Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.O[C:27]1[C:32]([F:33])=[CH:31][C:30]([CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[CH:29][C:28]=1[F:41]>>[F:33][C:32]1[CH:31]=[C:30]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH:29]=[C:28]([F:41])[C:27]=1[O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13]
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: CS(=O)(=O)OCc1c(-c2ccc(C(F)(F)F)cc2)nsc1C(F)(F)F
Product: O=C(O)CCc1cc(F)c(OCc2c(-c3ccc(C(F)(F)F)cc3)nsc2C(F)(F)F)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (5-(trifluoromethyl)-3-(4-(trifluoromethyl)phenyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-3,5-difluorophenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 7.99 (d, J=8.1 Hz, 2H), 7.82 (d, J=8.1 Hz, 2H), 6.86 (d, J=13.5 Hz, 2H), 5.23 (s, 2H), 2.87 (t, J=7.2 Hz, 2H), 2.60 (t, J=7.5 Hz, 2H). Mass spectrum (ESI, m/z): Calcd. for C21H13F8NO3S, 510.1 (M−H). found 509.9.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[C:7]([OH:13])(=O)[CH2:8][CH2:9][CH2:10][CH3:11]>[Pd]>[CH2:7]([O:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4])[CH2:8][CH2:9][CH2:10][CH3:11].[CH3:2][CH2:3][O:13][CH2:7][CH3:8]
Reactant: CCCCC(=O)O
Reactant: OCC(O)CO
Agent: [Pd]
Product: CCCCCOCC(O)CO
Product: CCOCC
Temperature: 120 °C
Yield: 69 %

Procedure:
A stirred autoclave was charged, at room temperature, with 65.85 g (715 mmol) of glycerol, 1.80 g (17.6 mmol) of valeric acid, 0.18 g (10 wt %) of AMBERLYST® (a polymer based catalyst) 35 resin and 0.39 g (1.0 mol %) of Pd/C at 5%. The autoclave was then pressurized at 50 bar of dihydrogen gas H2, and then it was heated at 120° C. for 16 h, stirring vigorously. After 16 h of reaction, the reaction mixture was brought back to room temperature. The catalyst was filtered on a MILLIPORE® filter (a membrane filter) (0.1 μm) and was rinsed with absolute ethanol. The solvents were evaporated and the organic products were extracted from the glycerol phase by extraction with CH2Cl2 (3×50 ml). The organic phase was washed with water (2×30 ml) and the CH2Cl2 was then evaporated at reduced pressure. The crude reaction product was purified on a flash silica column (eluent: cyclohexane/ethyl acetate=4:1˜1:1). 1-O-pentyl-glycerol ether was obtained at an isolated yield of 69%. After the reaction, the mixture of catalysts (AMBERLYST® (a polymer based catalyst) 35 resin and Pd/C) was immersed in 5 ml of methanol, and then transferred to the autoclave. The latter was dried under an argon stream for 4 h at room temperature. After complete evaporation of the solvent, the substrates (glycerol and valeric acid) were added for a fresh reaction (cf. example 31).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[I:10]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCOCC1.CN1CCCC1=O>[I:10][C:7]1[CH:6]=[C:5]([CH3:9])[C:3]([NH2:4])=[C:2]([CH3:1])[CH:8]=1
Reactant: II
Reactant: Cc1cccc(C)c1N
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1cc(I)cc(C)c1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a solution of 2,6-dimethyl aniline (50 gm) in 1,4-dioxane (400 ml) and N-methylpyrrolidone (40 ml) was added iodine (157.3 gm) slowly at 0° C. The solution was stirred for 1 hour at 0° C. and the temperature was raised to room temperature. The solution was stirred for 1 hour at room temperature and then added a saturated solution of sodium thiosulfate. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried with anhydrous sodium sulfate and the solvent was evaporated in vacuum to obtain 91 gm of 4-iodo-2,6-dimethyl benzenamine.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[OH:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13].[P:21](Cl)(Cl)([O:23][CH3:24])=[O:22]>CCOCC>[CH2:15]([O:14][C:12]([C:11]1[CH:17]=[CH:18][C:19]2[O:20][P:21]([O:23][CH3:24])(=[O:22])[O:8][C:9]=2[CH:10]=1)=[O:13])[CH3:16]
Reactant: COP(=O)(Cl)Cl
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2c(c1)OP(=O)(OC)O2
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
Triethylamine (2.211 g, 21.86 mM) was added to a solution of1.989 g (10.93 mM) of ethyl 3,4-dihydroxybenzoate in 30 ml of ether. The mixture was cooled to -30° C. to -20° C. and a solution of 1.627 g (10.93 mM) of methyl dichlorophosphate in 10 ml of ether was added thereto dropwise with stirring over 10 minutes. The reaction mixture was stirred at the same temperature for 5 minutes, the bath was then removed and the temperature was allowed to rise to 20° C. Filtration and washing were carried out by the procedure of Reference Example 1, and the filtrate and washings were concentrated at room temperature (20°~25° C.) under reduced pressure. There was obtained 2.387 g (84.6% yield) of 5-ethoxycarbonyl-2-methoxy-2-oxo-1,3,2-benzo-dioxaphosphole as a viscous oil.
Reaction SMILES: [C:1]([CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5])#[N:2].P(Cl)(Cl)(Cl)(Cl)Cl.[F:19][C:20]1[C:25](O)=[C:24]([F:27])[C:23]([F:28])=[C:22]([F:29])[C:21]=1[F:30].N1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.ClCCl>[F:19][C:20]1[C:25]([O:5][C:4](=[O:6])[CH:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:1]#[N:2])=[C:24]([F:27])[C:23]([F:28])=[C:22]([F:29])[C:21]=1[F:30]
Reactant: N#CC(C(=O)O)c1ccccc1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC(C(=O)Oc1c(F)c(F)c(F)c(F)c1F)c1ccccc1
Temperature: 0 °C

