Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:46])[N:20]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:21](=[O:39])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][C:25]=1[F:38])[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:46])[N:20]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:21](=[O:39])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][C:25]=1[F:38])[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)n(-c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(-c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
A mixture of hydroxylammonium chloride (1.50 g), sodium hydrogen carbonate (2.50 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-[(4-butyl-2-methyl-6-oxo-1-phenyl-1,6-dihydropyrimidin-5-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (1.28 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.65 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.6 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.84 g, 62%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:5][CH2:4][NH:3]1.CCN=C=NCCCN(C)C.Cl.[CH:28]1([C:32]2[C:40]([C:41]3[NH:45][C:44]([CH2:46][CH3:47])=[N:43][N:42]=3)=[CH:39][C:35]([C:36](O)=[O:37])=[C:34]([CH3:48])[CH:33]=2)[CH2:31][CH2:30][CH2:29]1>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH:28]1([C:32]2[C:40]([C:41]3[NH:45][C:44]([CH2:46][CH3:47])=[N:43][N:42]=3)=[CH:39][C:35]([C:36]([N:3]3[CH2:4][CH2:5][CH:6]([C:8]4[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=4)[CH2:7][CH:2]3[CH3:1])=[O:37])=[C:34]([CH3:48])[CH:33]=2)[CH2:29][CH2:30][CH2:31]1
Reactant: CC1CC(c2ccc(C#N)cc2)CCN1
Reactant: CCc1nnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3C)c(C)cc2C2CCC2)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 0.9 %

Procedure:
To a round-bottom flask was added a solution of 4-(2-methylpiperidin-4-yl)benzonitrile (compound 176.3, 210 mg, 0.940 mmol, 1.00 equiv, 90%) in N,N-dimethylformamide (2 mL). EDC.HCl (404 mg, 2.11 mmol, 2.00 equiv), 4-dimethylaminopyridine (257 mg, 2.10 mmol, 2.00 equiv), and 4-cyclobutyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid (compound 176.4, 300 mg, 1.05 mmol, 1.00 equiv) were added to the reaction mixture. The resulting solution was stirred for 4 h at 25° C., then diluted with 50 mL of ethyl acetate. The resulting mixture was washed with 2×30 mL of NH4Cl (aq., sat.) and 2×30 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified using silica gel column chromatography with dichloromethane/methanol (20:1) as eluent. The crude product (˜20 mg) was further purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (48% CH3CN up to 49% in 8 min, up to 100% in 3 min, down to 48% in 2 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 3.8 mg (1%) of the title compound as a white solid. m/z (ES+) 468 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH:14]=O)[CH:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17].[NH2:20][C@@H:21]([CH2:25][OH:26])[CH:22]([CH3:24])[CH3:23].C(O)(=O)C.C([BH3-])#N>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH2:14][NH:20][C@H:21]([CH:22]([CH3:24])[CH3:23])[CH2:25][OH:26])[CH:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17]
Reactant: O=Cc1cccc(-c2ccc(F)c(C(F)(F)F)c2)n1
Reactant: CC(C)[C@@H](N)CO
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)[C@H](CO)NCc1cccc(-c2ccc(F)c(C(F)(F)F)c2)n1
Reaction time: 2 h
Yield: 58.8 %

Procedure:
To a solution of Example 267A (0.500 g, 1.86 mmol) in methanol (20 mL) at ambient temperature was added D-valinol (0.20 mL, 1.9 mmol) and acetic acid (0.40 mL, 7.4 mmol) followed by MP-cyanoborohydride (2.49 mmol/g; 1.0 g). After 2 hours, the mixture was filtered, concentrated and the residue partitioned between ether and 1M NaOH. The organic extract was concentrated and purified by chromatography to provide 390 mg (59%) of the title compound. MS (DCI+) m/z 270 (M+H); 1H NMR (500 MHz, CDCl3) δ 8.28 (dd, J=6.8, 2.0 Hz, 1H), 8.24-8.15 (m, 1H), 7.76 (t, J=7.7 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.34-7.25 (m, 2H), 4.04 (q, J=14.5 Hz, 2H), 3.70 (dd, J=10.9, 4.0 Hz, 1H), 3.49 (dd, J=10.8, 6.9 Hz, 1H), 2.53 (td, J=6.7, 4.1 Hz, 1H), 1.97-1.85 (m, 1H), 1.04 (d, J=6.8 Hz, 3H), 0.97 (d, J=6.9 Hz, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7]#[C:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2[NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:22]([CH3:33])[CH:21]=1)=[O:4].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C1(C)C=CC=CC=1>[CH3:33][C:22]1[CH:21]=[C:20]([NH:19][C:12]2[C:11]3[C:16](=[CH:17][CH:18]=[C:9]([C:8]#[C:7][CH2:6][NH:5][C:3](=[O:4])[CH2:2][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH:10]=3)[N:15]=[CH:14][N:13]=2)[CH:25]=[CH:24][C:23]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1cc(Nc2ncnc3ccc(C#CCNC(=O)CCl)cc23)ccc1Oc1ccccc1
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Product: Cc1cc(Nc2ncnc3ccc(C#CCNC(=O)CN4CCOCC4)cc23)ccc1Oc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 2-Chloro-N-{3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide (63 mg; 0.12 mmol) in toluene (10 ml) was added 3 equivalents of morpholine (31 mg) and the mixture heated at reflux overnight. The reaction was cooled to room temperature and the morpholine salts were filtered out and the solvent removed from the filtrate. The residue was redissolved in CH2Cl2 with a small amount of methanol and HCl gas was bubbled through the solution for 2-3 minutes. The solution was then concentrated to 2-3 ml, diluted with ethyl acetate and filtered to obtain N-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-2-morpholin-4-yl-acetamide as a yellow/brown solid (65 mg; 94%). 1H NMR (400 MHz; CD3OD) δ 2.27 (3H, s), 3.21 (2H, m), 3.56 (2H, m), 3.87 (2H, m), 4.04 (2H, m), 4.09 (2H, s), 4.36 (2H, s), 6.93 (3H, d, J=8.4), 7.09 (1H, t, J=7.4 Hz), 7.34 (2H, t, J=8 Hz), 7.54 (1H, dd), 7.65 (1 H, s), 7.82 (1H, d, J=8.8 Hz), 8.06 (1H, d, J=8.4 Hz), 8.76 (1H, s), 8.80 (1H, s). Irms(M+): 508.0; (M−): 506.0.
Reaction SMILES: CCN=C=NCCCN(C)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[C:23]([C:26]([OH:28])=O)=[CH:22][CH:21]=[N:20]2)=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C.[CH3:38][O:39][C:40]1[CH:79]=[CH:78][C:43]([CH2:44][N:45]2[C:49]3=[N:50][CH:51]=[CH:52][C:53]([O:54][C:55]4[CH:60]=[CH:59][C:58]([NH2:61])=[CH:57][C:56]=4[F:62])=[C:48]3[C:47]([NH:63][C@H:64]3[CH2:69][CH2:68][N:67]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[CH2:66][C@H:65]3[F:77])=[N:46]2)=[CH:42][CH:41]=1.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:38][O:39][C:40]1[CH:41]=[CH:42][C:43]([CH2:44][N:45]2[C:49]3=[N:50][CH:51]=[CH:52][C:53]([O:54][C:55]4[CH:60]=[CH:59][C:58]([NH:61][C:26]([C:23]5[C:24](=[O:25])[N:19]([C:16]6[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=6)[N:20]=[CH:21][CH:22]=5)=[O:28])=[CH:57][C:56]=4[F:62])=[C:48]3[C:47]([NH:63][C@H:64]3[CH2:69][CH2:68][N:67]([C:70]([O:72][C:73]([CH3:76])([CH3:74])[CH3:75])=[O:71])[CH2:66][C@H:65]3[F:77])=[N:46]2)=[CH:78][CH:79]=1
Reactant: COc1ccc(Cn2nc(N[C@H]3CCN(C(=O)OC(C)(C)C)C[C@H]3F)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2nc(N[C@H]3CCN(C(=O)OC(C)(C)C)C[C@H]3F)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39 %

Procedure:
EDCI (43.6 mg, 0.227 mmol) was added to a stirred mixture of 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (53.2 mg, 0.227 mmol, prepared according to the procedure for Example 19, Step C), HOBt-hydrate (34.8 mg, 0.227 mmol) and DIEA (0.0792 ml, 0.455 mmol) in DCM (1 mL) at ambient temperature, and the reaction mixture was stirred for 15 minutes at ambient temperature. ±(3R*,4S*)-tert-Butyl 4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)-3-fluoropiperidine-1-carboxylate (66 mg, 0.114 mmol) was then added. The resulting solution was stirred for 18 hours at ambient temperature. To a separate 1 dram vial was added an additional equivalent of the 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid, HOBt, DIEA, and EDCI in DCM (0.5 mL). This mixture was stirred for 15 minutes, then added to the original reaction mixture, which was stirred for an additional day at ambient temperature. The crude reaction mixture was loaded directly on to a preparative TLC plate (2 mm thickness) and eluted with 10% MeOH/DCM (Rf=0.70). A second preparative TLC plate (1 mm thickness, Rf=0.17) eluting with 1:1 EtOAc/hexanes was utilized to obtain pure product (35 mg, 39%)
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[C:27]3[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=1)[C:13]([CH3:29])=[C:12]2[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])C1C=CC=CC=1.Br.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[Cl:28][C:24]1[CH:23]=[C:22]2[C:27]([C:18]([N:14]3[C:15]4[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=4)[C:12]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:13]3[CH3:29])=[N:19][CH:20]=[N:21]2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)Cc1c(C)n(-c2ncnc3cc(Cl)ccc23)c2ccc(OCc3ccccc3)cc12
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Cc1c(C)n(-c2ncnc3cc(Cl)ccc23)c2ccc(O)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of ethyl 5-benzyloxy-1-(7-chloroquinazolin-4-yl)-2-methylindol-3-ylacetate (1.5g) in glacial acetic acid (5ml.) was treated with a 50% w/v solution of hydrogen bromide in glacial acetic acid (5ml.). The resulting dark red solution was stirred at room temperature for 10 minutes and then neutralised by the addition to a mixture of saturated sodium acetate solution (50ml.) and water (150ml.). The mixture was extracted with ethyl acetate (3 × 50ml.) and the extracts washed successively with water (2 × 40ml.), saturated sodium hydrogen carbonate solution (2 × 40ml.), water (40ml.) and then saturated sodium chloride solution (40ml.). After drying (MgSO4), the extracts gave on evaporation in vacuo a yellow-brown oil. Purification by chromatography on silica gel (200g.) in a mixture of 50% v/v ether and 50% v/v petroleum ether (b.p 40°-60° C.), gave ethyl 1-(7-chloroquinazolin-4-yl)-5-hydroxy-2-methylindol-3-ylacetate as a pale yellow glass [NMR: 2-CH3 at 7.7 τ; pure by TLC (systems A, C and D)].
Reaction SMILES: [F:1][C:2]([F:23])([P:13](=[O:22])([O:18]C(C)C)[O:14]C(C)C)[P:3](=[O:12])([O:8]C(C)C)[O:4]C(C)C.C[Si](Br)(C)C.C(N(CCCC)CCCC)CCC>C(#N)C.CN(C=O)C>[F:23][C:2]([F:1])([P:3](=[O:4])([OH:12])[OH:8])[P:13](=[O:14])([OH:18])[OH:22]
Reactant: CC(C)OP(=O)(OC(C)C)C(F)(F)P(=O)(OC(C)C)OC(C)C
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCCCN(CCCC)CCCC
Product: O=P(O)(O)C(F)(F)P(=O)(O)O
Temperature: 41 °C
Reaction time: 24 h
Yield: 300.4 %

Procedure:
To a stirred solution of tetraisopropyl difluoromethylenediphosphonate (2.0 g, 5.26 mmol) in anhydrous acetonitrile (30 mL) was added dropwise trimethylsilyl bromide (4.17 mL, 31.58 mmol). The resulting solution was stirred at 40-42° C. for 24 h, concentrated to dryness, and coevaporated with anhydrous acetonitrile once. The residue was re-dissolved in an acetonitrile/water mixture, and then coevaporated with DMF. The residue was dissolved in a DMF solution of tributylamine (1.93 g, 2.48 mL, 10.43 mmol), transferred into multiple small flasks, concentrated to dryness, and coevaporated with anhydrous DMF three times. The residue was dried in a vacuum oven at 40° C. for 4 h to give a slightly yellow residue (3.35 g).
