Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:27]2[CH2:31][CH:30]([CH2:32][O:33][P:34](=[O:45])([O:40]C(C)(C)C)[O:35]C(C)(C)C)[O:29][C:28]2=[O:46])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([O:14][CH:15]2[CH2:20][O:19][C:18]3=[N:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][N:17]3[CH2:16]2)=[CH:12][CH:13]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[F:1][C:2]1[CH:3]=[C:4]([N:27]2[CH2:31][CH:30]([CH2:32][O:33][P:34](=[O:35])([OH:45])[OH:40])[O:29][C:28]2=[O:46])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([O:14][CH:15]2[CH2:20][O:19][C:18]3=[N:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][N:17]3[CH2:16]2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OP(=O)(OCC1CN(c2ccc(-c3ccc(OC4COc5nc([N+](=O)[O-])cn5C4)nc3)c(F)c2)C(=O)O1)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1OC(COP(=O)(O)O)CN1c1ccc(-c2ccc(OC3COc4nc([N+](=O)[O-])cn4C3)nc2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
Phosphoric acid mono-(3-{3-fluoro-4-[6-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxy)-pyridin-3-yl]-phenyl}-2-oxo-oxazolidin-5-ylmethyl) ester was prepared according to the scheme shown in FIG. 17. Phosphoric acid di-tert-butyl ester 3-{3-fluoro-4-[6-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxy)-pyridin-3-yl]-phenyl}-2-oxo-oxazolidin-5-ylmethyl ester (13 mg) was dissolved with 1 mL TFA/CH2Cl2 (v/v, ½). The resulting solution was stirred at room temperature for 1 hour before all the solvent was removed. The residue was washed with 3 mL CH2Cl2, 3 mL EtOAc and 3 mL MeOH consequently. The residue was dried in vacuo to give the titled compound (8 mg) as white solid. ESI MS m/z 552 (M+H).
Reaction SMILES: C([O:4][C:5]1[C:6]([O:33][CH3:34])=[CH:7][C:8]2[C:21]3[C:12](=[C:13]4[C:18](=[CH:19][N:20]=3)[C:17]([O:22]CC3C=CC=CC=3)=[C:16]([O:30][CH3:31])[CH:15]=[CH:14]4)[CH:11]=[CH:10][C:9]=2[CH:32]=1)(C)C.[C:35]1(C)C=CC(S(OC)(=O)=O)=CC=1.[ClH:47]>CO>[Cl-:47].[OH:4][C:5]1[C:6]([O:33][CH3:34])=[CH:7][C:8]2[C:21]3[C:12](=[C:13]4[C:18](=[CH:19][N+:20]=3[CH3:35])[C:17]([OH:22])=[C:16]([O:30][CH3:31])[CH:15]=[CH:14]4)[CH:11]=[CH:10][C:9]=2[CH:32]=1
Reactant: Cl
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: COc1cc2c(ccc3c4ccc(OC)c(OCc5ccccc5)c4cnc23)cc1OC(C)C
Solvent: CO
Product: COc1cc2c(ccc3c4ccc(OC)c(O)c4c[n+](C)c23)cc1O
Product: [Cl-]

Procedure:
2-isopropoxy-3,8-dimethoxy-7-benzyloxybenzo[c]phenanthridine (compound D-4) and methyl p-toluenesulfonate were subjected to a reaction operation in a manner similar to that of Example 16 to produce compound E-4, which was further treated with dilute hydrochloric acid in the presence of methanol, so that compound A-4, wherein X- =Cl-, was obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Cl:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13](O)[CH:12]=[N:11]2>P(Cl)(Cl)(Cl)=O>[Cl:2][C:13]1[CH:12]=[N:11][C:10]2[C:15](=[CH:16][C:17]([Cl:18])=[C:8]([Cl:7])[CH:9]=2)[N:14]=1
Reactant: Oc1cnc2cc(Cl)c(Cl)cc2n1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1cnc2cc(Cl)c(Cl)cc2n1
Reaction time: 1 h

