Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4([CH2:36][O:37][CH3:38])[CH2:35][CH2:34]4)=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:39][O:40]C(=O)C)(=O)C.O[Li].O>C1COCC1.CO.O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C@H:8]2[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:39][OH:40])[O:7]2)=[CH:20][C:21]=1[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2([CH2:36][O:37][CH3:38])[CH2:34][CH2:35]2)=[CH:31][CH:32]=1
Reactant: COCC1(c2ccc(Cc3cc([C@@H]4O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc3Cl)cc2)CC1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COCC1(c2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)cc2)CC1
Reaction time: 2.5 h

Procedure:
To a solution of the above crude (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(1-(methoxymethyl)cyclopropyl)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (intermediate BD) (25 mg) in THF:MeOH:H2O (2:3:1) (1 mL) was added LiOH.H2O (4.66 mg). After stirring for about 2.5 h, the volatiles were removed with a rotary evaporator. The residue was taken up with water (5 mL) and AcOEt (20 mL), the organic layer was separated, and the aqueous layer was extracted 3× with AcOEt. The combined organic phase was washed 1× with brine prior to drying over Na2SO4. Concentration and purification of the crude product by preparative HPLC afforded compound BE (7.5 mg). 1H NMR (CD3OD, 400 MHz) δ 7.35-7.33 (m, 2H), 7.27 (dd, J=8.0, 2.0 Hz, 1H), 7.21 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H), 4.11-4.01 (m, 3H), 3.87 (d, J=9.6 Hz, 1H), 3.70-3.66 (m, 1H), 3.48 (s, 2H), 3.45-3.34 (m, 4H), 3.26 (s, 3H), 0.83-0.82 (m, 4H); MS ESI (m/z): 449 (M+H)+, 466 (M+NH4)+, 493 (M+HCO2)−.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([N+:13]([O-])=O)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.O.NN>[Ni].CO>[CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([NH2:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Cc1cc([N+](=O)[O-])c2ncccc2c1C
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Cc1cc(N)c2ncccc2c1C
Yield: 77.4 %

Procedure:
In a similar fashion using route 6 general procedure 14, 5,6-dimethyl-8-nitroquinoline (Intermediate 43) (200 mg, 0.9 mmol), Raney nickel (40 mg, 20 wt), hydrazine hydrate (200 μl, 3.9 mmol) and MeOH (5 ml) gave the title compound (120 mg, 77%) which was used in the next step without purification.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](F)[C:5]([O:9][CH3:10])=[CH:4][CH:3]=1.Br.Br.[NH:13]1[CH2:19][CH:18]([OH:20])[CH2:17][NH:16][CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>C(O)(C)C>[Br:1][C:2]1[N:7]=[C:6]([N:13]2[CH2:19][CH:18]([OH:20])[CH2:17][NH:16][CH2:15][CH2:14]2)[C:5]([O:9][CH3:10])=[CH:4][CH:3]=1
Reactant: OC1CNCCNC1
Reactant: COc1ccc(Br)nc1F
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1ccc(Br)nc1N1CCNCC(O)C1
Temperature: 100 °C
Yield: 37.5 %

Procedure:
A mixture of 6-bromo-2-fluoro-3-methoxy-pyridine (2.660 mmol; 547.9 mg), 1,4-diazepan-6-ol dihydrobromide (3.989 mmol; 1109 mg), and N,N′-diisopropylethylamine (10.64 mmol; 1389 mg; 1.87 mL) in Isopropanol (10 mL) in a sealed pressure vial was heated at 100° C. overnight. The mixture was cooled to room temperature and concentrated. The residue was purified on silica eluted with 0 to 10% MeOH in DCM to afford 1-(6-bromo-3-methoxy-2-pyridyl)-1,4-diazepan-6-ol (301.2 mg, 37%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:22][CH3:23])([O:20][CH3:21])[CH:17]([OH:19])[CH3:18])=[CH:12][CH:11]=1)[CH:7]([CH3:9])[CH3:8].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:1][S:2]([O:19][CH:17]([CH3:18])[C:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:6][CH:7]([CH3:9])[CH3:8])=[CH:11][CH:12]=1)([O:22][CH3:23])[O:20][CH3:21])(=[O:4])=[O:3]
Reactant: COC(OC)(c1ccc(CC(C)C)cc1)C(C)O
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(OC)(c1ccc(CC(C)C)cc1)C(C)OS(C)(=O)=O
Reaction time: 1.5 h

