Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(C)(C)C.[N:5]([CH2:8][C:9]1[N:10]=[N:11][C:12]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])=[CH:13][CH:14]=1)=[N+]=[N-].[Si:23]([O:30][C@@H:31]1[C@@H:36]([CH3:37])[CH2:35][N:34]([C:38]2[CH:43]=[CH:42][N:41]=[CH:40][C:39]=2[N:44]=[C:45]=S)[CH2:33][C@H:32]1[NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C1COCC1.CCOC(C)=O>[Si:23]([O:30][C@@H:31]1[C@@H:36]([CH3:37])[CH2:35][N:34]([C:38]2[CH:43]=[CH:42][N:41]=[CH:40][C:39]=2[NH:44][C:45]2[N:10]3[N:11]=[C:12]([C:15]4[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=4[F:22])[CH:13]=[CH:14][C:9]3=[CH:8][N:5]=2)[CH2:33][C@H:32]1[NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:24])[CH3:25]
Reactant: [N-]=[N+]=NCc1ccc(-c2c(F)cccc2F)nn1
Reactant: C[C@H]1CN(c2ccncc2N=C=S)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H]1CN(c2ccncc2Nc2ncc3ccc(-c4c(F)cccc4F)nn23)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.6 %

Procedure:
PMe3 (1.0 M solution in THF) (0.95 mL, 0.95 mmol) was added dropwise to a solution of 3-(azidomethyl)-6-(2,6-difluorophenyl)pyridazine (Preparation I, 235 mg, 0.95 mmol) in THF (6.0 mL) at RT. The reaction turned purple and an evolution of gas was observed. The reaction was stirred for 15 min at RT. A solution of tert-butyl ((3R,4R,5S)-4-((tert-butyl(dimethyl)silyl)oxy)-1-(3-isothiocyanato-4-pyridinyl)-5-methyl-3-piperidinyl)carbamate (Preparation XIII, 455 mg, 0.95 mmol) in THF (5.0 mL) was added. After 15 min at RT, the mixture was diluted with EtOAc and washed with brine. The aqueous phase was extracted with EtOAc (2×). The combined organic layers were dried over anh. Na2SO4, filtered and concentrated. The crude material was purified by silica gel chromatography (0-3% MeOH in CH2Cl2) to provide tert-butyl ((3R,4R,5S)-4-((tert-butyl(dimethyl)silyl)oxy)-1-(3-((2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-yl)amino)-4-pyridinyl)-5-methyl-3-piperidinyl)carbamate (450 mg, 0.68 mmol, 71% yield) as an orange solid. MS (ESI, pos. ion) m/z: 666.3 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 9.76 (s, 1 H), 8.21 (d, J=5.09 Hz, 1 H), 7.77 (d, J=9.39 Hz, 1H), 7.70 (br. s., 1 H), 7.34-7.47 (m, 2 H), 7.05 (t, J=8.12 Hz, 2 H), 6.93 (d, J=5.28 Hz, 1H), 6.51 (d, J=9.39 Hz, 1 H), 4.49 (br. s., 1 H), 3.67 (br. s., 1 H), 3.40 (d, J=10.76 Hz, 1H), 3.14-3.28 (m, 2 H), 2.81 (t, J=10.07 Hz, 1 H), 2.29 (t, J=11.15 Hz, 1 H), 1.89-2.03 (m, 1 H), 1.40 (br. s., 9 H), 0.93 (s, 12 H), 0.11 (d, J=11.15 Hz, 6 H).
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].[C:13](O)(=O)[CH3:14]>>[CH3:13][C:14]1[N:4]2[C:5]3[C:10]([CH:11]=[CH:12][C:3]2=[N:1][N:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: NNc1ccc2ccccc2n1
Reactant: CC(=O)O
Product: Cc1nnc2ccc3ccccc3n12

Procedure:
2-Hydrazinoquinoline (5.0 grams) was placed in a 250-milliliter three-necked flask equipped with a mechanical stirrer and a reflux condenser. To this flask was added 100 milliliters of acetic acid. The reaction mixture was refluxed for twelve hours, then allowed to cool; acetic acid was removed by evaporation. The solid which remained consisted of pure 1-methyl-s-triazolo(4,3-a)quinoline. The product was recrystallized from ethanol, m.p., 166°-7°C.
