Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]2[O:10][CH2:11][O:12][C:8]=2[C:7]=1[C:15]1[C:16]2[NH:23][CH:22]=[C:21]([C:24]([OH:26])=O)[C:17]=2[N:18]=[CH:19][N:20]=1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([NH:40][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:4][CH2:3][O:2][CH3:1])[C:16]=3[NH:23][CH:22]=2)=[O:26])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)O)c[nH]c13)OCO2
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A72) and commercially available 4-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound was obtained as colorless solid.
Reaction SMILES: C1C=CC2N(O)N=[N:7]C=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.CCN(C(C)C)C(C)C.[I:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH:40]([CH2:44][CH3:45])[C:41](O)=[O:42].C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CN(C=O)C>[I:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH:40]([CH2:44][CH3:45])[C:41]([NH2:7])=[O:42]
Reactant: On1nnc2ccccc21
Reactant: CCC(C(=O)O)c1ccccc1I
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(C(N)=O)c1ccccc1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
HOBt (325 mg, 2.40 mmol), EDCl.HCl (461 mg, 2.40 mmol) and DIPEA (1.40 mL, 8.02 mmol) were added to a stirred solution of 2-(2-iodophenyl)butanoic acid (I1) (465 mg, 1.60 mmol) in dry THF (6 mL) and dry DMF (1 mL) under an atmosphere of nitrogen. After 10 minutes ammonium carbonate (770 mg, 8.02 mmol) was added in one portion and the resulting mixture stirred at room temperature for 24 hours. The volatiles were removed in vacuo and EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL) were added to the residue. The aqueous phase was extracted with EtOAc (2×50 mL), then the combined organic extracts were washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the resulting solid was purified by silica gel column chromatography (Biotage Isolera, SiO2 cartridge, 0-50% EtOAc in petroleum benzine 40-60° C.) to give the title compound I2 as a white solid (398 mg, 86%); NMR (400 MHz, d6-DMSO) δ 7.85 (dd, J=7.9, 1.2 Hz, 1H), 7.46 (dd, J=7.8, 1.7 Hz, 1H), 7.39 (s, 1H), 7.35 (td, J=7.6, 1.2 Hz, 1H), 7.02-6.92 (m, 2H), 3.59 (dd, J=8.8, 6.0 Hz, 1H), 1.92-1.78 (m, 1H), 1.65-1.51 (m, 1H), 0.86 (t, J=7.3 Hz, 3H). LCMS-A: rt 5.463 min; m/z 290 [M+H]+.
Reaction SMILES: CN(C=O)C.CS(C)=O.[S:10](Cl)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[CH3:21][O:22][C:23](=[O:38])[C@H:24]([CH2:36][OH:37])[NH:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].C(N(CC)CC)C>CN(C=O)C>[CH2:29]([O:28][C:26]([NH:25]/[C:24](=[CH:36]\[O:37][S:10]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11])/[C:23]([O:22][CH3:21])=[O:38])=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)/C(=C/OS(=O)(=O)c1ccc(C)cc1)NC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 92.5 %

Procedure:
To a pre-cooled (−30° C.) solution of DMF:DMSO (1:1, 200 mL) under nitrogen was added TsCl (76.3 g, 0.4 mol) in small portions over 30 min. NOTE: This reaction is highly exotermic and careful temperature control is essential! The solution was stirred at −10° C. for 10 min, then again taken to −30° C. A solution of cbz-L-serine methyl ester (20.3 g, 0.08 mol, CAS 1676-81-9) in DMF was added dropwise, again with careful temperature control. After stirring for 10 min at −30° C. triethylamine (110 mL, 0.79 mol) was added and the reaction was slowly taken to 0° C. and kept at this temperature for 2 h. The reaction was quenched by addition of ice-cold water. The solution was extracted with 3×EtOAc, then the combined organic layer was washed extensively with brine and water. Drying and evaporation gave product as yellow oil (30 g, 94%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[CH:17][O:16][CH:15]=2)=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:23][C:24](=O)[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=1)=[O:27])C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[CH:17][O:16][CH:15]=2)=[CH:10][C:9]=1[NH:19][C:24](=[O:23])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=1)=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccoc2)cc1N
Reactant: CCOC(=O)CC(=O)c1cccc(C#N)c1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccoc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
Prepared from (2-amino-4-furan-3-yl-phenyl)-carbamic acid tert.-butyl ester (Example G11) and 3-(3-cyano-phenyl)-3-oxo-propionic acid ethyl ester (Pol. J. Chem. 1978, 25) according to the general procedure K. Obtained as an orange solid (460 mg).
