Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH3:10][C:11]1([CH3:37])[C:20]2[C:15](=[C:16](C(O)=O)[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)[CH:25]=2)[CH2:12]1.[C:38](N1C=CN=C1)(N1C=CN=C1)=[O:39]>CN(C)C=O.O>[CH3:37][C:11]1([CH3:10])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:38]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:39])[CH:19]=2)[NH:14][CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]3)[CH:25]=2)[CH2:12]1
Reactant: NS(=O)(=O)C1CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN1CCN(c2cccc(C3CC(C)(C)c4cccc(C(=O)O)c4N3)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc(C3CC(C)(C)c4cc(C(=O)NS(=O)(=O)C5CC5)ccc4N3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.3 %

Procedure:
To a suspension of 60% sodium hydride (448 mg, 11.2 mmol) in N,N-dimethylformamide (3 mL) was added cyclopropanesulfonic acid amide (1.35 g, 11.2 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A51. A solution of 4,4-dimethyl-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (564 mg, 1.5 mmol) and 1,1′-carbonyldiimidazole (519 mg, 3.2 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B51. Solution B51 was added to Solution A51 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid {4,4-dimethyl-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-amide (140 mg, 10%) as a white solid: MS (ESI) M+1=483.3.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:6])[CH3:5])[CH3:2].[H-].[Na+].[CH3:9][C:10]1[N:11]=[C:12](S(CC2C=CC=CC=2)=O)[O:13][CH:14]=1.O>CN(C)C=O>[CH2:1]([N:3]([C:12]1[O:13][CH:14]=[C:10]([CH3:9])[N:11]=1)[C:4](=[O:6])[CH3:5])[CH3:2]
Reactant: CCNC(C)=O
Reactant: Cc1coc(S(=O)Cc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(C)=O)c1nc(C)co1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
N-Ethyl-acetamide (1.18 g, 0.0135 m) in dry dimethylformamide (10 ml) was stirred at room temperature under nitrogen during the portionwise addition of 50% sodium hydride/oil dispersion (0.65 g, 0.0135 m). After the addition, the mixture was warmed to 50° C. and then 4-methyl-2-phenylmethylsulphinyloxazole (3.0 g, 0.0135 m) was added. The mixture was stirred at 50° C. for 5 hours and then hydrolysed with water. The solvent was evaporated in vacuo and the residue extracted with diethyl ether. Column chromatography on silica using ether gave a pale yellow oil which gave the title product as a colourless oil on distillation, b.p. 50°-51° C./0.05 mm.
Reaction SMILES: C([N-][CH:5]([CH3:7])[CH3:6])(C)C.[Li+].[CH3:9][O:10][C:11](=[O:15])C(C)C.Br[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20].[Cl-].[Na+]>CCCCCC.CS(C)=O.O1CCCC1>[CH3:9][O:10][C:11](=[O:15])[C:5]([CH3:6])([CH3:7])[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20]
Reactant: COC(=O)C(C)C
Reactant: CC(C)=CCBr
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)C(C)(C)CC=C(C)C
Reaction time: 1 h

Procedure:
300 g. of a 10% solution of lithium diisopropylamide in hexane was introduced into 90 ml. of absolute tetrahydrofuran, cooled to 0°, and combined dropwise under agitation with a solution of 28 g. of isobutyric acid methyl ester in 150 ml. of absolute tetrahydrofuran. The reaction solution was stirred for one hour at 0°, then cooled to -40° and subsequently added to a solution of 58 g. of 4-bromo-2-methyl-2-butene (dimethylallyl bromide) in 60 ml. of absolute dimethyl sulfoxide maintained at -20°. While allowing the temperature of the solution to rise to room temperature, the solution was stirred for 6 hours and then combined with saturated sodium chloride solution. The organic phase was separated, the aqueous phase was extracted five times with respectively 200 ml. of a 1/1 mixture of ether and hexane. The combined organic phases were washed neutral with 0.5N hydrochloric acid and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated on a forced circulation evaporator. The residue was distilled under vacuum, thus obtaining 20.7 g. of the title compound, b.p. (13 mm.) 74°.
Reaction SMILES: C(O)(=O)C[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.C(O)CC[CH2:14][OH:15].C(O)[CH2:18][O:19]CCO>O1CCCC1>[CH2:14]([C:5]([CH2:6][OH:8])([CH2:18][OH:19])[CH2:4][CH3:3])[OH:15]
Reactant: OCCOCCO
Reactant: OCCCCO
Reactant: O=C(O)CCCCC(=O)O
Solvent: C1CCOC1
Product: CCC(CO)(CO)CO