Reaction SMILES: Cl[C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]#[N:5].[F-:15].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[Cl:10][C:9]1[C:2]([F:15])=[C:3]([C:6]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: N#Cc1c(C(F)(F)F)ccc(Cl)c1Cl
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1c(C(F)(F)F)ccc(Cl)c1F
Temperature: 100 °C
Reaction time: 6 h
Yield: 72.7 %

Procedure:
To a solution of 0.96 g of 2,3-dichloro-6-trifluoromethylbenzonitrile in 7 ml of N,N-dimethylformamide was added 0.46 g of spray-dried potassium fluoride and 0.1 g of 18-crown-6-ether and the mixture was stirred for 6 hours at 100° C. under a nitrogen atmosphere. After cooling, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous magnesium sulfate. After distilling the solvent under reduced pressure, the crude product obtained was purified by using silica gel column chromatography to obtain 0.65 g of the title compound(mp. 43-44° C.).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]>ClCCl.CO.O=[Mn]=O>[CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(CO)cn3)nc2n1C1CCCC1
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CO
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C=O)cn3)nc2n1C1CCCC1
Temperature: 38 °C
Reaction time: 12 h
Yield: 85.1 %

Procedure:
7-Cyclopentyl-2-(5-hydroxymethyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (4.49 g, 11.8 mmol) is dissolved in dichloromethane (175 ml) and methanol (75 ml). Activated MnO2 85% (51.1 g, 503 mmol) is added in 4 portions over period of 48 h with continual stirring. After a further 16 hours the mixture is filtered. The filtrate is heated to 38° C. and more MnO2 (24 g, 236 mmol) is added as 2 batches over 5 hours. After stirring for a further 12 hours, the mixture is cooled and filtered. Concentration in vacuo gave a solid which is triturated with MeOH (10 ml) to give 7-cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (3.8 g, 85%). MS (ESI) m/z 379.2 (M+H)+ (method B).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:10]([O:17][C@H:18]([C@H:20]([N:24]1[CH:28]=[C:27]([C:29]([NH2:31])=[O:30])[N:26]=[CH:25]1)[CH2:21][CH2:22]O)[CH3:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:10]([O:17][C@H:18]([C@H:20]([N:24]1[CH:28]=[C:27]([C:29]([NH2:31])=[O:30])[N:26]=[CH:25]1)[CH2:21][CH2:22][O:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH3:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[C@H](OCc1ccccc1)[C@@H](CCO)n1cnc(C(N)=O)c1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](OCc1ccccc1)[C@@H](CCOc1ccc(Cl)c(Cl)c1)n1cnc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.9 %

Procedure:
To a stirred mixture of 3,4-dichlorophenol (129 mg, 0.791 mmol), 1-[(2S,3R)-2-benzyloxy-5-hydroxy-3-pentyl]imidazole-4-carboxamide (80 mg, 0.264 mmol), and triphenylphosphine (90 mg, 0.343 mmol) in tetrahydrofuran (5 ml) was added dropwise diethyl azodicarboxylate (59.7 mg, 0.343 mmol) at ice-bath temperature. After the mixture was stirred for 2 h at room temperature, the solvent was removed in vacuo. The residue was purified by silica gel (10 g) chromatography eluting with chloroform/methanol (100:1 to 30:1) to give a mixture (120.6 mg, 102%) of 1-[(2S,3R)-2-benzyloxy-5-(3,4-dichlorophenoxy)-3-pentyl]imidazole-4-carboxamide (3) and by-products. This material was used without further purification.