Procedure:
Phosphorus oxychloride (50 ml) and phosphorus pentachloride (10 g) were added to 6,7-dichloro-2-hydroxyquinoxaline (6.6 g) and the mixture was stirred for a period of 1 hour. The mixture was then poured onto ice and the precipitate collected by filtration to give 2,6,7-trichloroquinoxaline, mp 137° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[SH:18].[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]=[C:34]=S)=[CH:29][CH:28]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1.[OH-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:17][O:16][C:14]1[CH:13]=[CH:12][C:11]2[S:18][C:34]([NH:33][C:30]3[CH:31]=[CH:32][C:27]([O:26][CH2:25][CH2:24][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:28][CH:29]=3)=[N:9][C:10]=2[CH:15]=1
Reactant: S=C=Nc1ccc(OCCN2CCCC2)cc1
Reactant: COc1ccc(S)c(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc2sc(Nc3ccc(OCCN4CCCC4)cc3)nc2c1

Procedure:
Triethylamine (0.7 ml.) is added to a suspension of 2-amino-4-methoxybenzenethiol hydrochloride (0.96 g.) in toluene (20 ml.) under nitrogen. 4-(2-Pyrrolidin-1-ylethoxy)phenyl isothiocyanate (1.24 g.) is added and the mixture stirred and heated under reflux for 16 hours. Ethyl acetate and 10% sodium hydroxide are added and the organic layer separated, washed with water and dried. The organic layer is passed through a column of silica gel (2 × 20 cm.) and the filtrate rejected. The column is eluted with methanol, which, on concentration gives 5-methoxy-2-[4-(2-pyrrolidin-1-ylethoxy)anilino]benzothiazole, m.p. 167° - 168°C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[C:10]([F:22])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[N:28][CH:29]=1.Cl.[F:34][C:35]1([F:41])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[F:34][C:35]1([F:41])[CH2:40][CH2:39][N:38]([C:12]2[N:11]=[C:10]([F:22])[C:9]3[O:8][C:5]4[C:4]([C@@:15]5([CH2:19][O:18][C:17]([NH2:20])=[N:16]5)[C:14]=3[CH:13]=2)=[CH:3][C:2]([C:26]2[CH:27]=[N:28][CH:29]=[C:24]([F:23])[CH:25]=2)=[CH:7][CH:6]=4)[CH2:37][CH2:36]1
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Reactant: FC1(F)CCNCC1
Reactant: OB(O)c1cncc(F)c1
Agent: Cl
Product: NC1=N[C@@]2(CO1)c1cc(-c3cncc(F)c3)ccc1Oc1c2cc(N2CCC(F)(F)CC2)nc1F

Procedure:
The title compound was synthesized by steps analogous to those described in method CC4 above, but using (S)-7-bromo-3-chloro-1-fluoro-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (prepared as described in Method BB33), 5-fluoropyridin-3-ylboronic acid and 4,4-difluoropiperidine hydrochloride.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11](Br)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH2:20]([Mg]Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOCC>C(OCC)C.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: Cl[Mg]Cc1ccccc1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: CCN1CCN(c2nc(Cc3ccccc3)cc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
To a mixture solution of 1-(4-ethylpiperazin-1-yl)-3-bromoisoquinoline (0.71 g) cooled to 0° C. and [1,3-bis(diphenylphosphino)propane]dichloronickel(II) (0.05 g) in diethyl ether (20 ml) was dropwise added 1M benzylmagnesium chloride/ether solution (4.5 ml) in nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. The reaction solution was diluted with ether (30 ml), washed with water and brine, and then dried over magnesium sulfate. The solvent was removed, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/acetone system), to give the title compound (0.44 g; 59.5%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)=[CH:22][CH:21]=3)[C:16]([C:17]([NH2:19])=[O:18])=[C:12]2[NH:11][CH2:10][CH2:9]1.[C:34](Cl)(=[O:37])[CH:35]=[CH2:36]>>[C:34]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)=[CH:22][CH:21]=3)[C:16]([C:17]([NH2:19])=[O:18])=[C:12]2[NH:11][CH2:10][CH2:9]1)(=[O:37])[CH:35]=[CH2:36]
Reactant: C=CC(=O)Cl
Reactant: NC(=O)c1c(-c2ccc(Oc3ccc(F)cc3)cc2)nn2c1NCCC2c1ccccc1N
Product: C=CC(=O)Nc1ccccc1C1CCNc2c(C(N)=O)c(-c3ccc(Oc4ccc(F)cc4)cc3)nn21

