Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:5]=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[SH:18].C([O-])(=O)C.[Pb+4].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[S:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: Nc1ccccc1S
Reactant: O=Cc1cc(Br)cc(Br)c1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)O
Solvent: O
Product: Brc1cc(Br)cc(-c2nc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.03 g (19.1 mmol) of 3,5-dibromobenzaldehyde and 3.1 mL (28.6 mmol) of 2-aminothiophenol were dissolved in 60 mL of acetic acid. The solution was agitated at room temperature for 30 minutes. 9.78 g (21.0 mmol) of lead(IV) acetate was added thereto. The resulting mixture was agitated at 50° C. for 1 hour. Then, water was poured into the reactant. It was extracted with ethyl acetate. The extract was separated through a column and dried, obtaining 4.74 g (Y=67%) of a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[CH:7]([O:41]C(=O)C)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]([C:18]2[N:19]=[C:20]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[NH:21][C:22]=2[CH2:23][CH2:24][C:25]23[CH2:34][CH:29]4[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]4)[CH2:26]2)[CH2:32]3)=[O:17])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:1]([O:5][C:6](=[O:45])[CH:7]([OH:41])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]([C:18]2[N:19]=[C:20]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[NH:21][C:22]=2[CH2:23][CH2:24][C:25]23[CH2:32][CH:31]4[CH2:33][CH:27]([CH2:28][CH:29]([CH2:30]4)[CH2:34]2)[CH2:26]3)=[O:17])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(Cc1cccc(NC(=O)c2nc(C3CCCCC3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)C(O)Cc1cccc(NC(=O)c2nc(C3CCCCC3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)c1
Yield: 63.1 %

Procedure:
A solution of the product of step c (282 mg, 0.46 mmol) and potassium carbonate (96 mg, 0.70 mmol) in methanol (3 ml) and water (0.3 ml) was stirred at room temperature for 3 h. The reaction was quenched with 10% aqueous citric acid (1 ml), then diluted with ethyl acetate (20 ml). The organic phase was washed with water (20 ml), brine (20 ml), dried (MgSO4) and the solvent was evaporated. The residue was purified by flash chromatography (silica, hexane/ethyl acetate 2:1) to afford colourless foam (167 mg, 63%). 1H NMR (300 MHz, CDCl3) 9.05 (1H, br s), 8.62 (1H, br s), 7.60 (2H, m), 7.25 (1H, m), 6.98 (1H, d), 4.34 (1H, m), 3.13-3.02 (4H, m), 2.93 (1H, m), 2.85 (1H, d), 2.68 (1H, m), 2.05-1.35 (36H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:29]=[CH:30][C:31]=2[F:32])[CH2:22][CH2:21]1>>[F:32][C:31]1[CH:30]=[CH:29][C:28]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])=[CH:27][C:26]=1[CH:23]1[CH2:22][CH2:21][N:20]([CH2:19][CH2:18][CH2:17][NH:16][C:13]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10][CH2:11][CH2:12]2)=[O:15])[CH2:25][CH2:24]1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCC1
Reactant: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCC3)CC2)c1

Procedure:
Example 129 was prepared from 1-(4-fluorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.42–7.38 (m, 1H), 7.31–7.20 (m, 2H), 6.94–6.83 (m, 4H), 6.46–6.40 (m, 1H), 3.19 (q, 2H, J=5.6 Hz), 2.85–2.79 (m, 2H), 2.73–2.64 (m, 1H), 2.49–2.38 (m, 3H), 2.22 (t, 2H, J=6.4 Hz), 1.94–1.84 (m, 5H), 1.75–1.47 (m, 9H), 1.17 (d, 6H, J=6.8 Hz); ESMS m/e: 512.3 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([CH2:9][OH:10])[O:6][N:5]=1)(=[O:3])[NH2:2].N1C=CC=CC=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:19]>ClCCl>[C:18](=[O:19])([O:20][C:21]1[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=1)[O:10][CH2:9][C:7]1[O:6][N:5]=[C:4]([C:1](=[O:3])[NH2:2])[CH:8]=1
Reactant: NC(=O)c1cc(CO)on1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: NC(=O)c1cc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)on1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2.0 g (14.07 mmol) of 3-carbamoylisoxazol-5-ylmethanol, 1.71 ml (21.11 mmol) of pyridine and 0.17 g (1.41 mmol) of N,N-dimethylaminopyridine in 15 mL of dichloromethane, cooled to about 0° C., are added portionwise 2.84 g (14.07 mmol) of 4-nitrophenyl chloroformate. The medium is kept stirring at 0° C. for 1 hour and then at room temperature for 1 hour.
Reaction SMILES: [C:1]([C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]O)#[N:2].S(Cl)(C)(=O)=O.[I-:22].[Na+]>C(#N)C.C(N(CC)CC)C>[C:1]([C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][I:22])#[N:2]
Reactant: CC(C)C(C#N)(CCCO)c1ccccc1
Reactant: [I-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)C(C#N)(CCCI)c1ccccc1
Reaction time: 0.42 h

