Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(S[CH:4]1[N:7]([CH:8]([C:22]([O:24][CH:25]2[CH2:30][O:29][CH2:28][O:27][CH2:26]2)=[S:23])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[C:6](=[O:31])[CH:5]1[CH2:32][CH2:33][O:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:36])C.[Cl:48]Cl>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Cl:48][CH:4]1[N:7]([CH:8]([C:22]([O:24][CH:25]2[CH2:30][O:29][CH2:28][O:27][CH2:26]2)=[S:23])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[C:6](=[O:31])[CH:5]1[CH2:32][CH2:33][O:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:36]
Reactant: CCSC1C(CCOC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=S)OC1COCOC1
Reactant: ClCl
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(OCCC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)C(=S)OC2COCOC2)C1Cl)OCc1ccc([N+](=O)[O-])cc1
Temperature: -20 °C
Reaction time: 1.25 h

Procedure:
A solution of 6.90 g of p-nitrobenzyl 2-(4-ethylthio-3-p-nitrobenzyloxycarbonyloxyethyl-2-oxo-1-azetidinyl)-2-(1,3-dioxan-5-yl-oxythiocarbonyl)-acetate in 110 ml methylene chloride was cooled to -20° C. under a nitrogen atmosphere. A solution of chlorine in carbon tetrachloride (98 ml of 0.1M solution) was then added. The reaction mixture was stirred at -20° C. for 75 min., then allowed to warm to 0° C. and was washed successively with 75 ml saturated aqueous sodium bicarbonate solution (5° C.), 75 ml H2O (5° C.) and 75 ml saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo yielding 5.97 g of crude title compound. The NMR spectraum in deuterochloroform shows absorptions at 1.5 (d, 3H); 3.4 (m, 1H); 3.8-4.14 (c, 5H); 4.75 (s, 2H); 4.98-5.5 (c, 6 H); 5.8-6.2 (c, 1H); 7.5 (m, 4H); 8.2 (m, 4H) ppm.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][S:10][CH2:11][CH2:12][NH2:13])[N:8]=1.[CH3:14][N:15]1[CH:17](SC)[CH:16]1[N+:20]([O-:22])=[O:21]>O>[CH3:14][NH:15][C:17]([NH:13][CH2:12][CH2:11][S:10][CH2:9][C:7]1[N:8]=[C:4]([CH2:3][NH:2][CH3:1])[S:5][CH:6]=1)=[CH:16][N+:20]([O-:22])=[O:21]
Reactant: CSC1C([N+](=O)[O-])N1C
Reactant: CNCc1nc(CSCCN)cs1
Solvent: O
Product: CNCc1nc(CSCCNC(=C[N+](=O)[O-])NC)cs1

Procedure:
Following the above procedure, 2-(2-methylaminomethyl-4-thiazolylmethylthio)ethylamine and N-methyl- 1-methylthio-2-nitroethyleneamine were reacted in water solution. The reaction was worked up and the product isolated by the above procedure to yield N-methyl-N'-2-(2-methylaminomethyl-4-thiazolylmethylthio)ethyl 2-nitro-1,1-ethenediamine melting at 105°-107° C. after recrystallization from acetonitrile followed by recrystallization from ethanol.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:24])=[C:21]([CH:23]=1)[NH2:22]>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:24])=[C:21]([CH:23]=1)[NH:22][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: COc1ccc(C)c(N)c1
Product: COc1ccc(C)c(Nc2cc(C)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and 5-methoxy-2-methylaniline (33 mg, 0.243 mmol) similar to Example 13 and isolated as a tan oil (45 mg, 60%). 1H NMR (CDCl3): 8.78-8.77 (m, 1H), 8.44 (d, J=8.1 Hz, 1H), 7.81-7.75 (m, 1H), 7.34-7.30 (m, 1H), 7.16 (d, J=8.4 Hz, 1H), 6.91 (d, J=2.7 Hz, 2H), 6.72 (dd, J=2.7, 8.7 Hz, 1H), 6.30 (s, 1H), 3.76 (s, 3H), 2.42 (s, 3H), 2.17 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH:19]4[CH2:22][O:21][CH2:20]4)[CH2:15][C:14]3([CH3:24])[CH3:23])[N:8]2[CH3:11])=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:3]=1.[CH2:31]([C:33]1[NH:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)[CH3:32].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[CH3:24][C:14]1([CH3:23])[CH2:15][N:16]([CH:19]2[CH2:22][O:21][CH2:20]2)[CH2:17][CH2:18][N:13]1[CH2:12][C:7]1[N:8]([CH3:11])[C:9]2[C:5]([N:6]=1)=[C:4]([N:25]1[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1)[N:3]=[C:2]([N:34]1[C:35]3[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=3[N:37]=[C:33]1[CH2:31][CH3:32])[N:10]=2
Reactant: Cn1c(CN2CCN(C3COC3)CC2(C)C)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CCc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C4COC4)CC3(C)C)n(C)c2n1
Temperature: 150 °C
Yield: 47.1 %

