Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][CH:9]([CH2:14][CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:24])[C:10]([O:12][CH3:13])=[O:11])=[O:7])=[CH:4][CH:3]=1.[C:27](=O)([O-])[O-].[Na+].[Na+].CI>CC(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH:9]([CH2:14][C:15]2([CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:24])[C:10]([O:12][CH3:13])=[O:11])=[O:7])=[CH:25][CH:26]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C(CC1C(=O)Nc2ccccc21)NC(=O)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CI
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C(CC1(C)C(=O)Nc2ccccc21)NC(=O)c1ccc(Cl)cc1

Procedure:
2.4 Grams of methyl 2-(4-chlorobenzoylamino)-3-(oxindol-3-yl)propionate prepared in Example 57 was dissolved in 30 ml of acetone and 10 ml of water, then 0.34 g of sodium carbonate and 1 g of methyl iodide were added thereto and the reaction mixture was refluxed for 6 hours. Acetone was removed by evaporation, and the residue was extracted with chloroform, the chloroform layer was washed with water, dried with anhydrous magnesium sulfate, then the solvent was removed by evaporation. The residue was purified by means of a silica gel column chromatography (euting agent: chloroform/methanol=100/1) then recrystallized from hexane-ethyl acetate to obtain 0.5 g of methyl 2-(4-chlorobenzoylamino)-3-(3-methyloxindol-3-yl)propionate in the form of colorless needel-like crystals. Melting point: 201°-202° C.
Reaction SMILES: [CH2:1]([Li])CCC.C[Si](C)(C)N[Si](C)(C)C.[C:15]([O:19][C:20]([N:22]1[C@@H:26]([CH2:27][C:28]([CH:31]=O)([CH3:30])[CH3:29])[CH2:25][O:24][C:23]1([CH3:34])[CH3:33])=[O:21])([CH3:18])([CH3:17])[CH3:16]>CCCCCC.O1CCCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:15]([O:19][C:20]([N:22]1[C@@H:26]([CH2:27][C:28]([CH3:30])([CH3:29])[CH:31]=[CH2:1])[CH2:25][O:24][C:23]1([CH3:34])[CH3:33])=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C=O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CC(C)(C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 30 °C
Reaction time: 0.25 h

Procedure:
255 ml of a 1.6M butyllithium solution in hexane are added to a solution of 85 ml of hexamethyldisilazane in 800 ml of tetrahydrofuran at -40° C. After 15 min, 140 g of methyltriphenylphosphonium bromide are added at 0° C. and the reaction mixture is stirred at 30° C. for 30 min. 77 g of 3-tert-butoxycarbonyl-2,2-dimethyl-4(S)-(2-formyl-2-methylpropyl)-1,3-oxazolidine, dissolved in 200 ml of tetrahydrofuran, are then added to the reaction solution at -30° C. The reaction mixture is stirred at room temperature for 1 h, and 600 ml of hexane are then added at 0° C. The triphenylphosphinoxide which has precipitated out is filtered off and, after dilution with 400 ml of saturated ammonium chloride solution, the filtrate is extracted with diethyl ether. The crude product is purified by means of FC (400 g of silica gel, mobile phase G): Rf (D)=0.55, Rf (ethyl acetate)=0.44; [α]D =+4.2 (c=1.25 in CHCl3); MS: (M)+ =283.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:11](=[O:28])[N:10]2[C:29](OC2C=CC([N+]([O-])=O)=CC=2)=[O:30])[CH:5]=[CH:6][C:7]=1[F:8].Cl.Cl.[NH2:43][CH2:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][C:50]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=2[C:61]#[N:62])([C:53]#[N:54])[CH2:49][CH2:48]1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:11](=[O:28])[N:10]2[C:29](=[O:30])[NH:43][CH2:44][CH2:45][CH2:46][N:47]2[CH2:48][CH2:49][C:50]([C:53]#[N:54])([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=3[C:61]#[N:62])[CH2:51][CH2:52]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(CN2C(=O)N(C(=O)Oc3ccc([N+](=O)[O-])cc3)C(c3ccc(F)c(F)c3)c3ccccc32)cc1
Reactant: N#Cc1ccccc1C1(C#N)CCN(CCCN)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2C(=O)N(C(=O)NCCCN3CCC(C#N)(c4ccccc4C#N)CC3)C(c3ccc(F)c(F)c3)c3ccccc32)cc1
Reaction time: 2 h