Procedure:
8 g. (0.05 moles) of α-cyano-phenylacetic acid are dissolved in 80 ml. of dichloromethane. 10.2 g. (0.05 moles) of phosphorus pentachloride are added and the mixture is stirred for two hours at the boiling point of dichloromethane. The solvent is distilled off and the residue is taken up in carbontetrachloride and the solution is added dropwise to 9.2 g. (0.05 moles) of pentafluorophenol and 4 ml. (0.05 moles) of pyridine-dissolved in 200 ml. of carbontetrachloride. The reaction mixture is cooled to 0° C. and the pyridine chlorohydrate is washed with 2n hydrochloride acid. The organic layer is washed twice with 40 ml. of water, dried over magnesium sulfate and evaporated. The α-cyano-phenylacetic acid-pentafluorophenyl ester is recrystallized from petrolether
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]([F:15])([F:14])[O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)C.[OH-].[Na+]>CO.C1COCC1.O>[F:15][C:5]([F:14])([O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[C:4]([OH:16])=[O:3]
Reactant: CCOC(=O)C(F)(F)Oc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C(F)(F)Oc1ccc(F)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of 2,2-difluoro-2-(4-fluorophenoxy)acetic acid ethyl ester (2.9 g, 12 mmol) in a mixture of MeOH (20 ml) and THF (10 ml) was added a solution of NaOH (1.48 g, 37 mmol) in water (10 ml). The reaction mixture was stirred 20 h at rt and 1 h at 40° C. The reaction mixture was concentrated and the remaining aqueous solution was diluted with water (10 ml) and washed with hexanes. The solution was acidified to pH 3 by adding 1N HCl and the heterogeneous mixture was extracted with ethyl acetate. The combined extracts were washed with brine and after drying over sodium sulfate, the solvent was removed to obtain 2,2-difluoro-2-(4-fluorophenoxy)acetic acid as
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[I:10]Cl.O>C(O)(=O)C>[OH:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[C:4]([CH:3]=1)[C:5]#[N:6]
Reactant: ClI
Reactant: N#Cc1cccc(O)c1
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cc(O)ccc1I
Yield: 6.5 %

