Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[C:40]([CH2:41][CH2:42][OH:43])=[C:39]([CH3:44])[O:38][N:37]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:43][CH2:42][CH2:41][C:40]3[C:36]([CH3:35])=[N:37][O:38][C:39]=3[CH3:44])=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1noc(C)c1CCO
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1noc(C)c1CCOc1ccc(-c2c(C)nc(C)c([C@H](OC(C)(C)C)C(=O)O)c2N2CCC(C)(C)CC2)cc1
Reaction time: 18 h
Yield: 41.1 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (50 mg, 0.107 mmol), 2-(3,5-dimethylisoxazol-4-yl)ethanol (75 mg, 0.533 mmol) and Ph3P-resin (139 mg, 0.533 mmol) in THF (2 mL) was added DIAD (0.104 mL, 0.533 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1NNaOH (1.067 mL, 1.067 mmol) in MeOH (2 mL) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(5-(4-(2-(3,5-dimethylisoxazol-4-yl)ethoxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid (25 mg, 0.044 mmol, 41.6% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.20 (d, J=8.8 Hz, 1H), 7.07-6.92 (m, 3H), 5.75 (s, 1H), 4.17-4.01 (m, 2H), 3.41 (br. s., 1H), 3.17 (s, 2H), 2.79 (t, J=6.2 Hz, 2H), 2.42 (s, 3H), 2.34 (s, 3H), 2.21 (s, 3H), 2.17 (d, J=12.5 Hz, 1H), 2.06-2.02 (m, 2H), 1.93 (br. s., 1H), 1.49 (br. s., 1H), 1.29 (br. s., 1H), 1.16 (d, J=13.6 Hz, 1H), 1.11 (s, 9H), 1.01 (d, J=9.9 Hz, 1H), 0.84 (br. s., 3H), 0.61 (br. s., 3H). LCMS (M+H)=564.4.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[CH:24](OCC)(OCC)OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:24]=[N:15][C:14]=2[CH:16]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc2oc(-c3ccc4c(c3)ncn4C3CCOCC3)nc2c1
Temperature: 100 °C
Yield: 31.5 %

Procedure:
To 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (0.20 g, 0.646 mmol), triethyl orthoformate (5 mL) was added a catalytic amount of p-toluenesulfonic acid monohydrate, and this was heated to 100° C. for 1.5 hours. The reaction mixture was cooled, ethyl acetate and water added, and this was extracted. This was washed with water, dried over magnesium sulfate, and after concentration the precipitated crystals were filtered off. These were washed with a hexane/ethyl acetate mixture solution, and dried to yield the title compound (65 mg, 31.5% yield) as light reddish-brown crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[NH:11][C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:9]2)=O)C.[Li+].[BH4-].O>CO>[OH:3][CH2:4][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[NH:11][C:10]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[CH:9]2
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c2[nH]c(-c3ccccc3)cc2c1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1cc(CO)cc2cc(-c3ccccc3)[nH]c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Phenyl-7-nitro-1H-indole-5-carboxylic acid ethyl ester (10 g, 29 mmol) prepared in Step A of Example 28 was dissolved in methanol (100 mL), and LiBH4 (1M THF solution, 4 mL) was added thereto at 0° C. After warming to room temperature, the mixture was stirred for 3 h. A small amount of water was added to quench the reaction. Methanol was removed under reduced pressure. 1N HCl was added to the residue, which was then extracted with EtOAc, dried, and used in the next reaction without further purification.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:24])([F:23])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.[N+:32]([C:35]1[CH:36]=[C:37]([S:40](Cl)(=[O:42])=[O:41])[S:38][CH:39]=1)([O-:34])=[O:33]>C(Cl)Cl>[N+:32]([C:35]1[CH:36]=[C:37]([S:40]([N:20]2[CH2:21][CH2:22][N:17]([C:14]3[CH:13]=[CH:12][C:11]([C:5]([OH:10])([C:6]([F:9])([F:8])[F:7])[C:4]([F:3])([F:23])[F:24])=[CH:16][CH:15]=3)[CH2:18][CH2:19]2)(=[O:42])=[O:41])[S:38][CH:39]=1)([O-:34])=[O:33]
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1csc(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1csc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 19.7 %

