Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:6]=[CH:5][N:4]=1>CN(C=O)C.[Pd]>[CH3:1][S:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:6]=[CH:5][N:4]=1
Reactant: COC(=O)Cc1ccccc1C#Cc1ccnc(SC)n1
Agent: [Pd]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1CCc1ccnc(SC)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 52.1 %

Procedure:
A suspension of methyl 2-(2-((2-(methylthio)pyrimidin-4-yl)ethynyl)phenyl)acetate (A1) (323 mg, 1.08 mmol) and 10% Pd/C (300 mg) in DMF (15 mL) was stirred under a hydrogen atmosphere at room temperature for 20 hours. The resulting mixture was filtered through Celite, washing with EtOAc (100 mL). The filtrate was evaporated in vacuo to yield a brown oil which was dissolved in DMF (10 mL). A slurry of 10% Pd/C (330 mg) in DMF (5 ml) was added and the resulting suspension was stirred under a hydrogen atmosphere at room temperature for a further 20 hours. The resulting mixture was filtered through Celite, washing with EtOAc (100 mL) then the filtrate was evaporated in vacuo. The resulting residue was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 12 g SiO2 cartridge, 0-20% EtOAc in petroleum benzine 40-60° C.) to yield the title compound A2 as a clear oil (170 mg, 52%); 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J=5.0 Hz, 1H), 7.25-7.14 (m, 4H), 6.75 (d, J=5.1 Hz, 1H), 3.69 (m, 5H), 3.11-3.04 (m, 2H), 2.99-2.91 (m, 2H), 2.57 (s, 3H). LC-MS-A: rt 6.060 min; m/z 303.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N+:13]([O-])=[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]2=[N:10]1.C1(C)C=CC=CC=1.CNC.[H][H]>[Ni].O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]2=[N:10]1
Reactant: [H][H]
Reactant: Cc1ccc(O)c(-n2nc3ccccc3[n+]2[O-])c1
Agent: [Ni]
Agent: CNC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Yield: 67 %

Procedure:
24.1 g (0.1 mol) of 2-(2'-hydroxy-5'-methylphenyl)benzotriazole-N-oxide, 9.6g of Raney nickel (produced by Kawaken Fine Chemical Co., Ltd.), 150 ml of a solvent mixture comprising toluene and water (ratio by volume, 4:1) and 7 g of 50% dimethylamine were charged into a 500-ml four neck flask. After the air in the flask had been replaced by nitrogen, the resultant mixture was agitated at room temperature. Hydrogen was then supplemented to allow for the amount of hydrogen absorbed by the mixture, which was then subjected to reaction until no more hydrogen was absorbed by it. After the reaction had bee completed, the catalyst was filtered off, and part of the filtrate was subjected to quantitative analysis using gas chromatography (GC). The results revealed a yield of 67% of 2-(2'-hydroxy-5'-methylphenyl)benzotriazole. The solvent was then distilled off from the filtrate, and the residual solid was crystallized using ethanol and then washed with ethanol to obtain 12.4 g of 2-(2'-hydroxy-5'-methylphenyl)benzotriazole (yield, 55%; melting point, 128° to 130° C.).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][C:12]=3[O:30][CH3:31])[CH:9]=2)[N:4]([S:32]([C:35]2[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH:3]=1.[F:42][C:43]1[CH:44]=[C:45]([CH:63]=[CH:64][CH:65]=1)[CH2:46][N:47]1[C:51]([CH3:52])=[C:50](B2OC(C)(C)C(C)(C)O2)[C:49]([CH3:62])=[N:48]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[F:42][C:43]1[CH:44]=[C:45]([CH:63]=[CH:64][CH:65]=1)[CH2:46][N:47]1[C:51]([CH3:52])=[C:50]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[CH:13][C:12]=4[O:30][CH3:31])[CH:9]=3)[N:4]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:3]=2)[C:49]([CH3:62])=[N:48]1
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1-c1cnc2c(c1)c(I)cn2S(=O)(=O)c1ccc(C)cc1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1-c1cnc2c(c1)c(-c1c(C)nn(Cc3cccc(F)c3)c1C)cn2S(=O)(=O)c1ccc(C)cc1

