Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([CH3:10])=[CH:8][N:7](CC3C=CC(C4C=CC=CC=4C4N(C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)N=NN=4)=CC=3)[N:5]2[N:6]=1.[CH3:48][C:49]1[N:50]([CH2:58][C:59]2[CH:64]=[CH:63][C:62]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=3[C:71]3[N:75]([C:76]([C:89]4[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=4)([C:83]4[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=4)[C:77]4[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=4)[N:74]=[N:73][N:72]=3)=[CH:61][CH:60]=2)[C:51]2[N:52]([N:54]=[CH:55][C:56]=2[CH3:57])[N:53]=1>>[CH3:48][C:49]1[N:50]([CH2:58][C:59]2[CH:60]=[CH:61][C:62]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=3[C:71]3[N:75]([C:76]([C:77]4[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=4)([C:89]4[CH:90]=[CH:91][CH:92]=[CH:93][CH:94]=4)[C:83]4[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=4)[N:74]=[N:73][N:72]=3)=[CH:63][CH:64]=2)[C:51]2[N:52]([N:54]=[CH:55][C:56]=2[CH3:57])[N:53]=1.[CH3:1][C:2]1[NH:3][C:4]2[N:5]([N:7]=[CH:8][C:9]=2[CH3:10])[N:6]=1
Reactant: Cc1nc2c(C)cn(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)n2n1
Agent: Cc1cnn2nc(C)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c12
Product: Cc1nn2ncc(C)c2[nH]1

Procedure:
In the same manner as described in Example 38, 1.5 g of 2,7-dimethyl-5-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole (compound 45a) and 560 mg of 2,7-dimethyl-1-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-1 H-pyrazolo[1,5-b][1,2,4]triazole (compound 45b) were obtained from 500 mg of 2,7-dimethyl-1H-pyrazolo[1,5-b][1,2,4]triazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:17]([C:16]3[CH:19]=[CH:20][C:13]([N+:10]([O-:12])=[O:11])=[CH:14][CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Product: O=[N+]([O-])c1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1

Procedure:
The title compound was prepared from 5-bromo-2,3-diaminopyridine (0.94 g, 5 mmol) and 4-nitrobenzaldehyde (0.76 g, 5 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10]C2N=C(NC3CCCCCC3)N=C(N(C)C3CCN(C)CC3)N=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N:34]1[C:41]([Cl:42])=[N:40][C:38]([Cl:39])=[N:37][C:35]=1Cl.ClC1C=C(C=CC=1OC)N.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:35]2[N:34]=[C:41]([Cl:42])[N:40]=[C:38]([Cl:39])[N:37]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: COc1ccc(Nc2nc(NC3CCCCCC3)nc(N(C)C3CCN(C)CC3)n2)cc1Cl
Agent: COc1ccc(N)cc1Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1Cl

Procedure:
This reaction scheme illustrates synthesis of compound 137 by reaction of cyanuric chloride with 3-chloro-4-methoxyaniline using sodium hydroxide (NaOH) as base at 0–5° C. to yield (3-chloro-4-methoxy phenyl)-(4,6-dichloro-[1,3,5] triazine-2-yl) amine (compound 101), which on reaction with cycloheptylamine in presence of NaOH under reflux gave 6-chloro-N-(3-Chloro-4-methoxyphenyl)-N′-cycloheptyl-[1,3,5]triazine-2,4-diamine (compound 133). Compound 133 on reaction with 1-methyl-(4-methylamino)piperidine yields, the final compound 137.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:6][CH2:7][C:8]1[S:9][C:10]2[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:15]=2[N:16]=1.[Br:29][C:30]1[CH:40]=[CH:39][C:33]([O:34][CH2:35][C:36](O)=[O:37])=[CH:32][CH:31]=1>>[NH2:23][C:12]1[N:13]=[C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:36](=[O:37])[CH2:35][O:34][C:33]3[CH:39]=[CH:40][C:30]([Br:29])=[CH:31][CH:32]=3)[CH2:21][CH2:22]2)[C:15]2[N:16]=[C:8]([CH2:7][CH2:6][C:5]3[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:3]([O:2][CH3:1])[CH:4]=3)[S:9][C:10]=2[N:11]=1
Reactant: COc1ccc(CCc2nc3c(N4CCNCC4)nc(N)nc3s2)cc1OC
Reactant: O=C(O)COc1ccc(Br)cc1
Product: COc1ccc(CCc2nc3c(N4CCN(C(=O)COc5ccc(Br)cc5)CC4)nc(N)nc3s2)cc1OC
Yield: 74 %