Procedure:
A solution of 150 g of a polyester having a molecular weight of 1,000 and obtained from adipic acid and butane-1,4-diol, 31.8 g of diethylene glycol, 4.47 g of trimethylolpropane and 200 g of tetrahydrofuran was added dropwise to a solution containing 108.75 g of toluylene diisocyanate (isomer ratio 8:2) and 114 g of tetrahydrofuran in the course of 2 hours at 60° C. 1 drop of dibutyl-tin dilaurate was added before the beginning of the addition, and a further drop 1 hour after the addition was complete. The solution was stirred at 60° C. until the NCO content was 1.72%, after which it was cooled to 45° C. and 18.78 g of methylethanolamine were added.
Reaction SMILES: [CH3:1][C@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]1([CH3:16])C=CC=CC=1.[C:17]([OH:21])(=[O:20])[CH:18]=O>O>[C:3]1([C@@H:2]([N:9]=[CH:18][C:17]([O:21][CH2:10][CH3:16])=[O:20])[CH3:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccccc1
Reactant: C[C@H](N)c1ccccc1
Reactant: O=CC(=O)O
Solvent: O
Product: CCOC(=O)C=N[C@@H](C)c1ccccc1
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
The synthesis was performed according to the procedure reported in the literature. (S)-(−)-α-Methylbenzylamine (238.6 g, 1.964 mol) was added into 2 L round bottom flask equipped a stirrer bar. Toluene (520 mL) was added. The reaction mixture was cooled to −5° C., and was allowed to stir for 10 min. Glyoxylic acid (200 g, 1.96 mol) was tranferred to a dropping funnel and was added slowly to the cooled reaction mixture for approximately 15 min. As the addition of the glyoxylic acid proceeded, the reaction mixture became cloudy and the flask became warm. The mixture was allowed to stir for 10 min after the addition. When the reaction was complete, the water generated during the reaction was removed. The organic layer was dried over Na2SO4, filtered via Buchner funnel, rinsed with toluene, concentrated in vacuo to yield an oil which was used directly in the next step.
Reaction SMILES: O=P(Cl)(Cl)Cl.[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]=[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]2[CH:23]=1)([O-:8])=[O:7].[OH-].[Na+].CN([CH:29]=[O:30])C>>[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]=[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]2[C:23]=1[CH:29]=[O:30])([O-:8])=[O:7]
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1ccccc1-c1cn2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(-c2ccccc2[N+](=O)[O-])nc2ccccn12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
In a dry flask charged with DMF (2.7 g, 37 mmol) and cooled to 0° C. was added slowly POCl3 over 5 minutes. The solution was stirred for 10 min at 0° C. was warmed to room temperature over 1 hour. To the deep red color solution recooled to 0° C. was added 2-(2-Nitro-phenyl)-imidazo[1,2-a]pyridine (1.0 g, 4.18 mmol) in DMF (8 ml). The reaction was stirred for 5.5 hours; LC-MS indicated some product formation. A second addition of the Vilsmeier complex (from 2.7 g of DMF and 1.47 g POCl3) was charged and the reaction stirred overnight, then heated to 50° C. for 3 hours until reaction completion. The reaction was cooled to room temperature, poured onto ice, adjusted to pH=7 with 1N NaOH. The product was extracted into CH2Cl2 (3×50 ml), washed with brine, dried over Na2SO4 and concentrated to obtain the product as a white solid (1.03 g, 92% yield). (MS, M++H=268.0)
Reaction SMILES: [Mg].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[CH2:17][Mg]Cl.[C:23](=[C:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])([CH3:25])[CH3:24].Cl>C(OCC)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:9](=[CH:10][CH:11]=1)[C:14](=[O:13])[CH2:15][C:16]([CH3:20])([CH3:17])[CH2:7]2.[CH2:30]([O:29][C:27](=[O:28])[CH:26]([C:23]([CH3:24])([CH3:25])[CH2:17][C:16]1[CH:20]=[CH:21][CH:22]=[C:14]([O:13][CH3:12])[CH:15]=1)[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:31]
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)C
Reactant: COc1cccc(CCl)c1
Reactant: COc1cccc(C[Mg]Cl)c1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCOC(=O)C(C(=O)OCC)C(C)(C)Cc1cccc(OC)c1
Product: COc1ccc2c(c1)CC(C)(C)CC2=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The title compound was synthesized by referring to J. Org. Chem., 1971, 36, 3260. To a suspension of magnesium (2.7 g) in diethyl ether (5 ml) was added a solution of 3-methoxybenzyl chloride (15 ml) in diethyl ether (90 ml) dropwise on an ice bath under a nitrogen atmosphere, the solution was stirred for 20 minutes at room temperature. To a resulting solution of 3-methoxybenzyl magnesium chloride in diethyl ether, which was cooled on an ice, was added dropwise solution of diethyl 2-isopropylidenemalonate (14.8 g) in diethyl ether (9 ml) thereto, then diethyl ether (30 ml) was added thereto followed by stirring overnight at room temperature. The solution was brought to pH 2 by adding 5N hydrochloric acid on an ice bath, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide 2-[2-(3-methoxyphenyl)-1,1-dimethylethyl]malonic acid diethyl ester (19.7 g). To a solution of the total amount of this compound in ethanol (200 ml) was added an aqueous solution of 5N sodium hydroxide (40 ml), and the solution was refluxed overnight. Water was added thereto followed by stirring, then ethanol was evaporated in vacuo, then the solution was washed with diethyl ether, and the resulting aqueous solution was brought to pH 1 with concentrated hydrochloric acid. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was washed with a hexane-diethyl ether system, and the resulting 2-[2-(3-methoxyphenyl)-1,1-dimethylethyl]malonic acid (13.4 g) was heated for 30 minutes at 180° C. to provide 4-(3-methoxyphenyl)-3,3-dimethylbutyric acid (11.2 g). To a solution of the total amount of this compound in toluene (70 ml) was added thionyl chloride (15 ml), the solution was stirred for 1 hour at 100° C., then the solvent was evaporated in vacuo, and the resulting 4-(3-methoxyphenyl)-3,3-dimethylbutyryl chloride (12.5 g) was used according to an analogous synthetic method to Preparation Example 66 to provide the title compound (8.0 g).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][CH2:35][CH2:36][C@@H:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[OH:38]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:34][CH2:35][CH2:36][C@H:37]([OH:38])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: NCC[C@H](O)c1ccccc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CON=C1C[C@@H](C(=O)NCC[C@H](O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and (1S)-3-amino-1-phenyl-1-propanol, the title compound was obtained in 93% purity by HPLC. MS(ESI+): m/z=472.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[CH:15][N:14]([C:17]4[S:18][C:19]([C:28](O)=[O:29])=[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:21]=4)[C:13]=3[CH:31]=2)[CH2:4][CH2:3]1.C[N:33](C(N(C)C)=[N+]1C2C(=NC=CC=2)N=N1)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[CH:15][N:14]([C:17]4[S:18][C:19]([C:28]([NH2:33])=[O:29])=[C:20]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:21]=4)[C:13]=3[CH:31]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(Cc2ccc3ncn(-c4nc(-c5ccccc5)c(C(=O)O)s4)c3c2)CC1
Reactant: CN(C)C(N(C)C)=[N+]1N=Nc2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc3ncn(-c4nc(-c5ccccc5)c(C(N)=O)s4)c3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
To a mixture of 0.022 g (0.05 mmole) of 2-[6-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-4-phenyl-thiazole-5-carboxylic acid (I.1b), 0.023 g (0.06 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium, 3-oxide, hexafluorophosphate(1-) (1:1), 0.004 g of ammonium chloride and 1 mL of dimethylformamide was added 0.026 mL (0.15 mmole) of ethyldiisopropylamine. The mixture was stirred at ambient temperature for 1 hour. Solids were removed by filtration and the filtrate purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 10:90-90:10) to give 0.014 g of 2-[6-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-4-phenyl-thiazole-5-carboxylic acid amide (I.1) as a white powder. MH+/Z=433.
Reaction SMILES: Cl.Cl.[C:3]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][NH:10][S:11]([CH2:14][CH2:15][N:16]2[CH2:23][CH:22]3[O:24][CH:18]([CH2:19][NH:20][CH2:21]3)[CH2:17]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)#[N:4].Br[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][S:11]([CH2:14][CH2:15][N:16]2[CH2:23][CH:22]3[O:24][CH:18]([CH2:19][N:20]([CH2:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=4)[CH2:21]3)[CH2:17]2)(=[O:13])=[O:12])=[CH:25][CH:26]=1)#[N:4]
Reactant: N#Cc1ccc(CNS(=O)(=O)CCN2CC3CNCC(C2)O3)cc1
Reactant: Fc1cccc(CCBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(CNS(=O)(=O)CCN2CC3CN(CCc4cccc(F)c4)CC(C2)O3)cc1
Temperature: 160 °C
Reaction time: 0.33 h
Yield: 30.3 %

