Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][C:28]2[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[CH:30][C:29]=2[F:36])[C:22]1=[O:37].C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:36][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([O:34][CH3:35])[C:28]=1[CH2:27][N:23]1[CH2:24][CH2:25][CH2:26][CH:21]([NH:20][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:19])[C:22]1=[O:37]
Reactant: Cc1cc(-c2n[nH]c3ccc(C(=O)O)cc23)ccn1
Reactant: COc1cccc(F)c1CN1CCCC(N)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc(F)c1CN1CCCC(NC(=O)c2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)C1=O
Temperature: 23 °C
Reaction time: 16 h

Procedure:
3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxylic acid (50 mg, 0.154 mmol), 3-amino-1-(2-fluoro-6-methoxybenzyl)piperidin-2-one (148 mg, 0.308 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (44.4 mg, 0.231 mmol) and hydroxybenzo-triazole (23.62 mg, 0.154 mmol) were combined in a sealed vial. DMF (0.8 ml) and N,N-diisopropylethylamine (0.269 ml, 1.542 mmol) were added and the reaction mixture stirred for 16 hours at a temperature of 23° C. The residue was then purified by preparative HPLC Normal phase, eluting with dichloromethane/MeOH (0-20%) to give N-(1-(2-fluoro-6-methoxybenzyl)-2-oxopiperidin-3-yl)-3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamide as a colorless solid. MS ESI calc'd. for C27H26FN5O3 [M+H]+488, found 488. 1H NMR (600 MHz, CDCl3) δ 10.80-10.49 (m, 1H), 8.60 (d, J=5.1 Hz, 1H), 8.53 (s, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.73 (s, 1H), 7.67 (d, J=4.9 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 7.46 (s, 1H), 6.75-6.65 (m, 3H), 5.00 (d, J=14.1 Hz, 1H), 4.51 (d, J=14.2 Hz, 1H), 4.49-4.42 (m, 1H), 3.84 (s, 3H), 3.35-3.21 (m, 2H), 2.65 (s, 3H), 1.95-1.82 (m, 2H), 1.65-1.55 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.[C@@H:18]1([NH2:28])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][NH:28][C@@H:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: O=Cc1cccc(Oc2ccc(Cl)c(Cl)c2)c1
Reactant: N[C@H]1CCCc2ccccc21
Product: Clc1ccc(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1Cl

Procedure:
3-(3,4-Dichlorophenoxy)benzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [CH3:1][Mg+].[Br-].CON(C)[C:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([CH3:15])[CH2:11][CH2:10]1)=[O:8]>C1COCC1>[CH3:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([C:7](=[O:8])[CH3:1])[CH2:10][CH2:11]1
Reactant: C[Mg+]
Reactant: CON(C)C(=O)[C@H]1CC[C@H](C)CC1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H](C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
MeMgBr (352 mL, 1.1 mol, 3 mol/L) was added dropwise slowly to a stirred solution of trans-N-methoxy-N,4-dimethylcyclohexanecarboxamide (130 g, 0.7 mol) in THF (1.2 L) at 0° C. The mixture was stirred at room temperature for 2 hours. TLC showed no starting material (petroleum ether/ethyl acetate=5:1) left. The mixture was cooled to 0-5° C., and quenched by the addition of saturated NH4Cl (0.1 L) and H2O (2 L). The mixture was extracted with ethyl acetate twice. The combined organic layer was washed with brine and dried over Na2SO4, filtered and concentrated under reduced pressure to give crude 1-(trans-4-methylcyclohexyl)ethanone, which was used for the next step without further purification. 1H NMR (400 MHz, CDCl3) δ: 2.27-2.19 (m, 1H), 2.10 (s, 3H), 1.90 (d, J=12.8 Hz, 2H), 1.70 (d, J=12.8 Hz, 2H), 1.35-1.23 (m, 3H), 0.96-0.85 (m, 5H).
Reaction SMILES: Cl[C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13]3[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][N:3]=1.[C:23]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>CCCCO>[C:23]([C:27]1[CH:28]=[CH:29][C:30]([NH:31][C:2]2[C:12]3[CH2:11][CH2:10][N:9]([C:13]4[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=4)[CH2:8][CH2:7][C:6]=3[N:5]=[CH:4][N:3]=2)=[CH:32][CH:33]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: FC(F)(F)c1cccnc1N1CCc2ncnc(Cl)c2CC1
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: CCCCO
Product: CC(C)(C)c1ccc(Nc2ncnc3c2CCN(c2ncccc2C(F)(F)F)CC3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a solution of 4-chloro-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine (27 mg, 0.085 mmol) in n-BuOH (1 mL) was added 4-tert-butylaniline (27 μL, 0.17 mmol). After 2 h at 135° C., the mixture was cooled to rt, quenched with saturated aqueous (satd. aq.) NaHCO3, and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified (FCC) to give the title compound (33 mg, 89%). MS (ESI): mass calcd. for C24H26F3N5, 441.21; m/z found, 442.2 [M+H]+. 1H NMR (CDCl3): 8.50 (s, 1H), 8.40-8.37 (m, 1H), 7.90-7.85 (m, 1H), 7.46-7.36 (m, 4H), 6.98-6.93 (m, 1H), 6.45 (s, 1H), 3.70-3.65 (m, 2H), 3.64-3.60 (m, 2H), 3.26-3.20 (m, 2H), 3.02-2.95 (m, 2H), 1.32 (s, 9H). Alternatively, the reaction of this step may be performed in the microwave at 180° C. for 30 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:20](=[O:21])[C:19]3[C:18]([OH:22])=[C:17]4[CH:23]=[CH:24][CH:25]=[CH:26][C:16]4=[C:15]([OH:27])[C:14]=3[C:13]2=[O:28])=[C:8]([Cl:29])[CH:7]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:38][CH3:39]>CC(C)=O>[Cl:29][C:8]1[CH:7]=[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:30])[CH:11]=[CH:10][C:9]=1[N:12]1[C:20](=[O:21])[C:19]2[C:18]([OH:22])=[C:17]3[CH:23]=[CH:24][CH:25]=[CH:26][C:16]3=[C:15]([O:27][CH2:38][CH3:39])[C:14]=2[C:13]1=[O:28]
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(O)c4ccccc4c3O)C2=O)c(Cl)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3O)C2=O)c(Cl)c1
Yield: 56.8 %