Procedure:
The 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol hydrochloride (306 mg, 0.84 mmol, Example 91, Step 1) was dissolved in CH2Cl2 (20 mL) and the solution was chilled to 0° C. To this solution was added triethylamine (292 μL, 2.10 mmol) followed by 4-nitrothiophene-2-sulfonyl chloride (210 mg, 0.923 mmol). The mixture was allowed to warm to room temperature and stirred for 2 h. Afterwards, the mixture was filtered and concentrated, the filtrate was purified via reverse-phase preparative HPLC using a Phenomenex Gemini C18 column (150×30 mm, 10 μm) eluting with 0.1% TFA in CH3CN/H2O (5% to 100% over 15 min) to give 2-(4-(4-((4-nitro-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (86 mg).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C:5]([NH2:8])([CH3:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+].[Cl:16][CH2:17][C:18](Cl)=[O:19]>C(OCC)(=O)C.O>[Cl:16][CH2:17][C:18]([NH:8][C:5]([CH3:7])([CH3:6])[C:4]([O:3][CH3:2])=[O:9])=[O:19]
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(C)(C)NC(=O)CCl
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.6 %

Procedure:
To a rapidly stirring biphasic solution of aminoisobutyric acid methyl ester hydrochloride (5.1 g, 33 mmol) in ethyl acetate (40 mL) and water (27 mL) was added potassium carbonate (13.7 g, 99.6 mmol) followed by chloroacetyl chloride (3.4 mL, 43 mmol). The reaction was cooled with an ice bath to prevent warming above ambient temperature, and stirred at room temperature for four hours. The mixture was diluted with ethyl acetate and the organic layer was successively washed with 10% citric acid and sat. NaCl, dried over sodium sulfate and concentrated in vacuo to give the desired product as a white solid (5.78 g, 29.9 mmol, 91%). 1H NMR (CDCl3, 400 MHz) δ 1.61 (s, 6H), 3.78 (s, 3H), 4.01 (s, 2H); LRMS (ESI/APCI) m/z 194 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:11])[CH2:4][S:5][CH2:6][CH:7]([OH:10])[CH2:8]Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[O:10]1[CH2:8][CH:7]1[CH2:6][S:5][CH2:4][CH:3]1[O:11][CH2:2]1
Reactant: OC(CCl)CSCC(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C1OC1CSCC1CO1
Temperature: 5 °C
Yield: 95 %

Procedure:
Next, bis(3-chloro-2-hydroxypropyl)sulfide described above was dripped into a reaction vessel containing a mixed solvent consisting of 410 g of toluene and 260 g of 32% aqueous solution of sodium hydroxide with the temperature of the solution in the reaction vessel being maintained at 0 to 10° C. At the point of the completion, no scum-like insoluble matter was generated. The aqueous layer was removed, and the organic layer was washed with 180 g of water three times. After that, no scum-like insoluble matter was generated. After that, the solvent was distilled away, thereby obtaining 138 g (total yield: 95%) of bis(β-epoxypropyl)sulfide (the compound represented by formula (2) above).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.[OH-].[K+]>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:20][C:17]3[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Agent: [K+]
Agent: [OH-]
Product: Nc1ccc2ccc(Oc3ccc(Cl)cc3)nc2n1
Temperature: 140 °C
Yield: 73.4 %