Procedure:
This compound was prepared from 2-(3,4-dimethoxyphenethyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-bromophenoxyacetic acid in a yield of 74%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:3]=1[O:4][CH2:5][C@H:6]([N:8]1C(=O)C2C(=CC=CC=2)C1=O)[CH3:7].NN.[ClH:26]>C(O)C.C(OCC)(=O)C.CCOCC>[ClH:26].[F:1][C:2]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:3]=1[O:4][CH2:5][C@H:6]([NH2:8])[CH3:7]
Reactant: C[C@H](COc1cc(F)ccc1F)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCOCC
Product: C[C@@H](N)COc1cc(F)ccc1F
Temperature: 25 °C

Procedure:
To 5.4 g (R)-2-[2-(2,5-difluorophenoxy)-1-methylethyl]-1H-isoindole-1,3(2H)-dione in 250 mL absolute ethanol was added 6.0 mL hydrazine. The solution was heated to reflux for 100 minutes. A white precipitate formed. The reaction was allowed to cool to room temperature and was filtered to remove the precipitate. Concentration of the filtrate gave a gummy paste which was taken up in ethyl acetate and washed once with brine and twice with 100 mL 1N hydrochloric acid. The combined acidic aqueous layers were basified with 1N sodium hydroxide and extracted three times with ethyl acetate. The combined organic extracts were dried and the solvent was removed to afford an oil. The oil was diluted with dry ether and 30 mL of 1N hydrochloric acid in ether was added. The resulting white precipitate was collected by filtration and dried to give the title compound of Step B as a white powder: mp 127-130° C., 1H NMR (Me2SO-d6) δ1.30 (d, 3H), 3.60 (m, 1H), 4.22 (m, 2H), 6.80 (m, 1H), 7.22 (m, 2H), 8.30 (br s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[S:13][CH2:12][CH2:11][CH2:10][S:9]1.[Li]CCCC.[CH:19]([NH:22][C:23]1[S:24][C:25]2[CH:31]=[C:30]([CH:32]=[O:33])[CH:29]=[CH:28][C:26]=2[N:27]=1)([CH3:21])[CH3:20].CCOC(C)=O.CCCCCC>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH:32]([C:30]2[CH:29]=[CH:28][C:26]3[N:27]=[C:23]([NH:22][CH:19]([CH3:20])[CH3:21])[S:24][C:25]=3[CH:31]=2)[OH:33])[S:9][CH2:10][CH2:11][CH2:12][S:13]1
Reactant: Fc1ccccc1C1SCCCS1
Reactant: CC(C)Nc1nc2ccc(C=O)cc2s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)Nc1nc2ccc(C(O)C3(c4ccccc4F)SCCCS3)cc2s1
Reaction time: 2.5 h
Yield: 74 %