Procedure:
To 2-(9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-ethanesulfonic acid 4-cyano-benzylamide dihydrochloride (0.127 g, 0.30 mmol; prep P above), 1-(2-bromo-ethyl)-3-fluoro-benzene (0.064 g, 0.315 mmol) and potassium carbonate (0.145 g, 1.05 mmol) was added acetonitrile (4 mL) and water (0.1 mL). The mixture was stirred for 20 minutes before it was heated by microwave irradiation (10 minutes, 160° C.) and was then filtered and evaporated. The crude product was purified by chromatography on silica gel using methanol saturated with ammonia in dichloromethane as eluent, which afforded 43 mg (30.3%) of the title compound.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]([F:31])([F:30])[O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][Cl:25]>CCO>[ClH:25].[F:19][C:20]([F:30])([F:31])[O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: FC(F)(F)Oc1ccccc1CCl
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Solvent: CCO
Product: Cl
Product: FC(F)(F)Oc1ccccc1CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 2-trifluoromethoxybenzyl chloride (0.331 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 202 mg of the product 215. 1H NMR (DMSO-d6) δ 11.32 (s, 2 H), 7.85 (d, 1 H), 7.70-7.40 (m, 3 H), 7.20-6.70 (m, 10 H), 5.80 (s, 2 H), 4.85 (s, 2 H); MS: m/z 429 (M++1).
Reaction SMILES: [CH:1]1([S:7][CH2:8][CH2:9][NH:10][C@H:11]([C:13]([OH:15])=[O:14])[CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[N:20]([O-])=[O:21].[Na+]>O>[CH:1]1([S:7][CH2:8][CH2:9][N:10]([N:20]=[O:21])[C@H:11]([C:13]([OH:15])=[O:14])[CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=N[O-]
Reactant: C[C@H](NCCSC1CCCCC1)C(=O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C[C@@H](C(=O)O)N(CCSC1CCCCC1)N=O
Reaction time: 2 h

