Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1.[CH3:12][NH:13][C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15]>CN1C(=O)CCC1>[CH3:12][N:13]([C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1
Reactant: CN[C@H](C)c1ccccc1
Reactant: Cc1nnc2ccc(Cl)nn12
Solvent: CN1CCCC1=O
Product: Cc1nnc2ccc(N(C)[C@H](C)c3ccccc3)nn12
Temperature: 200 °C

Procedure:
6-Chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine (150 mg, 0.890 mmol; commercially available or prepared according to patent WO2006/039325A2), (R)-N-methyl-1-phenylethanamine (481 mg, 3.56 mmol; available from Aldrich) and anhydrous NMP (1 mL) were charged into a microwave tube equipped with a magnetic stirbar. After the vessel was sealed, the mixture was heated at 200° C. for 60 min using microwave irradiation. The reaction was purified by normal phase (gradient of 0% to 20% MeOH in CH2Cl2 as eluent) and by reverse phase chromatography before being lyophilized to give the (R)-N,3-dimethyl-N-(1-phenylethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-amine (Compound 3) as an off-white solid (115 mg; 48% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.01 (d, J=10.1 Hz, 1H), 7.23-7.41 (m, 6H), 5.71 (q, J=6.8 Hz, 1H), 2.83 (s, 3H), 2.54 (s, 3H), 1.58 (d, J=7.1 Hz, 3H). LRMS [M+H]+: 268 m/z.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C@H:6]([O:10][CH2:11][CH:12]=O)[CH2:7][CH:8]=[CH2:9].[OH:14][N:15]=CCOC([C@@H]1C[C@H]1C)CC=C>>[OH:14][N:15]=[CH:12][CH2:11][O:10][C@@H:6]([C@@H:2]1[CH2:3][CH2:4][CH2:5][O:1]1)[CH2:7][CH:8]=[CH2:9]
Reactant: C=CCC(OCC=NO)[C@@H]1C[C@H]1C
Reactant: C=CC[C@@H](OCC=O)[C@@H]1CCCO1
Product: C=CC[C@@H](OCC=NO)[C@@H]1CCCO1

Procedure:
({(1R)-1-[(2S)-Tetrahydrofuran-2-yl]but-3-en-1-yl}oxy)acetaldehyde (C97) was converted to the product using the method described for the synthesis of N-hydroxy-2-({1-[(1R,2R)-2-methylcyclopropyl]but-3-en-1-yl}oxy)ethanimine (C84) in Example 20. Yield: 4.7 g, 23.6 mmol, 65% over 2 steps from (C95).
Reaction SMILES: [C:1]([O-:4])([O-])=[O:2].[K+].[K+].Br[C:8]1([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:18]>O1CCOCC1>[Cl:17][C:13]1[CH:12]=[C:11]2[C:16]([C:8]([NH:10][CH:9]([CH2:8][CH:16]([CH3:11])[CH3:15])[C:1]([OH:4])=[O:2])([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:9](=[O:18])[NH:10]2)=[CH:15][CH:14]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)CC(NC1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the aqueous solution K2CO3 (1.6 μL, 1N) was added (2S)-amino-4-methyl-pentanoic (106 mg, 0.81 mmol), then followed by the addition of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (200 mg, 0.54 mmol) in dioxane (5 mL). After the mixture was stirred at room temperature for 4 h, the reaction mixture was concentrated in vacuo. Water (10 mL) was added and the crude was acidified with HCl to PH=4. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layer was concentrated in vacuo. The residue was purified by chromatography (DCM: MeOH=80:1) to give 184 mg of rac-(2S)-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-4-methyl-pentanoic acid as a white solid. MS: 421 (M+H)+. H1-NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 7.12 (m, 5H), 6.93 (t, 1H), 6.76 (m, 2H), 3.32 (m, 1H), 3.16 (dd, 2H), 1.89 (m, 1H), 1.50 (m, 2H), 0.90 (dd, 6H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38]>CS(C)=O.O>[C:11]1([C:8]2[N:6]3[N:7]=[C:2]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38])[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: NCCCCO
Reactant: Clc1ccc2ncc(-c3cccc4ccccc34)n2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CS(C)=O
Product: OCCCCNc1ccc2ncc(-c3cccc4ccccc34)n2n1
Temperature: 100 °C
Yield: 50.4 %

