Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9]/[C:10](=[N:13]/[H])/[NH:11][OH:12].[O:15]=[C:16]1[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][CH2:18][N:17]1[CH2:34][C:35](O)=O.Cl.C(N=C=NCCCN(C)C)C>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]1[N:13]=[C:35]([CH2:34][N:17]2[CH2:18][CH2:19][CH2:20][C:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]2=[O:15])[O:12][N:11]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: [H]/N=C(/CCc1ccccc1Cl)NO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C1N(Cc2nc(CCc3ccccc3Cl)no2)CCCC1(c1ccccc1)c1ccccc1

Procedure:
A mixture of the product of Example 262A (180 mg, 0.91 mmol), the product of Example 68E (280 mg, 0.901 mmol), and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (347 mg, 1.81 mmol) in 1,2-dichloroethane (4 mL) was stirred at ambient temperature for 3.5 hours and then heated to reflux for 16 hours. The cooled reaction mixture was diluted with CH2Cl2, washed with 1 N aqueous HCl and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was chromatographed on silica gel twice using ethyl acetate/hexanes as eluant, then finally purified by preparative HPLC on a Phenomenex® Luna® C8(2) 5 um 100 Å AXIA column (30 mm×75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A). Samples were injected in 1.5 mL dimethyl sulfoxide:methanol (1:1). The dried down fractions were taken up in CH2Cl2 and combined and concentrated in vacuo. Hexane was added to the residue, which caused the product to solidify. The resulting material was collected by vacuum filtration and dried in the vacuum oven at 50° C. for 4 hours to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.46-7.41 (m, 1H), 7.35-7.16 (m, 13H), 4.83 (s, 2H), 3.56 (t, J=6.3, 2H), 3.20-3.10 (m, 2H), 3.09-3.00 (m, 2H), 2.62-2.55 (m, 2H), 1.79-1.67 (m, 2H); MS (ESI+) m/z 472 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[C:15]([Cl:25])[CH:14]=3)[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>>[Cl:25][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH2:12][N:9]1[C:10](=[O:11])[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:26]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:27])[C:7]=2[CH2:8]1
Reactant: O=COc1ccccc1
Reactant: O=C1c2ccnc(Cl)c2CN1Cc1ccc(OCC(F)(F)F)c(Cl)c1
Product: O=C(Oc1ccccc1)c1nccc2c1CN(Cc1ccc(OCC(F)(F)F)c(Cl)c1)C2=O
Yield: 49 %

Procedure:
The title compound is prepared in 49% yield (180 mg, brown solid) from 4-chloro-2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (300 mg, 0.76 mmol, Intermediate-71) and phenyl formate (190 mg, 1.5 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12](=[O:16])[C:13]([OH:15])=O)=[CH:10][C:4]=2[O:3]1.CN1CCOCC1.CN(C)C=O.C(OC(Cl)=O)C(C)C.Cl.[NH:38]1[CH2:43][CH2:42][CH:41]([CH2:44][C:45]2[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][CH:46]=2)[CH2:40][CH2:39]1>>[C:49]([C:48]1[CH:47]=[CH:46][C:45]([CH2:44][CH:41]2[CH2:42][CH2:43][N:38]([C:13](=[O:15])[C:12]([NH:11][C:9]3[CH:8]=[CH:7][C:5]4[NH:6][C:2](=[O:1])[O:3][C:4]=4[CH:10]=3)=[O:16])[CH2:39][CH2:40]2)=[CH:52][CH:51]=1)#[N:50]
Reactant: O=C(O)C(=O)Nc1ccc2[nH]c(=O)oc2c1
Reactant: N#Cc1ccc(CC2CCNCC2)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: N#Cc1ccc(CC2CCN(C(=O)C(=O)Nc3ccc4[nH]c(=O)oc4c3)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 7.9 %

Procedure:
To a mixture of 0.3g (1.5 mmol) of N-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-oxalamic acid, 0.165 ml (1.5 mmol) of N-methyl-morpholine in 8 ml of dimethylformamid 0.2 ml (1.5 mmol) of isobutyl-chloroformate is added dropwise at 0° C. and the mixture is stirred at 0° C. for 1 hour. Then 0.333 g (1.4 mmol) of 4-piperidin-4-ylmethyl-benzonitrile hydrochloride and 0.165 ml (1.5 mmol) of N-methyl-morpholine are added and the reaction mixture is stirred at 0° C. for 1 hour, at room temperature for 16 hours. The reaction mixture is concentrated and the residue is purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent to yield 0.045 g (8.0%) of the title compound. Rf.: 0.4. Melting Point: 259-260° C. (isopropanol).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]3)[CH:10]=2)=[CH:6][CH:5]=[C:4]([N+:21]([O-])=O)[N:3]=1.[NH4+].[Cl-]>CO.C(Cl)Cl.[Zn]>[CH3:1][C:2]1[N:3]=[C:4]([NH2:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([N:15]2[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]2)[CH:10]=1
Reactant: Cc1cn(-c2cc(Oc3ccc([N+](=O)[O-])nc3C)ccn2)cn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: ClCCl
Product: Cc1cn(-c2cc(Oc3ccc(N)nc3C)ccn2)cn1
Temperature: 40 °C
Yield: 75.2 %