Procedure:
To a solution of ethyl[3-chloro-4-(4,9-dihydroxy-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetate (2.0 g, 4.70 mmol) in acetone (50 ml), was added potassium carbonate (0.656 g, 4.75 mmol) followed by iodoethane (0.38 ml, 4.75 mmol). This was heated at reflux for 24 hours. The solvent was evaporated and water added to the residue. The resulting gummy brown solid was collected by filtration and dried in the vacuum oven. This was purified using reverse phase chromatography to give the title compound (1.21 g, 2.67 mmol). LC/MS: Rt=3.66, [MH]+ 454.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([C:16]3[C:21]([O:22]CC4C=CC(OC)=CC=4)=[CH:20][CH:19]=[CH:18][N:17]=3)[C:9](=O)[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[OH-].[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C:8]3[C:16]4[N:17]=[CH:18][CH:19]=[CH:20][C:21]=4[O:22][C:9]=3[C:10]([CH3:14])([CH3:13])[C:11]=2[CH:12]=1
Reactant: COc1ccc(COc2cccnc2C2Cc3ccc(OC)cc3C(C)(C)C2=O)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(C)(C)c1oc3cccnc3c1C2
Temperature: 70 °C
Yield: 49.8 %

Procedure:
To the mixture of 7-methoxy-3-[3-(4-methoxy-benzyloxy)-pyridin-2-yl]-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound GT15-2, 21 mg) and ethyl acetate (0.8 ml), sulfuric acid (0.2 ml) was added. The mixture was stirred and heated at 70° C. for 5 hrs. After cooling, the reaction mixture was neutralized with 2 N aqueous solution of sodium hydroxide. The mixture was diluted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium bicarbonate and saturated brine, and then concentrated under reduced pressure. The resulting residues were purified by silica gel column (ethyl acetate/hexane) to obtain the title compound (7 mg, 50%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([C:11]([O:13][CH3:14])=[O:12])[N:2]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].[CH3:25][Si](C)(C)N[Si](C)(C)C.[Na].CI>C1COCC1>[CH3:25][C:3]1([C:11]([O:13][CH3:14])=[O:12])[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1][N:2]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: COC(=O)C1Cc2ccccc2CN1C(=O)OCc1ccccc1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)Cc2ccccc2CN1C(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
Step-2: To a solution of 2-benzyl 3-methyl 3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate (3 g, 9.23 mmol) in THF (30 mL) at −80° C. was added sodium hexamethyldisilazane (1M, 23.1 mL, 23.1 mmol) and stirred for 20 min. Methyl iodide (1.44 mL, 23.1 mmol) was added and the reaction was allowed to warm to −20° C. and stirred at −20° C. for 6 h. The reaction was quenched with water, neutralized with 2N HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated to afford 2-benzyl 3-methyl 3-methyl-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate. MS (ES+): m/z 340.20 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:18](O)=[O:19])=[CH:11][N:12]([CH3:17])[C:13](=[O:16])[C:14]=2[F:15])=[C:4]([F:21])[CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)[N:41]=[N:40]C=2C=1.NN.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:18]([NH:40][NH2:41])=[O:19])=[CH:11][N:12]([CH3:17])[C:13](=[O:16])[C:14]=2[F:15])=[C:4]([F:21])[CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(Br)cc2F)c(F)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1cc(C(=O)NN)c(Nc2ccc(Br)cc2F)c(F)c1=O