Procedure:
To a solution of 2-(2-fluorophenyl)-1,3-dithiane (0.820 g, 3.83 mmol) in THF (25 mL) was added n-BuLi (1.6 M in hexane, 2.3 mL, 3.68 mmol) at −10° C. over 10 min. The resulting solution was stirred at −10° C. for 30 min before a solution of 2-(isopropylamino)benzo[d]thiazole-6-carbaldehyde (0.385 g, 1.75 mmol) in THF (5 mL) was added. The mixture was stirred at between −10° C. and 5° C. for 2.5 hr, and then quenched with saturated NH4Cl solution (25 mL). This was extracted with AcOEt (3×20 mL). The combined extract was washed with brine and dried over anhydrous MgSO4. The title compound (0.563 g, 74% yield) was isolated as a pale yellow solid by silica gel chromatography (35% AcOEt/hexane).
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([O:7][C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=2)=[C:20]([C:30]2[CH:35]=[CH:34][C:33]([O:36]C)=[CH:32][CH:31]=2)[N:19]=[CH:18]1)=[O:9])[CH3:6].O>ClCCl>[CH2:5]([O:7][C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[C:20]([C:30]2[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=2)[N:19]=[CH:18]1)=[O:9])[CH3:6]
Reactant: CCOC(=O)CCCCCCCn1cnc(-c2ccc(OC)cc2)c1-c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CCCCCCCn1cnc(-c2ccc(O)cc2)c1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.5 %

Procedure:
Boron tribromide (1.3 ml) was added to a solution of 1-(7-ethoxycarbonylheptyl)-4,5-bis(4-methoxyphenyl)-imidazole (1.25 g) in dry dichloromethane (30 ml). The reaction was stirred at room temperature for 4 h, cooled and water (20 ml) was carefully added. The resulting purple precipitate was collected and column chromatographyon silica gel eluted with a dichloromethane:methanol gradient, followed by recrystallisation from ethanol and water gave 1-(7-ethoxycarbonylheptyl)-4,5-bis(4-hydroxyphenyl)-imidazole as a white solid (0.58 g, 50%), m.p. 186°-187°.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:15]([CH3:17])[CH3:16])[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[C:21]([O:20][C:18]([N:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH:15]([CH3:17])[CH3:16])=[O:19])([CH3:23])([CH3:24])[CH3:22]
Reactant: CC(C)N(C(=O)OC(C)(C)C)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)N(C(=O)OC(C)(C)C)C1CCNCC1
Reaction time: 24 h
Yield: 98 %

Procedure:
A solution of 1-benzyl-4-(N-tert-butoxycarbonyl-N-isopropylamino)piperidine (79.0 g, 0.24 mol) in ethanol (140 mL) was flushed with nitrogen for 15 minutes. This solution was then added to a 2 L Parr flask containing a mixture of 10% palladium on carbon (15.8 g; ca. 50% wt. water) in ethanol (100 mL), which solution had been flushed with nitrogen for 15 minutes. This reaction mixture was placed on a Parr Shaker under hydrogen at 50 psi for 24 hours. The reaction mixture was filtered through a pad of Celite and the Celite washed with ethanol. The filtrate was then concentrated in vacuo to afford 57.0 g of the title intermediate as a white solid (>99% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26]C(=O)C)[C@@H:18]([O:19]C(=O)C)[C@H:13]3[O:14]C(=O)C)[C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].CC(O)=O>CO>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][OH:26])[C@@H:18]([OH:19])[C@H:13]3[OH:14])[C:6]=2[N:7]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3cnc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ncc2sc(=O)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a solution of 78 (0.52 g, 1.22 mmol) in MeOH (20 mL) was added K2CO3 (25 mg, 0.18 mmol). The reaction was stirred at room temperature overnight, then neutralized with AcOH (21 μL, 0.36 mmol). The resulting mixture was stirred at room temperature for additional 30 min, concentrated, and triturated with H2O (2 ml) to afford 0.33 g of compound 79 (89%) as a white solid: mp 220° C. (Dec); 1H (400 MHz, d6-DMSO) δ 8.34 (s, 1H), 6.85 (s, 2H), 5.90 (d, J=4.8 Hz, 1H), 5.31 (d, J=5.6 Hz, 1H), 4.98 (d, J=5.6 Hz, 1H), 4.81 (q, J=5.2 Hz, 1H), 4.67 (t, J=6.0 Hz, 1H), 4.11 (q, J=5.2 Hz, 1H), 3.77 (dd, J=10.8, 4.8 Hz, 3H), 358 (m, 1H), 3.44 (m, 1H); MS (+)-ES [M+H]+ m/z 301.1. Elemental Analysis calc'd for C10H12N4O5S.0.3H2O: C, 39.29; H, 4.15; N, 18.33; S10.49. Found: C, 39.51; H, 4.18; N, 17.95; S, 10.27.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[N:12]2[C:16](=[O:19])[NH:17][N:18]=[C:11]2[C:10](=[O:20])[NH:9]3)[CH:5]=[CH:4][N:3]=[CH:2]1.S(=O)(=O)(O)O.[Br:26]Br.[OH-].[Na+]>O.S([O-])([O-])(=O)=O.[Ag+2]>[Br:26][C:15]1[CH:14]=[C:13]2[C:8]([NH:9][C:10](=[O:20])[C:11]3[N:12]2[C:16](=[O:19])[NH:17][N:18]=3)=[CH:7][C:6]=1[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: BrBr
Reactant: O=c1[nH]c2cc(-n3ccnc3)ccc2n2c(=O)[nH]nc12
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: O=c1[nH]c2cc(-n3ccnc3)c(Br)cc2n2c(=O)[nH]nc12
Reaction time: 48 h

