Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N+:33]([O-])=O)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:24][CH3:25])=[N:6][CH:7]=1.O.[Cl-].[NH4+].CO>O1CCOCC1.C(Cl)(Cl)Cl.[Zn]>[NH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[O:26][C:3]1[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:24][CH3:25])[N:4]=1
Reactant: COc1cc(N2CCN(C(C)=O)CC2)ccc1Nc1ncc(Cl)c(Oc2ccccc2[N+](=O)[O-])n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COc1cc(N2CCN(C(C)=O)CC2)ccc1Nc1ncc(Cl)c(Oc2ccccc2N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-(4-(4-(5-chloro-4-(2-nitrophenoxy)pyrimidin-2-ylamino)-3-methoxyphenyl)piperazin-1-yl)ethanone (140 mg, 0.28 mmol) in 1,4-dioxane:water (10 mL:4 mL), Zinc dust (81 mg, 1.4 mmol) and ammonium chloride (74 mg, 1.4 mmol) were added, and the mixture was stirred at rt for 30 min. TLC showed completion of starting material (TLC system:5% methanol in chloroform (Rf): 0.3). The reaction mixture was filtered, concentrated, diluted with water (20 mL) and extracted with ethyl acetate (3×10 mL). The organic layer was separated, dried over sodium sulphate, and concentrated. Crude compound was washed with n-pentane to obtain 1-(4-(4-(4-(2-aminophenoxy)-5-chloropyrimidin-2-ylamino)-3-methoxy phenyl)piperazin-1-yl)ethanone as a pale yellow solid. (Yield: 90 mg, 68.7%). 1HNMR (DMSO-d6) δ 8.30 (s, 1H), 7.90 (s, 1H), 7.35 (d, 1H), 7.00 (m, 2H), 6.80 (d, 1H), 6.58 (m, 2H), 6.20 (br s, 1H), 4.90 (br s, 2H), 3.75 (s, 3H), 3.55 (m, 4H), 3.05 (m, 2H), 2.95 (m, 2H), 2.02 (s, 3H). Step-4. Preparation of N-(2-(2-(4-(4-acetylpiperazin-1-yl)-2-methoxyphenylamino)-5-chloro pyrimidin-4-yloxy)phenyl)acrylamide:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[N:9]=2)=[C:4]([NH:16][CH:17]([CH3:19])[CH3:18])[CH:3]=1.[NH2:20][C:21]1[CH:29]=[CH:28][C:24]2[N:25]=[CH:26][S:27][C:23]=2[CH:22]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C(#N)C.CO>[S:27]1[C:23]2[CH:22]=[C:21]([NH:20][C:2]3[N:7]=[CH:6][C:5]([C:8]4[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[N:9]=4)=[C:4]([NH:16][CH:17]([CH3:19])[CH3:18])[CH:3]=3)[CH:29]=[CH:28][C:24]=2[N:25]=[CH:26]1
Reactant: COc1cccc(-c2cnc(Cl)cc2NC(C)C)n1
Reactant: Nc1ccc2ncsc2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1cccc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)n1
Temperature: 110 °C
Reaction time: 0.05 h

Procedure:
6′-Chloro-N-isopropyl-6-methoxy-[2,3′-bipyridin]-4′-amine (25 mg, 0.090 mmol), 6-aminobenzothiazole (20.28 mg, 0.135 mmol), BINAP (1.121 mg, 1.800 μmol), sodium tert-butoxide (26.0 mg, 0.270 mmol) were dissolved in Toluene (1 ml) in a sealed tube and thoroughly purged with N2 for 5 minutes. Pd2(dba)3 (3.3 mg, 3.6 μmol) was added and the reaction mass was once again purged with N2 for 5 minutes. The pressure tube was sealed and heated at 110° C. overnight. The reaction was cooled to rt and passed through a celite bed and washed with DCM. The filtrate was concentrated, dissolved in 10 mL water and extracted with DCM (3×8 mL). The combined organic layers were dried, concentrated and purified via preparative HPLC to afford Example 176. 1H NMR: 400 MHz, CD3OD: δ 1.33 (d, J=6.40 Hz, 6H), 3.74-3.80 (m, 1H), 3.99 (s, 3H), 6.17 (s, 1H), 6.71 (d, J=8.00 Hz, 1H), 7.34 (d, J=7.60 Hz, 1H), 7.52 (dd, J=2.40, 8.80 Hz, 1H), 7.75 (t, J=8.00 Hz, 1H), 7.98 (d, J=8.80 Hz, 1H), 8.23 (s, 1H), 8.34 (s, 1H), 9.07 (s, 1H). LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 μm; Solvent A=10% MeOH: 90% H2O: 0.1% TFA; Solvent B=90% MeOH: 10% H2O: 0.1% TFA; gradient 0-100% B over 2 min (3 min run time); retention time: 1.713 min; LCMS (ES-API), m/z 392.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μl/min; Retention time: 7.274 min; Purity: 98.1%.