Procedure:
To a solution of 11 (0.060 g, 0.109 mmol) in 10 ml of CHCl3 was added N-(3-amino)propyl-4-(2-cyanophenyl)-4-cyanopiperidine dihydrochloride (Example 1) and diisopropyl ethylamine (0.057 mL, 0.329 mmol). The resulting solution was stirred for 2 hours and the crude material purified by PCTLC (5% MeOH in CHCl3/2%NH4OH) affording the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5](/[CH:6]=[N:7]/[OH:8])=[C:4]([O:11][CH2:12][C:13]#[C:14][C:15]2[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:17][N:16]=2)[CH:3]=1.BrN1C(=O)CCC1=O.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[C:6]3=[N:7][O:8][C:14]([C:15]4[C:19]([C:20]([F:23])([F:21])[F:22])=[C:18]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[O:17][N:16]=4)=[C:13]3[CH2:12][O:11][C:4]=2[CH:3]=1
Reactant: O/N=C/c1ccc(Br)cc1OCC#Cc1noc(-c2ccccc2)c1C(F)(F)F
Agent: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: FC(F)(F)c1c(-c2onc3c2COc2cc(Br)ccc2-3)noc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 44.6 %

Procedure:
To a solution of (E)-4-bromo-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)prop-2-ynyloxy)benzaldehyde oxime (Preparation 62E, 0.142 g, 0.305 mmol) in N,N-dimethylformamide (1.5 mL) at 0° C. was added N-bromosuccinimide (0.081 g, 0.458 mmol) followed by triethylamine (0.085 mL, 0.610 mmol). The resulting homogeneous reaction mixture was stirred at 0° C. for 10 min. and then at room temperature for 50 min. HPLC and LCMS analysis indicated that ˜65% of the starting material remained. The reaction mixture was then stirred at 75° C. for 60 min. HPLC analysis indicated that the reaction had progressed to ˜1:1 starting material to product. Additional N-bromosuccinimide (0.081 g, 0.458 mmol) and triethylamine (0.085 mL, 0.610 mmol) were added, and the reaction was heated for an additional 60 min. Very little change was noted upon HPLC analysis. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with a 10% aqueous solution of lithium chloride (2×), and washed with brine. The organic layer was collected, and the aqueous layers were sequentially extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The solid residue was triturated with methanol with sonication to afford 7-bromo-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4H-chromeno[4,3-c]isoxazole (0.063 g, 0.136 mmol, 45% yield) as a white solid.
Reaction SMILES: Cl[SiH2:2][Cl:3].[CH3:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH3:11])[NH:6]1.C(N(CC)CC)C.Cl>CCCCCC>[CH3:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH3:11])[N:6]1[SiH2:2][Cl:3]
Reactant: Cl[SiH2]Cl
Reactant: CC1CCCC(C)N1
Agent: Cl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC1CCCC(C)N1[SiH2]Cl
Temperature: -20 °C
Yield: 66 %