Procedure:
A mixture consisting of 2-amino-7-chloro-1,8-naphthyridine (1.8 g), 4-chlorophenol (12.85 g) and 85% strength potassium hydroxide pellets (1.1 g) is heated for 8 hours at 140° C. The reaction mixture is poured into distilled water (200 cc) and made alkaline to a pH of 10 with 4N sodium hydroxide. The suspension obtained is filtered and washed with distilled water to a pH of approximately 7. The solid obtained is air-dried to give 2-amino-7-(4-chlorophenoxy)-1,8-naphthyridine (2 g), m.p. 177° C.
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH2:35][CH3:36])[CH2:3][C:4]1[N:5]=[C:6]([C:9]2([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=4)=[CH:24][CH:23]=3)[CH2:13][CH2:12][CH2:11][N:10]2C(OC(C)(C)C)=O)[NH:7][CH:8]=1>FC(F)(F)C(O)=O>[CH3:1][C:2]([CH3:37])([CH2:35][CH3:36])[CH2:3][C:4]1[N:5]=[C:6]([C:9]2([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=4)=[CH:24][CH:23]=3)[CH2:13][CH2:12][CH2:11][NH:10]2)[NH:7][CH:8]=1
Reactant: CCC(C)(C)Cc1c[nH]c(C2(Cc3ccc(-c4ccc(F)cn4)cc3)CCCN2C(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)(C)Cc1c[nH]c(C2(Cc3ccc(-c4ccc(F)cn4)cc3)CCCN2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-[4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]-2-[4-(5-fluoropyridin-2-yl)benzyl]pyrrolidine-1-carboxylate (45 mg, 0.089 mmol) was dissolved in trifluoroacetic acid (1 mL). After stirring at ambient temperature overnight, the reaction mixture was concentrated in vacuo to afford the title compound. 1H NMR (500 MHz, CD3OD) δ 8.48 (d, J=2.5 Hz, 1H), 8.28 (br s, 1H), 7.83 (dd, J=8.7, 4.2 Hz, 1H), 7.79 (d, J=8.0 Hz, 2H), 7.64 (td, J=8.5, 3.0 Hz, 1H), 6.97 (d, J=8.0 Hz, 2H), 6.86 (s, 1H), 3.45-3.39 (m, 3H), 3.24-3.17 (m, 1H), 2.52-2.41 (m, 1H), 2.45 (s, 2H), 2.33-2.25 (m, 1H), 2.22-2.13 (m, 1H), 1.91-1.82 (m, 1H), 1.22 (q, J=15.0, 7.5 Hz, 2H), 0.84 (t, J=7.5 Hz, 3H), 0.81 (s, 6H). (M+H) found: 407.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:49][C:50]1[N:55]=[CH:54][C:53]([C:56]2[CH:57]=[C:58]([NH2:62])[CH:59]=[CH:60][CH:61]=2)=[CH:52][CH:51]=1>CN(C=O)C>[OH:49][C:50]1[N:55]=[CH:54][C:53]([C:56]2[CH:57]=[C:58]([NH:62][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:59]=[CH:60][CH:61]=2)=[CH:52][CH:51]=1
Reactant: Nc1cccc(-c2ccc(O)nc2)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccc(O)nc2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 18.6 %

Procedure:
DIEA (0.008 mL, 0.048 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.009 g, 0.043 mmol) and HATU (0.018 g, 0.048 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(6-hydroxy-pyridin-3-yl)-phenylamine (0.008 g, 0.043 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.003 g of product in 15% yield: LCMS (ESI) m/z 375 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH2:14])=[CH:8][CH:7]=2)=[CH:2]1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](Cl)=[O:23]>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH:14][C:22](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=3)=[CH:8][CH:7]=2)=[CH:2]1
Reactant: CC(CN)c1ccc(-c2ccsc2)cc1
Reactant: O=C(Cl)c1ccccn1
Product: CC(CNC(=O)c1ccccn1)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared 2-(4-(3-thienyl)phenyl)propylamine (see example 14) and picolinoyl chloride in a manner analogous to the procedure described in example 14. The NMR spectrum was consistent with the proposed title structure.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@H:13]1[CH2:16][O:15][C:14]1=[O:17].[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C>[N:18]([CH2:16][C@@H:13]([C:14]([OH:15])=[O:17])[NH2:12])=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: N[C@H]1COC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H](N)C(=O)O
Reaction time: 3.5 h
Yield: 96.5 %