Procedure:
To a solution of 6-chloro-3-(naphthalen-1-yl)imidazo[1,2-b]pyridazine (50 mg, 0.179 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonic acid monohydrate (35 mg, 0.184 mmol, 1.0 equiv) and 4-aminobutan-1-ol (200 mg, 2.24 mmol, 12.5 equiv) and heated to 100° C. for 24 h. The reaction mixture was diluted with water and extracted with ethyl acetate. Purification by column chromatography using 5% methanol in dichloromethane elution gave 30 mg of a white solid, 50%.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([NH:16][C:17]1[CH:29]=[C:28]([CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21]C(C)(C)C)=[O:20])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8]([NH:16][C:17]1[CH:29]=[C:28]([CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:27]=[CH:26][C:18]=1[C:19]([OH:21])=[O:20])(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCCCc2ccccc2)cc1NC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(CCCCc2ccccc2)ccc1C(=O)O)c1ccccc1

Procedure:
4.9 mL solution of trifluoroacetic acid containing 0.50 g of tert-butyl 2-(benzamido)-4-(4-phenylbutyl)benzoate was stirred at room temperature for 2 hours and 30 minutes. A solid substance was separated by filtration to obtain 0.16 g of 2-(benzamido)-4-(4-phenylbutyl)benzoic acid as white solid.
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH:10]12[O:16][CH:15]1[CH2:14][CH2:13][CH2:12][CH2:11]2>C(O)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C@@H:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:15]2[OH:16])=[CH:5][CH:4]=1
Reactant: C1CCC2OC2C1
Reactant: Oc1ccc(Br)cc1
Agent: [Na]
Solvent: CCO
Product: O[C@@H]1CCCC[C@H]1Oc1ccc(Br)cc1

Procedure:
Sodium metal (2.58 g, 112 mmol) was combined with absolute ethanol (200 mL) and allowed to react completely. 4-Bromophenol (19.4 g, 112 mmol) was added, and the reaction was stirred for 20 minutes, at which point 7-oxabicyclo[4.1.0]heptane (10.0 g, 102 mmol) was added, and the solution was heated at reflux for 15 hours. After removal of solvent in vacuo, the residue was partitioned between water (300 mL) and ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL), and the combined organic layers were washed with water (2×200 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting light tan solid was recrystallized from heptane (roughly 200 mL) to provide trans-2-(4-bromophenoxy)cyclohexanol as a fluffy white solid. Yield: 12.5 g, 46.1 mmol, 45%. 1H NMR (400 MHz, CDCl3) δ 1.26-1.46 (m, 4H), 1.75-1.79 (m, 2H), 2.08-2.14 (m, 2H), 2.52 (d, J=2.1 Hz, 1H), 3.72 (m, 1H), 3.96 (ddd, J=10.3, 8.6, 4.4 Hz, 1H), 6.84 (d, J=9.0 Hz, 2H), 7.37 (d, J=9.0 Hz, 2H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][CH:25]4[CH2:27][O:26]4)[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][O:29][C:30]1[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=1[O:32][CH2:33][CH2:34][NH2:35]>>[C:1]1([S:7]([N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][CH:25]([OH:26])[CH2:27][N:35]([CH2:17][C:16]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH2:34][CH2:33][O:32][C:31]4[CH:36]=[CH:37][CH:38]=[CH:39][C:30]=4[O:29][CH3:28])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccccc1OCCN
Reactant: O=S(=O)(c1ccccc1)n1c2ccccc2c2c(OCC3CO3)cccc21
Product: COc1ccccc1OCCN(Cc1ccccc1)CC(O)COc1cccc2c1c1ccccc1n2S(=O)(=O)c1ccccc1

Procedure:
reaction of 9-benzenesulfonyl-4-oxiranylmethoxy-9H-carbazole with benzyl-[2-(2-methoxy-phenoxy]-ethyl-amine to give a 1-(9-benzenesulfonyl-9H-carbazol-4-yloxy)-3-{benzyl-[2-(2-methoxy-phenoxy)ethyl]-amino}-propan-2-ol;
Reaction SMILES: Br[C:2]1[C:3]([O:10][CH3:11])=[N:4][CH:5]=[N:6][C:7]=1[O:8][CH3:9].[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C.C1COCC1>[CH3:11][O:10][C:3]1[C:2]([C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)=[C:7]([O:8][CH3:9])[N:6]=[CH:5][N:4]=1
Reactant: COc1ncnc(OC)c1Br
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ncnc(OC)c1-c1ccncc1
Temperature: 70 °C
Yield: 82.4 %