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:6][N:5]([C:7](=[O:10])[CH2:8][OH:9])[C@H:4]([C:11]([NH2:13])=[O:12])[CH2:3]1.CN(C)CCCN(C)C.C(N(CC)CC)C.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(#N)C.[Cl-].[Na+].O.C(OCC)(=O)C>[C:31]1([S:37]([O:9][CH2:8][C:7]([N:5]2[CH2:6][C:2]([F:1])([F:14])[CH2:3][C@H:4]2[C:11]([NH2:13])=[O:12])=[O:10])(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC(=O)[C@@H]1CC(F)(F)CN1C(=O)CO
Agent: CN(C)CCCN(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: NC(=O)[C@@H]1CC(F)(F)CN1C(=O)COS(=O)(=O)c1ccccc1
Reaction time: 1 h

Procedure:
(2S)-4,4-difluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carbox amide (1.66 g) was suspended in acetonitrile (40 mL). To this suspension, N,N,N′,N′-tetramethyl-1,3-propanediamine (133 μL) and triethylamine (2.20 mL) were added. While the mixture was cooled in a salt-ice bath, benzenesulfonyl chloride (1.20 mL) was added dropwise. The reaction mixture was then stirred at the same temperature for 1 hour, followed by the addition of saturated brine (20 mL) and extraction with ethyl acetate (2×80 mL). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the resulting residue, a mixture of ethyl acetate and methanol (20:1, 30 mL) was added and the resulting crystal was collected by filtration to give (2S)-1-[2-(benzenesulfonyloxy)acetyl]-4,4-difluoropyrrolidine-2-carboxamide as a white crystal (1.60 g). The filtrate was concentrated under reduced pressure and the residue was purified on a silica gel column (ethyl acetate:methanol=20:1) to give additional (2S)-1-[2-(benzenesulfonyloxy)acetyl]-4,4-difluoropyrrolidine-2-carboxamide (0.58 g). The total amount of the product was 2.18 g (79% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH2:15])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].CCN(C(C)C)C(C)C.[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:27]=1[C:28](Cl)=[O:29].CO>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:28](=[O:29])[C:27]2[C:31]([CH3:35])=[CH:32][CH:33]=[CH:34][C:26]=2[Cl:25])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: Cc1cccc(Cl)c1C(=O)Cl
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)c2c(C)cccc2Cl)Cc2ccccc2C1
Yield: 115.9 %

Procedure:
A test tube (25×150 mm) containing a stirring bar and 2-amino-indan-2-carboxylic acid ethyl ester (0.53 g, 2.58 mmol) is charged with dry DCM (3 mL). Stirring is initiated. After dissolution, the DIPEA (1.50 mL, 8.6 mmol) and 4-dimethylaminopyridine (2 mg, 17 μmol) are added. A solution of 2-chloro-6-methylbenzoyl chloride (5.8 mmol) in dry DCM (4 mL), as prepared above, is added to the reaction tube. After stirring for 18 h, tlc analysis (silica, 10% CH3OH in DCM) indicates complete consumption of the amine. The reaction mixture is diluted with DCM (10 mL) and washed with 5% aqueous HCl (2×5 mL) and brine (5 mL), dried over MgSO4 filtered and evaporated by pumping to constant weight gives 1.07 g of light brown solid. This material is purified by chromatography (silica, 2% to 20% EtOAc in DCM) on the ISCO Companion using a 40 g cartridge. Fractions 6-10 are combined, evaporated and pumped to yield a constant weight 550 mg of white amorphous solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].Cl[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:20])=[C:15]([C:17](=[O:19])[CH3:18])[CH:16]=1.Cl>CN(C)C=O>[C:17]([C:15]1[CH:16]=[C:11]([CH2:10][N:3]2[CH2:7][CH2:6][CH2:5][C:4]2=[O:8])[CH:12]=[CH:13][C:14]=1[OH:20])(=[O:19])[CH3:18]
Reactant: O=C1CCCN1