Procedure:
5.00 g 23.0 mmol of 4-Cyano-5-methyl-4-phenylhexanol disclosed in Example 2 or 3 of JP 11-70613-A was added to and dissolved in acetonitrile 150 ml and triethylamine 3.53 ml. Mesyl chloride, 1.96 ml 25.3 mmol, was added thereto. After 25 minutes, sodium iodide 20.7 g was added thereto. The reaction mixture was partitioned by adding brine and ethyl acetate. The organic layer was washed with aqueous sodium thiosulfate and then with brine, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane system), whereby the title compound, 5. 89 g 18.0 mmol, 78.2%, was obtained as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[OH:24].I[CH3:27].[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:15][CH2:16]2)=[CH:6][C:5]=1[O:24][CH3:27]
Reactant: CI
Reactant: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1OC

Procedure:
4-(N-t-Butoxycarbonyl-4-piperidinyloxy)-2-hydroxybenzoic acid methyl ester from Step 1 was methylated with iodomethane and sodium hydride in DMF using the procedure in Step 2 of Example 11. The crude product was purified by pressurized silica gel column chromatography using a gradient elution of 20-40% EtOAc-hexane. 4-(N-t-Butoxycarbonyl-4-piperidinyloxy)-2-methoxybenzoic acid methyl ester was obtained as an oil (88% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].[Br:22][CH2:23]/[CH:24]=[CH:25]/[CH2:26]Br>O1CCOCC1.O>[Br:22][CH2:23]/[CH:24]=[CH:25]/[CH2:26][NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6]
Reactant: BrC/C=C/CBr
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)cc(NC/C=C/CBr)c1Oc1ccccc1

Procedure:
A solution of 3-amino-4-phenoxy-5-sulfamylbenzoic acid (2 g) and 1,4-trans-dibromo-2-butene (3.2 g) in dioxane (35 ml) was heated to reflux overnight. The solvent was removed under reduced pressure and the dark, gummy residue was chromatographed on a silica gel column using chloroform/benzene/acetic acid/methanol (80:10:10:2.5) as the eluting solvent. The fractions containing the product were combined and concentrated leaving an acetic acid solution of it. This was diluted with water to give a cream colored powder which was filtered, dried and washed with pet. ether to remove unreacted dibromobutene. The resulting 3-(4-bromo-trans-2-butenylamino)-4-phenoxy-5-sulfamylbenzoic acid was an off-white solid 0.75 g (26%) with m.p. 191°-194°; ir (Nujol) 3350, 3200, 2600 (broad), 1690, 1605, 1585, and 1530 cm-1 ; nmr (CDCl3 /d6 -DMSO) 3.7-4.5 (m, 5H incl. NH), 5.73 (t, 2H, vinyl), 6.27 (s, SO2NH2), 6.8-7.4 (m, C6H5), 7.57 (d, J=2, CH), and 8.03 ppm (d, CH); mass spectrum is of decomposition products.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(#N)C.C([O-])([O-])=O.[Na+].[Na+]>CCOC(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>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][CH3:22])=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccccc1B(O)O
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(Br)cc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
Into a 500 mL round bottomed flask were added 5-Bromo-3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (11.80 g, 20.96 mmol), 2-methoxyphenyl boronic acid (3.76 g, 24.74 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.756 g, 1.08 mmol), acetonitrile (100 mL) and 100 mL of 2M Na2CO3 (aq). The flask was fitted with a reflux condenser and heated at 60° C. with rapid stirring under N2 for 8 h. The reaction mixture was filtered to obtain a grey-tan precipitate, which was dissolved in EtOAc and washed with water followed by brine. Concentration of this solution afforded 7.70 g (80%) of the title compound as a tan powder. 1H-NMR (500 MHz, d6-DMSO) δ 8.50 (d, J=2.0 Hz, 1H), 8.14 (d, J=2.5 Hz, 1H), 8.07 (s, 1H), 8.03 (d, J=8.0 Hz, 2H), 7.54 (dd, J=1.5, 7.5 Hz, 1H), 7.43 (d, J=8.0 Hz, 2H), 7.39 (m, 1H), 7.15 (d, J=7.5 Hz, 1H), 7.05 (t, J=7.0 Hz, 1H), 3.80 (s. 3H), 2.34 (s, 3H); MS: m/z 456.9/458.9 [MH+].
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([S:22](=[O:24])(=[O:23])[N:25]([CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:20][CH:21]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Nc1ccc(S(=O)(=O)N(Cc2ccccc2)Cc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(S(=O)(=O)N(Cc3ccccc3)Cc3ccccc3)cc2)CC1
Yield: 54.6 %