Procedure:
A mixture of 5-bromo-4,6-dimethoxypyrimidine (2.18 g, 10 mmol), pyridine-4-boronic acid (1.85 g, 15 mmol), K2CO3 (2.76 g, 20 mmol), and PXPd (539 mg, 1.0 mmol) in ethanol/THF (1:1, 25 mL) under argon was heated at 70° C. for 3 h. Analysis by HPLC/MS indicated that the reaction was complete. After the reaction mixture was cooled to room temperature, the solvent mixture was removed under reduced pressure. The residue was dissolved in EtOAc (30 mL) and washed with saturated aqueous NaCl (20 mL), then dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography eluted with ethyl acetate-hexanes to obtain the title compound (1.79 g) as a white solid. 1H NMR (CDCl3): δ 3.97 (s, 6H), 7.36 (d, 2H), 8.47 (s, 1H), 8.64 (d, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][C@@H:28]1[CH2:32][CH2:31][O:30][CH2:29]1>>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][C@@H:28]2[CH2:32][CH2:31][O:30][CH2:29]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCC[C@@H]1CCOC1
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CC[C@@H]3CCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 215 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and (3S)-3-(2-bromoethyl)tetrahydrofuran.
Reaction SMILES: [CH2:1]([C:8]1([C:21](=[O:35])[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])[CH:24]=2)[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>CO>[CH3:33][N:31]([CH3:32])[C:30](=[O:34])[O:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([NH:22][C:21]([C:8]2([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[O:35])[CH:24]=1
Reactant: CN(C)C(=O)Oc1cccc(NC(=O)C2(Cc3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN(C)C(=O)Oc1cccc(NC(=O)C2(Cc3ccccc3)CCNCC2)c1
Temperature: 50 °C

Procedure:
To a solution of tert-butyl 4-benzyl-4-(3-(dimethylcarbamoyloxy)-phenylcarbamoyl)piperidine-1-carboxylate from step A (0.162 g, 0.336 mmol) in MeOH (5 mL) was added 4 M HCl in dioxane (0.250 mL, 1.00 mmol). The reaction was heated at 50° C. for 1 hour, and then concentrated under vacuum, re-dissolved in MeOH and re-concentrated twice to give the title compound as the hydrochloride salt. MS (ES+) [M+H]+=382.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([N:15]2[C:19](=[O:20])[N:18]([CH2:21][CH2:22][CH3:23])[N:17]=[N:16]2)=[CH:10][C:3]=1[O:4][CH2:5][C:6]([O:8]C)=[O:7].[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([N:15]2[C:19](=[O:20])[N:18]([CH2:21][CH2:22][CH3:23])[N:17]=[N:16]2)=[CH:10][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCCn1nnn(-c2cc(OCC(=O)OC)c(Cl)cc2Cl)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCn1nnn(-c2cc(OCC(=O)O)c(Cl)cc2Cl)c1=O
Yield: 41.2 %

Procedure:
A stirred solution of 0.5 g (0.0014 mole) of methyl 2,4-dichloro-5-(1,4-dihydro-5-oxo-4-propyltetrazol-1-yl)phenoxyacetate (compound 83) and 0.08 g (0.0021 mole) of sodium hydroxide in 10 mL of methanol was heated at reflux temperature for 1.5 hours. The reaction mixture was cooled, then evaporated under reduced pressure to leave a solid residue. The residue was dissolved in 20 mL of water, and the solution acidified with concentrated hydrochloric acid. A solid precipitate formed and was collected by filtration and washed with cold water. Recrystallization from diethyl ether:pentane provided 0.2 g of 2,4-dichloro-5-[1,4-dihydro-5-oxo-4-propyltetrazol-1-yl)phenoxyacetic acid, mp 134°-136° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:33])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[C:13]([F:32])[CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1>>[F:32][C:13]1[CH:12]=[C:11]([N:10]([C:8]([C:5]2[CH:6]=[N:7][C:2]([O:41][C:38]3[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=3)=[CH:3][CH:4]=2)=[O:9])[CH3:33])[CH:16]=[CH:15][C:14]=1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]1
Reactant: Oc1ccc(F)cc1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Cl)nc3)cc2F)CCN1C(=O)OC(C)(C)C
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Oc4ccc(F)cc4)nc3)cc2F)CCN1C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2S)-4-({4-[[(6-chloro-3-pyridinyl)carbonyl](methyl)amino]-2-fluorophenyl}methyl)-2-methyl-1-piperazinecarboxylate (D70) and 4-fluorophenol using a method similar to that described for D55 in Description 55 although the reaction temp./time was 130° C. for 8 h and purification was carried out by column chromatography. δH (CDCl3, 400 MHz) 8.07 (1H, dd), 7.70 (1H, dd), 7.33 (1H, t), 7.05 (4H, m), 6.78 (3H, m), 4.19 (1H, br.s), 3.81 (1H, d), 3.47 (5H, m), 3.07 (1H, td), 2.71 (1H, d), 2.53 (1H, d), 2.18 (1H, dd), 2.04 (1H, m), 1.46 (9H, s), 1.20 (3H, d).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].F[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[O:12][CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18].O>C(O)C>[CH2:2]([O:1][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[O:12][CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH3:3]
Reactant: C[Si](C)(C)CCOCOc1cnccc1F
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1ccncc1OCOCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.6 %