Reactant: CC(=O)c1cc(CCl)ccc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(CN2CCCC2=O)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 0.80 g, 20.0 mmol) in 15 mL dry dimethylformamide under argon, cooled in an ice-bath was added dropwise a solution of 2-pyrrolidinone (1.70 g, 20.0 mmol) in 5 mL dimethylformamide. The ice-bath was removed, the mixture was stirred 30 minutes, and a solution of 5'-(chloromethyl)-2'-hydroxyacetophenone (1.85 g, 10.0 mmol) in 5 mL dimethylformamide was added dropwise. The mixture was stirred four hours, poured into 75 mL ice water, acidified with 7 mL 3N hydrochloric acid, and extracted with methylene chloride (3×75 mL). The extract was washed with water (25 mL) and brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give crude product which was purified by flash chromatography on silica gel eluting with 2:98 methanol:chloroform to give 1.92 g (82%) product as a viscous oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)=[CH2:14].[CH:20](OCC)=[O:21].[Cl-].[NH4+]>O1CCCC1>[CH:13]([N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[CH:20]=[O:21])=[CH2:14]
Reactant: C=Cn1ccnc1
Reactant: CCOC=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=Cn1ccnc1C=O
Reaction time: 0.5 h
Yield: 43.5 %

Procedure:
To a cold (-78° C.) solution of 6.55 ml (0.047 mole) of diisopropylamine in 125 ml of tetrahydrofuran was added 16.99 ml (, 042 mole) of a 2.5M solution of n-butyl lithium over a period of 15 minutes and the resulting reaction allowed to stir for 30 minutes. 1-Vinylimidazole (3.85 ml 0.042 mole) was added over a 10 minute period and the mixture stirred for one hour. Ethyl formate (3.43 ml, 0.042 mole) was then added over 5 minutes and the mixture stirred for one hour and was then poured into a saturated ammonium chloride solution. The product was extracted with ethyl acetate, and the extracts combined, dried over magnesium sulfate and concentrated to an orange oil. The residue was chromatographed on 200 g of silica gel using 10% ethyl acetate in chloroform to give 2.23 g of the product as a crystalline material.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[N+:9]([O-])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Cl:18][C:10]1[N:9]=[CH:8][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:12][CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cccc(Oc2ccc(Cl)cc2)c1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Clc1ccc(Oc2ccc(Cl)nc2)cc1

Procedure:
A solution of 22 g of 3-(p-chlorophenoxy)pyridine N-oxide in 500 ml of chloroform is added dropwise to 77 g of refluxing phosphorous oxychloride. The mixture is refluxed 30 minutes, cooled and concentrated at reduced pressure. The resulting oil is dissolved in 400 ml of dichloromethane, washed with 40 ml ice cold concentrated ammonium hydroxide and the dichloromethane solution is dried over anhydrous MgSO4. The mixture is filtered, concentrated under reduced pressure and distilled to yield the mixture of desired chlorinated pyridines; bp 103°-105° C./0.1 mm. The oil is dissolved in 100 ml of toluene and chromatographed over 400 g of silica gel in toluene to yield in the first eluate, 6-chloro-3-(p-chlorophenoxy)pyridine. Continued elution with toluene yields 2-chloro 3-(p-chlorophenoxy)pyridine. Finally, elution with toluene-methanol (50:50) yields 4-chloro-3-(p-chlorophenoxy)pyridine.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:8]([CH:10]1[O:14][C:13](=[O:15])[NH:12][CH2:11]1)[CH3:9].[F:16][CH:17]([F:37])[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([C:32]3[CH:33]=[N:34][NH:35][CH:36]=3)[N:26]=2)[CH:19]=1>CN(C=O)C.[Cl-].[Na+].O>[F:37][CH:17]([F:16])[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]2[N:26]=[C:27]([C:32]3[CH:36]=[N:35][N:34]([C:10]4([CH2:8][CH3:9])[O:14][C:13](=[O:15])[NH:12][CH2:11]4)[CH:33]=3)[CH:28]=[C:29]([CH3:31])[CH:30]=2)[CH:19]=1