Procedure:
A solution of (S)-3-amino-2-oxetanone p-toluenesulfonic acid salt (53.0 mg, 0.204 mmol) in DMF (1 mL) was added to NaN3 (14.6 mg, 0.225 mmol) in DMF (5 mL) and the mixture was stirred 3.5 h. The solvent was removed in vacuo at 25° C. The residue was dissolved in H2O (0.3 mL) and applied to a column of Bio-Rad Ion Retardation Resin Ag11 A8 (trademark) (15 g, 1×20 cm) and eluted with H2O (0.3 mL/min). Fractions containing amino acid were pooled and lyophilized to yield 25.6 mg (96%) of pure β-azido-L-alanine. For the optimum melting point this material was recrystallized by dissolving in a minimal volume of H2O at 40° C., adding MeOH (3 vol.) and acetone (until cloudy) and cooling to -20° C.: mp 174°-175° C. (dec); [α]D 25 +37.2 (± 0.5) (c 0.5, H2O); IR (K8r disk) 3420 (m, br), 3070 (s, br), 2113 (s), 1600 (vs, br), 1440 (s) cm-1 ; 1H NMR (300 MHz, d4 -MeOD)δ 3.63 (dd, 1H, 4.5, 12 Hz, CHHN3), 3.53 (dd, 1H, 7.2, 12 Hz, CHN3), 3.37 (dd, 1H, 4.5, 7.2 Hz, CH); 1H NMR (300 MHz, D2O)δ 3.93 (dd, 1H, 5.0, 17.5 Hz, CHHN3), 3.92 (m, 1H, CH), 3.84 (dd, 1H, 7.0, 17.5 Hz, CHHN3); EI-MS: 131.0570 (MH+, Calc. 131.0570 for C3H7N4O2), 88.0400 (MH+ -HN3), 85.0515 (M-CO2H), 74.0245 (Base peak, M-CH2N3); POSFAB-MS (glycerol) 131 (MH+); Rf 0.80 (System A; UV active; brown-purple with ninhydrin).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:31]N1C(=O)CCC1=O.O>C(Cl)Cl>[Cl:31][CH2:10][CH:9]=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(C=CCO)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C=CCCl)cc1
Yield: 42.7 %

Procedure:
Compound 102-1 (2.50 g) was dissolved in methylene chloride (60 ml), triphenylphosphine (4.86 g) and N-chlorosuccinimide (2.84 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr. Triphenylphosphine (4.86 g) and N-chlorosuccinimide (2.84 g) were further added, and the mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate) to give the object product (1.20 g) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH:14](=O)[CH2:15][CH3:16].[BH3-]C#N.[Na+]>>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[N:8]([CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCN2
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCN1CCOc2cc([N+](=O)[O-])ccc21
Yield: 69.8 %