Procedure:
A suspension of 2-methyl-3-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)-6-nitropyridine (1.50 g, 4.82 mmol) and NH4Cl (6.00 g, 112 mmol) in MeOH (30 mL) was treated with zinc dust (3.00 g, 45.9 mmol) and heated at 40° C. for 3 h. The mixture was diluted with DCM, the solids removed via filtration, washed with MeOH/DCM and the filtrate concentrated to dryness. The residue was treated with DCM, the solids again removed via filtration and the filtrate concentrated to dryness to afford 6-methyl-5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-amine (1.02 g, 75%). 1H NMR (400 MHz, DMSO-d6): δ 8.37 (d, J=1.4 Hz, 1H), 8.26 (d, J=5.8 Hz, 1H), 7.61 (t, J=1.3 Hz, 1H), 7.28 (d, J=2.2 Hz, 1H), 7.20 (d, J=8.7 Hz, 1H), 6.60 (dd, J=5.8, 2.2 Hz, 1H), 6.34 (d, J=8.7 Hz, 1H), 5.97 (s, 2H), 2.13 (s, 3H), 2.07 (s, 3H); MS (ESI) m/z: 282.1 (M+H+).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])=[C:8]([C:18]([F:21])([F:20])[F:19])[CH:7]=1.C(O)(=O)C>S(=O)(=O)(O)O.C(OC(=O)C)(=O)C>[Br:5][C:6]1[CH:7]=[C:8]([C:18]([F:20])([F:21])[F:19])[C:9]([NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])=[C:10]([N+:1]([O-:4])=[O:2])[CH:11]=1
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)Nc1ccc(Br)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)Nc1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 61 %

Procedure:
To acetic anhydride (10 ml) was added dropwise conc. nitric acid (d=1.42, 1.300 ml) during 10 minutes in an ice bath and added one drop of conc. sulfuric acid (96%). To this solution was added a solution of ethyl 4-bromo-2-(trifluoromethyl)phenylcarbamate in acetic anhydride (7 ml)/acetic acid (1 ml) during 30 minutes in an ice bath. After stirring for 2.5 hours, the reaction mixture was poured into ice-water, and the precipitated solid product was filtered. The resultant solid product was purified by silica gel column (120 g, hexane:ethyl acetate=15:1) to give the title compound (2.3265 g, 61%).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH:5]([C:29]1[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=1)[CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH:20]=[CH2:21])=[CH:14][CH:13]=2)[N:9]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[N:8]=1)C.[Li+].[OH-]>C1COCC1.O>[CH2:19]([NH:18][C:15]1[CH:14]=[CH:13][C:12]([C:10]2[N:9]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[N:8]=[C:7]([CH2:6][CH:5]([C:29]3[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=3)[C:4]([OH:36])=[O:3])[CH:11]=2)=[CH:17][CH:16]=1)[CH:20]=[CH2:21]
Reactant: C=CCNc1ccc(-c2cc(CC(C(=O)OCC)c3cccc(C)c3)nn2-c2ccc(C)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCNc1ccc(-c2cc(CC(C(=O)O)c3cccc(C)c3)nn2-c2ccc(C)cc2)cc1
Reaction time: 3 h
Yield: 77.5 %