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-methoxyphenyl)piperazine-1-carboxylate (intermediate 52) (30 mg, 0.043 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (17 mg, 0.052 mmol) in sodium carbonate (14 mg, 0.13 mmol), Pd(PPh3)2Cl2 (1.5 mg, 0.00218 mmol), Toluene/ethanol/water (2/1/0.5 ml) to afford 156.0 mg (crude) of titled compound. MS: m/z=766.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:10]=[C:9]2[NH:17]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:17][C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:10]=1
Reactant: COC(=O)c1cnc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1-c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cnc(N)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 1-(4-fluorophenyl)-2-(tritylamino)-1H-imidazole-5-carboxylate (66) (200 mg, 0.419 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (5 mL). The reaction was stirred at room temperature overnight, concentrated and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered, and concentrated and in vacuo to afford methyl 2-amino-1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (67) as a yellow solid.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].Cl[C:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)=[O:21].C(N(CC)CC)C.O1CCCC1>O>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:20]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)=[O:21])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc1
Temperature: 25 °C
Yield: 96 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (0.5 g), methyl 4-(chlorocarbonyl)benzoate (397 mg), triethylamine (0.836 mL), and tetrahydrofuran (10 mL) was stirred at room temperature for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography (NH-silica gel, 90:10-50:50 hexane/ethyl acetate) to provide the title compound (628 mg, 96%) as crystals.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14]([NH2:16])=[O:15])=[CH:11][CH:10]=[C:9]([CH:17]=[CH2:18])[CH:8]=2)=[O:3]>CO.[Pd]>[NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14]([NH2:16])=[O:15])=[CH:11][CH:10]=[C:9]([CH2:17][CH3:18])[CH:8]=2)=[O:3]
Reactant: C=Cc1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.7 %

Procedure:
5% Palladium-activated carbon (19 mg) was added to a solution of 2-aminocarbonylamino-6-vinylindole-3-carboxamide (Compound 4-38, 18 mg, 0.073 mmol) in methanol (3 mL), and was stirred at room temperature for 4 hours under hydrogen atmosphere. After the reaction mixture was filtered throught Celite® pad, the filtrate was concentrated under reduced pressure to give the title compound (9.3 mg) as an off-white solid (yield 52%).
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:24])([F:23])[C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[CH2:15][CH2:16][C:17]#[C:18][Si](C)(C)C.Cl>CO>[CH2:15]([C:6]1[CH:7]=[CH:8][C:9]([C:11]([F:12])([F:14])[F:13])=[CH:10][C:5]=1[C:4]([F:3])([F:23])[F:24])[CH2:16][C:17]#[CH:18]
Reactant: C[Si](C)(C)C#CCCc1ccc(C(F)(F)F)cc1C(F)(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#CCCc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.1 %

