heated at 180° C. for 2 hours. The reaction was allowed to cool, diluted with water (170 ml), made basic to pH8/9 with 0.88 ammonia and stirred with activated charcoal (2.0 g). The mixture was filtered through Celite and the filtrate acidified to pH4/5 with acetic acid. The precipitate was obtained by filtration and dried in a dessicator to yield the desired product (4.21 g) as a tan 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][CH2:13][OH:14].ClCCl.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(N(CC)CC)C>[CH3:18][S:19]([O:14][CH2:13][CH2:12][O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1ccc2ccccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1ccc2ccccc2c1

Procedure:
As described in Example 2, 13.5 g. of 2-(2-naphthyloxy)ethanol in 400 ml. of dichloromethane is reacted with 9.5 g. of methanesulfonyl chloride in the presence of 11.4 g. of triethylamine to give the product as tan crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[C:17](=O)[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[N:9]2[C:23]=1[CH3:24])=[O:5])[CH3:2].C(Cl)([Cl:27])=O.C1(C)C=CC=CC=1>CN(C=O)C>[Cl:27][C:17]1[C:8]2[N:9]([C:23]([CH3:24])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:19]([F:22])([F:21])[F:20])=[CH:12][CH:11]=2
Reactant: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1C
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2c(Cl)nc3cc(C(F)(F)F)ccc3n2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a suspension of 2-ethoxycarbonyl-1-methyl-7-trifluoromethylimidazo[1,2-a]quinoxalin-4(5H)-one (Example 1) (88 g, 259 mmol) in DMF (1.5 l) was dropwise added a solution of 28% phosgene in toluene (0.5 l, 960 mmol). The mixture was stirred at 50° C. for 1 h and overnight at 25° C. followed by evaporation in vacuo. The residue was stirred with ice-cooled water. The solid was collected by filtration and washed with water to yield 83,4 g (95%) of 4-chloro-2-ethoxycarbonyl-1-methyl-7trifluoromethylimidazo[1,2-a]quinoxaline. M.p. 182°-183° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C:8]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][C:20]=3[NH2:25])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1.C1N=C[N:29]([C:32]([N:34]2C=NC=C2)=[O:33])C=1.CCN(C(C)C)C(C)C>C1COCC1>[NH2:29][C:32]([NH2:34])=[O:33].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C:8]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][C:20]=3[NH2:25])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Nc1cnccc1Nc1cc(-c2cc(Cl)ccc2F)nc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NC(N)=O

Procedure:
N*4*-[2-(5-Chloro-2-fluoro-phenyl)-quinolin-4-yl]-pyridine-3,4-diamine (cf. Example 7) was treated in THF with CDI and DIPEA over night at ambient temperature. After work up the urea derivative was isolated with correct mass M+H+ 391 and Rt˜1.78 min in LC-MS system 1.