Reactant: Cc1cc(Nc2cc(C(F)F)ccn2)nc(-c2cn[nH]c2)c1
Reactant: CC(I)C1CNC(=O)O1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC1(n2cc(-c3cc(C)cc(Nc4cc(C(F)F)ccn4)n3)cn2)CNC(=O)O1
Temperature: 80 °C

Procedure:
Cesium carbonate (320 mg, 0.99 mmol) and 5-(1-iodoethyl)-1,3-oxazolidin-2-one (160 mg, 0.66 mmol) were added to a solution of N-[4-(difluoromethyl)pyridin-2-yl]-4-methyl-6-(1H-pyrazol-4-yl)pyridin-2-amine (100 mg, 0.33 mmol) in DMF (1 mL) under a nitrogen atmosphere at 20° C. The mixture was stirred under nitrogen and heated to 80° C. for 12 hours. The reaction mixture was cooled to 20° C. and then diluted with brine (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by prep-TLC (ethyl acetate) to afford racemic 5-[4-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methylpyridin-2-yl)-1H-pyrazol-1-yl]-5-ethyl-1,3-oxazolidin-2-one. MS ESI calc'd. for C20H21F2N6O2 [M+H]+ 415. found 415. Racemic 5-[4-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methylpyridin-2-yl)-1H-pyrazol-1-yl]-5-ethyl-1,3-oxazolidin-2-one was separated by SFC (Chiralpak AD, 3 um particle size; 60% [ethanol with 0.05% diethylamine] in CO2) to afford:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([CH:22]([NH2:24])[CH3:23])[C:16]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[C:15]2[C:31]1[O:35][N:34]=[C:33]([CH3:36])[N:32]=1.CCN(C(C)C)C(C)C>C(O)CCC.C(Cl)Cl.CCCCCC>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:24][CH:22]([C:17]2[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[C:15]([C:31]3[O:35][N:34]=[C:33]([CH3:36])[N:32]=3)[C:14]3[C:19](=[CH:20][CH:21]=[C:12]([F:11])[CH:13]=3)[N:18]=2)[CH3:23])[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: Cc1noc(-c2c(-c3ccccn3)c(C(C)N)nc3ccc(F)cc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Solvent: CCCCO
Product: Cc1noc(-c2c(-c3ccccn3)c(C(C)Nc3ncnc(N)c3C#N)nc3ccc(F)cc23)n1
Temperature: 120 °C
Reaction time: 14.5 h

Procedure:
A mixture of 4-amino-6-chloropyrimidine-5-carbonitrile (0.068 g, 0.440 mmol), 1-(6-fluoro-4-(3-methyl-1,2,4-oxadiazol-5-yl)-3-(pyridin-2-yl)quinolin-2-yl)-ethanamine (0.1536 g, 0.440 mmol), and n,n-diisopropylethylamine (0.383 mL, 2.198 mmol) in 1-butanol (4.40 mL) was stirred at 120° C. After 14.5 h, the mixture was removed from the heat and to the cooled mixture was added water (50 mL) and DCM (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography eluting with a gradient of 0% to 50% DCM:MeOH:NH4OH (89:9:1) in DCM, to provide a tan solid. The tan solid was suspended in DCM-hexane (1:1) and filtered to give 4-amino-6-((1-(6-fluoro-4-(3-methyl-1,2,4-oxadiazol-5-yl)-3-(2-pyridinyl)-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.55-8.62 (1H, m), 8.27 (1H, dd, J=9.2, 5.5 Hz), 7.86-7.93 (2H, m), 7.76-7.85 (2H, m), 7.58 (1H, d, J=7.0 Hz), 7.44-7.51 (1H, m), 7.37 (1H, ddd, J=7.6, 4.9, 1.0 Hz), 7.23 (2H, br. s.), 5.55 (1H, quin, J=6.7 Hz), 2.38 (3H, s), 1.39 (3H, d, J=6.7 Hz); LC-MS (ESI) m/z 468.