Procedure:
To a solution of 0.94 g (~3.5 mmol) of 7-(1H-Imidazol-1-yl)[1,2,4]triazolo [4,3-a]quinoxaline-1,4(2H,5H)-dione in 7.5 ml concentrated (95-97%) sulfuric acid was added first 1.22 g (~3,9 mmol) silver sulfate and then 0.2 ml (~3.9 mmol) bromine. Stirring was continued at 24° C. for 48 h. The reaction mixture was filtered from silver bromide and then poured into 40 ml ice-water. The precipitate was filtered off to give a crude product. To a solution of the crude product in water was added 4N sodium hydroxide to pH=6 to give the title compound as a precipitate (0.42 g; 35%). M.p.>300° C. (decomp.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11]([C:13]1[CH:21]=[C:20]2[C:16]([C:17](/[CH:22]=[CH:23]/[C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=3)=[N:18][NH:19]2)=[CH:15][CH:14]=1)=O>>[O:10]=[C:2]1[NH:1][C:9]2[C:4](/[C:3]/1=[CH:11]/[C:13]1[CH:21]=[C:20]3[C:16]([C:17](/[CH:22]=[CH:23]/[C:24]4[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=4)=[N:18][NH:19]3)=[CH:15][CH:14]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=C1Cc2ccccc2N1
Reactant: COC(=O)c1ccc(/C=C/c2n[nH]c3cc(C=O)ccc23)cc1
Product: COC(=O)c1ccc(/C=C/c2n[nH]c3cc(/C=C4\C(=O)Nc5ccccc54)ccc23)cc1
Yield: 47.5 %

Procedure:
The title compound (40 mg, 83%) was synthesized as an orange solid according to the method described for Example A67 (oil temp 75° C., reflux 150 min) using indolin-2-one (26.6 mg, 0.2 mmol) and (E)-methyl 4-(2-(6-formyl-1H-indazol-3-yl)vinyl)benzoate (61.2 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.60 (s, 1H), 10.70 (s, 1H), 9.00 (s, 1H), 8.29 (d, J=8.0 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.00 (s, 1H), 7.98 (d, J=8.0 Hz, 2H), 7.88 (d, J=8.0 Hz, 2H), 7.77 (d, J=8.4 Hz, 1H, partially overlapping with the doublet at 7.74), 7.74 (d, J=17.2 Hz, 1H, partially overlapping with the doublet at 7.77), 7.63 (d, J=17.2 Hz, 1H), 7.23 (t, J=7.6 Hz, 1H), 7.01 (t, J=7.6 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 3.86 (s, 3H); MS ESI 422.3 [M+H]+, calcd for [C26H19N3O3+H]+ 422.1.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[CH:4][C:3]=1[C:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl.[CH3:19][O:20][NH2:21].N1C=CC=CC=1>CCO>[CH3:19][O:20][N:21]=[C:11]([C:3]1[CH:4]=[C:5]([C:9]#[N:10])[C:6](=[O:8])[NH:7][C:2]=1[CH3:1])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CON
Reactant: CCCCCC(=O)c1cc(C#N)c(=O)[nH]c1C
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCCCCC(=NOC)c1cc(C#N)c(=O)[nH]c1C
Temperature: 25 °C