Procedure:
The desired product was prepared from 7-(2-aminophenyl)-2-(4-(4-fluorophenoxyl)phenyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrimidine-3-carboxamide and acryloyl chloride using the procedure similar to that for compound 8. 1H NMR (400 MHz, CD3OD-d4) δ 7.47 (d, J=8.4 Hz, 2H), 7.39 (t, J=7.6 Hz, 1H), 7.33 (t, J=7.6 Hz, 1H), 7.26 (t, J=7.6 Hz, 1H), 7.12-7.00 (m, 6H), 6.81 (d, J=8.0 Hz, 1H), 6.53-6.46 (m, 1H), 6.39-6.35 (m, 1H), 5.87-5.76 (m, 1H), 5.73-5.69 (m, 1 H), 3.36-3.30 (m, 1H), 3.22-3.17 (m, 1H), 2.45-2.39 (m, 1 H) and 2.17-2.14 (m, 1H). MS (ESI) m/e [M+1]+ 497.9.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.[CH3:22][C:23]1([CH3:31])[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][C:24]1=[O:30].CC(C)(O)C#N>C(Cl)(=O)C(Cl)=O.CN(C)C=O.ClCCl>[OH:30][C:24]1[C:23]([CH3:31])([CH3:22])[CH2:28][CH2:27][C:26](=[O:29])[C:25]=1[C:4]([C:3]1[C:2]([CH3:1])=[N:10][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:7]=1)=[O:6]
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)O
Agent: CC(C)(O)C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(O)C(C)(C)CCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
The resulting 2-methyl-6-trifluoromethyinicotinic acid (1.026 g, 0.005 mol) is dissolved in 20 ml of oxalyl chloride. Three drops of dimethylformamide are added and the mixture is refluxed for 1 hour. The mixture is then concentrated on a rotary evaporator and the residue (2-methyl-6-trifluoromethylnicotinoyl chloride) is taken up in 100 ml of methylene chloride. At a temperature of 0° C., 1.6 ml (0.0115 mol) of triethylamine and 0.7 g (0.005 mol) of 4,4-dimethylcyclohexane-1,3-dione are added. After 2 hours at a temperature of 22° C., the solvent is removed on a vacuum rotary evaporator, the residue which remains is dissolved in 55 ml of acetonitrile, and 0.15 ml (0.0016 mol) of acetone cyanohydrin and 0.79 ml (0.0057 mol) of triethylamine are added in order to subject the intermediate to a rearrangement reaction. After the reaction solution has been stirred for 4 hours at room temperature, it is evaporated. The syrup which remains is chromatographed on silica gel. Elution with a mixture of toluene, ethyl alcohol, dioxane, triethylamine and water (100:40:20:20:5 parts by volume) gives a pale yellow viscous oil (Rf=0.39 on the abovementioned mixture as mobile phase), which is dissolved in dichloromethane and washed in succession with 75 ml of 5% hydrochloric acid and 75 ml of water. Evaporation to dryness of the organic solution which has been dried with Na2SO4 yields 1.05 g (63%) of pure 3-hydroxy-4,4-dimethyl-2-(2-methyl-6-trifluoromethylpyrdine-3-carbonyl)cyclohex-2-enone in the form of white crystals of melting point 75-77° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:24][CH2:25][CH:26]([CH2:44][F:45])[O:27][C:28]1[C:29]([CH3:43])=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][C:29]([CH3:43])=[C:28]([O:27][CH:26]([CH2:25][F:24])[CH2:44][F:45])[CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cc1OC(CF)CF
Product: Cc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1OC(CF)CF