Procedure:
A solution of 6.25 g of methanesulfonyl chloride in 20 ml of dry methylene chloride is added dropwise to a mixture of 12.37 g of 1-(4-isobutylphenyl)-1,1-dimethoxypropan-2-ol and 80 ml of dry methylene chloride containing 6.5 g of dry triethylamine at 5°-10° C. The addition takes place over about 40 minutes and the reaction mixture is stirred for an additional 1.5 hours at 5°-10° C. after that addition is completed. After that time, an additional 0.6 g of methanesulfonyl chloride is added at 5°-10° C. and stirring is continued for an additional 50 minutes. An additional 1.5 g of triethylamine is added to the reaction mixture and then the reaction mixture is poured into 50 ml of water. The aqeuous and organic phases are separated and the aqueous phase is extracted with methylene chloride. The combined methylene chloride layers then are washed with 50 ml of saturated aqueous sodium chloride and the methylene chloride layer is dried over sodium sulfate. After filtration to remove the sodium sulfate, the methylene chloride is evaporated on a rotary evaporator under reduced pressure to afford 1-(4-isobutylphenyl)-1,1-dimethoxyprop-2-yl methanesulfonate [which is characterized by an NMR spectra in deuterochloroform of τ=9.10 (doublet, J=2.2), 8.8 (doublet, J=2.1), 8.12 (septet, J =2.1), 7.48 (doublet, J =2.3), 6.88, 6.75, 6.67, 4.92 (quartet, J =2.1) and 2.5-2.9 (aromatic AB pattern)].
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH2:10][CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH:14]=2)[CH:4]=1>Cl.O1CCOCC1>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)(F)c1ccnc(C2=CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 147.3 %

Procedure:
tert-Butyl 4-(trifluoromethyl)-3′,6′-dihydro-2,4′-bipyridine- 1′(2′H)-carboxylate (380.0 mg, 1.157 mmol) was dissolved in a 4 M solution of HCl in 1,4-dioxane (12.0 mL) to form a light yellow clear (then cloudy) solution. After being stirred at room temperature for 1 h, the reaction mixture was concentrated in vacuo to afford 389 mg of product as a yellow gum. LC-MS calculated for C11H11F3N2:(M+H) 229; found 229.1.
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.[NH2:30][C:31]1[C:36]([C:37](=[O:42])[C:38]([F:41])([F:40])[F:39])=[CH:35][CH:34]=[C:33]([NH:43][CH:44]2[CH2:49][CH2:48][CH2:47][NH:46][CH2:45]2)[N:32]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:30][C:31]1[C:36]([C:37](=[O:42])[C:38]([F:40])([F:41])[F:39])=[CH:35][CH:34]=[C:33]([NH:43][CH:44]2[CH2:49][CH2:48][CH2:47][N:46]([C:3]3[N:8]4[N:9]=[C:10]([CH:12]5[CH2:17][CH2:16][N:15]([CH:18]([CH3:19])[CH3:20])[CH2:14][CH2:13]5)[N:11]=[C:7]4[CH:6]=[C:5]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[Cl:28])[N:4]=3)[CH2:45]2)[N:32]=1
Reactant: Nc1nc(NC2CCCNC2)ccc1C(=O)C(F)(F)F
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4Cl)nc(Cl)n3n2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4Cl)nc(N4CCCC(Nc5ccc(C(=O)C(F)(F)F)c(N)n5)C4)n3n2)CC1
Temperature: 130 °C