Procedure:
This compound was prepared by General Method 3 (EXAMPLE 1) from 3,4-dihydro-7-nitro-2H-1,4-benzoxazine (EXAMPLE 1) (530 mg, 2.9 mmol), propionaldehyde (1.61 g, 28 mmol) and NaBH3CN (872 mg, 14 mmol) to afford 450 mg (69%) of 3,4-dihydro-7-nitro-4-propyl-2H-1,4-benzoxazine, an orange oil. Data for 3,4-dihydro-7-nitro-4-propyl-2H-1,4-benzoxazine: Rf 0.57 (2:1 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 7.80 (dd, 1H, J=9.1, 2.6), 7.66 (d, 1H, J=2.6), 6.56 (d, 1H, J=9.0), 4.22 (t, 2H, J=4.5), 3.49 (t, 2H, J=4.5), 3.33 (t, 2H, J=7.5), 1.67 (sext, 2H, J=7.4), 0.98 (t, 3H, J=7.4).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-])=[O:25])=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].[C:28]1([N:34]2[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([N:34]2[CH2:35][CH2:36][CH:37]([NH:40][C:24]([C:21]3[O:22][C:23]4[C:15]([N:12]5[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:2]6[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=6)[CH2:10][CH2:11]5)=[CH:16][CH:17]=[CH:18][C:19]=4[CH:20]=3)=[O:25])[CH2:38][CH2:39]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NC1CCN(c2ccccc2)CC1
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Agent: [Li+]
Product: O=C(NC1CCN(c2ccccc2)CC1)c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (70 mg, 0.18 mmol) and 1-phenylpiperidin-4-amine (39 mg, 0.22 mmol). Yield: 34 mg (34%).
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[O:16].[I-].[Na+]>C(#N)C>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]([O:16][Si:2]([CH3:5])([CH3:4])[CH3:3])=[CH:14][CH3:13])=[CH:22][CH:21]=1
Reactant: C[Si](C)(C)Cl
Reactant: CCC(=O)c1ccc(Cl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC=C(O[Si](C)(C)C)c1ccc(Cl)cc1
Reaction time: 15 h
Yield: 94.3 %

Procedure:
13.47 g of chlorotrimethylsilane are slowly added to 12.55 g of triethylamine, under a nitrogen atmosphere, at 20°±3° C. 16.86 g of 4-chloropropiophenone (endothermic mixture) and then a solution of 18.58 g of sodium iodide in 125 ml of acetonitrile are further added while maintaining the temperature at 18°±2° C. The mixture is then heated for 3 hours at 40°±5° C., the acetonitrile is removed under reduced pressure and 150 ml of toluene are added to the solid residue. 50 ml of solvent are distilled under reduced pressure to drive the residual acetonitrile off. The inorganic materials are extracted with 100 ml of iced water, the organic phase is washed with 100 ml of iced water and dried over magnesium sulfate. The toluene is removed under reduced pressure and complete removal of the solvents is performed for 15 hours at 60° C. under a pressure of 1 mbar to give 22.7 g of an oil. NMR run at 200 MHz (CDCl3) 0.13 ppm:s:9H 1.7 ppm:d:3H 5.28 ppm:q:1H 7.21-7.39 ppm:m:4H.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:37])[CH2:8][CH2:9][N:10]([CH3:36])[C:11]1[C:12]([NH2:35])=[CH:13][C:14]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[CH:27]=[N:28][N:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=34)[CH:23]=[CH:22][N:21]=2)=[C:15]([O:17][CH3:18])[CH:16]=1>C(Cl)Cl.CO.C(Cl)Cl>[CH3:37][N:7]([CH3:6])[CH2:8][CH2:9][N:10]([CH3:36])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[CH:27]=[N:28][N:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=34)[CH:23]=[CH:22][N:21]=2)=[CH:13][C:12]=1[NH:35][C:1](=[O:4])[CH:2]=[CH2:3]
Reactant: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4ccccc34)n2)c(OC)cc1N(C)CCN(C)C
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
A solution of acryloyl chloride (63 μL, 0.78 mmol) in CH2Cl2 (3.60 mL) was added dropwise over 5 minutes to N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,2,4-triamine (Intermediate 158, 320 mg, 0.74 mmol) in CH2Cl2 (10.8 mL), which was cooled in an ice/CH3OH bath. The mixture was stirred for 0.5 h, and was then diluted with 10% CH3OH/CH2Cl2. The resulting solution was washed with sat. NaHCO3, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-5% methanolic ammonia in CH2Cl2 gave the title compound (228 mg, 63%) as a pale pink solid after trituration with diethyl ether; 1H NMR: 2.22 (6H, s), 2.33 (2H, t), 2.74 (3H, s), 2.91 (2H, t), 3.82 (3H, s), 5.73 (1H, dd), 6.19 (1H, dd), 6.41 (1H, dd), 7.02-7.06 (2H, m), 7.25 (1H, d), 7.29-7.34 (1H, m), 8.17 (1H, s), 8.34 (1H, d), 8.44 (1H, d), 8.75-8.79 (2H, m), 8.82 (1H, s), 10.06 (1H, br s); m/z: ES+ MH+ 487.72.
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]2[CH2:7][CH2:8][O:9][C:10]3[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:11]=3[C:12]=2[N:13]=1)=[N+:2]=[N-:3].[CH3:19][CH:20]([CH3:23])[C:21]#[CH:22]>>[Br:18][C:16]1[CH:15]=[CH:14][C:11]2[C:12]3[N:13]=[C:4]([N:1]4[C:21]([CH:20]([CH3:23])[CH3:19])=[CH:22][N:3]=[N:2]4)[S:5][C:6]=3[CH2:7][CH2:8][O:9][C:10]=2[CH:17]=1
Reactant: C#CC(C)C
Reactant: [N-]=[N+]=Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(C)c1cnnn1-c1nc2c(s1)CCOc1cc(Br)ccc1-2