Reaction SMILES: Cl.O1CCOCC1.[NH2:8][C:9]([C:11]1[CH:16]=[C:15]([Cl:17])[N:14]=[C:13]([N:18]2[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:31])OC(C)(C)C)[CH2:20][CH2:19]2)[CH:12]=1)=[O:10].[Br:32][C:33]1[CH:34]=[C:35](C(OC2C(F)=C(F)C(F)=C(F)C=2F)=O)[NH:36][C:37]=1[CH3:38].C(N(CC)C(C)C)(C)C.Cl.NC1CCN(C2C=C(C=C(Cl)N=2)C(N)=O)CC1>CC(N(C)C)=O>[Br:32][C:33]1[CH:34]=[C:35]([C:25]([NH:24][CH:21]2[CH2:20][CH2:19][N:18]([C:13]3[CH:12]=[C:11]([CH:16]=[C:15]([Cl:17])[N:14]=3)[C:9]([NH2:8])=[O:10])[CH2:23][CH2:22]2)=[O:31])[NH:36][C:37]=1[CH3:38]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(C(N)=O)cc(Cl)n2)CC1
Reactant: Cc1[nH]c(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1Br
Agent: Cl
Agent: NC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(N)=O)cc(Cl)n3)CC2)cc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 22.5 %

Procedure:
4 N HCl/dioxane solution (10 ml) was added to tert-butyl 1-[4-(aminocarbonyl)-6-chloropyridin-2-yl]piperidin-4-ylcarbamate (Intermediate 16, 100 mg, 0.282 mmol). The mixture was stirred at room temperature for 90 minutes. The solvent was removed in vacuo and the anhydrous diethylether (25 ml) was added. The solvent was removed in vacuo and light brown solid that resulted was dried under vacuum for several hours. LCMS indicated a pure product 2-(4-aminopiperidin-1-yl)-6-chloroisonicotinamide hydrochloride salt (MS M+H:255). Pentafluorophenyl 4-bromo-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 17) (104 mg, 0.282 mmol), and N,N-diisopropyl ethylamine (98 μl, 0.564 mmol) were added to 2-(4-aminopiperidin-1-yl)-6-chloroisonicotinamide hydrochloride salt (82 mg, 0.282 mmol) in anhydrous DMA (4 ml). The mixture was stirred at room temperature 18 h and was filtered and purified by semi-preparative HPLC using CH3CN/H2O (0.1% TFA) to give the title compound (28 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N+:11]([O-])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(OC(=O)C)(=[O:17])C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:17])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: [O-][n+]1ccc(-c2ccc(Cl)cc2)cc1
Product: O=c1cc(-c2ccc(Cl)cc2)cc[nH]1
Yield: 48 %

Procedure:
4-(4-Chlorophenyl)pyridine 1-oxide (1.04 g, 5.07 mmol) and acetic anhydride (25 mL) were heated to reflux for 24 h. The mixture was then concentrated, and 1 N NaOH (10 mL) in MeOH (10 mL) was added. The reaction mixture was heated to reflux for 1 h, then cooled, concentrated, and purified by flash column chromatography (silica gel, methylene chloride/MeOH 100:0 to 98:2 to 95:5 then 90:10) providing the title compound (500 mg, 48%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 11.64 (s, 1H), 7.73 (d, J=8.6 Hz, 2H), 7.54 (d, J=8.6 Hz, 2H), 7.46 (d, J=6.8 Hz, 1H), 6.60 (d, J=1.4 Hz, 1H), 6.50 (dd, J=6.9, 1.8 Hz, 1H).