Procedure:
In a 2000 ml 3-necked round bottom flask equipped with mechanical stirror and an addition funnel, 1000 ml hexane was added. With the flask was cooled to −20° C. using a dry ice IPA cold bath, 101 g (1.0 mol) dichlorosilane was condensed and dissolved into hexane. With stirring, a mixture of 113 g (1.0 mol) 2,6-dimethylpiperidine and 111 g (1.1 mol) triethylamine was added dropwise to the flask. After the addition was complete, the reaction mixture was stirred at −20° C. for 1 hour, and then let warming up to room temperature. A salt byproduct precipitate of HCl.Et3N was removed by vacuum filtration in a glove bag purging with N2 to prevent the product reacting with the moisture in the air. A GC/MS analysis on the filtrate confirmed the product 2,6-dimethylpiperidinochlorosilane, showing the product with a molecular ion mass of 177 and supporting mass fragment of mass M —CH3 of 162. The solvent hexane was removed by distillation and the product was separated by vacuum distillation. The boiling point was 60° C. at 10 torr. The yield was 66%.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[NH:14][CH:13]=[C:12]([CH:15]3[CH2:20][CH2:19][CH:18]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:17][CH2:16]3)[C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4].I[C:30]1[CH:42]=[CH:41][C:33]([CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[CH:32][CH:31]=1.CNC1CCCCC1NC>CN1C(=O)CCC1.CCOC(C)=O.[Cu]I>[CH2:1]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[N:14]([C:30]3[CH:31]=[CH:32][C:33]([CH2:34][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[CH:41][CH:42]=3)[CH:13]=[C:12]([CH:15]3[CH2:16][CH2:17][CH:18]([O:21][Si:22]([C:25]([CH3:27])([CH3:26])[CH3:28])([CH3:23])[CH3:24])[CH2:19][CH2:20]3)[C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ncc2[nH]cc(C3CCC(O[Si](C)(C)C(C)(C)C)CC3)c2n1
Reactant: Ic1ccc(CN2CCOCC2)cc1
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCCCNc1ncc2c(n1)c(C1CCC(O[Si](C)(C)C(C)(C)C)CC1)cn2-c1ccc(CN2CCOCC2)cc1
Temperature: 195 °C
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
A solution of N-butyl-7-(4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (59 mg, 0.14653 mmol) and 4-iodobenzyl morpholine (67 mg, 0.22 mmol) in NMP (1 mL) was added CuI (3 mg, 0.022 mmol) and N,N′-dimethylcyclohexane-1,2-diamine (2 mg, 0.044 mmol). The reaction mixture was stirred under microwave irradiation at 195° C. for 30 min. Then the reaction was diluted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by ISCO to provide the desired product (85 mg, 99%). 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 7.36 (d, J=8 Hz, 2H), 7.25 (d, J=8 Hz, 2H), 7.17 (s, 1H), 4.86 (s, 1H), 3.71-3.52 (m, 4H), 3.44-3.38 (m, 4H), 3.32-3.17 (m, 1H), 2.81-2.71 (m, 2H), 2.45-2.33 (m, 4H), 2.15-2.04 (m, 2H), 1.96-1.83 (m, 2H), 1.61-1.29 (m, 8H), 0.94-0.75 (m, 12H), 0.00 (s, 6H). MS m/z 578.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([O:15]C)=[O:14])[C:5]2[O:10][CH2:9][CH2:8][N:7]([CH3:11])[C:6]=2[CH:12]=1.[OH-].[Na+].CO.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[C:5]2[O:10][CH2:9][CH2:8][N:7]([CH3:11])[C:6]=2[CH:12]=1
Reactant: COC(=O)c1cc(Cl)cc2c1OCCN2C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1CCOc2c(C(=O)O)cc(Cl)cc21
Temperature: 70 °C