Procedure:
3-Hydroxy-benzonitrile (15 g, 0.126 mol) and iodine monochloride (28 g, 0.172 mol) is heated in acetic acid for 15 hours at 45° C. H2O is added to precipitate the product out. After the precipitate is collected and washed with Na2SO3, the residue is chromatographed with chloroform to get the product (2 g, 7%).
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:6]([OH:8])=O)[CH2:3][CH2:2]1.[CH3:16][NH:17][C@H:18]1[CH2:37][N:22]2[C:23]3[C:28]([C:29]([CH2:30][C:31]([O:33]CCC)=[O:32])=[C:21]2[CH2:20][CH2:19]1)=[CH:27][CH:26]=[CH:25][CH:24]=3>>[CH:1]1([CH2:4][CH:5]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:6]([N:17]([CH3:16])[C@H:18]2[CH2:37][N:22]3[C:23]4[C:28]([C:29]([CH2:30][C:31]([OH:33])=[O:32])=[C:21]3[CH2:20][CH2:19]2)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:8])[CH2:2][CH2:3]1
Reactant: O=C(O)C(CC1CC1)c1ccc(F)cc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)C(CC1CC1)c1ccc(F)cc1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from 3-cyclopropyl-2-(4-fluorophenyl)propanoic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 449.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][CH2:14][C:15]1([CH2:18][OH:19])[CH2:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:19][CH2:18][C:15]1([CH2:14][O:13][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:16][CH2:17]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1(COCc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(COCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
Methane sulfonyl chloride (5.2 mL, 68.7 mmol) was added drop wise to an ice cooled solution of {1-[(benzyloxy)methyl]cyclopropyl}methanol (Compound 63E, 11 g, 57.2 mmol) and triethylamine (15.5 mL, 114 mmol) in dichloromethane (50 mL). The reaction mixture warmed to RT and allowed to stir overnight. The reaction mixture was filtered to remove solids. The filtrate was washed with saturated sodium bicarbonate solution followed by brine, dried over magnesium sulfate, filtered and concentrated to give 12 g (77%) of the desired product as light yellow oil which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.25-7.41 (m, 5H), 4.58 (s, 2H), 4.21 (s, 2H), 3.42 (s, 2H), 2.96 (s, 3H), 0.61-0.75 (m, 4H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[CH:17][CH:16]=2)[CH:10]=3)[CH2:3][CH2:2]1.[Br:32]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C(OCC)(=O)C>[Br:32][C:14]1[C:13]2[C:9](=[CH:10][N:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:29]([CH3:31])[CH3:30])=[CH:17][CH:16]=3)[N:12]=2)[CH:8]=[CH:7][C:6]=1[O:5][CH2:4][CH:1]1[CH2:2][CH2:3]1
Reactant: CC(C)[Si](Oc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1)(C(C)C)C(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)[Si](Oc1ccc(-n2cc3ccc(OCC4CC4)c(Br)c3n2)cc1)(C(C)C)C(C)C
Temperature: 80 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
To a solution of 6-(cyclopropylmethoxy)-2-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-2H-indazole (1.31 g) in ethyl acetate (15 mL) were added N-bromosuccinimide (0.56 g) and azobisisobutyronitrile (99 mg), and the mixture was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as an orange oil (1.41 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:11])[NH:9][N:10]=[C:4]2[C:3]=1[O:12][CH3:13].BrC1C=CN2C(=O)NN=C2C=1O.CCN(C(C)C)C(C)C.Cl[CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:11])[N:9]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:10]=[C:4]2[C:3]=1[O:12][CH3:13]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1c(Br)ccn2c(=O)[nH]nc12
Agent: O=c1[nH]nc2c(O)c(Br)ccn12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1c(Br)ccn2c(=O)n(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 20 %