Reaction SMILES: C(OC([NH:11][C:12]1[C:13](=[O:26])[N:14]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:15]=[CH:16][CH:17]=1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C:12]1[C:13](=[O:26])[N:14]([CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)Cn1cccc(N)c1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2.00 g of tert-butyl 2-(3-(benzyloxycarbonylamino)-2-oxopyridin-1(2H)-yl)acetate are dissolved under nitrogen atmosphere in 70 mL of ethanol. To this solution 200 mg of Pd/C (10%) is added and stirred under hydrogen atmosphere at atmosphere pressure for 1.5 h at RT. The catalysis is separated by filtration over silica gel, before the solvent is removed in vacuo. The crude product is used for further processing without purification.
Reaction SMILES: C([O:8][C:9](=[O:45])[CH2:10][C@H:11]([NH:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[C:12]([NH:14][C:15]1[CH:20]=[C:19]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:32])[NH:24][N:23]=2)[CH:18]=[CH:17][C:16]=1[F:33])=[O:13])C1C=CC=CC=1.CC1C=CC(COC(NNC(C2C=NC=CN=2)=O)=O)=CC=1>C(=O)([O-])[O-].[Na+].[Na+]>[CH2:38]([O:37][C:35]([NH:34][C@H:11]([C:12]([NH:14][C:15]1[CH:20]=[C:19]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:32])[NH:24][N:23]=2)[CH:18]=[CH:17][C:16]=1[F:33])=[O:13])[CH2:10][C:9]([OH:45])=[O:8])=[O:36])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(C[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)OCc1ccccc1
Agent: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.1 %

Procedure:
A mixture of the above crude (S)-3-benzyloxycarbonylamino-N-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]succinamic acid benzyl ester (0.57 g) and saturated aqueous sodium carbonate solution (pH 9; 10 ml) was stirred at ambient temperature for 72 hours. The pH of the mixture was adjusted to pH10 by the addition of further saturated aqueous sodium carbonate solution, then the mixture was stirred at 70° C. for 4 hours until a clear solution was obtained. The cooled solution was washed with ethyl acetate (2×5 ml) and the aqueous layer was acidified by the addition of 10% hydrochloric acid. The resulting solid was collected by filtration and dried in vacuo to give (S)-3-benzyloxycarbonylamino-N-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]succinamic acid (0.35 g) as an off-white solid, m.pt. 188–190° C., which was used without further purification.