Procedure:
A mixture of 1,2-dihydro-6-methyl-2-oxo-5-(1-oxohexyl)-3-pyridinecarbonitrile (0.80 g, 0.0034 mol), methoxyamine hydrochloride (0.32 g, .0038 mol) and pyridine (2.0 ml) were heated and stirred at reflux overnight in EtOH (30.0 ml). The solution was allowed to cool to room temperature and the solvent was removed on the rotary evaporator. The pasty residue was triturated with H2O, filtered and recrystallized (EtOH-H2O) giving 0.5 g (56%) m.pt. 159°-165° C. One more recrystallization gave the analytical sample m.pt. 170°-171° C.
Reaction SMILES: [Na].[NH2:2][OH:3].O.C[O:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH:20]([C:21]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:19][CH2:18][CH2:17][CH:16]2[C:28]2[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=2)=[C:10]([CH2:35][O:36][CH3:37])[CH:9]=1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH3:34][C:33]1[C:28]([CH:16]2[CH2:17][CH2:18][CH2:19][CH:20]([C:21]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[N:15]2[CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:2][OH:3])=[O:6])=[CH:9][C:10]=2[CH2:35][O:36][CH3:37])=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: NO
Reactant: COCc1cc(C(=O)OC)ccc1CN1C(c2ncccc2C)CCCC1c1ncccc1C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COCc1cc(C(=O)NO)ccc1CN1C(c2ncccc2C)CCCC1c1ncccc1C
Reaction time: 16 h
Yield: 35.2 %

Procedure:
To a stirred solution of sodium (100 mg, 4.2 mmol) in anhydrous MeOH (4 mL) was added NH2OH.H2O (260 mg, 3.7 mmol) followed by a solution of 4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-3-methoxymethyl-benzoic acid methyl ester (170 mg, 0.37 mmol) in anhydrous MeOH (4 mL). The mixture was stirred for 16 hours, diluted with CHCl3 (50 mL) and poured into a saturated NaHCO3 solution (50 mL). The aqueous layer was extracted with CHCl3 (5×25 mL). The combined organic portions were dried over Na2SO4 and concentrated. The resultant crude material was purified on a silica gel column (10 g, eluted with 5% NH4OH/10% MeOH/CH2Cl2) and dried under high vacuum to give COMPOUND 46 (60 mg, 35%) as a white solid. 1H NMR (CDCl3) δ 1.57-1.71 (m, 2H), 1.80-2.14 (m, 2H), 2.31-2.40 (m, 2H), 2.44 (s, 6H), 3.25 (s, 3H), 3.61 (s, 2H), 4.12 (s, 4H), 6.61-6.71 (m, 1H), 6.74-6.84 (m, 2H), 6.88-6.97 (m, 1H), 7.20 (s, 3H), 8.22 (s, 2H), 9.85 (s br, 1H); ES-MS m/z 461 (M+H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([CH2:11][C:12]1([C:23]([O:25]C)=[O:24])[O:16]N=[C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]O)[CH2:13]1)([O:9]C)=[O:8].C(N(CC)CC)C.Cl.[H-].[Na+].[Br-].[F:38][C:39]([F:71])([F:70])[C:40]1[CH:65]=[C:64]([C:66]([F:69])([F:68])[F:67])[CH:63]=[CH:62][C:41]=1[CH2:42][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl.CS(C)=O>[F:38][C:39]([F:70])([F:71])[C:40]1[CH:65]=[C:64]([C:66]([F:67])([F:68])[F:69])[CH:63]=[CH:62][C:41]=1[CH2:42][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C@@H:14]1[O:25][C:23](=[O:24])[C@@:12]([CH2:11][C:7]([OH:9])=[O:8])([OH:16])[CH2:13]1
Reactant: FC(F)(F)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C(F)(F)F)c1
Reactant: COC(=O)CC1(C(=O)OC)CC(CCCCCO)=NO1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Br-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(O)C[C@]1(O)C[C@H](CCCCCCc2ccc(C(F)(F)F)cc2C(F)(F)F)OC1=O
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 35.3 %