Procedure:
To a stirred suspension of the mixture of 7-bromo-8-methoxy-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one and 7-bromo-8-hydroxy-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one (from step 4) in DCM (120 mL) at 0° C. was added DIPEA (35 mL, 0.2 mol). After 5 min, (2-chloromethoxy-ethyl)-trimethylsilane (11.9 mL, 67.2 mmol) was added. The mixture was stirred at 0° C. for 1 hour and at RT for a further 2 hours. The resulting mixture was diluted with DCM (200 mL) and washed successively with 0.5 M HCl (aq) (400 mL) and water, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 15 to 30% ethyl acetate in cyclohexane) to afford the title compound (1.30 g, 20%) as a yellow solid. Fractions containing 7-bromo-8-(2-trimethylsilanyl-ethoxymethoxy)-2-(2-trimethylsilanyl-ethoxymethyl)-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one were evaporated and the resultant residue was dissolved in MeOH (120 mL). The solution was stirred for 8 days at RT before evaporating to dryness. The resultant residue was dissolved in DMF (25 mL), cooled to 0° C., and cesium carbonate (13 g, 40 mmol) and iodomethane (3.11 mL, 50 mmol) were added. The reaction mixture was stirred at RT for 16 hours. EtOAc and water were added, the aqueous phase was isolated and extracted twice with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 15 to 30% EtOAc in cyclohexane) to afford a further quantity of the title compound (3.26 g, 51%) as a yellow solid. LCMS (Method A): RT=4.70 min, [M+H]+=396/398.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][O:25][CH3:26])[NH:13][C:12](=[O:27])[N:11]=2)[CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].[C:28]([O:31]C(=O)C)(=O)[CH3:29].C([O-])(=O)C.[K+].[N:40](OCCC(C)C)=O>C(Cl)(Cl)Cl>[CH3:2][C:1]1[C:3]2[C:4](=[CH:6][CH:7]=[C:8]([C:10]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:22][CH2:23][CH2:24][O:25][CH3:26])[NH:13][C:12](=[O:27])[N:11]=3)[CH:9]=2)[N:5]([C:28](=[O:31])[CH3:29])[N:40]=1
Reactant: CC(C)CCON=O
Reactant: CC(=O)OC(C)=O
Reactant: CCc1cc(-c2cc(-c3ccccc3OCCOC)[nH]c(=O)n2)ccc1N
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: COCCOc1ccccc1-c1cc(-c2ccc3c(c2)c(C)nn3C(C)=O)nc(=O)[nH]1
Temperature: 40 °C
Yield: 63.7 %

Procedure:
A flask was charged with 4-(2-ethylanilin-4-yl)-6-[2-(2-methoxyethoxy)phenyl]-pyrimidin-2(1H)-one (5.5 g, 15 mmol), chloroform (150 mL), acetic anhydride (6.2 mL, 66.7 mmol) and potassium acetate (2.54 g, 30 mmol). The mixture was heated at 40° C. for 2 hours followed by the addition of isoamyl nitrite (5.24 mL, 39 mmol). The resulting mixture was heated to 60° C. overnight, concentrated under reduced pressure, neutralized with sodium bicarbonate, and extracted with EtOAc. The organic layer was concentrated under reduced pressure, and purified by column chromatography to give 4-(3-methyl-1-acetyl-1H-indazol-5-yl)-6-(2-{[2-(methyloxy)ethyl]oxy}phenyl)pyrimidin-2(1H)-one (4.0 g, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:14]([NH:15][CH:16]([CH:20]4[CH2:22][CH2:21]4)[CH:17]4[CH2:19][CH2:18]4)=[N:13][CH:12]=[C:11]([C:23]#[N:24])[C:7]=3[NH:8][C:9]=2[CH:10]=1.C(=O)([O-])[O-:26].[K+].[K+].OO>CS(C)=O.CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:14]([NH:15][CH:16]([CH:20]4[CH2:22][CH2:21]4)[CH:17]4[CH2:18][CH2:19]4)=[N:13][CH:12]=[C:11]([C:23]([NH2:24])=[O:26])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: N#Cc1cnc(NC(C2CC2)C2CC2)c2c1[nH]c1cc(Cl)ccc12
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: NC(=O)c1cnc(NC(C2CC2)C2CC2)c2c1[nH]c1cc(Cl)ccc12
Temperature: 85 °C

Procedure:
To a stirred solution of 7-chloro-1-[(dicyclopropylmethyl)amino]-5H-pyrido[4,3-b]indole-4-carbonitrile (10.1 g, 30 mmol) in DMSO (300 mL) were added potassium carbonate (24.9 g, 180 mmol) and 30% H2O2 (36.8 mL, 360 mmol). The reaction mixture was heated to 85° C. for 5 h, treated with additional reagents (30.7 mL of 30% H2O2 and 20.8 g of potassium carbonate), heated to 85° C. for 3 h, cooled to room temperature, and diluted with EtOAc and water. The mixture was extracted with EtOAc (×3). The combined organics were washed with brine, dried (sodium sulfate), concentrated, and purified by flash chromatography to provide the title compound. 1H NMR (500 MHz, CD3SOCD3) δ 11.67 (s, 1H); 8.47 (s, 1H); 8.41 (d, 1H); 7.83 (br s, 1H); 7.78 (d, 1H); 7.26 (dd, 1H); 7.18 (br s, 1H); 6.57 (d, 1H); 3.61 (q, 1H); 1.35 (m, 2H); 0.51 (m, 2H); 0.32-0.40 (m, 6H). LRMS (APCI) calc'd for (C19H19ClN4O) [M+H]+, 355.1. found 355.1.
Reaction SMILES: [F:1][S:2]([F:13])([F:12])([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Br[C:15]1[C:24]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([CH3:29])[CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:28][S:25]([C:24]1[C:15]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([S:2]([F:10])([F:11])([F:12])([F:13])[F:1])[CH:4]=2)=[CH:16][C:17]([CH3:29])=[C:18]([CH:23]=1)[C:19]([O:21][CH3:22])=[O:20])(=[O:26])=[O:27]
Reactant: Oc1cccc(S(F)(F)(F)(F)F)c1
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(Br)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(S(C)(=O)=O)c(Oc2cccc(S(F)(F)(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.9 %