Procedure:
7.1 Grams of methyl 6-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate and 3.8 g of sodium hydroxide were dissolved in a mixed solvent obtained by mixing 50 ml of methanol and 100 ml of water, and the resulting solution was heated at 70° C. for 2 hours with stirring. The liquid reaction mixture was added to 300 ml of water, and 6 ml of concentrated hydrochloric acid was added thereto. The resulting insoluble substance was filtered off, washed with water, and dried, thereby obtaining 5.8 g of 6-chloro-4-methyl- 3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid. Melting point: 202°-204° C.
Reaction SMILES: C([Sn](CCCC)(CCCC)/C=C/C1C(C(C)C)=NC(C2C=CC=CC=2)=CC=1C1C=C[C:17]([F:20])=CC=1C)CCC.Br[CH2:40][C@@H:41](O)[CH2:42][C:43]([O:45]C)=O.[CH3:48][C:49](N=NC(C#N)(C)C)([C:51]#N)C.II>CCOCC>[F:20][CH2:17][C:43]([C:42]1[CH:41]=[CH:40][CH:51]=[CH:49][CH:48]=1)=[O:45]
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: CCCC[Sn](/C=C/c1c(-c2ccc(F)cc2C)cc(-c2ccccc2)nc1C(C)C)(CCCC)CCCC
Reactant: COC(=O)C[C@H](O)CBr
Agent: II
Solvent: CCOCC
Product: O=C(CF)c1ccccc1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
A mixture of (E)-3-[2-(Tributylstannyl)ethenyl]-4-(4-fluoro-2-methylphenyl)-2-(1-methylethyl)-6-phenylpyridine (7.18 gm, 24.7 mmol), acetylene 1 (4.500 gm, 13.7 mmol) and AIBN (0.084 gm, 5.1 mmol) were heated at 140° C. for 1.5 hours. The solution was cooled to room temperature and diluted with ether (30 ml). Iodine (7.16 gm, 27.1 mmol) was added and an unexpectedly strong exothermic reaction occurred and approximately half the solution foamed out of the flask. The flask was recapped and allowed to stir 16 hours. The solution was then quenched with 10% Na2S2O3 in saturated NaHCO3. The solution was diluted with ether, washed with 10% Na2S2O3 in saturated NaHCO3 (twice) and brine, then dried over Na2SO4, filtered and concentrated to a yellow oil. The oil was purified by flash chromatography on Merck silica gel in 1% EtOAc in hexane. The desired fractions were combined and concentrated to afford a white solid, which was recrystallized from hexane to give product A as hard, off-white crystals (2.830 gm, 45%).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=C[CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2[F:35])=CSC=1C(OC)=O.C(OCC)(OCC)OCC.C(N)CCC>C(O)(=O)C>[CH2:1]([N:7]1[C:12](=[O:13])[C:11]2[S:14][CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:35])[C:10]=2[N:9]=[CH:8]1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1scc(-c2ccccc2F)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Solvent: CCCCN
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: CCCCn1cnc2c(-c3ccccc3F)csc2c1=O
Yield: 93.6 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate (100 mg, 0.40 mmol), triethyl orthoformate (1.0 ml), n-butylamine (0.076 ml, 0.76 mmol), and acetic acid (0.1 ml) were used to give 113.2 mg (0.37 mmol, 93.6% yield) of the title compound.
Reaction SMILES: Br[C:2]1[C:3]([OH:25])=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13])[N:8]=[CH:7]2.[CH3:26][NH:27][CH2:28][CH2:29][OH:30]>[Cl-].[NH4+]>[OH:25][C:3]1[C:2]([N:27]([CH2:28][CH2:29][OH:30])[CH3:26])=[C:10]2[C:6]([CH:7]=[N:8][N:9]2[CH2:11][C@@H:12]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:13])=[CH:5][CH:4]=1
Reactant: CC(Cn1ncc2ccc(O)c(Br)c21)NC(=O)OCc1ccccc1
Reactant: CNCCO
Agent: [Cl-]
Agent: [NH4+]
Product: C[C@@H](Cn1ncc2ccc(O)c(N(C)CCO)c21)NC(=O)OCc1ccccc1
Temperature: 80 °C
Yield: 68 %

Procedure:
To a stirred solution of the product from Step A (0.24 g, 0.59 mmol) was added 2-(methyamino)ethanol (2.0 mL) and the solution was heated at 80° C. for 18 h. A saturated aqueous solution of ammonium chloride (20 mL) was added to the reaction mixture, which was extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine (10 mL), dried (MgSO4) and evaporated to give a residue which was purified by chromatography (silica, 30% ethyl acetate in hexane) to give an oil (0.16 g, 68%): 1H NMR (CDCl3) δ 8.50 (1H, brs), 8.01 (1H, s), 7.30 (6H, m), 6.77 (1H, d, J=8.4 Hz), 5.02 (2H, m), 4.59 (2H, m), 4.77 (1H, brs), 4.09 (1H, m), 3.69 (1H, m), 3.36 (2H, m), 2.93 (3H, s), 1.26 (3H, d, J=6.4 Hz); MS (ES) m/z 399 (M+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][CH2:14][C@@H:15]1[O:19][C:18]([CH3:21])([CH3:20])[O:17][C@H:16]1[CH2:22][OH:23])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:1][S:2]([O:23][CH2:22][C@H:16]1[C@H:15]([CH2:14][O:13][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:19][C:18]([CH3:20])([CH3:21])[O:17]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)O[C@@H](CO)[C@H](COCc2ccccc2)O1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)O[C@@H](COCc2ccccc2)[C@H](COS(C)(=O)=O)O1
Reaction time: 0.33 h
Yield: 100 %

