Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].CN(C=O)C.[N-:16]=[N+:17]=[N-:18].[Na+]>C(Cl)Cl>[N:16]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)CCCCCCBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: [N-]=[N+]=NCCCCCCC(=O)O
Temperature: 60 °C

Procedure:
7-azidoheptanoic acid (64) was synthesized from 7-bromoheptanoic acid 63 as shown above. To 914 mg of 7-bromoheptanoic acid (63) (commercially available from Matrix Scientific, Columbia, S.C.) (4.4 mmol) was added 15 mL anhydrous DMF. To the stirring solution was added 914 mg NaN3 (14 mmol, 3.2 eq) at room temperature. The clear solution was warmed to 60° C. for a period of 6 h. The solution was then cooled to room temperature and diluted with 50 mL CH2Cl2. The organic layer was washed with cold 1N HCl (7×50 mL) and brine (2×50 mL), then dried over anhydrous Na2SO4. Filtration and removal of solvent afforded 709 mg crude 7-azidoheptanoic acid 64 in 94% yield which was of suitable purity for continued progression enroute to materials 65 and 66. An NMR analysis was performed where: 1H NMR (400 MHz, CDCl3) δ 11.55 (bs, 1H), 3.14 (t, J=6.8 Hz, 2H), 2.22 (t, J=7.2 Hz, 2H), 1.56-1.45 (m, 4H), 1.30-1.24 (m, 4H); 13C NMR (400 MHz, CDCl3) δ 178.3, 51.1, 33.7, 28.5, 28.4, 26.2, 24.4. HRMS (ESI) calculated. for C7H13N3O2 (M−H): 170.0930, measured: 170.0930.
Reaction SMILES: N([N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:17]C(C)=O)=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[CH2:7][CH2:6]1)C(C)=O.[ClH:21]>CO>[ClH:21].[NH2:17][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][C:11]=1[N+:14]([O-:16])=[O:15])[NH:5][CH2:6][CH2:7]2
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])N(NC(C)=O)CC2
Agent: Cl
Solvent: CO
Product: Nc1cc2c(cc1[N+](=O)[O-])NCC2
Yield: 82.5 %

Procedure:
21.4 g of 1,5-diacetamino-6-nitro-indoline were dissolved in 2.5 l of methanol, boiled under reflux overnight with 750 ml of 4N hydrochloric acid in methanol and then evaporated. There were obtained 14.2 g (82.5% of theory) of 5-amino-6-nitro-indoline hydrochloride of melting point 259° C.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[CH3:10][C:11]1[CH:12]=[C:13]([C:17](=O)[CH3:18])[CH:14]=[CH:15][CH:16]=1.[C:20](#[N:24])[CH2:21][C:22]#[N:23]>C(O)(=O)C.O>[CH3:10][C:11]1[CH:12]=[C:13]([C:17](=[C:21]([C:20]#[N:24])[C:22]#[N:23])[CH3:18])[CH:14]=[CH:15][CH:16]=1
Reactant: N#CCC#N
Reactant: CC(=O)c1cccc(C)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC(=O)O
Solvent: O
Product: CC(=C(C#N)C#N)c1cccc(C)c1
Temperature: 70 °C
Yield: 106.4 %

Procedure:
To a stirred solution of acetic acid (10 mL) was added dropwise hexamethyldisilazane (3.89 mL, 18.65 mmol) over ca. 30 min with the temperature kept below 40° C. throughout the addition. This resulting solution was subsequently added to a stirred solution of 1-(3-methylphenyl)ethanone (2.03 mL, 14.91 mmol) and malononitrile (1.88 mL, 29.8 mmol) in acetic acid (10 mL) and the mixture heated to 70° C. under nitrogen overnight. The reaction mixture was then cooled to RT, diluted with water (ca. 50 mL) and extracted with toluene (ca. 50 mL×2). The combined organic layer was passed through a phase separator and the solvent concentrated in vacuo, to give the title compound (2.89 g) which was used in next step without further purification. LCMS (A) m/z: 181 [M−1]−, Rt 1.23 min (acidic).
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.[H-].[Na+].[C:16](Cl)([Cl:18])=[O:17]>ClCCl.C1(C)C=CC=CC=1>[C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][C:4]([O:7][C:16]([Cl:18])=[O:17])=[CH:5][CH:6]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Cl)Oc1ccc(-c2ccccc2)cc1
Reaction time: 3 h