Procedure:
To a stirred solution of sodium ethoxide (0.9 g, 13 mmol) in ethanol (10 mL) was added all at once 10 (1.07 g, 4.4 mmol). The resulting mixture was stirred at room temperature for 48 hours, then poured into water (100 mL). The resulting mixture was extracted with ether (3×50 mL). The ether extracts were combined, dried (MgSO4) and concentrated. The resulting amber oil was chromatographed (silica gel, hexane-acetone, 4:1) to give 11 as a yellow oil (0.6 g).
Reaction SMILES: [CH3:1][C:2]1[N+:11]([O-:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]2)=[N+:4]([O-:13])[C:3]=1[C:14]([O:16][CH3:17])=[O:15].[Br:18]Br.CO>CN(C)C=O>[Br:18][CH2:1][C:2]1[N+:11]([O-:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]2)=[N+:4]([O-:13])[C:3]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: BrBr
Reactant: COC(=O)c1c(C)[n+]([O-])c2ccccc2[n+]1[O-]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1c(CBr)[n+]([O-])c2ccccc2[n+]1[O-]
Reaction time: 1.5 h

Procedure:
Methyl 3-methyl-2-quinoxalinecarboxylate-1,4-dioxide (1.2 moles) were suspended in 475 ml of dimethylformamide and 64 ml of bromine was added dropwise with stirring over 1.5 hours while the temperature rose to 42° C. After additional stirring for 48 hours 1.5 liters of methanol were added and stirred for about 1/2 hour. The precipitated product was removed by filtration, washed with water and dried. Yield, 251 grams (68%); m.p. 113°-16° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.[CH3:31][CH2:32][N:33](C(C)C)C(C)C.C(N)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:32]([NH:33][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[CH:20][CH:21]=1)[CH3:31]
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
(S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (75.0 mg, 0.184 mmol) was suspended in DMF (1.0 mL) and DIPEA (0.15 mL) was added followed by ethylamine (30 mg, 0.665 mmol) and HATU (85.0 mg, 0.224 mmol). The reaction mixture was stirred at ambient temperature for 2 h and another portion of HATU (60.0 mg, 0.158 mmol) was added. The reaction mixture was stirred overnight and purified using HPCL (10-75% acetonitrile in water, NH4HCO3 buffered). The fractions were concentrated in vacuo and the resulting residue was crystallized with MeOH-water (1:10, 5 mL) to afford the title compound as a light green solid (24.0 mg, 30%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.09 (t, J=7.20 Hz, 3 H) 1.85-2.01 (m, 3 H) 2.18 (dt, J=5.37, 2.75 Hz, 1 H) 2.43-2.48 (m, 4 H) 3.18-3.28 (m, 6 H) 3.35 (s, 2 H) 3.37-3.45 (m, 1 H) 3.54-3.67 (m, 1 H) 3.94-4.05 (m, 1 H) 6.92 (d, J=9.09 Hz, 2 H) 6.99 (d, J=2.02 Hz, 1 H) 7.62 (d, J=2.02 Hz, 1 H) 7.71 (d, J=9.09 Hz, 2 H) 8.17 (t, J=5.56 Hz, 1 H) 10.44 (s, 1 H); [M+H] calc'd for C24H30N6O2, 435; found, 435.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+].[Br:18][CH2:19][CH2:20][CH2:21]Br>CN(C=O)C.O>[Br:18][CH2:19][CH2:20][CH2:21][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(OCCCBr)cc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A solution of 4-methyl-3-nitrophenol (1.00 g, 6.53 mmol) in DMF (6 mL) was treated with K2CO3 (0.903 g, 6.53 mmol) and 1,3-dibromopropane (6.63 mL, 65.3 mmol) and heated to 100° C. for 2.5 h. The cooled mixture was diluted with water and extracted with DCM. The combined organics were dried (MgSO4), filtered and evaporated before purification by column chromatography (SiO2; eluting with 20% EtOAc in cyclohexane) to afford the desired product V-h as a mobile yellow oil (1.05 g, 59%). 1H NMR (300 MHz, CDCl3) δ 7.52 (d, J=2.7 Hz, 1H), 7.23 (d, J=8.5 Hz, 1H), 7.06 (dd, J=8.5, 2.7 Hz, 1H), 4.14 (t, J=5.8 Hz, 2H), 3.60 (t, J=6.4 Hz, 2H), 2.53 (s, 3H), 2.40-2.24 (m, 2H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1.[H-].[Na+].[CH:10]1([CH2:16][CH2:17]Br)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>O1CCCC1>[CH:10]1([CH2:16][CH2:17][N:1]2[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=Cc1c[nH]cn1
Reactant: BrCCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cn(CCC2CCCCC2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Imidazole-4-carboxaldehyde (4.8 g, 50 mmol) was added portionwise to a suspension of sodium hydride (2.20 g, 60% dispersion in mineral oil, 55 mmol) in tetrahydrofuran (150 ml), and the mixture was then stirred at room temperature for 1 hour. 2-Cyclohexylethyl bromide (8.6 ml, 55 mmol) was added, and the mixture was heated under reflux for 18 hours. The cooled mixture was evaporated under reduced pressure and the residue was partitioned between water (500 ml) and dichlorornethane (500 ml). The layers were separated, and the organic phase was dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of toluene:ethyl acetate (100:0 to 96:4) to afford the title compound, 1.78 g. 1H-NMR (CDCl3, 400 MHz) δ: 0.98 (m, 2H), 1.20 (m, 4H), 1.68 (m, 7H), 4.00 (t, 2H), 7.4 (s, 1H), 7.60 (s, 1H), 9.80 (s, 1H). LRMS: m/z (TSP+) 207.2 [MH+].
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:12][S:13]([NH:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)(=[O:15])=[O:14]>>[NH2:11][C:9]1[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:21]3[CH:22]=[C:17]([NH:16][S:13]([CH3:12])(=[O:14])=[O:15])[CH:18]=[CH:19][CH:20]=3)[N:7]2[N:8]=1
Reactant: Nc1nc2cccc(Br)n2n1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Product: CS(=O)(=O)Nc1cccc(-c2cccc3nc(N)nn23)c1
Yield: 18 %