Procedure:
A solution of 19.21 g of methanesulfonyl chloride (168 mmol) in methylene chloride (90 ml) was added to a solution of 35.27 g of {(4S,5S)-5-[(benzyloxy)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl}methanol obtained in Reference Example (1a) (140 mmol) and 29.2 ml of triethylamine (210 mmol) in methylene chloride (270 ml) under ice-cooling over 30 minutes, and the mixture was stirred at the same temperature for 20 minutes. 0.76 ml of water (42 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure and diluted with water, followed by extraction with ethyl acetate. Then, the organic layer was washed with water, a saturated sodium bicarbonate aqueous solution and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 46.19 g of the crude title compound.
Reaction SMILES: [C:1]([C:3]1[C:7]([CH3:8])=[N:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[C:4]=1[NH:19][C:20](=O)[CH3:21])#[N:2].C([OH:25])C.[OH-].[K+].OO>O.CO.C(O)(=O)C>[CH3:18][S:15]([C:12]1[CH:13]=[CH:14][C:9]([N:5]2[C:4]3[N:19]=[C:20]([CH3:21])[NH:2][C:1](=[O:25])[C:3]=3[C:7]([CH3:8])=[N:6]2)=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: CC(=O)Nc1c(C#N)c(C)nn1-c1ccc(S(C)(=O)=O)cc1
Reactant: CCO
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nc2c(c(C)nn2-c2ccc(S(C)(=O)=O)cc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In to a 50 mL round-bottomed equipped with a stir bar and a reflux condenser was added, N-[4-cyano-2-(4-methanesulfonyl-phenyl)-5-methyl-2H-pyrazol-3-yl]-acetamide (30 mg, 0.079 mmol), H2O (0.6 mL), and ethanol (1 mL) followed by 20% aquous KOH (0.33 mL). The reaction mixture turned purple and the solid dissolved after addition of KOH. Hydrogen peroxide (0.25 mL) was then added to the above solution. After stirring 15 min at room temperature, the reaction mixture was heated at 75° C. overnight. After cooled to room temperature acetic acid was added slowly until the pH attained a range between 6-6.5. The mixture was then diluted with H2O and methanol. The resulting precipitate was collected by filtration and washed with H2O, methanol, diethyl ether and dried under vacuum. The crude product was used directly in the next step without further purification. 1H NMR (DMSO-d6, 400 MHz) δ 1.71 (s, 2H), 2.39 (s, 3H), 2.51 (s, 1H), 3.25 (s, 3H), 8.05 (d, 2H), 8.46 (d, 2H). LCMS: calculated C14H14N4O3S 318.08, observed 319.1 (MH+)
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].C1COCC1.Cl[CH:17]([F:19])[F:18]>O>[F:18][CH:17]([F:19])[O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)Oc1ccc(I)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
100 g (0.455 mol) of 4-iodophenol and 54.6 g (1.365 mol) of sodium hydroxide are added to a mixture of 300 ml of THF and 30 ml of water. After stirring for about 1/2 hour, the mixture is evaporated in a rotary evaporator; this is repeated after the addition of 200 ml of toluene. The residue is taken up in 400 ml of THF. The mixture is cooled to 0° C., 47.1 g (0.545 mol) of chlorodifluoromethane are introduced, and the mixture is then stirred for 1 hour. It is then stirred at about +5° C. for 18 hours. The solution above the resulting slurry-like precipitate was decanted off. It was evaporated in a rotary evaporator, and the residue was chromatographed through a silica gel column, using petroleum ether as eluent.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[CH:21]([OH:28])[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C1C[O:32][CH2:31][CH2:30]1.CC(O)=O.B(F)(F)F>CCOCC.C(O)CO>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([C:1]3([CH3:2])[O:32][CH2:31][CH2:30][O:3]3)=[CH:9][CH:8]=2)(=[O:11])=[O:12])=[C:15]([C:21]([C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)=[O:28])[CH:16]=1
Reactant: C1CCOC1
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(O)c2ccncc2)cc1
Agent: FB(F)F
Solvent: OCCO
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC1(c2ccc(S(=O)(=O)Nc3ccc(Cl)cc3C(=O)c3ccncc3)cc2)OCCO1