Procedure:
To a solution of KOH (358 mg) in MeOH (30 mL) was added {4-[2,4-bis(trifluoromethyl)phenyl]but-1-yn-1-yl}(trimethyl)silane (1.8 g), followed by stirring at room temperature for 18 hours. The reaction liquid was neutralized with 1 M hydrochloric acid and extracted with ether. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc=100:0) to obtain 1-but-3-yn-1-yl-2,4-bis(trifluoromethyl)benzene (426 mg) as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:26][CH3:27])[C:22](OC)=[O:23])[C:11](=[O:28])[C@:10]([CH2:30][CH:31]3[CH2:35][O:34][C:33]([CH3:37])([CH3:36])[O:32]3)([CH3:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Li+]>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:26][CH3:27])[CH2:22][OH:23])[C:11](=[O:28])[C@:10]([CH2:30][CH:31]3[CH2:35][O:34][C:33]([CH3:36])([CH3:37])[O:32]3)([CH3:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](C(=O)OC)N1C(=O)[C@@](C)(CC2COC(C)(C)O2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Product: CC[C@@H](CO)N1C(=O)[C@@](C)(CC2COC(C)(C)O2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S)-methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)butanoate prepared above in Step B (734 mg, 1.34 mmol) in ether (12.2 mL) was added lithium borohydride (58.3 mg, 2.68 mmol) at 0° C. After being stirred at 0° C. for 30 min, the reaction was quenched (ice cold 10% citric acid), extracted (2×EtOAc) and washed (sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure provided the title compound as a colorless film. The product was used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5](O)[C:4]=2[N:3]=[CH:2]1.P(Cl)(Cl)([Cl:17])=O.[OH-].[NH4+]>CN(C)C=O>[Cl:17][C:5]1[C:4]2[N:3]=[CH:2][NH:1][C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=1
Reactant: Oc1nc2ccccc2c2[nH]cnc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Clc1nc2ccccc2c2[nH]cnc12

Procedure:
To a mixture of 7.7 g (0.0416 mole) of 1H-imidazo[4,5-c]quinolin-4-ol and 50 mL of N,N-dimethylformamide was added in small portions 12 mL (0.13 mole) of phosphorus oxychloride. The mixture was heated on a steam bath for 1.5 hour, poured onto ice and basified with concentrated ammonium hydroxide. The solid precipitate was separated by filtration, washed with water and dried to provide 4-chloro-1H-imidazo[4,5-c]quinoline as a tan powder corresponding to the product of Example 30.
Reaction SMILES: C(OC([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([CH3:17])=[N:12][CH:11]=[CH:10]2)=O)C.[OH-].[Na+].[Cl-].[NH4+]>C(O)C>[NH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([CH3:17])=[N:12][CH:11]=[CH:10]2
Reactant: CCOC(=O)Nc1ccc2c(C)nccc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: Cc1nccc2cc(N)ccc12
Yield: 72 %

Procedure:
6-Ethoxycarbonylamino-1-methylisoquinoline (0.629 g, Production Example 32b) was dissolved in ethanol (20 ml), to which was then added an aqueous 8 N sodium hydroxide solution (6.8 ml), followed by heating under reflux for 1.5 hours. After cooling as it was to room temperature, an aqueous saturated ammonium chloride was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, to give the title compound (0.311 g, 72%) as pale yellow crystals.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:11][C:12]#[C:13][C@H:14]([OH:24])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.[OH-].[Na+]>CCOCC.O>[Br:11]/[CH:12]=[CH:13]\[C@H:14]([OH:24])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1
Reactant: O[C@@H](C#CBr)COc1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: O[C@@H](/C=C\Br)COc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.4 %

Procedure:
AlCl3 (2.79 g, 21 mmol) was added in portions to a mixture of lithium aluminum hydride (LAH) (1.06 g, 28 mmol) and ether (70 mL). A solution of (3S)-1-bromo-4-(4-fluorophenoxy)-3-hydroxy-1-butyne (14 mmol) in ether (10 mL) was added cautiously. A vigorous reaction with evolution of gas was observed. The mixture was warmed to reflux on a water bath for 30 minutes. The reaction mixture was then cooled to 0° C. and treated with 2.8 mL water (slowly, vigorous reaction), 2.8 mL 15% NaOH, and finally 8.4 mL water. The resulting suspension was then stirred 10 minutes, filtered and the solids were washed with THF and ether. The solution was concentrated under vacuum to afford 2.94 g (81% yield for two steps) of (1Z, 3S)-1-bromo-4-(4-fluorophenoxy)-3-hydroxy-1-butene, a compound of formula (DD); 1H NMR (CDCl3) δ 2.41 (t, 1H), 3.85 (dd, 1H), 3.99 (dd, 1H), 4.50 (m, 1H), 6.31 (dd, 1H), 6.52 (dd, 1H), 6.83 (m, 2H), 6.97 (t, 2H) ppm.
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH:9]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[NH:20][C:21]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=5)[N:25]([CH3:36])[CH:24]=4)=[CH:22][C:15]=23)[CH2:10]1)(C)(C)C.[OH-].[Na+]>CO.ClCCl.O>[CH3:33][O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:34][CH3:35])[N:25]([CH3:36])[CH:24]=[C:23]2[C:21]1[NH:20][C:16]2=[N:17][CH:18]=[CH:19][C:14]([CH2:13][N:11]3[CH2:12][CH:9]([NH2:8])[CH2:10]3)=[C:15]2[CH:22]=1
Reactant: COc1cc2c(-c3cc4c(CN5CC(NC(=O)OC(C)(C)C)C5)ccnc4[nH]3)cn(C)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(-c3cc4c(CN5CC(N)C5)ccnc4[nH]3)cn(C)c2cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 19.7 %