Procedure:
80 mg (0.17 mmol) of 5-chloro-7-(2-chloro-4-fluorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]triazolo[1,5-c]pyrimidine hydrochloride, 64.9 mg (0.2 mmol) of 1-[2-amino-6-(piperidin-3-ylamino)pyridin-3-yl]-2,2,2-trifluoroethanone hydrochloride (Example 22A) and 0.17 ml (0.99 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 32 mg (28% of theory) of the product as a solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)C=O.[OH:12]O>[OH-].[Na+]>[Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:4]([OH:12])[C:3]=1[OH:11]
Reactant: O=Cc1cc(Cl)cc(Br)c1O
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Product: Oc1cc(Cl)cc(Br)c1O
Temperature: 25 °C
Yield: 99 %

Procedure:
To a stirred suspension of 3-bromo-5-chloro-2-hydroxybenzaldehyde (49.5 g, 0.21 mol) in 0.5N aqueous NaOH (500 ml, 0.25 mol) at 40° C. was added dropwise hydrogen peroxide (21.4 g of a 35% aqueous solution, 0.22 mol) over 15 minutes and the resultant mixture stirred for 16 hours. The mixture was cooled to room temperature, diluted with 1 N aqueous NaOH (200 ml) and washed with diethyl ether (3×300 ml). The aqueous layer was acidified with concentrated HCl to pH 2 and extracted with Et2O (3×200 ml). The organic extracts were combined, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the desired product as a red/brown solid (46.0 g, 99%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.[C:19]([O-:22])([O-])=[O:20].[Na+].[Na+]>[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:10]1([CH3:9])[CH:11]=[CH:12][CH:13]=[C:14]([C:6]2[N:7]=[CH:2][N:3]=[C:4]([C:10]3[CH:11]=[CH:12][C:13]([C:19]([OH:22])=[O:20])=[CH:14][CH:15]=3)[CH:5]=2)[CH:15]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc(B(O)O)c1
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cccc(-c2cc(-c3ccc(C(=O)O)cc3)ncn2)c1
Temperature: 100 °C
Yield: 13.8 %

Procedure:
Part A. A 50 mL three-neck round-bottom flask is charged with 2,4-dichloropyrimidine (0.58 g, 3.89 mmol), 3-methylphenylboronic acid (0.31 g, 2.28 mmol), Na2CO3 (0.73 g, 6.88 mmol), tetrakis(triphenylphosphine) palladium (13.0 mg, 1.12×10−2 mmol). The flask is evacuated, and refilled with N2. DMF (15 mL, anhydrous) is then added to the flask. The flask is evacuated again, and refilled with N2, repeated two times. The reaction is heated to 100° C. overnight. The reaction mixture is partitioned between ethyl ether and water. The organic layer is washed with brine, dried over MgSO4, and then removed. The residue is further purified by flash column chromatography, eluting with methylene chloride/hexanes (1:10) to afford 45.7 mg (5.8% yield) of desired product. The obtained compound (4-chloro-6-m-tolyl-pyrimidine) is >80% pure as determined by LC-MS. MS (ES+): m/e 205.23.
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[NH:8][CH:7]=[C:6]([C:9]2([NH:15]C=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4]1>CO>[ClH:1].[NH2:15][C:9]1([C:6]2[CH:5]=[CH:4][C:3](=[O:2])[NH:8][CH:7]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=CNC1(c2ccc(=O)[nH]c2)CCCCC1
Agent: Cl
Solvent: CO
Product: NC1(c2ccc(=O)[nH]c2)CCCCC1
Yield: 14.4 %

Procedure:
A solution of N-[1-(1,6-dihydro-6-oxo-3-pyridinyl)cyclohexyl]formamide hydrochloride (43.0 g) in 700 ml of methanol was heated at reflux for 17 hours, and then cooled and concentrated. The residual oil was triturated with methanol affording 13.1 g of a white powder. Recrystallization from methanol gave 5.5 g of crystals, m.p. 233°-234° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([Cl:11])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[Si:19]([O:26][CH2:27][CH2:28]Br)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:28][CH2:27][O:26][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[C:6]([Cl:11])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCO[Si](C)(C)C(C)(C)C)c(Cl)c1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a solution of 2.50 g of 3-chloro-4-hydroxybenzoic acid methyl ester in 25 ml of DMF, 2.78 g of potassium carbonate and 4.31 ml of 2-(tert-butyldimethylsilyloxy)ethylbromide were added, and the mixture was stirred at 50° C. for 15 hours. The solvent was evaporated, EtOAc was added to the residue, and the organic layer was washed with water and brine and dried over sodium sulfate. After the evaporation of the solvent, the obtained residue was purified by silica gel column chromatography (eluent: hexane-EtOAc=10:1˜5:1) to obtain 4.88 g of 4-[2-(tert-butyldimethylsilyloxy)ethoxy]-3-chlorobenzoic acid methyl ester.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[C:12]=1[O:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[Br:17][C:13]1[C:12]([O:18][CH3:19])=[C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1c(Br)cccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1c(Br)cccc1-c1ccccc1
Reaction time: 8 h
Yield: 86.7 %