Reaction SMILES: O[C:2]1([C:12]([NH2:14])=[O:13])[CH:10](O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>ClC(Cl)Cl>[C:22]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][C@H:2]1[C:12]([NH2:14])=[O:13])(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: NC(=O)C1(O)Nc2ccccc2C1O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N1c2ccccc2C[C@H]1C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
2,3-Dihydroxy-1H-indole-2-carboxamide (0.030 mol) was suspended in trichloromethane (400 ml). The mixture was cooled to 0° C. Triethylamine (0.045 mol) was added. Acetyl chloride (0.045 mol) was added over 2 minutes. After 30 minutes, TLC showed the reaction was incomplete. While the flask was still cool, more Triethylamine (6.26 ml) was added, followed 15 minutes later with more acetyl chloride (3.21 ml). TLC showed the reaction was still incomplete. The reaction was continued to allow to stir, cooled to 0° C., and more triethylamine (6.26 ml) was added. Over 2 minutes, more acetyl chloride (3.21 ml) was added neat. TLC showed 80% completion after 60 minutes, and no progress after 30 more minutes. A third portion of acetyl chloride and triethylamine was added. After an additional 15 minutes, ice cold water (200 ml) was added. The mixture was stirred for 10 minutes, filtered, and rinsed with water (3×100 ml) and trichloromethane (2×75 ml). The sample was allowed to dry overnight, yielding 4.71 g of (S)-1-acetyl-2,3-dihydro-1H-indole-2-carboxamide (intermediate 1, mp. >260° C.). b) Intermediate (1) (0.02022 mol) was suspended in DCM (175 ml). The mixture was cooled to 0° C. Triethylamine (0.06066 mol) was added neat. Trichloroacetyl chloride (0.03033 mol) in DCM (20 ml) was added dropwise over 20 minutes. After 2 hours, ice water (200 ml) was added, the phases separated and the organic phase reextracted with 3 N HCl and then with a saturated aqueous NaHCO3 solution. The organic phase was dried, filtered, and stripped to leave 4.61 g brown solid. The solid was triturated with ice cold diethylether (30 ml), filtered, and rinsed with ice cold diethylether (twice), yielding 3.12 g (83%) of (S)-1-acetyl-2,3-dihydro-1H-indole-2-carbonitrile (intermediate 2, mp. 134-135° C.). c) Intermediate (2) (0.0151 mol) was suspended in diethylether (200 ml). Ethanol (0.0214 mol) was added, and the mixture was cooled to 0° C. HCl (gas) was bubbled in for 45 minutes. The mixture was removed from the ice bath and stirred. After 20 minutes, a residue collected on the wall sides. The walls were scratched, and a white solid precipitated out. After 1 hour the sample was filtered, rinsed with diethylether, air dried quickly, yielding 3.99 g of (S)-ethyl 1-acetyl-2,3-dihydro-1H-indole-2-carboximidate monohydrochloride (intermediate 3). In analogy, ethyl 1-acetyl-2,3-dihydro-1H-indole-2-carboximidate monohydrochloride (intermediate 6) was prepared starting from 1-acetyl-2,3-dihydro-1H-indole-2-carbonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([OH:20])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH2:21][C:22]([NH:24][CH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1)=[O:23].Br[CH2:40][CH:41]([F:43])[F:42]>>[F:42][CH:41]([F:43])[CH2:40][O:20][C:15]1[C:16]([O:18][CH3:19])=[CH:17][C:12]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:21][C:22]([NH:24][CH:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26]3)=[O:23])[CH:7]([CH2:6][C:5]3[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:13]=2[CH:14]=1
Reactant: FC(F)CBr
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CCC2
Product: COc1ccc(CC2c3cc(OCC(F)F)c(OC)cc3CCCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide with 2-bromo-1,1-difluoroethane.
