Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.CN(C)C=O.[I-:24].[K+].II>N.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=2)=[CH:6][C:7]=1[I:24]
Reactant: CCOC(=O)c1cccc(-c2ccc(O)cc2)c1
Reactant: [I-]
Agent: II
Agent: N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccc(-c2ccc(O)c(I)c2)c1
Reaction time: 1 h

Procedure:
The product from Example 143A (7.71 g, 31.8 mmol) was dissolved into N,N-dimethylformamide (30 mL), diluted with concentrated aqueous ammonia (320 mL), and treated with a solution of potassium iodide (27.72 g, 167 mmol) and iodine (8.48 g, 33.4 mmol) in water (100 mL) all at once. After the mixture was stirred for one hour, the ammonia was removed under reduced pressure on a rotary evaporator. The remaining solution was neutralized to pH 7 with aqueous hydrochloric acid, diluted with EtOAc (200 mL), worked up as usual, dried (Na2SO4), concentrated, and chromatographed on silica with a 33 to 100% gradient of CH2Cl2/hexanes to provide the title compound as a white microcrystalline solid (37% yield). 1HNMR (300 MHz, d6-DMSO) δ 1.35 (t, 3H), 4.35 (q, 2H), 7.00 (d, 1H), 7.53-7.60 (m, 2H), 7.84-7.91 (m, 2H), 7.97 (d, 1H), 8.08 (dd, 1H), 10.55 (bs, 1H).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:25]1[NH:30][C:29](=[O:31])[NH:28][C:27](=[O:32])[CH:26]=1>O1CCOCC1>[O:1]([CH2:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][N:14]([C:25]2[NH:30][C:29](=[O:31])[NH:28][C:27](=[O:32])[CH:26]=2)[CH2:15][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(OCCCN2CCNCC2)cc1
Reactant: O=c1cc(Cl)[nH]c(=O)[nH]1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=c1cc(N2CCN(CCCOc3ccccc3)CC2)[nH]c(=O)[nH]1
Yield: 75.2 %

Procedure:
1.1 g of 1-(3-phenoxypropyl)piperazine, 0.8 ml of triethylamine and 0.59 g of 6-chloro-2,4(1H,3H)-pyrimidinedione were dissolved in 15 ml of dioxane, followed by heating under reflux for 1 hour. After cooling, the precipitated crystals were collected by filtration, and then washed with water and hot ethanol to obtain 1.0 g (yield 66% ) of 6-[4-(3-phenoxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:33]=[CH:32][C:21]([C:22]([NH:24][CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:23])=[CH:20][CH:19]=3)[O:15][C:16]=2[CH3:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>CS(C)=O>[CH3:17][C:16]1[O:15][C:14]([C:18]2[CH:33]=[CH:32][C:21]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[O:23])=[CH:20][CH:19]=2)=[N:13][C:12]=1[CH2:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CN1CCNCC1
Reactant: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(F)cc1
Solvent: CS(C)=O
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(N2CCN(C)CC2)cc1
Temperature: 130 °C
Reaction time: 16 h
Yield: 31 %