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:22](COCC[Si](C)(C)C)[C:21]([O:31][C@H:32]3[C@H:36]4[O:37][CH2:38][CH:39]([CH2:40][C:41]([CH3:44])([OH:43])[CH3:42])[C@H:35]4[O:34][CH2:33]3)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl.CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:31][C@H:32]3[C@H:36]4[O:37][CH2:38][CH:39]([CH2:40][C:41]([CH3:44])([OH:43])[CH3:42])[C@H:35]4[O:34][CH2:33]3)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(O)CC1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2n1COCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(O)CC1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1-[(3aR,6R,6aS)-6-[6-chloro-5-(4-phenylphenyl)-1-(2-trimethylsilylethoxymethyl)-imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]-2-methyl-propan-2-ol (66 mg, 0.104 mmol) in TFA (0.5 mL) and DCM (1.0 mL) was stirred at room temperature. After 1.5 hours, the reaction mixture was concentrated under reduced pressure to give an oil. The oil was dissolved in EtOH (1 mL) and purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-80% acetonitrile/water+0.05% TFA gradient. The desired fractions were lyophilized to give the title compound as a solid. Major isomer LC-MS: calculated for C28H28ClN3O4 505.18 observed m/e: 506.23 (M+H)+ (Rt 1.16/2 min); 1H NMR δ (ppm) (CD3OD): 7.87 (s, 1H), 7.75 (ABq, 4H), 7.71 (d, 2H), 7.48 (dd, 2H), 7.38 (dd, 1H), 5.56 (qt, 1H), 4.96 (t, 1H), 4.54 (t, 1H), 4.10-4.00 (m, 3H), 3.51 (dd, 1H), 2.63 (m, 1H), 2.59 (m, 1H), 1.95 (dd, 1H), 1.58 (dd, 1H) and 1.25 (s, 3H).
Reaction SMILES: [O:1]1[C:6]2=[CH:7][CH:8]=[CH:9][C:10]3[C:11](=[O:14])[C:12](=[O:13])[N:4]([C:5]=32)[CH2:3][CH2:2]1.[N+:15]([O-])([OH:17])=[O:16]>C(OC(=O)C)(=O)C>[N+:15]([C:8]1[CH:7]=[C:6]2[O:1][CH2:2][CH2:3][N:4]3[C:12](=[O:13])[C:11](=[O:14])[C:10]([CH:9]=1)=[C:5]23)([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: O=C1C(=O)N2CCOc3cccc1c32
Solvent: CC(=O)OC(C)=O
Product: O=C1C(=O)N2CCOc3cc([N+](=O)[O-])cc1c32
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
To a stirred solution of 2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine-5,6-dione (33.1 g) in acetic acid-acetic anhydride (200 ml, 1:1) under ice-cooling was added fuming nitric acid (9.4 ml) dropwise. The mixture was stirred for 0.5 hours at the same temperature (0° C.) and for an hour at room temperature. The reaction mixture was poured into ice water (500 ml) and the resultant precipitate was collected by filtration. This precipitate was washed with water and dried to give 26.9 g (65.5%) of the title compound. The filtrate was extracted with chloroform, washed with water, saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride solution successively and then dried over anhydrous sodium sulfate. Evaporation of chloroform further afforded 2.9 g of the title compound. This compound was recrystallized from acetonitrile to give yellow needles, mp 230-°232° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C1(C)C=CC=CC=1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:18]1([S:24]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ccc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.1 %

Procedure:
A mixture of 5-bromoindole (5 g, 25.5 mmol) and tetra-n-butylammonium hydrogen sulfate (866 mg, 2.55 mmol) in 50% NaOE (50 mL) and toluene (200 mL) is stirred at room temperature for 5 min. Benzenesulfonyl chloride (3.57 mL, 28 mmol) is added and the mixture stirred for 1 hr. The mixture is diluted with water (500 mL) and extracted with EtOAc (3×100 mL). The extracts are washed with brine (250 mL), dried over MgSO4, filtered and evaporated to a yellow oil. The oil is purified by medium-pressure column chromatography on silica gel eluting with 10% EtOAc/hexanes to give the title compound as a white solid (7.81 g).