Procedure:
To a solution of 3-[5-(4-allylamino-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid ethyl ester (90 mg, 0.2 mmol) was added LiOH (14 mg, 0.58 mmol, 3 equiv) in 2:1 THF/H2O (1 mL). After 3 h at 45° C., the mixture was purified by preparative reversed-phase HPLC (acetonitrile/water) to afford the desired compound (70 mg, 77 %). MS (ESI): mass calculated for C29H29N3O2, 451.23; m/z found, 452.6 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.21-7.03 (m, 8H), 6.93 (d, J=8.8, 2H), 6.26 (s, 1H), 5.88-5.83 (m, 1H), 5.29-5.24 (m, 2H), 4.06 (dd, J=10.4, 5.1 Hz, 1H), 3.79(d, J=6.3 Hz, 2H), 3.54 (dd, J=15.0, 10.4 Hz, 1H), 3.09 (dd, J=15.0 5.1 Hz, 1H), 2.33 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][C@@H:10]1[O:20][CH2:21][CH:22]=[CH2:23])=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:8][C@@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][C@@H:10]1[O:20][CH2:21][CH:22]=[CH2:23]
Reactant: C=CCO[C@H]1CN(C(=O)OCC)CC[C@H]1NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCO[C@H]1CN(C(=O)OCC)CC[C@H]1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl (3S,4R)-4-[(tert-butoxycarbonyl)amino}-3-(prop-2-en-1-yloxy)piperidine-1-carboxylate (Intermediate 17, 5 g, 12.7 mmol) was dissolved in dichloromethane (200 mL) and trifluoroacetic acid (9.79 mL, 127 mmol) was added. The reaction mixture was allowed to stir for 3 h at room temperature. The reaction mixture was basified with saturated sodium bicarbonate solution (pH ˜8) and the layers were separated. The aqueous layer was extracted with dichloromethane; organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 2.7 g (93.24%). MS (ES) (M+H): 228. for C11H20N2O3.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([NH:9][C:10](=O)CC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)[C:3]=1[OH:28].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[O:28]1[C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=2[N:9]=[CH:10]1
Reactant: CC(C)(C)c1cc(CC(=O)Nc2cc(Cl)cc(Br)c2O)cc(C(C)(C)C)c1O
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc2ocnc2c1
Yield: 368 %

Procedure:
A solution of 2-bromo-4-chloro-6-(3,5-di-t-butyl-4-hydroxy-phenylacetyl-amino)-phenol (35.67 g, 76.1 mmol) and phosphorus oxychloride (41.8 ml, 457 mmol) in toluene was heated under reflux for 1 hour. Volatiles were removed in-vacuo and residual amounts of phosphorus oxychloride removed by azeotropic distillation with toluene (2×50 ml). The residue was taken up in acetone (50 ml) and ether (100 ml), and treated with water (100 ml) and saturated aqueous sodium bicarbonate solution (100 ml). The organic solvents were removed in-vacuo and the precipitate collected to give 33.36 g (93.6%) of crude benzoxazole. The crude benzoxazole was dissolved in dichloromethane (100 ml), filtered, and the filtrate diluted with methanol (100 ml). The dichloromethane was removed by distillation and the resulting crystals collected, washed, and dried in-vacuo to give 28.86 g (80.9%) of the title compound (mp 133-6° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23]([OH:25])=O)=[CH:21][N:22]=2)[CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:59][C:60]1[CH:66]=[CH:65][C:63]([NH2:64])=[CH:62][CH:61]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23]([NH:64][C:63]3[CH:65]=[CH:66][C:60]([F:59])=[CH:61][CH:62]=3)=[O:25])=[CH:21][N:22]=2)[CH:19]=1
Reactant: O=C(O)c1cnc2ccc(N3CCCC3c3cc(F)ccc3F)cn12
Reactant: Nc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)cc1)c1cnc2ccc(N3CCCC3c3cc(F)ccc3F)cn12
Reaction time: 0.17 h
Yield: 9.4 %

Procedure:
To a stirred solution of 6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (Int-15) (0.15 g, 0.44 mmol) in dry DMF (1.5 ml) was added HATU (0.215 g, 0.57 mmol), DIPEA (0.084 g, 0.65 mmol) under N2 atm at RT and stirred for 10 min, then added 4-fluoroaniline (0.053 g, 0.48 mmol) and stirred for 16 h at RT. After completion of reaction, quenched with ice water and solid was filter. Solid thus obtained was dried under high vacuum to afford 6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(4-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxamide (0.018 g, 9.7% Yield) MS (ESI): m/z 437.1 (M+H); 1H NMR (300 MHz, CDCl3) δ 10.07 (1H, s), 8.72-8.71 (1H, d J=3 Hz), 8.41 (1H, s), 7.74-7.71 (2H, m), 7.59-7.57 (1H, d J=6 Hz), 7.35-7.28 (1H, m), 7.23-7.12 (3H, m), 7.00-6.94 (2H, m), 5.02-5.00 (1H, d), 3.80-3.77 (1H, t), 2.05-1.89 (3H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6](=[O:19])[C:7]1[CH:15]=[C:14]([NH2:16])[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cc(N)cc(C(=O)O)c1
Reaction time: 24 h
Yield: 98 %