Procedure:
Dimethylsulphoxide (0,692 ml, 9.74 mmol) was injected dropwise into a stirred solution of oxalyl chloride (0,425 ml, 4.87 mmol) in dichloromethane (10 ml) at -78° under argon. After 2 min, a solution of ±5-(carbomethoxymethyl)-3-(5 -hydroxypentyl)-5-methoxycarbonyl-4,5-dihydroisoxazole (1.00 g, 3.48 mmol) in dichloromethane (5 ml) was added by cannula, and the mixture stirred for 30 min. Triethylamine (2.13 ml, 15.3 mmol) was injected, then the mixture allowed to warm to room temperature, poured into aqueous HCl, and extracted with dichloromethane. The extracts were washed with water, saturated aqueous NaCl, and dried (MgSO4). The solvent was removed under reduced pressure, and the crude aldehyde dried by evaporation of a toluene solution. Sodium hydride (60% oil suspension, 146 mg, 3.65 mmol) was washed with petroleum ether 40°-60° under argon, then heated with dimethylsulphoxide (5 ml) at 70-90° until all solid had dissolved. After cooling in a water bath, a solution of 2,4-bis(trifluoromethyl)benzyltriphenylphosphonium bromide (1.98 g, 3.48 mmol) in dimethylsulphoxide (15 ml) was added by cannula, and the mixture stirred at room temperature for 15 min. A solution of the crude aldehyde in dimethylsulphoxide (5 ml) was added, the mixture stirred for 20 h, then poured into aqueous HCl and extracted with ether. The extracts were washed with water, saturated aqueous NaCl, and dried (MgSO4). The solvent was removed under reduced pressure, and the residue purified by chromatography on silica gel (50-70% ether/petroleum ether 40°-60° ) to give the title compound (0.56 g, 33%) as a mixture of E and Z isomers.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[N:3]=1.[F:23][C:24]([F:30])([F:29])[CH2:25][N:26]=[C:27]=[S:28]>C(#N)C>[F:23][C:24]([F:30])([F:29])[CH2:25][NH:26][C:27](=[S:28])[NH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:13](=[O:22])[C:14]3=[CH:21][CH:20]=[CH:19][CH:18]=[C:15]3[C:16]2=[O:17])[N:3]=1
Reactant: Nc1ccnc(CCCCN2C(=O)c3ccccc3C2=O)n1
Reactant: FC(F)(F)CN=C=S
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCCc1nccc(NC(=S)NCC(F)(F)F)n1
Reaction time: 18 h
Yield: 69.8 %

Procedure:
A mixture of 4-amino-2-(4-phthalimidobutyl)pyrimidine (1 g.), 2,2,2-trifluoroethylisothiocyanate (1 g.) and acetonitrile was stirred at 70° for 18 hours. The mixture was diluted with acetonitrile (10 ml.), cooled in ice and then filtered to give 4-[3-(2,2,2-trifluoroethyl)thioureido]-2-(4-phthalimidobutyl)pyrimidine (1.03 g.), m.p. 204°-205°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]4[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=4)[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl>[OH-].[Na+].O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]4[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=4)[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(Nc2nc3cccc(-c4cccc(Cl)c4)n3n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(Nc2nc3cccc(-c4cccc(Cl)c4)n3n2)cc1
Reaction time: 3 h