Procedure:
Following the procedure for 414, Step 3, 2-azido-8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 3-methyl-1-butyne to afford the title compound as a beige solid. LCMS (Method A): RT=4.88 min, [M+H]+=391 and 393. 1H NMR (CDCl3): 8.12 (1H, d, J=8.5 Hz), 7.59 (1H, s), 7.30-7.25 (2H, m), 4.41 (2H, t, J=5.0 Hz), 3.98-3.90 (1H, m), 3.36 (2H, t, J=5.0 Hz), 1.44 (3H, s), 1.42 (3H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>>[OH:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:23][CH:22]=1
Reactant: Nc1ccc(OCCCO)cc1
Reactant: Cc1cccc(Nc2cc(Cl)ncn2)c1
Product: Cc1cccc(Nc2cc(Nc3ccc(OCCCO)cc3)ncn2)c1
Yield: 18 %

Procedure:
Using an analogous reaction procedure to that described in Example 6, 4-chloro-6-(3'-methylanilino)pyrimidine (1.35 g) was reacted with 4-(3-hydroxypropoxy)aniline.(1.0 g). The product so obtained was chromatographed on silica and triturated under methylene chloride to give 4-[4'-(3-hydrox-ypropoxy)anilino]6-(3'-methylanilino)pyrimidine in 18% yield, m.p. 196°-200° C.;
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[O:6][C:7]1[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([Cl:16])[N:10]=[C:9]([Cl:17])[N:8]=1.[C:22]([O-:25])(=[O:24])[CH3:23].[Na+]>CN(C=O)C>[Cl:17][C:9]1[N:8]=[C:7]([O:6][C:5]2[CH:4]=[C:3]([CH:20]=[C:19]([CH3:21])[CH:18]=2)[CH2:2][O:25][C:22](=[O:24])[CH3:23])[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([Cl:16])[N:10]=1
Reactant: Cc1cc(CBr)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc(C)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
To a stirred solution of (3) (14.4 g, 36.9 mmol) in anhydrous DMF (50 ml), was added sodium acetate (6.05 g, 73.8 mmol) and the mixture was stirred in an oil bath (90˜100° C.) for overnight. After cooling to room temperature, the mixture was partitioned between ether and water. The ether layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ether: hexanes (from 1:9 to 1:4)) to afford 10 g (73%) of a white solid. m.p. 76-77° C.; 1H NMR (200 MHz, CDCl3) δ 1.41 (6H, d, J=7.2 Hz), 2.12 (3H, s), 2.39 (3H, s), 3.58 (1H, m), 5.09 (2H, s), 6.88 (1H, s), 6.93 (1H, s), 7.08 (1H, s).