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-(2-fluoro-1-fluoromethyl-ethoxy)-2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 189.1.1) to give the title compound as a white foam. (HPLC: tR 2.26 min (Method A); M+H=479 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.19-8.17 (m, 1H), 8.14-8.10 (m, 2H), 8.00-7.95 (m, 1H), 7.58-7.52 (m, 2H), 5.16-5.01 (m, 1H), 4.92-4.66 (m, 4H), 3.89 (s, 3H), 3.58 (s, 3H), 2.41 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: Br[C:2]1[C:3]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])=[N:6][CH:7]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:3]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]3[CH2:15][CH2:14][NH:13][C:12]3=[O:16])=[N:6][CH:7]=2)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C1NCCN1CCNc1ncc(Br)c(-c2cccs2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: O=C1NCCN1CCNc1ncc(-c2ccc(Cl)cc2)c(-c2cccs2)n1
Temperature: 80 °C

Procedure:
1-(2-(5-Bromo-4-(thiophen-2-yl)pyrimidin-2-ylamino)ethyl)imidazolidin-2-one (0.1 g, 0.27 mmol), 4-chlorophenylboronic acid (0.085 g, 0.54 mmol), sodium carbonate (0.27 mL of 2.0 M solution, 0.52 mmol) were added to a flask containing dioxane (1 mL). The flask was flushed with nitrogen and tetrakis(triphenylphosphine)palladium (0.062 g, 0.054 mmol) was added. The reaction was heated to 80° C. overnight. The reaction was cooled down to ambient temperature and diluted with ethyl acetate and water. The organic layer was filtered through a pad of celite and washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, concentrated and purified by column chromatography using a gradient 2 to 10% of methanol in dichloromethane to afford an off-white solid. Yield=0.04 g. MS (M+H)+ 400.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])[C:5]([O:7]C)=[O:6].O.[OH-].[Li+].O.CO>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(C(C)Oc2ccccc2)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(Oc1ccccc1)c1ccc(C(=O)O)cc1Cl
Temperature: 20 °C
Reaction time: 5 h
Yield: 66.9 %

Procedure:
A mixture of methyl 3-chloro-4-(1-phenoxyethyl)benzoate (750 mg, 2.7 mmol), lithium hydroxide monohydrate (571 mg, 13.6 mmol), water (5 mL) and methanol (5 mL) in tetrahydrofuran (15 mL) was stirred at 20° C. for 5 hours. The reaction mixture was concentrated. The residue was acidified to pH=2 with concentrated hydrochloride solution. The mixture was extracted with ethyl acetate (20 mL×2). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to give 3-chloro-4-(1-phenoxyethyl)benzoic acid as a white solid (500 mg, 71%). LRMS (M+H+) m/z: 276.06. found 276.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=1)[CH2:11][NH:12]C(=O)OC(C)(C)C)=[NH:5].C(=O)(OCC1C=CC=C(CN)C=1)N>FC(F)(F)C(O)=O>[NH2:12][CH2:11][C:10]1[CH:9]=[C:8]([CH:22]=[CH:21][CH:20]=1)[CH2:7][NH:6][C:4](=[NH:5])[CH2:3][O:2][CH3:1]
Reactant: COCC(=N)NCc1cccc(CNC(=O)OC(C)(C)C)c1
Agent: NCc1cccc(COC(N)=O)c1
Solvent: O=C(O)C(F)(F)F
Product: COCC(=N)NCc1cccc(CN)c1
Yield: 61.8 %

Procedure:
The intermediate tert-butyl N-(3-((2-methoxyacetimidoyl) aminomethyl)benzyl)-carbamate (360 mg) prepared from tert-butyl N-(3-(aminomethyl)benzyl carbamate and intermediate G analogous to example 1 was deprotected in trifluoroacetic acid at 20° C. for 16 h. The crude product was purified by C18 reverse phase chromatography eluting with water (0.1% trifluoroacetic acid) to yield 150 mg of N-(3-(Aminomethyl)benzyl)-2-methoxyacetamidine as a yellowed, viscous oil (freeze-dried). Mass spectrum (CI) 208.0 (MH+, 100%). 1H NMR (200 MHz, D2O) δ 7.5-7.3 (m, 4H), 4.57 (s, 2H), 4.37 (s, 2H), 4.15 (s, 2H), 3.44 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:32]=[CH:31][C:21]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:20][CH:19]=3)[C:11]3=[N:12][CH:13]=[C:14](Br)[CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1>C(O)C.C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:32]=[CH:31][C:21]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:20][CH:19]=3)[C:11]3=[N:12][CH:13]=[C:14]([C:7]4[CH:2]=[N:3][CH:4]=[CH:5][CH:6]=4)[CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-n2c(-c3cccnc3N)nc3cc(Br)cnc32)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1ccc(-n2c(-c3cccnc3N)nc3cc(-c4cccnc4)cnc32)cc1
Temperature: 100 °C
Yield: 197.5 %