Reaction SMILES: [CH3:1][C:2]([N:7]=[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[I:17])[C:10](=[O:18])[O:9]1)([CH3:6])[CH2:3][S:4][CH3:5].[CH3:19][C:20]1[CH:21]=[C:22]([CH:37]=[CH:38][C:39]=1[NH2:40])[CH2:23][N:24]1[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][C:26]([C:33]([F:36])([F:35])[F:34])=[N:25]1>C(#N)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:36][C:33]([F:34])([F:35])[C:26]1[CH:27]=[C:28]([C:29]([F:32])([F:30])[F:31])[N:24]([CH2:23][C:22]2[CH:37]=[CH:38][C:39]([NH:40][C:10](=[O:18])[C:11]3[C:16](=[C:15]([I:17])[CH:14]=[CH:13][CH:12]=3)[C:8]([NH:7][C:2]([CH3:6])([CH3:1])[CH2:3][S:4][CH3:5])=[O:9])=[C:20]([CH3:19])[CH:21]=2)[N:25]=1
Reactant: CSCC(C)(C)N=C1OC(=O)c2cccc(I)c21
Reactant: Cc1cc(Cn2nc(C(F)(F)F)cc2C(F)(F)F)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: CSCC(C)(C)NC(=O)c1c(I)cccc1C(=O)Nc1ccc(Cn2nc(C(F)(F)F)cc2C(F)(F)F)cc1C
Temperature: 60 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
3-(1,1-Dimethyl-2-methylsulfanyl-ethylimino)-4-iodo-3H-isobenzofuran-1-one (0.53 g) and 1-(3-methyl-4-aminobenzyl)-3,5-bis(trifluoromethyl)-1H-pyrazole (0.45 g) were dissolved in acetonitrile (15 ml), to which p-toluenesulfonic acid monohydrate (0.01 g) was added and the mixture was stirred at 60° C. for 3 hours. After finishing the reaction, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to obtain N1-[4-(3,5-bistrifluoromethylpyrazol-1-ylmethyl)-2-methylphenyl]-N2-(1,1-dimethyl-2-methylsulfanylethyl)-3-iodophthalamide (0.91 g). mp. 83-87° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][O-:11].[Na+]>CO>[NH2:1][C:2]1[C:3]([O:11][CH3:10])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: C[O-]
Reactant: Nc1cnc(Cl)nc1Cl
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)ncc1N

Procedure:
A mixture of 5-amino-2,4-dichloropyrimidine (0.32 g) (obtained as described in Chem. Pharm. Bull., (JAPAN), 1958, 6, 343-346) and a solution of sodium methoxide in methanol (from sodium (0.05 g) and methanol (25 ml)) was heated at reflux for 15 minutes and allowed to cool. Volatile material was removed by evaporation and a small volume of water added. The mixture was extracted twice with ether and the combined extracts were dried (MgSO4) and evaporated to give 5-amino-2-chloro-4-methoxypyrimidine (0.2 g) as an oil; 1H NMR (d6-DMSO): 3.92 (s, 3H), 5.25 (s, 2H), 7.72 (s, 1H); mass spectrum (+ve CI): 160 (M+H)+.