Procedure:
N-[3-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-phenyl]-methanesulfonamide was prepared from 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (1.80 g, 8.45 mmol) and 3-methylsulfonylaminophenyl boronic acid (2.0 g, 9.30 mmol), in a manner analogous to Step 73c. The residue was purified on an 80 g Isco silica gel column using a gradient of 0-7% methanol in dichloromethane as an eluent. N-[3-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-phenyl]-methanesulfonamide (461 mg, 18%) was isolated as a beige powder. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.94 (s, 1H), 7.72 (s, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.51 (m, 2H), 7.38 (d, J=8.6 Hz, 1H), 7.32 (d, J=7.5 Hz, 1H), 6.97 (d, J=7.5 Hz, 1H), 6.03 (br s, 2H), 3.08 (s, 3H). MS=304 (MH)+. 83b) 5 N-[3-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-phenyl]-methanesulfonamide (162 mg, 0.534 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (150 mg, 0.587 mmol) were combined in a manner analogous to Example 77 to yield N-(3-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-phenyl)-methanesulfonamide TFA salt (13.75 mg, 5%) as a yellow powder following purification via preparative HPLC on a Phenomenex Luna column using 0.1% TFA in MeCN and 0.1% TFA in Water as eluent. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.99 (s, 1H), 9.41 (s, 1H), 7.81 (s, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.64 (t, J=8.3 Hz, 1H), 7.50-7.61 (m, 3H), 7.08-7.42 (m, 3H), 6.93 (d, J=7.2 Hz, 2H), 3.67 (m, 2H), 3.18 (m, 4H), 3.07 (s, 3H), 2.86 (br s, 5H). MS=478 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:6]=2[N:7]=1.Cl.[OH-:23].[Na+]>>[NH2:1][C:2]1[NH:3][C:4](=[O:23])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:6]=2[N:7]=1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(Cl)nc(N)nc21
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(=O)[nH]c(N)nc21

Procedure:
A mixture of product from Step B (90 mg, 0.3 mmol) in aqueous NaOH (2N, 9 mL) was heated at reflux temperature for 5 h, then neutralized at 0° C. with 2 N aqueous HCl and evaporated to dryness. Purification on a silica gel column with CH2Cl2/MeOH, 5/1 as eluent afforded the title compound as a white solid (70 mg).