Procedure:
2.00 g (11.75 mmol) of [1,1′-biphenyl]-4-ol in suspension in 50 ml of dichloromethane are introduced into a 50-ml three-necked flask, 0.47 g (11.75 mmol) of 60% sodium hydride in mineral oil is added portionwise, and the solvent is evaporated off under reduced pressure. A white solid is obtained which is added over 1 h to 6.84 ml (12.92 mmol) of a 20% solution of phosgene in toluene at 30° C. and left in contact for 3 h.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:31][CH2:32][N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24](OC(C)(C)C)=O)[CH2:20][CH2:19]2)=[O:17])=[CH:11][CH:10]=1.C(N(CC)C(C)C)(C)C.ClC1[C:49]2[C@H:56]([CH3:57])[CH2:55][CH2:54][C:50]=2[N:51]=[CH:52][N:53]=1>C(Cl)Cl.O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:31][CH2:32][N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[C:16]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[C:49]4[C@H:56]([CH3:57])[CH2:55][CH2:54][C:50]=4[N:51]=[CH:52][N:53]=3)[CH2:22][CH2:23]2)=[O:17])=[CH:11][CH:10]=1
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Reactant: CCN(CC)CCN(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCN(CC)CCN(C(=O)N1CCN(c2ncnc3c2[C@H](C)CC3)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.1 %

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl 4-(N-(4-chlorophenyl)-N-(2-(diethylamino)ethyl)carbamoyl)piperazine-1-carboxylate (311 mg, 0.7 mmol) in DCM (5 mL). The mixture was stirred at room temperature for 3 hours, and then concentrated in vacuo. The residue was dissolved in n-butanol (2 mL). N,N-Diisopropylethylamine (0.5 mL, 3.6 mmol) was added followed by (R)-4-chloro-6,7-dihydro-5-methyl-5H-cyclopenta[d]pyrimidine (113 mg, 0.84 mmol). The reaction mixture was heated at 80° C. for 16 hours. The mixture was then diluted with H2O, and extracted with DCM (2×20 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by preparative HPLC to give N-(4-chlorophenyl)-N-(2-(diethylamino)ethyl)-4-((R)-6,7-dihydro-5-methyl-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxamide (39.9 mg, 12%). MS (APCI+) [M+H]+ 471.3. 1H NMR (CDCl3, 400 MHz) δ□: 8.49 (s, 1H), 7.40-7.35 (m, 2H), 7.17-7.13 (m, 2H), 4.06-3.95 (m, 4H), 3.77-3.70 (m, 2H), 3.51-3.44 (m, 1H), 3.39-3.02 (m, 11H), 2.42-2.32 (m, 1H), 1.88-1.82 (m, 1H), 1.33 (t, J=7.2 Hz, 6H), 1.15 (d, J=6.8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29]CC)=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=[O:28])([CH3:25])[CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(F)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(F)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 65 °C
Yield: 69.3 %

Procedure:
A mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-fluoro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (300 mg, 0.52 mmol), NaOH (41 mg, 1.03 mmol), H2O (1 mL) and THF (10 mL) was heated at 65° C. for 1 h. After cooled to room temperature, the solution was concentrated and the residue was acidified to “pH” 2-3 by addition of concentrated aqueous HCl. The white solid was collected by filtration, dried to give the title compound (200 mg).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>O.[Pd]>[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:12]=1
Reactant: Oc1cccc(I)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Oc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 170 °C