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:17][C:18]([OH:24])=[C:19]([C:21]([NH2:23])=[O:22])[N:20]=2)=[CH:12][CH:11]=1)(=O)C1C=CC=CC=1.C[O-].[Na+].C(OC(C)C)(C)C>CO>[OH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[NH:17][C:18]([OH:24])=[C:19]([C:21]([NH2:23])=[O:22])[N:20]=2)=[CH:14][CH:15]=1
Reactant: NC(=O)c1nc(-c2ccc(OC(=O)c3ccccc3)cc2)[nH]c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)OC(C)C
Product: NC(=O)c1nc(-c2ccc(O)cc2)[nH]c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.8 %

Procedure:
To a chilled suspension of 2-(4-benzoyloxyphenyl)-5-hydroxyimidazole-4-carboxamide (323 mg) in anhydrous methanol (20 ml) was added sodium methoxide (216 mg). After stirring for 5 minutes at 0°-5° C. and 15 minutes at room temperature, N-hydrochloric acid aqueous solution (4 ml) and isopropylether (30 ml) were added. The precipitated crystal was separated by filtration, washed with isopropylether and dried under vacuum to give 2-(4-hydroxyphenyl)-5-hydroxy-1H-imidazole-4-carboxamide (190 mg).
Reaction SMILES: [N:1]12CCCN=[C:7]1CCCC[CH2:2]2.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[O:14].S(C[N+]#[C-])(C1C=CC(C)=CC=1)(=O)=O>ClCCl>[O:14]1[C:13]([C:12]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][N:1]=[CH:2]1
Reactant: CCOC(=O)C=O
Reactant: C1CCC2=NCCCN2CC1
Agent: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Solvent: ClCCl
Product: CCOC(=O)c1cnco1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.3 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.574 mL; 3.84 mmol) was added simultaneously with ethyl glyoxalate (50% in toluene, 0.659 mL; 3.33 mmol) to a mixture of tosylmethyl isocyanide (0.500 g; 2.560 mmol) in dichloromethane (10 mL) at 0° C. The resulting mixture was stirred at room temperature for 3 hours, diluted in dichloromethane and washed with sodium hydrogen sulphate, sodium carbonate, dried over magnesium sulphate and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 5 to 60% ethyl acetate in heptane) to yield 0.194 g (54%) of ethyl oxazole-5-carboxylate as a colorless oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:11][C:12]1[N:13]=[CH:14][N:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:16]=1
Reactant: Cc1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Temperature: 120 °C
Yield: 48.4 %

Procedure:
4-fluoronitrobenzene (32.3 g; 0.229 mol) and 4-methyl-1H-imidazole (25 g; 0.3 mol) are mixed at r.t., to this stirred mixture K2CO3 (44 g; 0.3 mol) is added. The reaction mixture is then heated at 120° C. overnight, then cooled at r.t. and poured in water (2 L), the resulting suspension is filtered and washed with water. The obtained solid is dried at 60° C. and recrystallized from ethyl acetate (600 mL), to provide the title compound as a yellow solid (22.5 g; 48.3%). The regioisomer, 4-(5-methyl-1H-imidazol-1yl)nitrobenzene remains in the crystallization mother liquor along with a certain amount of the titled product (TLC: hexane/AcOEt 3:2). C10H9N3O2, MW 203.2.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].C(=O)([O-])[O-].[K+].[K+].[Cl:15][C:16]1[C:23]([CH3:24])=[C:22](F)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[Cl:15][C:16]1[C:23]([CH3:24])=[C:22]([NH:1][C@H:2]([C@H:3]([OH:4])[CH3:5])[C:6]([OH:8])=[O:7])[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: C[C@@H](O)[C@@H](N)C(=O)O
Reactant: Cc1c(F)ccc(C#N)c1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