Procedure:
0.27 cm3 of hydrochloric acid (4N in dioxane) is added to a solution of 0.051 g of {1-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]azetidin-3-yl}carbamic acid tert-butyl ester in 3 cm3 of methanol and 0.5 cm3 of dichloromethane, at a temperature in the region of 20° C. The reaction medium is stirred at room temperature for 24 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up in 4 cm3 of water and is then neutralized with 1N sodium hydroxide to pH 10. 12 cm3 of dichloromethane are added. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. 0.008 g of 1-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]azetidin-3-ylamine is obtained, the characteristics of which are as follows:
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]([F:25])([C:21]([F:24])([F:23])[F:22])[CH2:18][CH2:19]O>>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][CH2:19][CH2:18][C:17]([F:25])([F:16])[C:21]([F:24])([F:23])[F:22])(=[O:8])=[O:9]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: OCCC(F)(F)C(F)(F)F
Product: O=S(=O)(OCCC(F)(F)C(F)(F)F)C(F)(F)F
Temperature: 56 °C
Reaction time: 2 h

Procedure:
198.49 g (703.51 mmol) of trifluoromethanesulphonic anhydride were initially charged under argon. The reaction flask was immersed into an oil bath at 70° C. and heated to internal temperature 56° C. 88.2 ml (738.68 mmol) of 3,3,4,4,4-pentafluorobutanol were added dropwise to the reaction mixture within 35 min and the mixture was stirred at bath temperature 70-73° C. and internal temperature 69° C. for two hours. The reaction mixture was concentrated on a rotary evaporator and the residue was taken up in 1500 ml of dichloromethane. The residue was washed once with 300 ml of cold water, once with 300 ml of cold saturated aqueous sodium hydrogencarbonate solution and once with 300 ml of cold water. The organic phase was dried with magnesium sulphate, filtered and concentrated. This gave 192.86 g (92.6% of theory) of the target compound.
Reaction SMILES: Cl.[C:2]([C:6]1[S:7][C:8]2[C:13](=[O:14])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]4[CH:26]=[C:25]([NH:27][C:28]5[CH:32]=[C:31]([CH3:33])[N:30]([CH3:34])[N:29]=5)[C:24](=[O:35])[N:23](COCC[Si](C)(C)C)[N:22]=4)[C:16]=3[CH3:44])[CH2:11][C:9]=2[N:10]=1)([CH3:5])([CH3:4])[CH3:3].C1(OC)C=CC=CC=1>CO>[C:2]([C:6]1[S:7][C:8]2[C:13](=[O:14])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]4[CH:26]=[C:25]([NH:27][C:28]5[CH:32]=[C:31]([CH3:33])[N:30]([CH3:34])[N:29]=5)[C:24](=[O:35])[NH:23][N:22]=4)[C:16]=3[CH3:44])[CH2:11][C:9]=2[N:10]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1c(-c2cc(Nc3cc(C)n(C)n3)c(=O)n(COCC[Si](C)(C)C)n2)cccc1N1Cc2nc(C(C)(C)C)sc2C1=O
Agent: Cl
Solvent: CO
Solvent: COc1ccccc1
Product: Cc1c(-c2cc(Nc3cc(C)n(C)n3)c(=O)[nH]n2)cccc1N1Cc2nc(C(C)(C)C)sc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.2 %