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A mixture of 4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (70 mg, 0.195 mmol), EDCl (112 mg, 0.585 mmol), and HOBt (79 mg, 0.585 mmol) in DMF (3 mL) was stirred for 30 minutes. Hydrazine (19 mg, 0.585 mmol) was added followed by Et3N (0.082 mL, 0.585 mmol). After 3 hours, the reaction mixture was diluted with EtOAc and washed with saturated NH4Cl solution, saturated NaHCO3 solution and brine. The organic layer was dried (MgSO4) and concentrated to yield 64 mg (89%) desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]=[C:13]=[S:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[CH:22][CH:21]=[C:20]2[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[C:32]([CH3:37])[CH:31]=1.C1(C)C=CC=CC=1>C(O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[CH:22][CH:21]=[C:20]2[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH:34][C:13]([NH:12][C:10](=[O:11])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[S:14])=[C:32]([CH3:37])[CH:31]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Reactant: O=C(N=C=S)c1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc([N+](=O)[O-])cc4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.9 %

Procedure:
Commercially available 4-nitro-1-benzenecarbonyl isothiocyanate (30 mg) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (41 mg, yield 49%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[C:10]([C:23]2[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH:28]=2)=[C:11]([NH:15]C(=O)OC(C)(C)C)[CH:12]=[N:13][CH:14]=1>C(Cl)Cl>[F:8][C:9]1[C:10]([C:23]2[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH:28]=2)=[C:11]([NH2:15])[CH:12]=[N:13][CH:14]=1
Reactant: CN1CC=C(c2c(F)cncc2NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CC=C(c2c(N)cncc2F)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 19 %

Procedure:
TFA (2 mL, 25.96 mmol) was added to a stirred solution of tert-butyl N-[5-fluoro-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-3-pyridyl]carbamate (483 mg, 1.571 mmol) in DCM (10 mL) and the reaction stirred at ambient temperature for 6 hours. The solvent was removed in vacuo and the residue azeotroped with DCM (×2) and ether (×2). The residue was passed through a 10 g SCX-2 cartridge and washed with MeOH/DCM mixtures. The product was eluted by washing the cartridge with 2M NH3 in MeOH/DCM mixtures and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 40 g column, eluting with 0 to 10% MeOH/DCM+1% NH4OH, loaded in DCM) to give 5-fluoro-1′-methyl-1′,2′,3′,6′-tetrahydro-[4,4′-bipyridin]-3-amine as an off-white solid (61 mg, 19% Yield over 2 steps). MS (ES+) 208.1.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:19][C:20]1[C:28]2[CH:27]=[CH:26][C:25]([F:29])=[CH:24][C:23]=2[N:22]2[CH2:30][CH2:31][N:32]3[C:40]4[C:35](=[CH:36][CH:37]=[C:38]([F:41])[CH:39]=4)[C:34]([CH2:42][CH:43]4[CH2:47][CH2:46][CH2:45][N:44]4[C:48](=[O:61])[CH:49]([NH:53]C(OC(C)(C)C)=O)[CH:50]([CH3:52])[CH3:51])=[C:33]3[C:21]=12)=[O:13])[CH:9]([CH3:11])[CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]([CH:9]([CH3:11])[CH3:10])[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:19][C:20]1[C:28]2[CH:27]=[CH:26][C:25]([F:29])=[CH:24][C:23]=2[N:22]2[CH2:30][CH2:31][N:32]3[C:40]4[C:35](=[CH:36][CH:37]=[C:38]([F:41])[CH:39]=4)[C:34]([CH2:42][CH:43]4[CH2:47][CH2:46][CH2:45][N:44]4[C:48](=[O:61])[CH:49]([NH2:53])[CH:50]([CH3:52])[CH3:51])=[C:33]3[C:21]=12)=[O:13]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)N1CCCC1Cc1c2n(c3cc(F)ccc13)CCn1c-2c(CC2CCCN2C(=O)C(NC(=O)OC(C)(C)C)C(C)C)c2ccc(F)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(N)C(=O)N1CCCC1Cc1c2n(c3cc(F)ccc13)CCn1c-2c(CC2CCCN2C(=O)C(N)C(C)C)c2ccc(F)cc21
Temperature: 0 °C