Procedure:
To a mixture of 10% Pd/C (cat), 3-iodophenol (220 mg, 1.00 mmol) and 4-(trifluoromethyl)phenylboronic acid (284 mg, 1.49 mmol) was added a solution of K2CO3 (415 mg, 3.01 mmol) in water (10 mL) and the reaction mixture was heated in a Biotage microwave (170° C., absorption high, pre-stirring 10 s) for 20 min. The crude reaction mixture was then extracted into EtOAc (40 mL×3) and dried over MgSO4 to yield 3-(4-(trifluoromethyl)phenyl)phenol as a yellow solid (212 mg, 89%, 99% purity by HPLC) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[C:5](/[CH:11]=[CH:12]/[C:13]#[N:14])=[CH:4][CH:3]=1>C(O)C.N.[Pd].[Rh]>[F:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[C:5]([CH2:11][CH2:12][CH2:13][NH2:14])=[CH:4][CH:3]=1
Reactant: N#C/C=C/c1ccc(F)c2occc12
Agent: [Pd]
Agent: [Rh]
Agent: N
Solvent: CCO
Product: NCCCc1ccc(F)c2c1CCO2
Reaction time: 18 h
Yield: 98.2 %

Procedure:
A solution of (E)-3-(7-fluoro-benzofuran-4-yl)-acrylonitrile (0.25 g) in ethanol (25 ml), ammonia (0.88; 10 ml) containing 10% palladium on charcoal (50 mg; 50% wet paste) and 5% rhodium on charcoal (50 mg) was hydrogenated at 70 psi and 70° for 18 h. The solution was filtered through hyflo and evaporated to dryness and the residue purified by column chromatography. Eluting with dichloromethane/ethanol/ammonia 100:8:1 gave the title compound (256 mg).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].[C:17](OC)(=[O:22])[C:18]([O:20][CH3:21])=[O:19].Cl>C1COCC1>[C:1]1(/[CH:7]=[CH:8]\[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccccc1C=Cc1ccccc1
Reactant: COC(=O)C(=O)OC
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1ccccc1/C=C\c1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
A solution of the Grignard reagent prepared from part of the mixture of isomers of 1-phenyl-2-(2-bromophenyl)-ethylene described above (5.58 g) and magnesium (0.63 g) in dry THF (20 ml) was added dropwise over 30 mins. to a stirred solution of dimethyl oxalate (5.06 g) in dry THF (40 ml) cooled to −15° C. The resulting mixture was stirred at about −15° C. for 30 minutes, then at room temperature for 1 hour, then poured into dilute hydrochloric acid and extracted with ether. The extracts were washed with water, dried, concentrated under reduced pressure, then chromatographed twice [(i) 30% ether in petrol; (ii) 20% hexane in dichloromethane] to give isomerically pure Z-methyl 2-(2′-phenylethenyl)-phenylglyoxalate (1.76 g, 31% yield) as a yellow oil, 1H nmr (CDCl3): delta 3.87 (3 H, s), 6.78 (centre of 2 doublets, each 1 H, J 12 Hz) p.p.m.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([CH2:21][OH:22])[CH:20]=1)[O:6][CH2:7][CH2:8][N:9]([CH3:17])[C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14].[CH3:23][Si](C=[N+]=[N-])(C)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[CH3:23][O:14][C:13](=[O:15])[CH2:12][CH2:11][C:10]([N:9]([CH2:8][CH2:7][O:6][C:5]1[CH:4]=[C:3]([CH2:2][OH:1])[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=1)[CH3:17])=[O:16]
Reactant: CN(CCOc1cc(CO)cc(CO)c1)C(=O)CCC(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)CCC(=O)N(C)CCOc1cc(CO)cc(CO)c1
Reaction time: 0.67 h