Procedure:
Using general procedure A, 1-Boc-4-piperidone (1.00 g, 5.03 mmol) and 4-amino-N,N-dibenzyl-benzenesulfonamide (Mikhura, I. V.; et al., Russ. J. Org. Chem., 36, 1, 2002, 64-68) (1.53 g, 4.34 mmol) afforded 4-(4-dibenzylsulfamoyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (1.27 g, 55%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[NH:22]1[CH2:25][CH:24]([CH2:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]3[NH:34][C:35]4[N:51]=[C:39]([NH:40][C:41]5[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=5)[CH2:46][CH2:47][C:48]=2[CH:49]=3)[N:38]=[CH:37][C:36]=4[Cl:52])=[O:28])[CH2:23]1.[CH3:53][C:54]1[O:58][N:57]=[C:56]([C:59](Cl)=[O:60])[CH:55]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:52][C:36]1[CH:37]=[N:38][C:39]2[NH:40][C:41]3[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=3)[CH2:46][CH2:47][C:48]3[CH:49]=[C:33]([NH:34][C:35]=1[N:51]=2)[CH:32]=[CH:31][C:30]=3[NH:29][C:27](=[O:28])[CH2:26][CH:24]1[CH2:23][N:22]([C:59]([C:56]2[CH:55]=[C:54]([CH3:53])[O:58][N:57]=2)=[O:60])[CH2:25]1
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: O=C(CC1CNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)C2)no1
Yield: 87 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 2-azetidin-3-yl-N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide tris(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as the starting materials in 87% yield. LCMS for C27H26ClN8O3 (M+H)+: m/z=545.0.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[CH2:29][CH:30]([CH3:32])[CH3:31]>CN(C=O)C>[CH3:31][CH:30]([CH3:32])[CH2:29][CH2:28][N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1
Reactant: CC(C)CCBr
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 80 °C
Yield: 129.3 %

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 50.7 mg, 0.1 mmol), K2CO3 (49.5 mg, 0.36 mmol), and isoamyl bromide (32 uL, 0.27 mmol) in DMF (1.0 mL). Heat at 80° C. for 6 hours. Pass through an SCX column, washing with methanol and then eluting with 2.0 M NH3 in MeOH. Concentrate the eluant and purify by flash chromatography, eluting with 70:22:8 EtOAc/CH2Cl2/2.0 M NH3 in MeOH to afford the title compound (45.7 mg, 72%): MS ES+ 354.0 (M+H)+, HRMS calcd for C21H28N3O2 354.2182 (M+H)+, found 354.2182, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=6.39 min, 100% purity; Anal. Calcd for C21H27N3O2.0.2CH2Cl2.0.1MeOH: C, 69.59; H, 5.98; N, 11.43. Found: C, 69.47; H, 6.25; N, 11.30.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=1>>[CH3:38][O:37][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][N:25]1[CH2:24][CH2:23][CH:22]([N:21]([CH3:28])[C:19](=[O:20])[CH2:18][O:17][C:4]2[N:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:6]([CH3:16])[N:5]=2)[CH2:27][CH2:26]1
Reactant: COc1cccc(CBr)c1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Product: COc1cccc(CN2CCC(N(C)C(=O)COc3nc(C)c(NC(=O)OC(C)(C)C)c(C)n3)CC2)c1