Procedure:
A solution containing 30 (1.09 g, 1.27 mmol) in DCM (20 mL) was cooled to 0° C. TFA (4 mL) was added via pipette and the reaction was monitored until TLC analysis revealed complete consumption of 30 (˜2 h). TLC analysis, 10% MeOH/DCM, Rf(30)=0.5; Rf(31)=0.4. The solvent was removed on a rotary evaporator and the residue was dissolved in EtOAc. The EtOAc solution was washed twice with saturated aqueous NaHCO3 and once with brine. The combined aqueous washes were back-extracted with EtOAc and the organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to afford 0.83 g (quant.) of 31 as a yellow solid which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ8.09 (dd, J=5.1, 8.7 Hz, 1H), 6.97 (m, 2H), 4.52 (m, 1H), 4.50 (d, J=8.7 Hz, 1H), 4.11 (m, 1H), 3.71 (br d, J=11.1 Hz, 1H), 3.51-3.32 (m, 2H), 2.74 (app t, J=12.6 Hz, 1H), 2.30 (br s, 4H), 1.92 (m, 1H), 1.68 (m, 2H), 1.41 (m, 1H), 1.03 (m, 6H) ppm. 13C NMR (CDCl3, 75 MHz) δ174.3, 171.4, 160.6 (d, JC-F=232.5 Hz), 136.8 (d, JC-F=7.5 Hz), 127.4 (d, JC-F=3.7 Hz), 125.0, 122.4 (d, JC-F=7.5 Hz), 109.6, 108.7 (d, JC-F=22.5 Hz), 95.2 (d, JC-F=22.5 Hz), 58.0, 47.3, 41.9, 30.0, 28.5, 28.5, 24.1, 19.9, 17.6 ppm.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:16](=[O:23])[NH:17][CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].O>ClCCl>[CH3:6][NH:7][C@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]([NH:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[O:23]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)NCC(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccccc1)C(=O)NCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 45.4 %

Procedure:
N-Methyl-N-((1R)-2-phenyl-1-((2,2,2-trifluoroethyl)carbamoyl)ethyl)carbamic acid tert-butyl ester (3.45 g, 9.57 mmol) was dissolved in dichloromethane (8 ml). The solution was cooled to 0° C. Trifluoroacetic acid (8 ml) was added. The reaction mixture was stirred for 45 min at 0° C. A saturated aqueous solution of sodium hydrogen carbonate (40 ml) was added. Solid sodium hydrogen carbonate was added until pH 7. Water (100 ml) was added, until a clear solution was obtained. The phases were separated. The aqueous phase was extracted with dichloromethane (3×30 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (180 g), using dichloromethane/methanol/25% aqueous ammonia as eluent to give 1.13 g of (2R)-2-methylamino-3-phenyl-N-(2,2,2-trifluoroethyl)propionamide.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:15][CH:10]([O:11]C(=O)C)[C@H:9]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:8]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:7]1[Cl:34])(=[O:3])[CH3:2].C(O)(=O)C.NN>CN(C=O)C>[C:1]([O:4][CH2:5][C@H:6]1[O:15][CH:10]([OH:11])[C@H:9]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:8]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:7]1[Cl:34])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1Cl
Agent: NN
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1OC(O)[C@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1Cl
Yield: 95.3 %

Procedure:
A solution of acetyl 6-O-acetyl-2,3-di-O-benzoyl-4-chloro-4-deoxy-D-galactopyranoside (68) (8.53 g, 17.4 mmol) and hydrazine acetate (2.4 g, 26.0 mmol, 1.5 eq) in 70 mL of DMF was stirred for 1 hour at room temperature. The reaction mixture was then evaporated, washed with water (5 times) and evaporated. The residue was chromatographed on a silica gel, eluting with hexane-ethyl acetate (2:1), to provide 6-O-acetyl-2,3-di-O-benzoyl-4-chloro-4-deoxy-D-galactopyranose (7.44 g, 95.3%). This material was dissolved in dichloromethane (50 mL) and the resulting solution was cooled to 0° C. Trichloroacetonitrile (8.3 mL, 82.9 mmol) was added and the mixture was stirred for 2 hours. The solvent was then evaporated and the residue was chromatographed on a silica gel column, eluting with hexane-ethyl acetate (3:1), to give imidate 69 (6.3 g, 64%).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:7][C:5]=1[NH2:6])([O-])=O.Cl>[Fe].C(O)C>[F:11][C:9]1[C:8]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:7][C:5]([NH2:6])=[C:4]([NH2:1])[CH:10]=1
Reactant: Nc1cc(N2CCCC2)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: Nc1cc(F)c(N2CCCC2)cc1N
Yield: 97.8 %