Procedure:
5-Nitro-isophthalic acid mono t-Butyl ester (2.38 g, 8.9 mmol) was dissolved in EtOAc (50 ml). 10% Palladium on activated charcoal was added and the mixture was hydrogenated at 1 atm and room temperature. After 24 h, the mixture was filtered through a glas microfiber filter and the filtrate was concentrated to give the title compound as white crystals in 98% yield (2.07 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:8]2[CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([NH:17][C:14]1[CH:13]=[N:12][C:11]([C:10]2[C:2]([Cl:1])=[CH:3][C:4]3[O:5][CH2:6][CH2:7][C:8]=3[CH:9]=2)=[CH:16][N:15]=1)=[O:22]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1cnc(-c2cc3c(cc2Cl)OCC3)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cnc(-c2cc3c(cc2Cl)OCC3)cn1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
To a solution of 5-(6-chloro-2,3-dihydrobenzo[3,4-b]furan-5-yl)pyrazine-2-ylamine (147) (7.8 mg, 0.031 mmol) in 1 ml DCM was added 2,6-difluorobenzoyl chloride (12 μl, 3 eq) followed by addition of DIEA (27 μl). The resulting solution was stirred at r.t. for overnight. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (100 μl) at 60° C. for 1 h and before worked up with EA/aq. NaHCO3. Prep HPLC purification furnished (2,6-difluorophenyl)-N-[5-(6-chloro(2,3-dihydrobenzo[b]furan-5-yl))pyrazin-2-yl]carboxamide (148) (4.2 mg, yield: 34.9%, purity>90%) as pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12])([O-:3])=[O:2].S(=O)(=O)(O)O.[OH-].[NH4+].[CH3:21]O>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([O:13][CH3:21])=[O:12])([O-:3])=[O:2]
Reactant: CO
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: COC(=O)Cc1ccccc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
To a solution of 2-nitrophenylacetic acid (2.00 kg) in methanol (4 l) at room temperature is added concentrated sulfuric acid (71.0 ml) all at once. The solution is stirred and refluxed for 6 hours, then allowed to stand at room temperature overnight. After cooling in an ice bath to 7°, the solution is adjusted to pH 8 by the addition of concentrated ammonium hydroxide (150 ml), keeping the temperature below 10°. The solution is concentrated in vacuo to a volume of 2 l and is then admixed with dichloromethane (2.5 l). The combined solution is washed with water (2×500 ml) and brine (500 ml), dried over anhydrous magnesium sulfate, and evaporated to yield crude product which is distilled to give methyl 2-nitrophenylacetate, b.p. 116°-131° (0.2 mm Hg).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24](C(=O)C)[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.Cl.C([O-])([O-])=O.[Na+].[Na+]>CCO>[CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]4)=[CH:19][CH:20]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: CC(=O)N1CCN(c2ccc(Nc3nccc(-c4sc(C)nc4C)n3)cc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(N4CCNCC4)cc3)n2)s1
Yield: 96.5 %

Procedure:
To a solution of 1-(4-{4-[4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino]-phenyl}-piperazin-1-yl)-ethanone (0.67 g, 1.64 mmol) in EtOH (3 mL) was added 2 M aq HCl (25 mL) in a steady stream. The mixture was heated at reflux for 1 h, cooled, and basified by addition of solid Na2CO3. The product was extracted with EtOAc. The combined organics were washed with brine, dried on Na2SO4, filtered, and evaporated to afford the title compound (580 mg) as a yellow solid. 1H-NMR (CDCl3)™: 2.62 (s, 3H, CH3), 2.63 (s, 3H, CH3), 2.99 (m, 4H, CH2), 3.06 (m, 4H, CH2), 6.81 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 6.89 (m, 3H, Ph-H, NH), 7.44 (m, 2H, Ph-H), 8.31 (d, 1H, J=5.4 Hz, pyrimidinyl-H). MS (ESI+) m/z 367 (C19H22N6S requires 366.5).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][CH:7]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>C(#N)C>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=2[N+:16]([O-:18])=[O:17])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: Cc1cccc(OS(=O)(=O)C(F)(F)F)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cccc(N2CCN(C(=O)OC(C)(C)C)CC2)c1[N+](=O)[O-]
Yield: 37.5 %