Procedure:
Hydrogen chloride gas was bubbled into 2-tert-butyl-5-(3-(5-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-3-yl)-2-methylphenyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one 110c (186 mg, 0.30 mmol) and anisole (0.163 mL, 1.50 mmol) in methanol (20 mL) at 0° C. for 5 min. The resulting mixture was allowed to warm to room temperature and continue stirring for 16 h. The reaction mixture was concentrated. The residue was purified by reverse phase HPLC: C-18 column eluted with 20 to 60% Acetronitrile in water with 1% ammonium hydroxide over 14 min to afford 2-tert-butyl-5-(3-(5-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)-2-methylphenyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one 110 (40 mg, 30%). M+1 490.1. 1H NMR (400 MHz, DMSO) δ 12.95 (s, 1H), 9.09 (s, 1H), 7.77 (s, 1H), 7.50 (dd, J=5.6, 3.6, 1H), 7.41-7.32 (m, 2H), 5.97 (s, 1H), 4.97 (s, 2H), 3.62 (s, 3H), 2.17 (d, J=19.6, 6H), 1.47 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[N:15][N:14]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[C:13]=3[CH:22]=2)[CH:5]=[C:4]([F:23])[C:3]=1[C:24]([F:27])([F:26])[F:25].S(Cl)(Cl)=O>CN(C)C=O.C(Cl)Cl.C(#N)C.C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[N:15][N:14]([CH:17]([CH3:21])[C:18]([O:20][CH2:7][CH:2]=[CH:3][CH3:4])=[O:19])[C:13]=3[CH:22]=2)[CH:5]=[C:4]([F:23])[C:3]=1[C:24]([F:27])([F:26])[F:25]
Reactant: CC(C(=O)O)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CC=CCOC(=O)C(C)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21

Procedure:
A mixture of 6-[(2-chloro-α,α,α,6-tetraflouro-p-tolyl)oxy]-α-methyl-1H-benzotriazole-1-acetic acid, thionyl chloride (0.8 ml, 0.011 mole), and 2 drops of dimethylformamide in methylene chloride is heated at reflux temperature for 2 hours, cooled and concentrated in vacuo to give a residue which is re-evaporated four times with toluene at 60° . The resultant residue is treated with 2-methylallyl alcohol and pyridine, shaken until reaction is complete by infrared spectral analysis and concentrated in vacuo to give a residue. The thus-obtained residue is dissolved in 1% acetonitrile in carbon tetrachloride and filtered through a pad of silica. The filtrate is concentrated in vacuo to give a solid residue. The solid residue is recrystallized from warm heptane to afford the title compound as a white solid, mp 71°-74° C., identified by elemental and NMR analyses.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=O)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.O=P(Cl)(Cl)Cl.[OH-].[Na+]>C(#N)C>[C:1]([NH:5][C:6]1[N:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8]#[N:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Nc1nc(Cl)ccc1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(C)Nc1nc(Cl)ccc1C#N
Temperature: 55 °C
Yield: 80.6 %

Procedure:
To a solution of 2-tert-butylamino-6-chloro-nicotinamide (3, 850 mg, 3.73 mmol) in acetonitrile (anhydrous, 40 mL) were added pyridine (2.42 mL, 29.9 mmol) and POCl3 (1.37 mL, 14.9 mmol). The reaction was heated at 55° C. for 3 hours. After cooling to room temperature, NaOH solution (10% aq.) was slowly added till pH 9. The solution was extracted with EtOAc (3×50 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification was accomplished by Biotage silica gel chromatography, eluting with 2%-30% EtOAc/hexanes gradient, to afford 630 mg (80% yield) of the title product.