Procedure:
The N-[2-(cyclohexylthio)ethyl]alanine prepared in Example 2 is suspended in 210 parts of acetic acid and that mixture is treated, over a period of 20 minutes, with a solution containing 7 parts of sodium nitrite and 70 parts of water. The resulting mixture is stirred for 11/2 hours, then filtered. The filtrate is added to 2000 parts of water and extracted with methylene chloride. The organic phase is separated, washed with water, dried over anhydrous sodium sulfate, filtered and then evaporated to dryness under reduced pressure to afford, as an oil, N-[2-(cyclohexylthio)ethyl] -N-nitrosoalanine.
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:12]O.P(Br)(Br)[Br:15].O>C(OCC)C>[Br:15][CH2:12][C:3]1[C:4]([C:8]([F:11])([F:10])[F:9])=[N:5][N:6]([CH3:7])[C:2]=1[F:1]
Reactant: BrP(Br)Br
Reactant: Cn1nc(C(F)(F)F)c(CO)c1F
Solvent: O
Solvent: CCOCC
Product: Cn1nc(C(F)(F)F)c(CBr)c1F
Temperature: -30 °C
Reaction time: 12 h
Yield: 67.3 %

Procedure:
A solution of 35.4 g (178.7 mmoles) of 5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-methanol dissolved in 500 ml of diethyl ether was cooled to −30° C. Thereto was added 54.0 g (199.5 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with diethyl ether. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 31.4 g (yield: 80.8%) of 4-bromomethyl-5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5](=O)[CH2:6][CH3:7].[CH3:10][NH2:11]>>[CH3:1][O:2][C:3](=[O:9])[CH:4]=[C:5]([NH:11][CH3:10])[CH2:6][CH3:7]
Reactant: CN
Reactant: CCC(=O)CC(=O)OC
Product: CCC(=CC(=O)OC)NC