Procedure:
A solution consisting of 0.21 g of 4-acetyl-N-[4-chloro-2-(hydroxy-pyridin-4-yl-methyl)-phenyl]-benzenesulfonamide, 2 mL anhydrous THF, 50 μL AcOH and 400 μL ethylene glycol was prepared in a vial. The vial was heated by swaying gently in front of a heat gun, cooled for one minute and 400 μL 46.5% BF3:Et2O were immediately added. The vial was quickly shaken, left standing and an LC-MS sample was taken after 1 minute of reaction. After another minute the reaction mixture was partitioned between 10 mL DCM and 10 mL H2O. To the reaction mixture was then added an additional 20 mL DCM and 20 mL aqueous 1 M NaOH. The pH of the aqueous layer was brought to 3 using HCl and then quickly brought to pH 8-9 using saturated NaHCO3. The DCM layer was collected, the aqueous layer was extracted with DCM (2×20 mL) and all organic layers were combined and concentrated by rotary evaporation. The product was isolated by preparative HPLC, and the fractions containing the product were concentrated to a volume of 15 mL. To this solution was added 3 mL 3 M NaOH and 0.52 g KMnO4. The reaction was stirred at RT, monitored by LC-MS and additional KMnO4 (0.55 g×2) was added at intervals of ca. 2 hours. After a total rxn time of ca. 5 h, the crude mixture was brought to pH 4 using 10% AcOH, extracted with DCM (125 mL) and washed with saturated aqueous NaHCO3. The DCM was removed by rotary evaporation and the product was obtained by preparative HPLC. MS: m/z 459 (M++1).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=3)=[N:17][N:18]([C:20]3[CH:21]=[CH:22][C:23]4[N:24]([CH:26]=[N:27][N:28]=4)[N:25]=3)[CH:19]=2)[CH:12]=[CH:11][N:10]=1)=O)(C)(C)C.C(OC(NC1C=C(C2C(C3C=CC=CC=3)=NN(C3C=CC4N(C=NN=4)N=3)C=2)C=CN=1)=O)(C)(C)C>>[NH2:8][C:9]1[CH:14]=[C:13]([C:15]2[C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=3)=[N:17][N:18]([C:20]3[CH:21]=[CH:22][C:23]4[N:24]([CH:26]=[N:27][N:28]=4)[N:25]=3)[CH:19]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2cccc(C(F)(F)F)c2)ccn1
Agent: CC(C)(C)OC(=O)Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccccc2)ccn1
Product: Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2cccc(C(F)(F)F)c2)ccn1
Yield: 65.8 %

Procedure:
The reaction was carried out in the same manner as in Example 37-2) except for using 2.35 g (4.50 mmol) of 4-(2-t-butoxycarbonylaminopyridin-4-yl)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-3-(3-trifluoromethylphenyl)-1H-pyrazole obtained in Example 41-1) in place of 4-(2-t-butoxycarbonylaminopyridin-4-yl)-3-phenyl-1-([1,2,4]triazolo[4,3-b]-pyridazin-6-yl)-1H-pyrazole to obtain 1.25 g of the title compound as a white powder. (Yield: 66%)
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.CC(C1CC[C@H]2C(=CC[C@H]3[C@@](C(O)=[O:27])(C)CCC[C@@]32C)C=1)C.[S:30]([O-:33])([O-:32])=[O:31].[Na+].[Na+]>O>[S:30]([CH:2]([CH2:3][C:4]([OH:27])=[O:5])[C:1]([OH:6])=[O:7])([OH:33])(=[O:32])=[O:31]
Reactant: O=S([O-])[O-]
Reactant: CC(C)C1=CC2=CC[C@@H]3[C@](C)(CCC[C@@]3(C)C(=O)O)[C@H]2CC1
Reactant: O=C1C=CC(=O)O1
Agent: [Na+]
Solvent: O
Product: O=C(O)CC(C(=O)O)S(=O)(=O)O
Reaction time: 1.12 h

Procedure:
98 Parts of maleic anhydride are added, while stirring, to 742 parts of the above rosin acid oxalkylation product at 50° to 80° C.; after diluting the mixture with water, 132.3 to 138.6 parts of sodium sulfite (as an aqueous solution) are stirred in at 40° to 80° C. within 15 to 120 minutes, until the mixture has formed a clear solution. Subsequently, stirring is continued for 1 hour. The amount of water added may be in the range of from 50 to 85% by weight of the final solution.