Reaction SMILES: Cl.[OH:2][CH:3]1[O:11][C@@H:10]([CH2:12][OH:13])[C@H:8]([OH:9])[C@@H:6]([OH:7])[C@@H:4]1[NH2:5].C([O-])(O)=O.[Na+].F[C:20]1[C:28]2[C:24](=[N:25][O:26][N:27]=2)[C:23]([N+:29]([O-:31])=[O:30])=[CH:22][CH:21]=1>O.CO>[CH:21]1[CH:22]=[C:23]([N+:29]([O-:31])=[O:30])[C:24]2[C:28](=[N:27][O:26][N:25]=2)[C:20]=1[NH:5][C@@H:4]([C@H:6]([OH:7])[C@@H:8]([OH:9])[C@@H:10]([OH:11])[CH2:12][OH:13])[CH:3]=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)c2nonc12
Reactant: N[C@@H]1C(O)O[C@@H](CO)[C@H](O)[C@H]1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C[C@@H](Nc1ccc([N+](=O)[O-])c2nonc12)[C@H](O)[C@@H](O)[C@@H](O)CO
Temperature: 37 °C
Reaction time: 2 h

Procedure:
In a brown flask, L-glucosamine hydrochloride (40.0 mg) and NaHCO3 (26.0 mg) were placed and dissolved in water (800 μl). A solution in which 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F) (92.0 mg) was dissolved in methanol (4.0 ml) was added thereto, and under an argon atmosphere, the resulting mixture was stirred for 2 hours at a bath temperature of 37° C. Thereafter, the mixture was stirred at room temperature for an additional 40 minutes. Methanol was removed by concentration under reduced pressure, and the resulting precipitates (unnecessary substances derived from NBD-F) were removed by filtration. The precipitates were washed with water, and the filtrate and the washing solution were combined, followed by purification by HPLC. A target fraction was collected and lyophilized, whereby a target product was obtained (yield: 48.7 mg, yield ratio: 76%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)CCCCCSc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)CCCCCSc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.4 %

Procedure:
To a degassed solution of 6-(4-bromo-phenylsulfanyl)-hexanoic acid methyl ester (500 mg, 1.58 mmol) in ethylene glycol dimethyl ether (20 mL) was added 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (131 mg, 0.16 mmol). The resulting mixture was stirred for 5 min at room temperature under an argon atmosphere. 4-Chlorophenylboronic acid (494 mg, 3.16 mmol) was added. A solution of cesium carbonate (1.8 g, 5.54 mmol) in water (3 mL) was added. The mixture was stirred at reflux for 1 hour, allowed to cool down to room temperature and concentrated under reduced pressure. The residue was taken up in ethyl acetate (75 mL). This solution was washed with saturated aqueous sodium hydrogen carbonate (2×50 mL), distilled water (2×50 mL) and brine (2×50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (5:95 to 10:90 diethyl ether:40-60° C. petroleum ether) to give a solid that was recrystallised from diethyl ether/40-60° C. petroleum ether to give the title compound (465 mg, 84%) as a solid, mp 87-88° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[C:20]([Cl:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])C.[OH-].[Na+]>C(#N)C.O>[C:4]([C:6]1[CH:7]=[C:8]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[C:20]([Cl:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cccc(Nc2nccc(-c3cccnc3Cl)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1cccc(Nc2nccc(-c3cccnc3Cl)n2)c1
Temperature: 25 °C
Yield: 56.7 %

Procedure:
A mixture of N-[3-ethoxycarbonyl-phenyl]-4-(2-chloro-3-pyridyl)-2-pyrimidineamine (1.15 g, 3.24 mmol), sodium hydroxide (300 mg, 7.5 mmol) in acetonitrile (15 mL) and water (5 mL) is heated to reflux for 4 hours. The reaction mixture is then cooled to room temperature and concentrated. The residue is dissolved in water and acidified with 10% hydrochloric acid. The solid is collected by filtration and washed with water, methanol and dried to give N-[3-carboxy-phenyl]-4-(2-chloro-3-pyridyl)-2-pyrimidineamine (600 mg); ESI-MS (m/z): 327.0 (M++H).