Procedure:
A mixture of fluoride 48 (112 mg, 0.24 mmol) and 1-methylpiperazine (1 mL) in DMSO (1 mL) was stirred in a sealed tube at 130° C. for 16 h. The solvent was evaporated and the residue was suspended in ice/water (50 mL) for 1 h. The mixture was partitioned between CHCl3 (200 mL) and water (50 mL) and the solvent evaporated. The mixture was dissolved in EtOAc (5 mL) and the precipitated filtered to give benzamide 49 (41 mg, 31%) as a white powder: mp (EtOAc) 210-215° C.; 1H NMR δ 9.23 (s, 1 H, CONH), 8.56 (br s, 1 H, H-2′), 8.46 (dd, J=4.8, 1.6Hz, 1 H, H-6′), 8.00 (d, J=8.6Hz, 2 H, H-2, H-6), 7.91 (d, J=8.6Hz, 2 H, H-3, H-5), 7.73 (dt, J=8.0, 2.0Hz, 1 H, H-4′), 7.50 (d, J=9.1Hz, 2 H, H-3″, H-5″), 7.36 (ddd, J=7.9, 4.7, 0.6Hz, 1 H, H-5′), 7.02 (d, J=9.1Hz, 2 H, H-2″, H-6″), 4.49-4.53 (m, 4 H, CH2SO2, CH2N), 3.30 (br t, J=4.9Hz, 4 H, 2×CH2N), 2.40 (br t, J=4.9Hz, 4 H, 2×CH2N), 2.20 (s, 3 H, CH3), 2.12 (s, 3 H, CH3); 13C NMR δ 165.5, 157.8, 154.0, 149.6, 148.8, 148.1, 135.3, 135.1, 134.9, 129.7 (2), 128.8, 128.0 (2), 126.4, 125.4 (2), 123.4 (2), 113.3 (2), 54.1 (2), 53.2, 46.4 (2), 45.6, 40.4, 9.6; MS m/z 546.8 (MH+, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH3:14])[NH:11][C@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH3:14])[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1Cc1ccccc1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a suspension of 10 g (46.66 mmol.) of cis-1-tert-butoxycarbonyl-3,5-dimethyl piperazine and 12.90 g (93.3 mmol.) of potassium carbonate in N,N-dimethylformamide (100 ml) was added, at room temperature, 11.97 g (70 mmol.) of benzyl bromide. The mixture was stirred for 16 hours at 120° C. To the reaction system was added water, which was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution, which was dried over magnesium sulfate, followed by distilling off the solvent. The residue was purified by means of a column chromatography (ethyl acetate/hexane 30%) to give the object compound as a pale yellow oily product. The yield was 13.56 g (95%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH2:26][OH:27])=[CH:20]2>>[C:1]([C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([CH2:26][OH:27])=[CH:20]3)=[O:15])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc2[nH]c(CO)cc2c1
Reactant: CC(C)(C)c1ccc(/C=C/C(=O)O)cn1
Product: CC(C)(C)c1ccc(/C=C/C(=O)Nc2ccc3[nH]c(CO)cc3c2)cn1

Procedure:
Analogous to the procedure used to prepare Example 1, (2E)-3-[6-(tert-butyl)(3-pyridyl)]prop-2-enoic acid, Example 44(b), (41 mg, 0.20 mmol) and (5-aminoindol-2-yl)methan-1-ol, Example 74(b), (32 mg, 0.20 mmol) provided, after purification by silica gel chromatography (20:80 hexane:EtOAc), the title compound as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 350 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].[CH3:12][CH:13]([NH:15][CH2:16][CH2:17][CH2:18][N:19]1[C:28]([S:29][C:30]2[CH:35]=[C:34]3[O:36][CH2:37][O:38][C:33]3=[CH:32][C:31]=2I)=[N:27][C:21]2[C:22]([NH2:26])=[N:23][CH:24]=[N:25][C:20]1=2)[CH3:14].C([O-])(O)=O.[Na+].CN(C=O)C>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.O>[NH2:26][C:22]1[N:23]=[CH:24][N:25]=[C:20]2[C:21]=1[N:27]=[C:28]([S:29][C:30]1[C:31]([C:6]3[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=3)=[CH:32][C:33]3[O:38][CH2:37][O:36][C:34]=3[CH:35]=1)[N:19]2[CH2:18][CH2:17][CH2:16][NH:15][CH:13]([CH3:12])[CH3:14]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CC(C)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NCCCn1c(Sc2cc3c(cc2-c2ccc(C=O)cc2)OCO3)nc2c(N)ncnc21
Temperature: 90 °C
Yield: 65.5 %