Procedure:
To a cooled (0° C.) solution of N-[2-(3,5-Bis-hydroxymethyl-phenoxy)-ethyl]-N-methyl-succinamic acid (225 mg) in methanol (1 mL), was added (trimethylsilyl)diazomethane 2M in hexanes (840 μL) until persistence of the yellow colour. After 40 min, ethyl acetate (5 mL) and acetic acid (50 μL) were added, then, one minute later, a saturated aqueous solution of sodium hydrogen carbonate until pH=7. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo to a residue. The residue was purified by silica gel chromatography (Merck SuperVarioFlash 25 g column, Si60 15-40 μm), using gradient elution with a mixture of DCM (A)/MeOH (B), (gradient: 98% A: 2% B down to 90% A: 10% B) to give N-[2-(3,5-Bis-hydroxymethyl-phenoxy)-ethyl]-N-methyl-succinamic acid methyl ester (103 mg). LC/MS (Method A3): ES: m/z 348 (M+Na)+; m/z 326 (M+H)+ m/z 308 (M−H2O+H)+; RT=0.43 min
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]3[NH:20][CH:19]=[N:18][N:17]=3)[C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:27]1([C:2]2[C:11]3[C:6](=[CH:7][N:8]=[CH:9][CH:10]=3)[C:5]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]4[NH:20][CH:19]=[N:18][N:17]=4)[C:4]=3[N:3]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Clc1nc2c(-c3nnc[nH]3)cccc2c2cnccc12
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(-c2nc3c(-c4nnc[nH]4)cccc3c3cnccc23)cc1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
To 5-chloro-7-(4H-1,2,4-triazol-3-yl)benzo[c][2,6]naphthyridine (21.3 mg), cesium carbonate (49 mg) and phenylboronic acid (19 mg) in dioxane (1 mL) was added PdCl2(dppf) under nitrogen atmosphere. The mixture stirred at 120° C. at 300 W (microwave) for 10 min. Water was added and residue obtained after extraction with dichloromethane was purified by preparative HPLC. LCMS (ES) m/z [M+1]+ 324.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.[N+:16]([O-])([OH:18])=[O:17]>>[N+:16]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:7]=1[F:6])[C:11]([OH:13])=[O:12])([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
150 ml of nitric acid with a density of 1.42 were added at 0° C. to 300 ml of concentrated sulfuric acid and 50 g of p-fluoro-benzoic acid were added thereto at 0° C. over 30 minutes. The mixture was stirred at 0° C. for one hour and the temperature was allowed to rise to 20° C. The mixture was stirred at 20° C. for 16 hours and was poured over ice. The mixture was vacuum filtered and the product was washed and dried to obtain 47.6 g of 3-nitro-4-fluoro-benzoic acid melting at 123°-124° C. The said product was reacted as in Step B of Example 1 to obtain 0-(2-nitro-4-carboxy-phenyl)-hydroxylamine melting at 215° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:40])[NH:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]2[C:20]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[CH:19][N:18]=[C:17]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-])=O)[CH:32]=3)[N:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N.O>C(O)C>[C:1]1([CH2:7][O:8][C:9](=[O:40])[NH:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]2[C:20]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[CH:19][N:18]=[C:17]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([NH2:37])[CH:32]=3)[N:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cnc(Nc2cccc([N+](=O)[O-])c2)nc1NCCCNC(=O)OCc1ccccc1
Agent: N
Solvent: CCO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cnc(Nc2cccc(N)c2)nc1NCCCNC(=O)OCc1ccccc1
Yield: 99.5 %

Procedure:
Phenylmethyl[3-[[5-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]-2-[(3-nitrophenyl)amino]pyrimidin-4-yl]amino]propyl]carbamate (244 mg), dissolved in ethanol (30 ml), was slowly added to a mixture of FeSO4 heptahydrate (1.25 g), concentrated ammonia solution (25%; 1.25 ml) and water (5 ml). After refluxing for 3 h the mixture was filtered and the filter cake washed with ethyl acetate. The filtrate was washed with water and brine, dried (Na2SO4), filtered and evaporated to yield the crude title compound (230 mg), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH2:19]Cl)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:24][N:25]([CH3:31])[C:26](=[O:30])[CH2:27][NH:28]C.CCN(C(C)C)C(C)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH2:19][NH:28][CH2:27][C:26]([N:25]([CH3:31])[CH3:24])=[O:30])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNCC(=O)N(C)C
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNCC(=O)N(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77 %