To a three-necked, 500 mL, round-bottomed flask fitted with a nitrogen inlet, mechanical stirring apparatus, and septum was added D-allo-threonine (24.98 g, 210 mmol) followed by anhydrous DMSO (250 mL) and potassium carbonate (63.7 g, 460 mmol). This mixture was stirred under nitrogen at room temperature for a period of 30 min. To this mixture was then added 2-chloro-4-fluoro-3-methylbenzonitrile (35.51 g, 210 mmol) followed by heating of the reaction mixture to 70° C. in an oil bath for a period of 48 hs. The reaction was then allowed to cool to room temperature followed by subsequent cooling to 0° C. and a 5% citric acid/water solution (1.5 Liters) was slowly added followed by careful addition of solid citric acid until evolution of gas was no longer observed. This solution was then extracted with EtOAc (5×μL). The combined organic extracts were then dried over Na2SO4 and decanted away from the drying agent. The solvent was then removed under reduced pressure using rotary evaporation to reveal a red oil that was purified by silica gel chromatography by first eluting with hexanes/EtOAc, 1/1 (2 L) followed by methanol/EtOAc 1/7 (5 L) to afford of (2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid as a light red oil/solid (27.05 g, 48%). 1H NMR (500 MHz, CD3OD, δ in ppm) 7.42 (d, J=8.7 Hz, 1H), 6.65 (d, J=8.7 Hz, 1H), 4.24 (m, 1H), 4.17 (m, 1H), 2.32 (s, 3H), 1.35 (d, J=6.6 Hz, 3H); 13C NMR (125.6 MHz, CD3OD) δ 174.2, 151.9, 137.16, 134.0, 122.6, 119.1, 110.1, 101.2, 69.1, 63.2, 20.0, 14.0.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[CH:13]=[C:12]([O:24][CH:25]([CH3:27])[CH3:26])[CH:11]=2)=[N:6][CH:7]=1.[CH2:29]([O:31][PH:32]([CH3:34])=[O:33])[CH3:30].CCN(CC)CC>C1(C)C=CC=CC=1.C(Cl)Cl.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.[Pd]>[CH2:29]([O:31][P:32]([C:2]1[CH:7]=[N:6][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[CH:13]=[C:12]([O:24][CH:25]([CH3:27])[CH3:26])[CH:11]=2)=[CH:4][CH:3]=1)([CH3:34])=[O:33])[CH3:30]
Reactant: CCO[PH](C)=O
Reactant: CC(C)Oc1cc(OCCc2ccsc2)cc(C(=O)Nc2ccc(Br)cn2)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOP(C)(=O)c1ccc(NC(=O)c2cc(OCCc3ccsc3)cc(OC(C)C)c2)nc1
Temperature: 90 °C
Yield: 92.3 %

Procedure:
To a stirred solution of N-(5-bromo-pyridin-2-yl)-3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzamide (1.69 g, 3.66 mmol) in toluene (40 mL) was added a solution of methylphosphinic acid ethyl ester (0.475 g, 4.40 mmol), palladium tetrakis(triphenylphosphine) (0.846 g, 0.733 mmol), and Et3N (1.54 mL, 10.9 mmol) in DCM (5.0 mL) at rt. The mixture was heated at 90° C. overnight. Cooled to rt and concentrated. EtOAc and water were added and the mixture was filtered through a pad of Celite to remove the insoluble solids. The organic layer was separated, washed with brine (1×), dried with anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography (6×25 cm, hexane/EtOAc, v/v=1:3, EtOAc, 1% MeOH in EtOAc). Fractions containing the product were pooled and concentrated to give {6-[3-Isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoylamino]-pyridin-3-yl}-methyl-phosphinic acid ethyl ester (1.65 g, 92%) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 8.74 (br, 1H), 8.68 (ddd, J=6, 2, 1 Hz, 1H), 8.49 (ddd, J=9, 2, 1 Hz, 1H). 