Procedure:
4-Formylphenylboronic acid (13 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO3 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H2O (0.1 mL) and Pd(PPh3)2Cl2 (8 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 90° C. for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH2Cl2:EtOAc:MeOH—NH3 (7N), 2:2:1:0.5) to give 18.8 mg (66%) of DZ3-50. 1H NMR (500 MHz, MeOH-d4) δ 10.01 (s, 1H), 8.15 (s, 1H), 7.85 (d, J=8.1 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.14 (s, 1H), 6.93 (s, 1H), 6.13 (s, 2H), 4.05 (t, J=6.8 Hz, 2H), 2.99 (septet, J=6.4 Hz, 1H), 2.62 (t, J=6.9 Hz, 2H), 1.99 (m, 2H), 1.24 (d, J=6.4 Hz, 6H); 13C NMR (125 MHz, MeOH-d4) δ 192.3, 154.1, 151.9, 151.0, 149.8, 148.8, 148.5, 146.4, 139.5, 135.3, 130.0, 129.4, 119.0, 117.7, 115.0, 110.8, 102.4, 49.9, 42.2, 40.3, 27.4, 20.2; HRMS (ESI) m/z [M+H]+ calcd. for C25H27N6O3S, 491.1865; found. 491.1877; HPLC: method A Rt=6.23, method B Rt=6.83.
Reaction SMILES: [F:1][C:2]1[C:12]([SH:13])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C1C(=O)N(Cl)C(=O)C1.[Cl:22][C:23]1[C:31]([F:32])=[C:30]2[C:26]([CH:27]=[C:28]([CH:40]3[CH2:42][CH2:41]3)[N:29]2[C:33]2[CH:34]=[N:35][N:36]([CH2:38][CH3:39])[CH:37]=2)=[CH:25][CH:24]=1>C(Cl)Cl.O>[Cl:22][C:23]1[C:31]([F:32])=[C:30]2[C:26]([C:27]([S:13][C:12]3[C:2]([F:1])=[C:3]([CH:9]=[CH:10][CH:11]=3)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:28]([CH:40]3[CH2:42][CH2:41]3)[N:29]2[C:33]2[CH:34]=[N:35][N:36]([CH2:38][CH3:39])[CH:37]=2)=[CH:25][CH:24]=1
Reactant: CCn1cc(-n2c(C3CC3)cc3ccc(Cl)c(F)c32)cn1
Reactant: CCOC(=O)c1cccc(S)c1F
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cnn(CC)c3)c3c(F)c(Cl)ccc23)c1F
Reaction time: 2 h
Yield: 80.9 %

Procedure:
To a stirred solution of ethyl 2-fluoro-3-mercaptobenzoate 6 (2.8 g, 14.0 mmol) in CH2Cl2 (30 mL) under inert atmosphere was added NCS (1.9 g, 14.0 mmol) at RT and allowed to stir for 2 h. To this, compound 5 (3.9 g, 12.8 mmol) in CH2Cl2 (10 mL) was added at RT and stirred for 16 h. After completion of the reaction by TLC, the reaction mixture was diluted with water (100 mL) and extracted with CH2Cl2 (2×80 mL). The combined organic extracts were washed with water (2×200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified by triturating with n-pentane (2×50 mL) to afford 7 (5.2 g, 81%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.66-7.7.60 (m, 3H), 7.18 (d, J=8.4 Hz, 1H), 7.08 (dd, J=8.4, 6.5 Hz, 1H), 6.93 (t, J=8.4 Hz, 1H), 6.79-6.75 (m, 1H), 4.40 (q, J=7.2 Hz, 2H), 4.26 (q, J=7.6 Hz, 2H), 1.74-1.68 (m, 1H), 1.56 (t, J=7.2 Hz, 3H), 1.41 (t, J=7.6 Hz, 3H), 1.08-1.04 (m, 2H), 0.89-0.84 (m, 2H); MS (ESI): m/z 502.5 (M+H+); HPLC: 97.5%; (column: Acquity BEH C-18 (50×2.1 mm, 1.7μ); RT 3.44 min; ACN: 0.025% TFA (aq); 0.5 mL/min.
Reaction SMILES: I[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([CH3:12])[CH:3]=1.[CH2:13]([N:15]1[CH2:19][CH2:18][C:17]2([CH2:23][CH2:22][NH:21][CH2:20]2)[CH2:16]1)[CH3:14].C(O)CO.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)(C)C.[Cu]I>[CH2:13]([N:15]1[CH2:19][CH2:18][C:17]2([CH2:20][N:21]([C:2]3[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([CH3:12])[CH:3]=3)[CH2:22][CH2:23]2)[CH2:16]1)[CH3:14]
Reactant: Cc1cc(I)cc([N+](=O)[O-])c1N
Reactant: CCN1CCC2(CCNC2)C1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: CCN1CCC2(CCN(c3cc(C)c(N)c([N+](=O)[O-])c3)C2)C1
Temperature: 90 °C
Yield: 59.8 %