Procedure:
N-(3-chloro-2-fluorophenyl)-6-(chloromethyl)-7-methoxyquinazolin-4-amine (0.21 g, 0.60 mmol) was added to a stirred solution of N1,N1,N2-trimethylglycinamide (Me2N-Gly-Nme) (0.348 g, 1.81 mmol) and DIPEA (0.234 g, 1.81 mmol) in dimethylformamide (1 ml) at 140° C., over a period of 5 minutes. The reaction mixture was stirred for 5 minutes, cooled to room temperature and purified by preparative LCMS (standard acidic system) to give N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N1,N1-dimethylglycinamide (0.193 g, 74.2%) as a white solid. 1H NMR Spectrum: (DMSO-d6) 2.27 (s, 3H), 2.80 (s, 3H), 2.98 (s, 3H), 3.71 (s, 2H), 3.94 (s, 3H), 7.19 (s, 1H), 7.27 (t, 1H), 7.47-7.52 (m, 2H), 8.30 (s, 1H), 8.43 (s, 1H), 9.85 (s, 1H); Mass Spectrum: (M+H)+ 432. Solid N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N1,N1-dimethylglycinamide (0.150 g, 0.348 mmol) was added over a period of 1 minute to a stirred solution of anhydrous lithium iodide (0.232 g, 1.74 mmol) in 2,4,6-collidine (0.5 ml) at 130° C., previously stirred for 30 minutes at 130° C. The reaction mixture was allowed to stir for 5 hours, cooled, concentrated and purified by preparative LCMS (standard acidic system) to afford N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-hydroxyquinazolin-6-yl}methyl)-N1,N1-dimethylglycinamide (0.080 g, 55.2%) as an orange foam; Mass Spectrum: (M+H)+ 418.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.CN1CCOCC1.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[C:43]([O:47][C:48](=[O:55])[N:49]([CH2:51][CH2:52][O:53][NH2:54])[CH3:50])([CH3:46])([CH3:45])[CH3:44]>O1CCCC1.C(OCC)(=O)C>[C:43]([O:47][C:48](=[O:55])[N:49]([CH2:51][CH2:52][O:53][NH:54][C:5]([C:4]1[CH:8]=[CH:9][C:10]([F:11])=[C:2]([F:1])[C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=1[F:20])=[O:7])[CH3:50])([CH3:46])([CH3:44])[CH3:45]
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: CN(CCON)C(=O)OC(C)(C)C
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(CCONC(=O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 73.3 %

Procedure:
A solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid (3.11 g, 7.91 mmol) in tetrahydrofuran (20 mL) was cooled with a −40° C. bath and treated with N-methylmorpholine (0.87 mL, 7.9 mmol). Diphenylphosphinic chloride (2.00 mL, 10.5 mmol) was added dropwise over 5 min and the reaction mixture was stirred for 90 min, during which time the temperature of the cooling bath slowly warmed to 0° C. The reaction mixture was again cooled to −40° C. and (2-aminooxy-ethyl)-methyl-carbamic acid tert-butyl ester (2.00 g, 10.5 mmol) was added as a solution in tetrahydrofuran (6 mL). After an additional 10 min, N-methylmorpholine (1.33 mL, 12.1 mmol) was added. The temperature of the cooling bath was allowed to warm to ambient temperature over 4 h and the reaction mixture was further stirred overnight. The reaction was diluted with ethyl acetate (40 mL) and washed with saturated aqueous ammonium chloride (2×10 mL). The organics were dried over magnesium sulfate, concentrated and purified by silica gel chromatography. Elution with 35% ethyl acetate-hexanes afforded [2-({1-[3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-phenyl]-methanoyl}-aminooxy)-ethyl]-methyl-carbamic acid tert-butyl ester (3.28 g, 73% yield) as an off-white foam: 1H NMR (400 MHz, DMSO-d6) δ 11.84 and 11.75 (br s, 1H total), 8.66 (br s, 1H), 7.54 (dd, J=10.9, 1.6 Hz, 1H), 7.36 (br t, J=8.8 Hz, 1H), 7.33 (br d, J=8.8 Hz), 7.20 (m, 1H), 6.64 (m, 1H), 3.85 (t, J=5.2 Hz, 2H), 3.34 (br s, 2H), 2.81 and 2.79 (br s, 3H total), 1.34 and 1.32 (s, 9H total); 19F NMR (376 MHz, DMSO-d6) δ −128.0 (d, J=32.9 Hz), −133.0, −144.2 (d, J=17.7 Hz); MS (APCI−)=564.1.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:11])[NH:10][C:5]2=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1.Cl>C(O)C.O>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:3]2[CH:4]=[C:5]3[NH:10][C:9](=[O:11])[NH:8][C:6]3=[N:7][C:2]=2[CH3:1])=[CH:13][CH:14]=1
Reactant: Cc1nc2[nH]c(=O)[nH]c2cc1-c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1nc2[nH]c(=O)[nH]c2cc1-c1ccc(N)cc1
Temperature: 25 °C
Yield: 128.2 %