Procedure:
Trifluoromethanesulfonic acid 3-methyl-2-nitrophenyl ester (26.7 g, 93.6 mmol), 1-tert-butoxycarbonyl piperazine (17 g, 91.3 mmol) and triethylamine (14 mL, 100 mmol) in 250 mL of acetonitrile was heated under reflux for 25 h. The mixture was concentrated in vacuo, diluted with water and extracted with ether. The ether was washed with aqueous ammonium hydroxide and brine, dried, and evaporated. Purification by silica gel chromatography (10% ethyl acetate-hexane) afforded 11 g of 4-(3-methyl-2-nitrophenyl)-piperazine-1-carboxylic acid tert-butyl ester as a golden solid, m.p. 101-102° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH2:20])(C)(C)C.CC1(C)O[C:27]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[C:32]#[N:33])=[CH:26][C:25](=[O:37])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:37]=[C:25]1[CH2:26][C:27]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[C:32]#[N:33])=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[NH:20]1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccnc2)cc1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(-c4cccnc4)cc3NC(=O)C2)c1

Procedure:
Prepared from (2-amino-4-pyridin-3-yl-phenyl)-carbamic acid tert.-butyl ester (Example G26) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a beige powder (161 mg).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[C:12]3[N:13]=[CH:14][N:15]=[C:16]([C:17]4[C:25]5[O:24][CH2:23][O:22][C:21]=5[CH:20]=[CH:19][C:18]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:11]=3[NH:10][CH:9]=2)=[O:7])[CH2:2]1.Cl[C:32]([CH2:34][O:35]C(=O)C)=[O:33]>>[OH:35][CH2:34][C:32]([N:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[C:12]3[N:13]=[CH:14][N:15]=[C:16]([C:17]4[C:25]5[O:24][CH2:23][O:22][C:21]=5[CH:20]=[CH:19][C:18]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:11]=3[NH:10][CH:9]=2)=[O:7])[CH2:2]1)=[O:33]
Reactant: O=C(NC1CNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(=O)OCC(=O)Cl
Product: O=C(NC1CN(C(=O)CO)C1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid azetidin-3-ylamide (example A172) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][C@H:4]([NH2:8])[C:5]([OH:7])=[O:6].[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:11]=1[C:12](Cl)=[O:13]>[OH-].[Na+].C1COCC1>[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:11]=1[C:12]([NH:8][C@@H:4]([CH2:3][CH:2]=[CH2:1])[C:5]([OH:7])=[O:6])=[O:13]
Reactant: C=CC[C@H](N)C(=O)O
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CC[C@H](NC(=O)c1c(Cl)cccc1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a mixed solvent of 2N aqueous sodium hydroxide solution (27.4 ml) and THF (55 ml), L-allylglycine (5.22 g) was dissolved, and 2,6-dichlorobenzoyl chloride (7.79 ml) was added dropwise thereto, followed by stirring the resulting mixture at room temperature for 1 hour. After concentrating the reaction solution to remove methanol, water (100 ml) was added thereto and the resulting mixture was washed with ether. Aqueous layer was acidified by adding 3N hydrochloric acid in small portions thereto, and extracted 3 times with ethyl acetate. Organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was recrystallized from hexane/ethyl acetate mixed solvent to obtain (S)-2-(2,6-dichlorobenzamido)pent-4-enoic acid (11.65 g). NMR (HL, CDCl3): δ 2.66-2.73 (1H, m), 2.80-2.86 (1H, m), 4.99 (1H, td, J=7.6, 5.6 Hz), 5.18-5.25 (2H, m), 5.76-5.86 (1H, m), 6.39 (1H, brd, J=7.6 Hz), 7.25-7.34 (3H, m) (2) Under an argon atmosphere, a solution of (S)-2-(2,6-dichlorobenzamido)pent-4-enoic acid (11.46 g) in methanol (120 ml) was cooled to 0° C. Thionyl chloride (5.22 ml) was added dropwise to the solution while keeping the reaction temperature not higher than 10° C., and thereafter the resulting mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and sodium hydrogen carbonate was added thereto in small portions to neutralize it. After concentrating the reaction solution to remove methanol, aqueous layer was extracted twice with ethyl acetate. Organic layers were washed 3 times with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was recrystallized from hexane/ethyl acetate mixed solvent to obtain (S)-2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (11.68 g). NMR (H1, CDCl3): δ 2.62-2.69 (1H, m), 2.76-2.83 (1H, m), 3.79 (3H, s), 4.96 (1H, td, J=7.8, 5.4 Hz), 5.14-5.21 (2H, m), 5.72-5.82 (1H, m), 6.42 (1H, brd, J=6.8 Hz), 7.25-7.34 (3H, m)