Procedure:
A suspension of 4-iodo-2-methyl-6-nitroaniline (1.39 g, 5 mmol), 2-ethyl-2,7-diaza-spiro[4.4]nonane (770 mg, 5 mmol), CuI (190.5 mg, 1.0 mmol), ethylene glycol (931 mg, 15 mmol) and K3PO4 (3.2 g, 15 mmol) in isopropanol (40 mL) was sealed and heated at 90° C. for 19 h. After cooled down to room temperature, the reaction mixture was concentrated. The residue was purified by chromatography (16:1 CH2Cl2/MeOH) to afford the title compound (910 mg, 60%). 1H NMR (CDCl3) δ 1.29 (t, J=8 Hz, 3H), 1.96-2.19 (4H), 2.24 (s, 3H), 2.77-3.01 (6H), 3.22-3.40 (4H), 5.78 (br s, 2H NH), 6.80 (s, 1H), 7.06 (s, 1H). ESI-MS m/z 305 (MH+).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[S:12]([N:15]([CH3:17])[CH3:16])(=[O:13])=[O:14]
Reactant: CN(C)S(=O)(=O)c1cc(F)ccc1CN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1cc(F)ccc1CN
Temperature: 80 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of intermediate 47, 2-azidomethyl-5-fluoro-N,N-dimethyl-benzenesulfonamide, (660 mg, 2.6 mmol) in tetrahydrofuran (10 mL) and water (2 mL) was added triphenylphosphine (740 mg, 2.8 mmol), and the mixture stirred under nitrogen for 1 hr. The tetrahydrofuran was evaporated in vacuo and a mixture of the residue and 6N HCl (3 mL) in MeOH (5 mL) was heated at 80° C. for 20 hrs. This was washed with CH2Cl2, and the aqueous phase basified with dilute NH4OH and extracted with CH2Cl2. The organic extract was dried (Na2SO4), filtered and concentrated to provide 210 mg (0.91 mmol, Yield 35%) of the title compound; 1H NMR (500 MHz, CDCl3) δ ppm: 2.84 (6H, s) 4.10 (2H, s) 7.23-7.29 (1H, m) 7.53-7.60 (2H, m); LC/MS m/z 233 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[CH2:8][S:7][C:6]1=[N:11][OH:12].[CH3:13][N:14]=[C:15]=[O:16]>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[CH2:8][S:7][C:6]1=[N:11][O:12][C:15](=[O:16])[NH:14][CH3:13]
Reactant: COCCN1C(=O)CSC1=NO
Reactant: CN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)ON=C1SCC(=O)N1CCOC