8.10 (ddd, J=11, 9, 2 Hz, 1H), 7.63-7.70 (m, 1H), 7.43-7.47 (m, 1H), 7.29 (dd, J=5.3 Hz, 1H), 7.09-7.10 (m, 1H), 7.04 (dd, J=5, 1 Hz, 1H), 6.99-7.03 (m, 2H), 6.64 (m, 1H), 4.60 (m, 1H), 4.22 (t, J=7 Hz, 2H), 4.07-4.15 (m, 1H), 3.84-3.92 (m, 1H), 3.14 (t, J=7 Hz, 2H), 1.70 (d, J=15 Hz, 3H), 1.35 (d, J=6 Hz, 6H), 1.23-1.31 (m, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)[N:8]=1.[C:24]1([NH2:31])[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH2:30].CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>C(#N)C>[NH2:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:31][C:19](=[O:21])[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][NH:13][C:9]2[N:8]=[C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)[CH:12]=[CH:11][N:10]=2)=[CH:23][CH:22]=1
Reactant: O=C(O)c1ccc(CNc2nccc(-c3cnccn3)n2)cc1
Reactant: Nc1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1ccccc1NC(=O)c1ccc(CNc2nccc(-c3cnccn3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.8 %

Procedure:
To a solution of 25a (1 g, 3.3 mmol) in dry acetonitrile (35 mL) was added 1,2-phenylenediamine (0.88 g, 8.1 mmol) followed by Et3N (2.7 mL, 19.1 mmol), HOBt.H2O (803 mg, 5.9 mmol) and EDCI.HCl (1.89 g, 9.9 mmol). The mixture was stirred at room temperature for 16 h to form a suspension which was collected by filtration, washed successively with MeCN, water and again MeCN, triturated with MeOH, filtered and dried to afford the title compound 26a (730 mg, 1.84 mmol, 55% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.57 (s, 1H), 9.43 (s, 1H), 8.75 (d, J=4.8 Hz, 2H), 8.49 (d, J=5.2 Hz, 1H), 8.11 (t, J=5.2 Hz, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.59-7.37 (m, 2H), 7.44 (d, J=5.2 Hz, 1H), 7.12 (d, J=7.6 Hz, 1H), 6.94 (td, J=7.6, 1.6 Hz, 1H), 6.75 (dd, J=8.0, 1.2 Hz, 1H), 6.57 (t, J=7.2 Hz, 1H), 4.86 (s, 2H), 4.66 (d, J=5.2 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[NH:18][CH2:19][CH2:20][O:21][CH3:22])[CH:5]=[CH:4][N:3]=1.[CH3:23][C:24]1[N:25]=[C:26]([C:29]([OH:33])([C:31]#[CH:32])[CH3:30])[S:27][CH:28]=1.C(N(CC)CC)C>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:32]#[C:31][C:29]([C:26]4[S:27][CH:28]=[C:24]([CH3:23])[N:25]=4)([OH:33])[CH3:30])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[NH:18][CH2:19][CH2:20][O:21][CH3:22])[CH:5]=[CH:4][N:3]=1
Reactant: C#CC(C)(O)c1nc(C)cs1
Reactant: COCCNc1nc2ccc(Br)cc2n1-c1ccnc(N)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COCCNc1nc2ccc(C#CC(C)(O)c3nc(C)cs3)cc2n1-c1ccnc(N)n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 11.8 %

Procedure:
A mixture of 1-(2-aminopyrimidin-4-yl)-6-bromo-N-(2-methoxyethyl)-1H-1,3-benzodiazol-2-amine (150 mg, 0.37 mmol), 2-(4-methyl-1,3-thiazol-2-yl)but-3-yn-2-ol (137.6 mg, 0.82 mmol), bis(triphenylphosphine)palladium(II) dichloride (150 mg, 0.21 mmol) and triethylamine (0.7 mL) in dimethylsulfoxide (1 mL) under nitrogen in a 10-mL sealed tube was stirred for 1 hr at 70° C. The reaction mixture was cooled to room temperature then purified on a silica gel column (dichloromethane/methanol, 8:1) to give 19.6 mg (11%) of 4-[1-(2-aminopyrimidin-4-yl)-2-[(2-methoxyethyl)amino]-1H-1,3-benzodiazol-6-yl]-2-(4-methyl-1,3-thiazol-2-yl)but-3-yn-2-ol as yellow oil: 1H NMR (300 MHz, DMSO) delta 8.40 (d, J=5.4 Hz, 2H), 8.22 (t, J=5.0 Hz 1H), 7.49 (s, 1H), 7.27 (d, J=8.1 Hz, 1H), 7.16 (t, J=10.5 Hz, 2H), 6.91 (d, J=5.4 Hz, 1H), 6.89 (s, 1H), 6.86 (s, 1H), 3.62-3.59 (m, 4H), 3.32 (d, J=12.3 Hz, 3H), 2.35 (s, 3H), 1.85 (s, 3H); LC-MS: m/z=+450 (M+H)+.