Procedure:
The nitroaniline derivative (5.0 g, 0.022 mol) (obtained in step 1 above) was reduced using Fe powder (12.6 g, 0.22 mol), conc. HCl (33 mL) and ethanol (33 mL) as described in preparation 10 (step 2) to yield 4-fluoro-5-(pyrrolidin-1-yl)-1,2-phenylenediamine (4.2 g, 97%) as viscous oil. IR (Neat) 3340, 1524 cm-1 ; 1H NMR (CDCl3) δd 1.93 (m, 4H, (CH2)2), 3.24 (m, 4H, N(CH2)2), 3.56 (brs, 4H, 2×NH2), 6.18 (d, J=7.2 Hz, 1H), 6.48 (d, J=13.2 Hz, 1H); Mass (m/z) 195 (M+.).
Reaction SMILES: Br[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]=3[Cl:21])[N:10]=[C:6]2[C:5]([F:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26][N:25]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:21][C:12]1[CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[CH:15]=[C:16]([Cl:17])[C:11]=1[N:9]1[CH:8]=[C:7]2[C:2]([NH:23][C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26][N:25]=3)=[N:3][CH:4]=[C:5]([F:22])[C:6]2=[N:10]1
Reactant: Cc1cc(N)ncn1
Reactant: O=[N+]([O-])c1cc(Cl)c(-n2cc3c(Br)ncc(F)c3n2)c(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cc([N+](=O)[O-])cc4Cl)cc23)ncn1
Temperature: 150 °C
Yield: 81.3 %

Procedure:
A mixture of 4-bromo-2-(2,6-dichloro-4-nitrophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine (200 mg, 0.49 mmol), 4-amino-6-methylpyrimidine (60 mg, 0.55 mmol), Pd2(dba)3 (11 mg, 0.012 mmol), Xantphos (28 mg, 0.049 mmol) and cesium carbonate (321 mg, 0.99 mmol) in dioxane (3 mL) was de-gassed and purged with nitrogen. The reaction mixture was heated at 150° C. in the microwave for 30 minutes. The resultant mixture was partitioned between ethyl acetate and water. The aqueous layer was further extracted with ethyl acetate (×4) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (50-100% ethyl acetate in cyclohexane) to afford the title compound as a pale yellow solid (173 mg, 72% yield). 1H NMR (300 MHz, CDCl3): δ 8.69 (s, 1H), 8.44-8.40 (m, 3H), 8.25 (s, 1H), 7.91 (d, J=3.2 Hz, 1H), 7.80 (br s, 1H), 2.55 (s, 3H).
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][CH2:8][C:9]([OH:11])=O)=[O:6])[CH:2]=[CH2:3].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:37][CH2:38][C:39]1[N:40]2[CH:46]=[N:45][CH:44]=[C:41]2[S:42][CH:43]=1>CN(C=O)C.ClCCl>[CH2:1]([O:4][C:5]([NH:7][CH2:8][C:9]([NH:37][CH2:38][C:39]1[N:40]2[CH:46]=[N:45][CH:44]=[C:41]2[S:42][CH:43]=1)=[O:11])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)NCC(=O)O
Reactant: NCc1csc2cncn12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCOC(=O)NCC(=O)NCc1csc2cncn12

Procedure:
A 5 ml portion of a dichloromethane solution containing 307 mg of N-allyloxycarbonyl glycine was cooled on ice, and 287 mg of 1-hydroxybenzotriazole and 438 mg of 1,3-dicyclohexylcarbodiimide were further added to the cooled mixture, followed by stirring under ice-cooling for 2 hours. Further, 5 ml of dichloromethane containing 3-aminomethylimidazo[5,1-b]thiazole and 10 ml of DMF were added thereto, and dichloromethane was then evaporated under reduced pressure, followed by stirring at room temperature for 1.5 hours. To the reaction solution, a saline solution was added, and extraction was then carried out three times with ethyl acetate. Afterward, the resulting organic layer was dried over anhydrous magnesium sulfate, and after the removal of the drying agent by filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by a silica gel column chromatograph to obtain 387 mg of the title compound.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[C:25]1([NH:31]N)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:23][S:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)(=[O:22])=[O:21]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: NNc1ccccc1
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)c1
Yield: 47 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and phenylhydrazine according to the method described for Example 1 in 47% yield. MS: M=393.0 (M+H)+