Procedure:
A solution of 5.4 g 3-(2-methoxyethyl)-2-oximino-4-thiazolidinone in 50 ml methylene chloride, 4.0 g of methylisocyanate and 4 drops of triethylamine was kept in a pressure bottle for 16 hours at ambient temperature. On concentration under reduced pressure the reddish brown liquid was dissolved in methanol, decolorized with charcoal and concentrated. The desired produced was crystallized from methanol. Weight 5.5 g., m.p. 153°-155°C.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Na].[N:19]#[C:20]Br>>[CH3:14][C:12]1[CH:11]=[C:10]([CH3:15])[N:9]=[C:8]([N:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:20]#[N:19])[N:13]=1
Reactant: Cc1cc(C)nc(Nc2ccccc2)n1
Reactant: N#CBr
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Product: Cc1cc(C)nc(N(C#N)c2ccccc2)n1

Procedure:
2-Anilino-4,6-dimethylpyrimidine (3.98 g) was treated with sodium hydride in a similar manner to that described in Example 8. The resulting sodium salt was then treated with cyanogen bromide (2.12 g) and the mixture heated under reflux for 4 hours. The mixture was then filtered through silica gel and eluted with dichloromethane and the solution evaporated. The residue was recrystallised from ethyl acetate to give N-(4,6-dimethylpyrimidin-2-yl)-N-phenylcyanamide, m.p. 153°-4°. (Compound 94).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:22]I>CN(C=O)C.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:22])[N:15]=[CH:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3[nH]ncc3c2)nc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc2cc(Oc3ccc([N+](=O)[O-])cn3)ccc21
Reaction time: 3.5 h

Procedure:
To a solution of 5-(5-Nitro-pyridin-2-yloxy)-1H-indazole (1.0 g, 3.9 mmol) in 15 mL of DMF is added sodium hydride (3.9 mmol) and methyl iodide (20 mmol). The resulting mixture is stirred at room temperature to 50° C. for 1-6 hours. The mixture is diluted with water, extracted 3× with ethyl acetate, and the combined organic layers are dried over sodium sulfate, filtered and concentrated in vacuo. Purification by column chromatography eluting with ethyl acetate-hexanes, affords 5-(5-Nitro-pyridin-2-yloxy)-1-methyl-1H-indazole.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[C:42]1([S:52](Cl)(=[O:54])=[O:53])[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44][CH:43]=1>C(#N)C>[C:42]1([S:52]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:54])=[O:53])[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3cccc4ccccc34)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 61.1 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0358 g, 0.0776 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0650 mL, 0.465 mmol) and 1-naphthalenesulfonyl chloride (0.0530 g, 0.233 mmol) to obtain 4-(1-naphthalenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0309 g, yield 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14]I)=[N:10][N:9]([C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:25])[CH3:24])[CH:19]=[CH:20][CH:21]=3)[C:8]2=[O:26])=[CH:4][CH:3]=1.[CH3:29][O-:30].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14][O:30][CH3:29])=[N:10][N:9]([C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:25])[CH3:24])[CH:19]=[CH:20][CH:21]=3)[C:8]2=[O:26])=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1cccc(-n2nc(CI)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1nn(-c2cccc(NC(C)=O)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 9 %

Procedure:
According to Scheme 7 Step 7: To a cooled solution of 14(A) (220 mg, 0.43 mmol) in DMF (2 mL) under nitrogen atmosphere was added dropwise at 0° C. sodium methoxide 2M (in methanol, 215 μL, 0.43 mmol). The mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with with water (100 mL) and the aqueous layer was extracted twice with DCM (100 mL). The organic layers were combined and successively dried over MgSO4, filtered and concentrated under reduced pressure to afford a brown solid. The crude solid was purified by flash chromatography with silica gel (Merck Flashmart prepacked column 25 g C18) using water/CH3CN 6/4 as eluant to afford N-(3-(4-(4-chlorobenzyl)-6-(methoxymethyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 14(B) (16 mg, 9%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:16]=3[CH3:17])=[C:5]2[O:4][N:3]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:17][C:16]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:10]1[CH:9]=[CH:8][N:7]=[C:6]2[C:2]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[N:3][O:4][C:5]=12
Reactant: C1COCCN1
Reactant: Cc1ccncc1-c1ccnc2c(Cl)noc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1ccncc1-c1ccnc2c(N3CCOCC3)noc12
Temperature: 90 °C
Yield: 75 %