Procedure:
A mixture of phenylboronic acid (3.4 g, 28.7 mmol), 2,6-dibromoanisole (22.3 g, 83.8 mmol, 3 equiv.) and palladium tetrakistriphenylphosphine (0.6 g) in ethylene glycol dimethyl ether (50 mL) and a solution of potassium carbonate (10.8 g, 0.078 mol) in water (50 mL) were kept at reflux under nitrogen with good stirring overnight. After cooling, the reaction mixture was partitioned between ethyl acetate (800 mL) and water (400 mL). The organic phase was washed with water (2×400 mL), dried over sodium sulfate and filtered. The solvent was removed in vacuo and the residue was chromatographed on silica (360 g) with heptane (5 L) to afford 6.55 g of pure product (87%).
Reaction SMILES: C(N(CC)CC)C.[ClH:8].[CH2:9]([O:11][C:12](=[O:21])[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]1)[CH3:10].Cl[C:23]1[C:24]([CH3:34])=[C:25]([S:30](Cl)(=[O:32])=[O:31])[CH:26]=[C:27]([CH3:29])[CH:28]=1.O>C(Cl)Cl>[CH2:9]([O:11][C:12](=[O:21])[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[S:30]([C:25]1[CH:26]=[C:27]([CH3:29])[C:28]([Cl:8])=[CH:23][C:24]=1[CH3:34])(=[O:32])=[O:31])[CH3:10]
Reactant: Cl
Reactant: Cc1cc(Cl)c(C)c(S(=O)(=O)Cl)c1
Reactant: CCOC(=O)CCC1CCCCN1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCC1CCCCN1S(=O)(=O)c1cc(C)c(Cl)cc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Triethylamine (30 g) was added dropwise to a solution of 3-(piperidin-2-yl)propionic acid ethyl ester hydrochloride (30 g) in methylene chloride (210 ml) at 0° C. and the mixture was then stirred at room temperature for 10 minutes. Chloro-2,5-dimethylbenzene-1-sulfonyl chloride (32.3 g) was then added slowly and the mixture was stirred for 2 hours. The reaction was observed by thin layer chromatography. Because of incomplete conversion, the mixture was stirred for a further 17 hours before the reaction was ended by addition of water (200 ml). The phases were separated and the aqueous phase was extracted with MC (150 ml). The combined organic phases were dried with Na2SO4, filtered and concentrated in vacuo. Purification of the crude product was carried out by chromatography on silica gel (5% ethyl acetate in hexane). The yield was 47.23 g (90%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[S:17][CH:18]=[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]=1[C:21]([O:23]CC)=[O:22])C(OC(C)(C)C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.O.[OH-].[K+]>C(O)(=O)C>[C:1]([O:5][C:6]([NH:8][C:16]1[S:17][CH:18]=[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]=1[C:21]([OH:23])=[O:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1c(-c2ccccc2)csc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1scc(-c2ccccc2)c1C(=O)O
Yield: 86.6 %