Procedure:
5.00 g of 3-pentafluorosulfanylphenol, 6.98 g of methyl 4-bromo-5-methanesulfonyl-2-methylbenzoate (Journal of Medicinal Chemistry (1997), 40(13), 2017) and 22.20 g of Cs2CO3 were stirred in 200 ml of anhydrous DMF at 100° C. for 2 h. The mixture was allowed to cool, and the reaction mixture was poured onto 1 of water and stirred at RT for 16 h. The product was then filtered off and dried under reduced pressure. 8.20 g of pale yellow crystals were obtained, mp 139° C. (with decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[S:43]1[CH:47]=[CH:46][N:45]=[C:44]1[C@H:48]([NH2:50])[CH3:49]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:35]([NH:50][C@@H:48]([C:44]2[S:43][CH:47]=[CH:46][N:45]=2)[CH3:49])=[O:41])=[C:18]([F:23])[CH:17]=1
Reactant: C[C@@H](N)c1nccs1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@H](C)c4nccs4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1R)-1-(1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (28 mg, yield 62%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][O:15][NH:14][C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:26]1([C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=2)=[O:39])[CH2:30][CH:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28](=[O:37])[O:27]1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][O:15][N:14]([C:26]2([C:38]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][C:45]([N+:48]([O-:50])=[O:49])=[CH:46][CH:47]=3)=[O:39])[CH2:30][CH:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:28](=[O:37])[O:27]2)[C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC(Cl)(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1c1ccccc1
Reactant: O=C(N[C@H]1CONC1=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CON(C2(C(=O)OCc3ccc([N+](=O)[O-])cc3)CC(c3ccccc3)C(=O)O2)C1=O)OCc1ccccc1
Yield: 68.9 %

Procedure:
Production of Compound(64): In 6 ml of dichloromethane was suspended 280 mg of (4S)-4-benzyloxycarbonylamino-3-isoxazolidinone. To the suspension were added, under ice-cooling and stirring, 0.36 ml of triethylamine and 490 mg of the Compound (63) obtained in Example 63 dissolved in 1 ml of dichloromethane. The reaction was solution stirred at room temperature for 30 minutes, which was washed with water and dried (MgSO4). The solvent was evaporated off, and the residue was chromatographed on silica gel, followed by elution with hexane-ethylacetate (3:1) to give 470 mg of the subject Compound (64) as colorless oily product. The IR and NMR spectra of this product were in agreement with those of the Compound (64) obtained in Example 64.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[OH:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([F:18])=[CH:4][N:3]=[C:2]([NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[C:20]([OH:19])[CH:21]=3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccc(Nc2nc(Cl)ncc2F)cc1Cl
Reactant: Nc1cccc(O)c1
Product: COc1ccc(Nc2nc(Nc3cccc(O)c3)ncc2F)cc1Cl

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and 3-hydroxyaniline were reacted to produce N4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.91 (d, 1H, J=5.4 Hz), 7.71 (d, 1H, J=2.4 Hz), 7.58 (dd, 1H, J=3.0 and 9.0 Hz), 7.15 (t, 1H, J=8.4 Hz), 7.06 (d, 1H, J=8.7 Hz), 6.92 (td, 1H, J=1.8 and 9.9 Hz), 6.88 (t, 1H, J=1.8 Hz), 6.61 (ddd, 1H, J=1.2, 2.4, and 8.1 Hz), 3.89 (s, 3H),; 19F NMR (282 MHz, CD3OD): −46612; LCMS: purity: 98%; MS (mite): 362(MH+).