Procedure:
tert-butyl 4-(2-(2-aminopyridin-3-yl)-6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)benzylcarbamate (4 g, 8 mmol) was suspended in a mixture of ethanol and toluene, 160 ml respectively and a solution of NaHCO3sat. was added (27 ml). The reaction mixture was degassed with nitrogen for 30 min. Subsequently it was heated to 100° C. overnight under nitrogen. After cooling down to room temperature it was diluted with 300 ml dichloromethane and 200 ml of water were added. The organic phase was separated and washed with brine (200 ml) and dried over Na2SO4. After filtration the solvent was removed under reduced pressure. The crude residue was purified by silica gel chromatography (2-20% methanol in ethyl acetate). The solvent was removed under reduced pressure, yielding 3.9 g tert-butyl 4-(2-(2-aminopyridin-3-yl)-6-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzylcarbamate (7.9 mmol, 99% yield). 400 M Hz 1H NMR (DMSO-d6) δ: 8.98 (d, J=1.9 Hz, 1H), 8.64 (d, J=2.0 Hz, 1H), 8.59 (dd, J=1.6 Hz and 4.7 Hz, 1H), 8.54 (d, J=2.0 Hz, 1H), 8.20 (m, 1H), 7.98 (m, 1H), 7.52 (m, 2H), 7.48-7.34 (m, 4H), 7.23 (m, 1H), 7.01 (s, br, 2H), 6.38 (m, 1H), 4.19 (m, 2H), 1.38 (s, 9H), MS 438.22, 494.00, [M-(t-Bu)+H, M+H].
Reaction SMILES: [F:1][C:2]([F:14])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[C:3]([F:6])([F:5])[F:4].[H-].[Na+].Br[CH2:18][C:19]([O:21]CC)=[O:20]>O1CCCC1>[F:1][C:2]([F:14])([C:3]([F:5])([F:4])[F:6])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:18][C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)CBr
Reactant: OCCCCCCC(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)COCCCCCCC(F)(F)C(F)(F)F
Temperature: 20 °C
Yield: 39.6 %

Procedure:
To a stirred solution of 6-(pentafluoroethyl)hexan-1-ol (500 mg) in tetrahydrofuran (10 ml) was added sodium hydride (60% dispersion in mineral oil; 118 mg) and the reaction was stirred at 20° C. for 30 mlnutes. Ethyl bromoacetate (379 mg) was added and the reaction was stirred for a further 3 hours. The reaction was quenched by the addition of ethanol (3 ml) followed by stirring for 30 mlnutes, then 2M sodium hydroxide (3 ml) was added and the reaction was stirred for a further 2 hours. The reaction mixture was partitioned between dichloromethane (100 ml) and water (100 ml). The aqueous layer was acidified to pH 1 by the addition of 2M hydrochloric acid and then extracted with dichloromethane (3×100 ml). The combined organic layers were dried over magnesium sulphate and the solvent was removed in vacuo to give the title compound as a white solid (250 mg).
Reaction SMILES: C([N:3](CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1[N:14]([CH3:36])[C:15]([CH2:34][CH3:35])=[C:16]([C:32]#[N:33])[C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2N)=[CH:20][CH:19]=1)=[O:12])[CH3:9].[CH:37]([S:40](Cl)(=[O:42])=[O:41])([CH3:39])[CH3:38]>C(Cl)Cl>[CH2:8]([O:10][C:11]([C:13]1[N:14]([CH3:36])[C:15]([CH2:34][CH3:35])=[C:16]([C:32]#[N:33])[C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([NH:3][S:40]([CH:37]([CH3:39])[CH3:38])(=[O:42])=[O:41])[CH:30]=2)=[CH:20][CH:19]=1)=[O:12])[CH3:9]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CCOC(=O)c1c(-c2ccc(Oc3ccccc3N)cc2)c(C#N)c(CC)n1C
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccc(Oc3cccc(NS(=O)(=O)C(C)C)c3)cc2)c(C#N)c(CC)n1C
Temperature: 0 °C
Yield: 112.4 %