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].C(N(CC)CC)C.[F:12][C:13]1[C:14]([C:22](F)=[O:23])=[N:15][C:16]([F:21])=[C:17]([F:20])[C:18]=1[F:19]>O>[F:12][C:13]1[C:14]([C:22]([O:4][CH:2]([CH3:3])[CH3:1])=[O:23])=[N:15][C:16]([F:21])=[C:17]([F:20])[C:18]=1[F:19]
Reactant: CC(C)O
Reactant: O=C(F)c1nc(F)c(F)c(F)c1F
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)c1nc(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
Anhydrous 2-propanol (0.361 g, 6 mmol) and anhydrous tri-ethylamine (0.405 g, 4 mmol) were added drop-wise at room temperature to the 3,4,5,6-tetrafluoropicolinoyl fluoride provided above. The mixture was stirred at room temperature overnight, poured into a reparatory funnel with water and extracted with ethyl ether. The organic phase was then washed with water and dried over MgSO4. The solvent was removed with a rotary evaporator. The concentrated crude product was purified using column chromatography (silica gel) with ethyl acetate/hexanes mixture (1/10) as eluent to give 0.454 g (48% yield, 96% GC purity, 93% LC purity) of desired product as a pale yellow liquid. GC/MS results were consistent with the chemical formula of isopropyl 3,4,5,6-tetrafluoropicolinate: 70 eV EIMS (GC) m/z=196 (31%), 178 (100%), 150 (45%), 100 (26%), 43 (34%). 1H NMR (400 MHz, CDCl3) δ 5.32 (hept, J=6.3 Hz, 1H), 1.42 (d, J=6.3 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 159.81 to 159.74 (m), 149.22 to 148.78 (m), 148.04 to 147.86 (m), 146.49 to 146.10 (m), 145.65 to 145.47 (m), 138.53 (dd, J=34.3, 11.2 Hz), 135.79 (dd, J=34.4, 11.2 Hz), 129.02 to 128.74 (m), 70.97 (s), 21.60 (s). 19F NMR (376 MHz, CDCl3) δ −80.31 to −80.49 (m), −136.04 to −136.18 (m), −137.10 to −137.25 (m), −149.81 to −149.95 (m).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[Cl:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][C:16]=1[F:17].C([O-])([O-])=O.[Cs+].[Cs+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.C(OC(=O)C)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:2]2[N:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: COc1cnnc(Cl)c1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cnnc(-c2ccc(F)c(Cl)c2)c1
Temperature: 90 °C

Procedure:
3-Chloro-5-methoxy-pyridazine (Bryant, R. D.; Kunng, F.-A.; South, M. S. J. Heterocycl. Chem. (1995), 32(5), 1473-6.), 3-chloro-4-fluorophenylboronic acid, Cs2CO3 and tris(dibenzylideneacetone)dipalladium chloroform complex are mixed and a solution of tri-tert-butylphosphine in degassed dioxane is added. The mixture is heated at about 90° C. for 22 hours then cooled to room temperature, ethylacetate is added, the solid is filtered and the filtrate is concentrated in vacuo to provide 3-(3-chloro-4-fluoro-phenyl)-5-methoxy-pyridazine (a compound of formula XI).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[F:20])=[C:10]([CH3:21])[C:9](=[O:22])[N:8]([CH3:23])[C:7]=1[CH2:24]Br)=O)C.[NH2:26][NH2:27]>CO.CCOC(C)=O>[F:20][C:14]1[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=1[NH:12][C:11]1[C:6]2[C:4](=[O:3])[NH:27][NH:26][CH2:24][C:7]=2[N:8]([CH3:23])[C:9](=[O:22])[C:10]=1[CH3:21]
Reactant: CCOC(=O)c1c(Nc2ccc(C)cc2F)c(C)c(=O)n(C)c1CBr
Reactant: NN
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(Nc2c3c(n(C)c(=O)c2C)CNNC3=O)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromomethyl-4-(2-fluoro-4-methylphenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (1 equivalent) in MeOH is added hydrazine (1.10 equivalents). After stirring for 2 hours at room temperature, the reaction mixture is heated to 40° C. for 8 hours. The reaction mixture is diluted with EtOAc and washed with water. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is purified by trituration or flash column chromatography to afford the desired product as necessary.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:17]([O:21][C:22]([N:24]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30])[CH3:25])=[O:23])([CH3:20])([CH3:19])[CH3:18].Cl.N1C=CC=C(CC(O)=O)C=1>>[CH2:10]([N:5]1[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][CH:34]=[C:26]([N:24]([C:22]([O:21][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:23])[CH3:25])[CH:27]=2)[N:3]=[CH:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(C(=O)O)c1