Procedure:
To a suspension of 10.11 g 1,3-dihydro-5-methyl-6-(4-nitrophenyl)-2H-imidazo[4,5-b]pyridin-2-one (Example 5) in 200 ml absolute ethanol and 80 ml water was added 25.34 g stannous chloride dihydrate (SnCl2.2H2O) and 120 ml concentrated hydrochloric acid. The reaction mixture was heated at reflux for 6 hours, then cooled to room temperature and allowed to stand until crystals formed. The latter was collected by decantation and additional product obtained by concentration of the mother liquors to 60% of the original volume. The total solid product was washed with ethanol and ether and dried (high vacuum at 120° C.) to give 11.52 g 6-(4-aminophenyl)-1,3-dihydro-5-methyl-2H-imidazo[4,5-b]pyridin-2-one in the form of its hydrochloride salt and containing ethanol of crystallization, m.p. 277°-283° C.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:21]=[N:20][CH:19]=[CH:18][C:14]=3[C:15]([OH:17])=O)=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[NH2:29][CH2:30][C:31]([CH3:34])([OH:33])[CH3:32]>>[OH:33][C:31]([CH3:34])([CH3:32])[CH2:30][NH:29][C:15]([C:14]1[CH:18]=[CH:19][N:20]=[CH:21][C:13]=1[NH:12][C:10]([C:8]1[C:7]([NH:22][C:23]2[CH:24]=[N:25][CH:26]=[N:27][CH:28]=2)=[N:6][CH:5]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[N:9]=1)=[O:11])=[O:17]
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Reactant: CC(C)(O)CN
Product: CC(C)(O)CNC(=O)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Yield: 74 %

Procedure:
According to the procedure described in step 3 of example 99, 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-isonicotinic acid (example 99, step 2) was reacted with 1-amino-2-methylpropan-2-ol, providing the title compound as yellow solid (74%).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH3:5][CH2:6][O:7][C:8]([CH2:10][C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=O)=[O:9]>>[CH:1]([NH:4][C:11]([CH2:10][C:8]([O:7][CH2:6][CH3:5])=[O:9])=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Reactant: CC(C)N
Product: CCOC(=O)C=C(CC(=O)OCC)NC(C)C
Temperature: -18 °C
Reaction time: 24 h
Yield: 36 %

Procedure:
Isopropylamine (60 ml, 0.712 mol) was added slowly to diethyl 1,3-acetonedicarboxylate (120 g, 0.5934 mol) with stirring at -18° C. After 24 hours at room temperature, the excess amine and water were removed under rotary evaporation and finally by azeotropic distillation with benzene to give a light yellow oil. It was kugelrohr distilled to give 52 g of light yellow oil as product (30%), nD25 1.4887.