Reaction SMILES: [NH3:1].O.[CH2:3]([CH:7]1[CH2:13][C:12](=[O:14])[O:11][C:9](=[O:10])[CH2:8]1)[CH:4]([CH3:6])[CH3:5]>C(OC)(C)(C)C>[C:9]([CH2:8][CH:7]([CH2:3][CH:4]([CH3:6])[CH3:5])[CH2:13][C:12]([OH:11])=[O:14])(=[O:10])[NH2:1]
Reactant: CC(C)CC1CC(=O)OC(=O)C1
Reactant: N
Solvent: COC(C)(C)C
Solvent: O
Product: CC(C)CC(CC(N)=O)CC(=O)O
Temperature: 15 °C

Procedure:
Aqueous ammonia (308 g of 28% ammonium hydroxide, 5.06 mol), water (431 g), and methyl tert-butyl ether (200 g) are combined and cooled to 15° C. 3-Isobutylglutaric acid anhydride is added and the reaction mixture is allowed to warm to 50° to 60° C. The reaction mixture is cooled to 20°-25° C. The solvent is evaporated and the pH of the solution is adjusted to 1.0 with concentrated hydrochloric acid. Water (200 mL) is added and the mixture is filtered. The solid is washed with water (200 mL). The solid is dried under reduced pressure to give 408 g of (±)-3-(carbamoylmethyl)-5-methylhexanoic acid as an off-white solid. (±)-3-(Carbamoylmethyl)-5-methylhexanoic acid has a melting point in the range of about 107.5° to about 108.5° C. 1H-NMR (DMSO-d6, 200 MHz): δ0.84 (d, 6H, J=6.5 Hz), 1.07-1.17 (m, 2H), 1.50-1.72 (m, 1H), 1.98-2.25 (m, 5H), 6.75 (s, 1H), 7.30 (s, 1H), 11.6 (s, 1H). IR (KBr): 592.0, 655.7, 700.0, 1010.5, 1133.9, 1214.9, 1241.9, 1278.6, 1294.0, 1427.1, 1461.8, 1585.2, 1668.1, 1700.9, 2514.7, 2622.7, 2962.1, 3220.5, 3367.1 cm-1.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:17]([C:18](OCC)=[O:19])=[N:16][N:15]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:14](=[O:29])[C:9]=3[N:10]([CH3:13])[C:11]=2[CH:12]=1.CO>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:17]([CH2:18][OH:19])=[N:16][N:15]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:14](=[O:29])[C:9]=3[N:10]([CH3:13])[C:11]=2[CH:12]=1
Reactant: CCOC(=O)c1nn(-c2ccccc2)c(=O)c2c1c1ccc(Cl)cc1n2C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c2cc(Cl)ccc2c2c(CO)nn(-c3ccccc3)c(=O)c21

Procedure:
2.5 g (66.1 mmol) of sodium borohydride are added to a solution of 4.04 g (10.6 mmol) of ethyl 7-chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxylate in 150 ml of tetrahydrofuran. 2.25 ml of methanol are then gradually added, with stirring, and then the mixture is heated under reflux for 5 h.
Reaction SMILES: [N:1]1([C:6]2[CH:15]=[CH:14][C:9]([C:10](=O)[CH2:11]Br)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][N:18]=1>C(#N)C>[I:23][C:20]1[CH:21]=[CH:22][C:17]2[N:18]([CH:11]=[C:10]([C:9]3[CH:14]=[CH:15][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[CH:2]4)=[CH:7][CH:8]=3)[N:16]=2)[CH:19]=1
Reactant: O=C(CBr)c1ccc(-n2cccc2)cc1
Reactant: Nc1ccc(I)cn1
Solvent: CC#N
Product: Ic1ccc2nc(-c3ccc(-n4cccc4)cc3)cn2c1
Temperature: 25 °C
Yield: 68.7 %

Procedure:
120 mg (corresponding to 0.454 mmol) of 4-(1H-pyrrole-1-yl)phenacylbromide and 99.9 mg (corresponding to 0.454 mmol) of 2-amino-5-iodopyridine were dissolved in 2.0 mL of acetonitrile. The resulting solution was heated under reflux for 2 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 10 mL of water and 10 mL of methanol. Then, about 20 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 20 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 120 mg (corresponding to 0.312 mmol) of 6-iodo-2-[4-(1H-pyrrole-1-yl)phenyl]imidazo[1,2-a]pyridine (FIG. 2, step 2).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[N:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH2:23][CH2:24][CH3:25])[NH:10][C:11](=[O:14])[C:12]=1[NH2:13].[CH:26](N)=O>>[CH2:22]([O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:9]1[N:8]=[C:7]2[C:12](=[N:13][CH:26]=[N:6]2)[C:11](=[O:14])[N:10]=1)[CH2:23][CH2:24][CH3:25]