Agent: Cl
Agent: O=C(O)Cc1cccnc1
Product: CN(C(=O)OC(C)(C)C)c1cccc(C(=O)Nc2ncn(Cc3ccccc3)c2C(N)=O)c1
Yield: 81 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 17, using 0.65 g (3.0 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide which was prepared in the same manner as in Reference Example 2 and 3-(N-t-butyloxycarbonyl-N-methylamino)benzoic acid, instead of 3-pyridylacetic acid hydrochloride, to obtain 1.09 g of 1-benzyl-4-(3-(N-t-butyloxycarbonyl-N-methylamino)benzoylamino)-5-imidazole carboxamide (yield 81%).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]2[C:15]([NH2:16])=[N:14][CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])[C:21]([NH2:33])=[N:20][CH:19]=1.[CH:34](O)=[O:35]>[Pd]>[C:1]1([C@H:7]([N:9]2[C:10]3=[N:11][CH:12]=[CH:13][N:14]=[C:15]3[NH:16][C:34]2=[O:35])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27]1([C@H:25]([NH:24][C:22]2[C:21]([NH2:33])=[N:20][CH:19]=[CH:18][N:23]=2)[CH3:26])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C[C@@H](Nc1nc(Br)cnc1N)c1ccccc1
Reactant: O=CO
Agent: [Pd]
Agent: C[C@@H](Nc1nccnc1N)c1ccccc1
Product: C[C@H](c1ccccc1)n1c(=O)[nH]c2nccnc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(R)—N2-(1-Phenylethyl)pyrazine-2,3-diamine. The title compound was prepared by dissolving (R)-6-bromo-N2-(1-phenylethyl)pyrazine-2,3-diamine (1.00 g, 3.37 mmol) in neat formic acid (15 mL), and adding 10% Pd/C (0.34 mmol). This solution was purged with hydrogen gas at 1 atm., and stirred for 4 hours at room temperature. Upon completion, the reaction was filtered through celite and concentrated. The crude material was purified using silica gel chromatography (0-10% methanol in dichloromethane). Clean fractions were combined and condensed to afford 0.65 g (3.03 mmol, 90%) of (R)—N2-(1-phenylethyl)pyrazine-2,3-diamine. MS (ESI) m/z 215.4 [M+1]+.
Reaction SMILES: C(OC([N:8]([C@H:20]([CH2:43][O:44][Si](C)(C)C)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:33]=[C:34]([CH:40]=[CH:41][CH:42]=2)[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:30])=[CH:24][CH:23]=1)[CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCCl>[OH:44][CH2:43][C@@H:20]([NH:8][CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:33]=[C:34]([CH:40]=[CH:41][CH:42]=2)[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:30])=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cccc(NC(=O)Nc2ccc(C[C@@H](CO[Si](C)(C)C)N(C[C@H](O)COc3ccccc3)C(=O)OC(C)(C)C)cc2)c1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cccc(NC(=O)Nc2ccc(C[C@@H](CO)NC[C@H](O)COc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of ethyl 3-[[[[4-[(2S)-2-[N-(tert-butoxycarbonyl)-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-[(trimethylsilyl)oxy]propyl]phenyl]amino]carbonyl]amino]-benzoate (204 mg) in 1,2-dichloroethane (2.0 ml) was added trifluroacetic acid (2.0 ml) and the solution was stirred at room temperature for 1 hour. The solvent was removed by evaporation and the residue was dissolved in ethyl acetate (10 ml). The solution was washed with aqueous saturated sodium bicarbonate solution (5 ml×1) and brine (10 ml×1) successively, dried over magnesium sulfate, and evaporated to give ethyl 3-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]amino]carbonyl]amino]-benzoate (148 mg) as a white solid.