Procedure:
Add triethylamine (43 mg, 1.5 Eq.) dropwise to 4-cyano-5-ethyl-1-methyl-3-[4-(2-amino-phenoxy)-phenyl]-1H-pyrole-2-carboxylic acid ethyl ester (110 mg, 0.28 mmol, prepared in example E-231) in methylene chloride (25 mL) while stirring at 0° C. under a nitrogen atmosphere. Immediately add isopropylsulfonyl chloride (48 mg, 1.2Eq.) dropwise and allow the reaction to warm to room temperature and stir overnight. Add water to the mixture and separate layers. Wash the organic layer once with water, dry over potassium carbonate, filter, and concentrate under reduced vacuum to give 156 mg of a solid. Purity the material by silica gel chromatography (Chromatotron™) eluting with methylene chloride/ethyl acetate 19:1 to provide 23 mg of the title compound as a viscous oil. (Bruker 300) 1H NMR (CDCl3) δ 7.30-7.35 (2H, d), 7.22-7.28 (1H, m), 6.99-7.03 (2H, d), 6.89-6.97 (2H, m), 6.75-6.79 (1H, d), 4.06-4.14 (2H, dd), 3.85-3.88 (3H, s), 3.29-3.36 (1H, m), 2.81-2.87 (2H, dd), 1.36-1.42 (6H, d), 1.25-1.32 (3H, t), 1.02-1.09 (3H, t).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[O:18][CH2:19][C:20]([F:23])([F:22])[F:21].C1C(=O)N([Br:31])C(=O)C1>C(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:18][CH2:19][C:20]([F:21])([F:22])[F:23])=[CH:4][C:5]([CH:8]([CH2:14][CH:15]2[CH2:16][CH2:17]2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][C:7]=1[Br:31]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(CC1CC1)c1ccc(N)c(OCC(F)(F)F)c1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)C(CC1CC1)c1cc(Br)c(N)c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.1 %

Procedure:
To a stirred solution of ethyl 2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (0.9 g, 2.7 mmol) in dry CHCl3 (50 mL), NBS (0.412 g, 2.3 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 h at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic solvents was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography to give ethyl 2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (1.02 g) as a yellow solid.
Reaction SMILES: CS([O:5][CH:6]([CH2:9][CH3:10])[C:7]#[N:8])(=O)=O.[CH3:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:13]=1O.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.O.C(OC)(C)(C)C>[CH3:11][C:12]1[C:17]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:15]=[CH:14][C:13]=1[O:5][CH:6]([CH2:9][CH3:10])[C:7]#[N:8]
Reactant: CCC(C#N)OS(C)(=O)=O
Reactant: Cc1c(O)cccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: COC(C)(C)C
Product: CCC(C#N)Oc1cccc(C(F)(F)F)c1C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(methanesulfonyloxy)-butyronitrile (449 mg, 2.75 mmol), 2-methyl-3-trifluoromethylphenol (440 mg, 2.5 mmol), potassium carbonate (432 mg, 3.13 mmol) and potassium iodide (42 mg, 0.25 mmol) in acetonitrile (20 ml) was stirred overnight at 80° C. The mixture was shaken between tBuOMe and water, washed with NaCl (aq. satd) and the ethereal phase dried with MgSO4 and evaporated. The crude product was chromatographed on silica with EtOAc and hexane to give 2-(2-methyl-3-trifluoromethyl-phenoxy)-butyronitrile. 1H-NMR (CDCl3) 1.20 t, 3H; 2.15 dt, 2H; 2.36 s, 3H; 4.75, t, 2H; 7.17, d, 1H; 7.28, t, 1H; 7.37 d, 1H.