Procedure:
A mixture of ethyl bis(t-butoxycarbonyl)amino-4-phenylthiophene-3-carboxylate (4.37 g, 9.76 mmol), 40 ml of ethanol, 20 ml of water and 2.19 g of potassium hydroxide was heated at reflux for 3 h. The mixture was cooled and acidified with 2.9 ml of--acetic acid. The precipitate was isolated to give 2.70 g (87%) of 2-t-butoxycarbonylamino4-phenylthiophene-3-carboxylic acid. M.p. 183° C. (dec.). 1H-NMR (DMSO-D6, δ): 1.5 (s, 9H), 6.7 (s, 1H), 7.3 (m, 5H), 11.5 (br.s, 1H).
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[F:16][C:17]([F:26])([F:25])[C:18]1[N:23]=[CH:22][C:21](O)=[CH:20][N:19]=1.CCN(C(C)C)C(C)C.P(=O)(O)(O)O>C(Cl)Cl.O>[F:15][C:12]([F:13])([F:14])[S:9]([O:8][C:21]1[CH:20]=[N:19][C:18]([C:17]([F:26])([F:25])[F:16])=[N:23][CH:22]=1)(=[O:10])=[O:11]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1cnc(C(F)(F)F)nc1
Agent: O=P(O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(Oc1cnc(C(F)(F)F)nc1)C(F)(F)F
Temperature: 4 °C
Reaction time: 2.5 h
Yield: 89.4 %

Procedure:
Triflic anhydride (13.9 g, 85 mmol) in dry DCM (70 mL) was added slowly to an ice-cold solution of 2-(trifluoromethyl)pyrimidin-5-ol (13.9, 85 mmol) (U.S. Pat. No. 4,558,039), DIPEA (16 mL, 93 mmol) and dry DCM (260 mL) at such a rate that the temperature was kept between 4° C. and 6° C. After the addition was complete, the solution was stirred for 2.5 h at 4° C. and then allowed to warm to RT. Water (50 mL) and 1M phosphoric acid (4.5 mL) were added and the phases were washed and separated. The organic phase was washed successively with water and saturated sodium bicarbonate, dried, filtered and carefully concentrated by rotary evaporation (pressure 300-400 mbar). The dark-red oil was purified by column chromatography with EtOAc-heptanes (1:8 through 1:4) as eluent to give 22.5 g (90%) of the title product as a colourless oil that crystallised in the cold. Alternatively, the product could be purified by distillation, b.p. 75-77° C./10 mbar.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>O1CCCC1.[Pd]>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(OCCCCCOc2ccc([N+](=O)[O-])cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(OCCCCCOc2ccc(N)cc2)cc1
Yield: 90 %

Procedure:
A mixture of 1,5-bis(4-nitrophenoxy)pentane (32.7 grams, 94.4 mmol; prepared as described in Part A of this Example) and Pd/C 10% (1.00 gram, obtained from Aldrich Chemical Co.) was stirred for 20 hours in tetrahydrofuran (400 milliliters) under 200 pounds per square inch of hydrogen gas. The mixture was then filtered over CELITE, and the solvent was removed by evaporation under reduced pressure. The resulting crude solid was recrystallized from ethanol to afford pure 1,5-bis(4-aminophenoxy)pentane (24.4 grams, 85.1 mmol, 90 percent yield) as small colorless crystals: mp 78-79° C.; IR (KBr) 3433, 3353, 3217, 2949, 2868, 1856, 1632, 1511, 1473, 1396, 1228, 1031, 1002, 825, 517 cm−1; 1H NMR (300 MHz, CDCl3) δ6.76 (d, 4H, 3J=8.8 Hz), 6.64 (d, 4H, 3J=8.8 Hz), 3.92 (td, 4H, 3J=6.4 Hz, 4J=1.4 Hz), 3.40 (s, 4H), 1.82 (q, 4H, 3J=6.8 Hz), 1.62 (q, 2H, 3J=6.8 Hz): 13C NMR (75 MHz, CDCl3) δ151.31, 140.06, 116.51, 115.78, 68.58, 29.32, 22.83; MS (FAB, 3-nitrobenzyl alcohol) m/e 286.7; Anal. Calcd for C17H22N2O2: C, 71.30; H. 7.74; N, 9.78. Found: C, 71.11; H, 8.22; N, 9.85.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[C:14]([CH2:16][NH:17][C:18]([C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)=[O:19])[CH:13]=[CH:12][C:11]=12.[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O>>[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[C:14]([CH2:16][NH:17][C:18]([C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH:5][CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1])=[O:25])=[CH:22][CH:21]=3)=[O:19])[CH:13]=[CH:12][C:11]=12
Reactant: CC(C)CCN
Reactant: O=C(O)c1ccc(C(=O)NCc2ccc3nccn3c2)cc1
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: CC(C)CCNC(=O)c1ccc(C(=O)NCc2ccc3nccn3c2)cc1