Procedure:
A solution of methyl 4-{[5-(3-chlorophenyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino}benzoate (0.50 g, 1.3 mmol, 1 equiv) in 2M sodium hydroxide aqueous solution and 1,4-dioxane was stirred at about 80-90° C. After 3 h, the reaction mixture was neutralized with 6N aqueous hydrochloride acid solution to pH=4-5. The resulting solid was filtered and rinsed sequentially with water, isopropanol, and hexanes. The resulting crude product was used for the next step without further purification (330 mg, >85% purity by HPLC). LCMS (ESI) m/z: 365.0.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH2:15][C:16]([OH:18])=O)=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.Cl.[CH3:34][NH:35][OH:36]>ClCCl>[CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH2:15][C:16]([N:35]([OH:36])[CH3:34])=[O:18])=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: CNO
Reactant: Cc1ccc(C)n1-c1ccc(SCC(=O)O)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C)n1-c1ccc(SCC(=O)N(C)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.0 g of 2-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenylthio]-acetic acid in 75 ml of dichloromethane and 0.8 ml. triethylamine, is cooled in an ice bath. To this solution is added 0.5 ml of trimethylacetyl chloride and the solution is stirred at room temperature overnight. Triethylamine (2 ml) is added followed by 1 g of N-methylhydroxylamine hydrochloride and the mixture is kept at room temperature for 20 hours. The mixture is washed with 0.3 N aqueous hydrochloric acid, ice cold dilute sodium bicarbonate and brine. The organic phase is dried over MgSO4 and filtered. The solvent is evaporated at 50° at reduced pressure, the residue is dissolved in diethyl ether and the solutions filtered through 10 g of silica gel to yield 2-[4-(2,5-dimethyl-1H-pyrrol-1-yl)phenylthio]-N-hydroxy-N-methylacetamide; NMR (DMSO-d6 : δ7.1, 5.85, 3.25, 1.95.
Reaction SMILES: N[C:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[CH:3][C:4]#[N:5].Cl.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][NH2:22].[OH-].[Na+]>Cl>[F:12][C:9]1[CH:8]=[CH:7][C:6]([C:2]2[CH:3]=[C:4]([NH2:5])[N:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH3:14])[N:22]=2)=[CH:11][CH:10]=1
Reactant: N#CC=C(N)c1ccc(F)cc1
Reactant: Cc1ccccc1NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccccc1-n1nc(-c2ccc(F)cc2)cc1N
Temperature: 25 °C
Yield: 85.3 %

Procedure:
To a solution of 3-amino-3-(4-fluorophenyl)acrylonitrile (600 mg, 3.70 mmol) in 1 N HCl (6 mL) was added (2-methylphenyl)hydrazine hydrochloride (558 mg, 3.51 mmol). The reaction was refluxed for 16 h, and then cooled to rt. The resulting mixture was basified to pH 12 by slow addition of 1 N aqueous sodium hydroxide. The precipitate was collected by filtration, and then recrystallized from EtOH/Et2O to afford the intermediate (800 mg, 81%) as a light orange solid. 1H NMR (400 MHz, CD2Cl2) δ 2.20 (s, 3H), 2.14 (br s, 2H), 5.91 (s, 1H), 7.06 (t, 2H), 7.36 (d, 4H), 7.75 (m, 2H). This material was used without further purification.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8]>C(Cl)(Cl)Cl>[Br:1][C:10]1[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: COc1ccccc1C#N
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COc1ccc(Br)cc1C#N
Temperature: 25 °C
Yield: 71.4 %

Procedure:
Bromine (13.7 g, 86.0 mmol) in CHCl3 (20 mL) was added to the solution of 2-(methyloxy)benzonitrile (10.9 g, 81.9 mmol) in CHCl3 (50 mL). The mixture was refluxed for 29 h. The reaction was allowed to cool to room temperature, and washed with saturated sodium bisulfite (50 mL), and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate. Evaporation of the solvent afforded 5-bromo-2-(methyloxy)benzonitrile (12.4 g, 71%).