Reactant: NC=O
Reactant: CCCCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Agent: O=S(=O)(O)O
Product: CCCCOc1ccccc1C1=NC(=O)C2=NC=NC2=N1

Procedure:
In a similar manner to Example 1 reaction of 4,5-diamino-2-(2-butoxyphenyl)pyrimidin-6-one sulphate (1.5 g) with formamide (5 ml) afforded the title compound, 0.65 g, m.p. 247°-248° C., (recrystallised from ethanol).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[CH:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].Br.Br[CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C(OCC)(=O)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.O>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[N:8]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:9]=[CH:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)OCC=N2
Reactant: BrCc1cccnc1
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)OC=CN2Cc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
To a dry reaction flask equipped with a reflux condenser, a magnetic stirring bar and a rubber septum with a N2 inlet was placed 7-nitrobenz[1,4]oxazine (1.0 g, 5.55 mmol), tetrabutyl ammonium chloride (56 mg), powdered NaOH (0.58 g) in dry DMF (10 mL). The reaction mixture was stirred at room temperature for 30 minutes. 3-(Bromomethyl)-pyridine hydrobromide (1.40 g, 5.55 mmol) was added. The reaction mixture was heated at 80° C. for over night, cooled to room temperature, poured in water (200 mL), left aside for 2 h, added ethyl acetate (200 mL). The organic layer was washed with water (2×200 mL), brine (200 mL), dried (Na2SO4) and concentrated. The solid was purified by silica gel column, eluted with EtOAc to give 0.67 g (44%) of the desired 7-nitro-4-(3-pyridylmethyl)benz[1,4]oxazine. 1H NMR (CDCl3, 300 MHz): δ 8.56 (d, 1H, J=4.8 Hz), 8.53 (s, 1H), 7.72 (m, 2H), 7.53 (m, 1H), 7.28 (dd, 1H, J=5.1 and 7.8 Hz), 6.57 (d, 1H, J=9.0 Hz), 4.61 (s, 2H), 4.29 (t, 2H, J=4.2 Hz), 3.59 (t, 2H, J=4.5 Hz); LCMS (m/z): 272 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:13]C(=O)OC(C)(C)C)([CH3:12])[CH2:9][NH:10][CH3:11])[CH:5]=[CH:6][CH:7]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH2:13])([CH3:12])[CH2:9][NH:10][CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CNCC(C)(NC(=O)OC(C)(C)C)c1cccc(Br)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCC(C)(N)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
tert-Butyl 2-(3-bromophenyl)-1-(methylamino)propan-2-ylcarbamate (CD3; R1=Me, R4=Me) (0.62 g, 1.8 mmol) was dissolved in 25% TFA in DCM (25 mL) and the mixture was left stirring at RT for 1 h. The mixture was concentrated in vacuo and the residue was redissolved in CHCl3 (20 mL). The solution was washed with 15% NaOH (10 mL) and the aqueous layer was extracted with CHCl3 (3×10 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo to give 0.33 g (76%) of crude 2-(3-bromophenyl)-N1-methylpropan-1,2-diamine as a colorless oil. 1H NMR (CDCl3) δ 7.65 (t, J=1.7 Hz, 1H), 7.41-7.34 (m, 2H), 7.21 (t, J=7.8 Hz, 1H), 2.86 (dd, J=11.7, 0.6 Hz, 1H), 2.64 (dd, J=11.7, 0.6 Hz, 1H), 2.38 (s, 3H), 1.54 (bs, 3H), 1.43 (s, 9H). MS (ESI) m/e 242.9 (M+H)+. The compound was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH:18]1([CH2:21][CH2:22][NH:23][C:24]([C:26]2[N:27]=[N:28][C:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[CH:30][CH:31]=2)=[O:25])[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][CH2:22][NH:23][C:24]([C:26]2[N:27]=[N:28][C:29]([N:32]3[CH2:37][CH2:36][N:35]([C:5](=[O:6])[C:4]4[CH:8]=[CH:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:3]=4[C:2]([F:17])([F:16])[F:1])[CH2:34][CH2:33]3)=[CH:30][CH:31]=2)=[O:25])[CH2:20][CH2:19]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1C(F)(F)F