Procedure:
The title compound was synthesized from Compound 31 and 1-(bromomethyl)-3-methoxybenzene in the same manner as in Example 32.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].CN1CCOCC1.ClC(OCC(C)C)=O.[Br:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([NH2:44])[C:35]=1[NH:36][C:37]1[CH:38]=[N:39][CH:40]=[C:41]([F:43])[CH:42]=1.[NH4+].[Cl-]>C(Cl)Cl>[Br:29][C:30]1[C:35]([NH:36][C:37]2[CH:38]=[N:39][CH:40]=[C:41]([F:43])[CH:42]=2)=[C:34]([NH:44][C:4](=[O:6])[C@@H:2]([NH:1][C:7](=[O:8])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:3])[CH:33]=[CH:32][CH:31]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1cccc(Br)c1Nc1cncc(F)c1
Agent: CC(C)COC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccc(Br)c1Nc1cncc(F)c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a −10° C. solution (NaCl-ice bath) of Boc-L-Ala-OH (6.36 g, 33.6 mmol) and N-methylmorpholine (3.88 mL, 35.3 mmol) in DCM (84 mL) was added isobutyl chloroformate (4.40 mL, 33.6 mmol). The resulting cloudy colorless mixture was stirred at −10° C. for 30 min. To the mixture was then added a solution of 6-bromo-N1-(5-fluoropyridin-3-yl)benzene-1,2-diamine (4.7437 g, 16.81 mmol) in DCM (84 mL). The resulting mixture was allowed to warm to rt with stirring. After 20 h, satd. NH4Cl (100 mL) was added to the mixture. The cloudy organic layer was separated. The aqueous mixture was extracted with DCM (1×100 mL) and the organic extracts concentrated in vacuo to provide a crude product. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (120 g), eluting with a gradient of 0% to 100% DCM:MeOH:NH4OH (89:9:1) in DCM, to provide (S)-tert-butyl 1-(3-bromo-2-(5-fluoropyridin-3-ylamino)phenylamino)-1-oxopropan-2-ylcarbamate as orange solid: LC-MS (ESI) m/z 453.0 [M+H (79Br)]+ and 455.0 [M+H (81Br)]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[O:9][CH3:10].C([Li])CCC.[C:16]1(=[O:20])[CH2:19][CH2:18][CH2:17]1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2([OH:20])[CH2:19][CH2:18][CH2:17]2)=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=C1CCC1
Reactant: COc1cc(I)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C2(O)CCC2)ccc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 12.2 %

Procedure:
To a solution of 2-bromo-5-iodoanisole (400 mg, 1.28 mmol) in tetrahydrofuran (5 mL) at −78° C. was added n-butyl lithium (2.5M in hexane, 0.62 mL, 1.55 mmol) dropwise over 15 minutes. The reaction mixture was stirred at −78° C. for 30 minutes, then treated with neat cyclobutanone (0.1 mL, 1.3 mmol) dropwise over 10 minutes and stirred at −78° C. for an additional 1.5 hours. The reaction was quenched with saturated aqueous ammonium chloride solution, warmed to room temperature and extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford a yellow oil, which was purified by flash chromatography (12 g silica, 0-50% ethyl acetate/heptane, 27 column volumes). Product fractions were combined and concentrated in vacuo to afford the title compound as a pale yellow oil (40 mg, 12% yield). GCMS 256/258 (M)+; 1H NMR (500 MHz, CDCl3) δ 7.53 (d, J=8.29 Hz, 1H), 7.09 (d, J=1.95 Hz, 1H), 6.98 (dd, J=8.17, 1.83 Hz, 1H), 3.94 (s, 3H), 2.51-2.61 (m, 2H), 2.35-2.46 (m, 2H), 2.02-2.10 (m, 1H), 1.66-1.79 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.Cl[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[O:20][N:19]=1>>[F:15][C:2]([F:14])([F:1])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=2)[O:20][N:19]=1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Reactant: FC(F)(F)c1ccc(-c2nc(CCl)no2)cc1
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3ccc(C(F)(F)F)cc3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 23 using 4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazole: MS (ES) m/z 437 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.[CH2:11]([Mg]Br)[CH3:12].C1COCC1.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH:8]([OH:9])[CH2:11][CH3:12])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1c(Cl)ncnc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCC(O)c1c(Cl)ncnc1Cl
Temperature: -10 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
Charge 4,6-dichloro-pyrimidine-5-carbaldehyde (2.5 g, 1.0 eq) and toluene (50 mL) in a round bottom flask. Cool the reaction mass to −10° C. Add ethyl magnesium bromide (3M) in THF solution (5.1 mL, 1.1 eq) drop wise at −10° C. Slowly allow the reaction mass to come to RT in 1 h. Charge chilled ammonium chloride solution to the reaction mass and extract with diethyl ether. Wash ether layer with saturated aq. sodium chloride solution. Dry the ether layer over anhydrous sodium sulfate and concentrated it under reduced pressure to get the desired product (2.3 g, 79.3%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[CH2:11]([CH2:18][C:19](=O)[CH3:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[CH2:11]([C:18]1[C:7]2[C:6](=[CH:5][CH:4]=[C:3]([Br:2])[CH:8]=2)[NH:9][C:19]=1[CH3:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NNc1ccc(Br)cc1
Reactant: CC(=O)CCc1ccccc1
Agent: Cl
Solvent: CCO
Product: Cc1[nH]c2ccc(Br)cc2c1Cc1ccccc1