Procedure:
The title compound was prepared as described in Example 1A, substituting 3-methylbutan-1-amine for 3-methylbutan-1-amine and 4-(imidazo[1,2-a]pyridin-6-ylmethylcarbamoyl)benzoic acid for 4-nitrobenzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.15 (t, J=5.8 Hz, 1H), 8.55-8.47 (m, 2H), 8.00-7.84 (m, 5H), 7.54 (dd, J=5.1, 4.1 Hz, 2H), 7.23 (dd, J=9.3, 1.7 Hz, 1H), 4.48 (d, J=5.8 Hz, 2H), 3.30-3.21 (m, 2H), 1.62 (dp, J=13.3, 6.6 Hz, 1H), 1.49-1.37 (m, 2H), 0.91 (d, J=6.6 Hz, 6H); MS (ESI(+)) m/e 365 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[CH:6]=[CH:5]2.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=1
Reactant: O=c1ccc2cc(I)ccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc2cc(I)ccc2n1
Yield: 87 %

Procedure:
A mixture of 6-iodo-1H-quinolin-2-one (6.23 g, 23 mmol) in phosphorus oxychloride (25 mL) was refluxed under N2 for 2 h. After cooling, the solvent was removed by rotary evaporator and then by the oil pump. Sat. sodium bicarbonate (100 mL) was slowly added. The solid was collected by filtration, washed with sat. sodium bicarbonate, water and dried to obtain 2-chloro-6-iodo-quinoline (5.78 g, 87%) as a black solid. LC-MS m/e 290 (MH+).
Reaction SMILES: CC(O)=O.C([N:12]1[CH2:19][CH:18]2[CH:14]([CH2:15][N:16]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=3)[CH2:17]2)[CH2:13]1)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:27][C:22]1[CH:23]=[C:24]([CH3:26])[N:25]=[C:20]([N:16]2[CH2:17][CH:18]3[CH:14]([CH2:13][NH:12][CH2:19]3)[CH2:15]2)[N:21]=1
Reactant: Cc1cc(C)nc(N2CC3CN(Cc4ccccc4)CC3C2)n1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 127.1 %

Procedure:
HOAc. To a 4 L high pressure autoclave equipped with mechanical stirring, temperature probe, heating jacket, and gas inlet were added 5% Pd/C (66.9 g, Johnson Matthey 5R338, 56.8% H2O, 3.45 mol %) and a solution of 2-benzyl-5-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole (160 g, 519 mmol) and acetic acid (30 mL, 519 mmol) in ethanol (3.2 L). The mixture was stirred at 50° C. under 50 psi of H2(g) for 4 h. The catalyst was removed and the resulting solution was then concentrated under reduced pressure to provide the desired product as a white solid (144 g, quantitative yield) as the HOAc salt. MS (ESI): mass calcd. for C12H18N4, 218.15; m/z found 219 [M+H]+. 1H-NMR (CDCl3, 400 MHz): 6.30 (s, 1H), 3.79-3.59 (m, 4H), 3.39 (m, 2H), 3.09-2.88 (m, 4H), 2.29 (s, 6H), 1.93 (s, 3H).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH3:16][CH:17]([CH3:23])[CH2:18][S:19](Cl)(=[O:21])=[O:20].[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][CH:26]=1>>[CH3:16][CH:17]([CH3:23])[CH2:18][S:19]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][CH:26]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Oc1ccc(N)cc1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: CC(C)CS(=O)(=O)Cl
Product: CC(C)CS(=O)(=O)N1CCC2(CCN(c3ccc(OS(C)(=O)=O)cc3)C2=O)CC1

Procedure:
Light brown solid. MS (ESI): 445.14 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-methyl-propane-1-sulfonyl chloride and methanesulfonic acid 4-amino-phenyl ester.