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 2,4-bis-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (29% yield). 1H NMR (400 MHz, CDCl3) δ 8.08, 8.02-7.98, 7.91, 7.54, 7.03, 3.97-3.86, 3.85-3.72, 3.57, 3.36, 1.52, 0.77-0.74, 0.49-0.46, 0.12-0.09.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([NH:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:19])=[CH:16][CH:15]=3)[N:11]=[C:10]([C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=3)[CH:9]=2)=[CH:4][CH:3]=1.[C:36]1(B(O)O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:2]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([NH:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:19])=[CH:16][CH:15]=3)[N:11]=[C:10]([C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCNC(=O)c1ccc(Cn2nc(-c3cc(Cl)cc(Cl)c3)cc2-c2ccc(Br)cc2)cc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)CCNC(=O)c1ccc(Cn2nc(-c3cc(Cl)cc(Cl)c3)cc2-c2ccc(-c3ccccc3)cc2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of the intermediate from example 79 step F (50 mg, 0.079 mmol) in toluene (1 mL) was added phenyl boronic acid (10 mg, 0.079 mmol), Na2CO3 solution (2.0M, 79 uL) and tetrakis triphenyl phosphine palladium (0) (5 mg, 0.003 mmol). The resulting mixture was placed in the CEM microwave instrument for 10 min at a temperature of 100° C. and power 150 W. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 3:10 ethyl acetate-hexanes to give the desired product, a colorless oil. To a solution of this material in DCM (2 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and lyophilized from acetonitrile-water to give the title compound. 1H NMR (DMSO, 500 MHz): δ 8.5 (t, J=5.5 Hz, 1H), 7.91 (d, J=1.9 Hz, 2H), 7.81 (d, J=8.2 Hz, 2H), 7.78 (d, J=8.5 Hz, 2H), 7.74 (d, J=7.3 Hz, 2H), 7.58 (m, 3H), 7.51 (t, J=7.6 Hz, 2H), 7.42 (t, J=7.6 Hz, 1H), 7.25 (s, 1H), 7.15 (d, J=8.2 Hz, 2H), 5.56 (s, 2H), 3.45 (q, J=7.1 Hz, 2H), 2.47 (t, J=7.1 Hz, 2H). LC-MS: 2.73 min; (M+H)=570.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][CH2:34][CH2:35][CH2:36][F:37]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][N:5]([S:15]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:33][CH2:34][CH2:35][CH2:36][F:37])=[CH:22][CH:23]=1)(=[O:17])=[O:16])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1
Reactant: FCCCCBr
Reactant: COC(=O)CN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(OCCCCF)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 1 g (2.74 mmol) of [(4-hydroxy-benzenesulfonyl)-(4-methoxy-benzyl)-amino]-acetic acid methyl ester and 1.14 g (8.22 mmol) of K2CO3 in 8 ml of DMF, 0.59 ml (5.47 mmol) of 1-bromo-4-fluorobutane is added dropwise at r.t. After stirring for 18 h at r.t., the reaction mixture is diluted with H2O and extracted with AcOEt. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (AcOEt:n-hexane=3:1) to give {[4-(4-fluorobutoxy)-benzenesulfonyl](4-methoxy-benzyl)-amino}-acetic acid methyl ester; NMR (CDCl3): 1.86–1.96 (m, 4H), 3.57 (s, 3H), 3.79 (s, 3H), 3.90 (s, 2H), 4.08 (t, 2H, J=6.04 Hz), 4.39 (s, 2H), 4.46 (t, 1H, J=6.04 Hz), 4.55–4.65 (m, 1H), 6.83 (d, 2H, J=8.56 Hz), 6.97 (d, 2H, J=9.08 Hz), 7.15 (d, 2H, J=8.56 Hz), 7.82 (d, 2H, J=9.08 Hz).