Procedure:
To a suspension of 3-chloro-7-(4-methylpyridin-3-yl)isoxazolo[4,5-b]pyridine (0.0069 g, 0.028 mmol) and morpholine (0.025 ml, 0.281 mmol) in DMSO (Volume: 0.100 ml) was added cesium carbonate (0.027 g, 0.084 mmol). The vial was sealed, heated at 90° C. for 4 hr, and then allowed to cool to room temperature. The reaction mixture was filtered through a disposable fritted funnel and the filter cake washed with CH2Cl2. The solvent was concentrated to afford a yellow liquid, which was further dried under high vacuum overnight. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (4 g column, 18 mL/min, 70-100% EtOAc in hexanes over 14 min, tr=4.5 min) gave 7-(4-methylpyridin-3-yl)-3-morpholinoisoxazolo[4,5-b]pyridine (6.5 mg, 0.021 mmol, 76% yield) as a white solid. ESI MS (M+H)+=297.2. HPLC Peak tr=1.56 minutes. Purity=97%. HPLC Conditions: C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: c1c[nH]cn1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-n2ccnc2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 33.8 %

Procedure:
A mixture of 4-fluorobenzaldehyde (4.96 g, 40 mmol), imidazole (2.86 g, 42 mmol), and potassium carbonate (6.08 g, 44 mmol) in DMSO (40 ml) was stirred at 110° C. overnight. The reaction mixture was allowed to return to room temperature, and poured into ice water (100 ml). The resulting precipitates were collected by filtration and washed with water and then with ethyl acetate to afford 4-(imidazol-1-yl)benzaldehyde (2.33 g, yield 34%) as a pale yellow crystalline powder.
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([CH2:9]O)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:31]>>[C:1]([N:5]1[CH2:8][CH:7]([CH2:9][Cl:31])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1CC(CO)C1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)N1CC(CCl)C1

Procedure:
A mixture of 3.0 g. (0.209 mol.) of N-t-butyl-3-hydroxymethylazetidine, 6.0 g. (0.0229 mol.) of triphenylphosphine and 50 ml. of carbon tetrachloride was refluxed for 48 hours. The mixture was cooled, filtered and the filtrate was extracted three times with 10% aqueous sulfuric acid. The combined extracts were basicified by addition of solid sodium carbonate and the basic solution was extracted with ether. The extract was dried (MgSO4), evaporated to dryness and the residue distilled to give N-t-butyl-3-chloromethylazetidine, b.p. 90°-96° (27 mm.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[C:19]([F:26])=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][NH2:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@H:9]1[C:14](=[O:16])[NH:22][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[C:18]([Cl:17])[C:19]=1[F:26])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1cccc(Cl)c1F
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1C(=O)NCc1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (2S,3S)-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (800 mg, 3.46 mmol; prepared according to J. Amer. Chem. Soc. 2005, 127, 15923-15932) in CH2Cl2 (35 mL) were added successively 3-chloro-2-fluorobenzylamine (0.435 mL, 3.46 mmol), HBTU (1.97 g, 5.19 mmol), DIPEA (1.21 mL, 6.92 mmol). After stirring at RT for 18 h, the reaction mixture was diluted with CH2Cl2 and the organics were washed with water (2×), 0.1N aqueous HCl (2×), aqueous NaHCO3 solution (2×) and brine, dried (phase separator) and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (EtOAc/c-hexane 1:2 to 4:1 then EtOAc) to afford the title compound as a colorless wax. TLC Rf (EtOAc/c-hexane 1:1)=0.32; MS (LC/MS): 373 [M+H]+, 395 [M+Na]+, 767 [2M+Na]+; tR (HPLC conditions C): 4.42 min.