Procedure:
The desired product was prepared using a procedure similar to step 1 of example 3. Thus, 4-bromophenylhydrazine, hydrochloride (4.694 g, 21 mmol) was reacted with benzylacetone (2.964 g, 20 mmol) in ethanol (60 ml) to give the product (3.199 g, 10.657 mmol, 51%) as a tan solid, mp 130-134° C. 1H NMR (DMSO-d6) δ 2.36 (s, 3H), 3.95 (s, 2H), 7.05 (dd, J=1.8, 8.4 Hz, 1H), 7.12 (t, J=7.2 Hz, 1H), 7.17-7.20 (m, 3H), 7.23 (t, J=7.8 Hz, 2H), 7.43 (d, J=1.7 Hz, 1H), 11.01 (s, 1H); [ESI(−)], m/z 298/300 (M−H)−.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[CH2:3].C(OOC(=O)C1C=CC=CC=1)(C)(C)C.[PH2:23]([OH:25])=[O:24]>>[CH3:3][CH:2]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:1][PH:23](=[O:24])[OH:25]
Reactant: C=C(C)CC(C)(C)C
Reactant: O=[PH2]O
Agent: CC(C)(C)OOC(=O)c1ccccc1
Product: CC(C[PH](=O)O)CC(C)(C)C

Procedure:
A mixture of diisobutylene (112 g, 1 mol) and hypophosphorous acid (30%, 230 mL) are reacted in the presence of t-butylperbenzoate. After aqueous work up, 45 g of oily product are obtained. It is characterized by 1H NMR and 31P NMR which shows formation of product (64% pure).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([N+:15]([O-])=O)[CH:7]=1.[CH3:18][C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([NH:28][C:29]([C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1)=[O:30])=[CH:23][CH:22]=2>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[N:12]=[C:35]([C:34]3[CH:33]=[CH:32][C:31]([C:29]([NH:28][C:24]4[CH:25]=[C:26]5[C:21](=[CH:22][CH:23]=4)[NH:20][C:19]([CH3:18])=[CH:27]5)=[O:30])=[CH:38][CH:37]=3)[NH:15][C:8]=2[CH:7]=1
Reactant: Cc1cc2cc(NC(=O)c3ccc(C=O)cc3)ccc2[nH]1
Reactant: COCCOc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Product: COCCOc1ccc2nc(-c3ccc(C(=O)Nc4ccc5[nH]c(C)cc5c4)cc3)[nH]c2c1

Procedure:
Compound 662 was prepared according to the procedure similar to that described in Scheme III from 1-(2-methoxyethoxy-3,4-dinitrobenzene and 4-(2-methyl-5-indolylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C26H24N4O3: 441.18; found: 441.02.
Reaction SMILES: Cl[C:2]1[C:3]([CH2:13][CH3:14])=[C:4]([CH3:12])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.[O-:15][CH2:16][CH3:17].[Na+]>C(O)C>[CH2:16]([O:15][C:2]1[C:3]([CH2:13][CH3:14])=[C:4]([CH3:12])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1)[CH3:17]
Reactant: CCc1c(Cl)nn2c(N)nnc2c1C
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nn2c(N)nnc2c(C)c1CC
Temperature: 55 °C
Yield: 97.4 %

Procedure:
6-Chloro-7-ethyl-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.007; 380 mg) was initially charged in ethanol (45 ml) at RT while stirring, admixed with sodium ethoxide (244 mg) and heated to 55° C. for 3 h. Then a further equivalent of sodium ethoxide was added and the mixture was stirred once again at 55° C. for 3 h. After leaving to stand over the weekend, the mixture was dried, and the residue was taken up with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 387 mg of the title compound were obtained.