Procedure:
Prepared according to the procedure described in Example 1, Step 1, using the following starting materials: 3-oxo-pentanoic acid methyl ester and methylamine.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=2[OH:11])[CH2:3][CH2:2]1.ClC1C=CC=CC=1Cl.[OH-].[Na+].[OH:22][C:23]1[CH:28]=[C:27]([Cl:29])[N:26]=[N:25][C:24]=1Cl>C(O)(C)(C)C>[Cl:29][C:27]1[N:26]=[N:25][C:24]([O:11][C:5]2[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:23]([OH:22])[CH:28]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: Clc1ccccc1Cl
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
To a mixture of 12.9 g (87.0 mmol) of 2-cyclopropyl-6-methylphenol and 1,2-dichlorobenzene (78.3 mL) was added 3.67 g (87.0 mmol) of 95% sodium hydroxide at room temperature. The resultant mixture was heated to 180° C. and subjected to azeotropic dehydration under reflux while stirring for 30 minutes. To the resultant solution was added dropwise the preliminarily prepared solution of 5.00 g (purity: 95.7%; 29.0 mmol) of 4-hydroxy-3,6-dichloropyridazine in t-butanol (95.0 g) at 160° C. over 5 hours. (The t-butanol was distilled off simultaneously with the dropwise addition of the solution.) After stirring at 180° C. for another 30 minutes, the reaction mixture was cooled to room temperature, and 78.7 g of pure water was added to the cooled mixture and stirred for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol added in an excess amount was separated. 50.0 g of toluene was added to the resultant aqueous phase and stirred at room temperature for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol was separated. This operation was repeated twice. Then, the resultant aqueous solution containing a sodium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was quantitatively determined by an HPLC internal standard analysis method, which showed that 6.52 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 81%) and 32 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.4%) were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[C:17]1[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=1.Br[C:26]1[N:30]2[N:31]=[CH:32][C:33]([C:35]([OH:38])([CH3:37])[CH3:36])=[N:34][C:29]2=[N:28][CH:27]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:26]2[N:30]3[N:31]=[CH:32][C:33]([C:35]([OH:38])([CH3:36])[CH3:37])=[N:34][C:29]3=[N:28][CH:27]=2)=[CH:4][C:3]=1[C:17]1[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Product: CC(C)(O)c1cnn2c(-c3ccc(F)c(-c4ccccc4C#N)c3)cnc2n1
Yield: 29 %

Procedure:
2′-Fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile was coupled to 2-(7-bromoimidazo[1,2-b][1,2,4]triazin-3-yl)-propan-2-ol in 29% yield using a similar procedure to that described in Example 3, step f, to give a yellow solid: mp 187° C.; 1H NMR (360 MHz, CDCl3) δ 1.71 (6H, s), 3.25 (1H, br s), 7.36-7.84 (5H, m), 8.09-8.16 (2H, m), 8.26 (1H, s), 8.76 (1H, s); MS (ES+) m/z 374 [M+H]+. Anal. Found: C, 67.34; H, 4.30, N. 18.47%. Required for C21H16FN5O: C, 67.55; H, 4.32; N, 18.76%.
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([C:28]#[C:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][NH:37]C(=O)C(F)(F)F)[C:24]([NH2:25])=[N:23][C:21]2=[O:22])[CH2:17][CH2:16]1)([O:4][P:5]([O:8][P:9]([OH:12])([OH:11])=[O:10])([OH:7])=[O:6])(=[O:3])[OH:2]>[NH4+].[OH-]>[P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([C:28]#[C:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][NH2:37])[C:24]([NH2:25])=[N:23][C:21]2=[O:22])[CH2:17][CH2:16]1)([O:4][P:5]([O:8][P:9]([OH:11])([OH:12])=[O:10])([OH:7])=[O:6])(=[O:2])[OH:3]
Reactant: Nc1nc(=O)n([C@H]2CC[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)cc1C#CCOCCOCCNC(=O)C(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Product: NCCOCCOCC#Cc1cn([C@H]2CC[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)nc1N
Temperature: 48 °C
Reaction time: 3 h

Procedure:
The purified protected triphosphate 22 was taken up in concentrated aqueous NH4OH (2 mL) and stirred for 3 h at approximately 48° C. The reaction mixture was concentrated to give compound 23 which was formulated with 0.1M TEAB pH 7.0 to a concentration of 3.5 mM. The concentration and purity of the formulated bulk were confirmed by UV/Vis spectroscopy and analytical ion pair HPLC as described above, respectively. See FIG. 12.