Procedure:
A mixture of 2-chloro-8-(2,2-dimethyl-4-oxetan-3-ylpiperazin-1-ylmethyl)-9-methyl-6-morpholin-4-yl-9H-purine (90 mg, 0.21 mmol), 2-ethylbenzimidazole (32 mg, 0.22 mmol), tris(dibenzylideneacetone)dipalladium (5 mg, 2.5 mol %), XPhos (9 mg, 10 mol %) and Cs2CO3 (95 mg, 0.29 mmol) in dioxane (1 mL) was purged with argon then heated at 150° C. for 1 h in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 1-3%) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 5-98%) affording 740 (54 mg, 48%). LCMS (method I): RT 2.62 min [M+H]+ 546.2. 1H NMR (CDCl3, 400 MHz): δ 8.01-8.01 (1 H, m), 7.75-7.74 (1 H, m), 7.31-7.22 (2 H, m), 4.64 (2 H, t, J=6.47 Hz), 4.57 (2 H, t, J=6.07 Hz), 4.34 (4 H, brd s), 3.90 (3 H, s), 3.86 (6 H, t, J=4.78 Hz), 3.36-3.35 (3 H, m), 2.52 (2 H, s), 2.24 (2 H, s), 2.11 (2 H, s), 1.45 (3 H, t, J=7.48 Hz), 1.24 (6 H, s)
Reaction SMILES: C[O-].[Na+].CO.C([O:14][C@@H:15]1[C@H:19]([O:20]C(=O)C2C=CC=CC=2)[C@@H:18]([CH2:29][O:30]C(=O)C2C=CC=CC=2)[S:17][C@H:16]1[N:39]1[CH:46]=[CH:45][C:43]([NH2:44])=[N:42][C:40]1=[O:41])(=O)C1C=CC=CC=1.C(O)(=O)C>CO>[C@@H:16]1([N:39]2[CH:46]=[CH:45][C:43]([NH2:44])=[N:42][C:40]2=[O:41])[S:17][C@H:18]([CH2:29][OH:30])[C@@H:19]([OH:20])[C@H:15]1[OH:14]
Reactant: Nc1ccn([C@@H]2S[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccn([C@@H]2S[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.7 %

Procedure:
0.1 mL of a 28% sodium methoxide/methanol solution was added to a suspension of 70 mg of 1-(2,3,5-tri-O-benzoyl-4-thio-β-D-ribofuranosyl)cytosine in 2.0 mL of methanol, and the obtained mixture was then stirred at room temperature for 1 hour and was then left overnight. Thereafter, 0.2 mL of acetic acid was added to the reaction mixture, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol=1/0 to 2/1), so as to obtain 18 mg of 1-(4-thio-β-D-ribofuranosyl)cytosine in the form of a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[CH:33]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:34]4[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4cccnc4)cc3)oc2C)cc1

Procedure:
To a 25 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (0.410 mmoles, 200 mg) (see Ex. 2, Part B), 3-pyridyl boronic acid (0.451 mmoles), toluene (5 mL), ethanol (5 mL), and sodium carbonate (0.819 mmoles, 0.410 mL of a 2M solution). This mixture was vacuum degassed and nitrogen was added in at a positive pressure. Pd(PPh3)4 (catalytic, spatula tip) was added and the reaction was heated to reflux for 3 h. Distilled water was added to the mixture. Subsequently, this was extracted with ethyl acetate and washed with brine. The organic layer was collected, filtered over a thin pad of silica gel, and concentrated in-vacuo. The crude mixture was then purified by chromatography on silica gel affording 2-(4-{2-[2-(4-pyrid-3-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[S:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[N+:13]([O-])([OH:15])=[O:14].S(=O)(=O)(O)O>C(O)(=O)C>[N+:13]([C:6]1[CH:5]=[C:4]([S:3][C:2]([F:11])([F:1])[F:12])[CH:9]=[CH:8][C:7]=1[OH:10])([O-:15])=[O:14]
Reactant: Oc1ccc(SC(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(SC(F)(F)F)ccc1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
To a mixture of 4.8 g of 4-(trifluoromethylthio)phenol and 20 ml of acetic acid, a mixture of 2.5 g of 70% nitric acid and 1 ml of acetic acid and then 1.5 ml of concentrated sulfuric acid were added dropwise with the internal temperature kept at 10-15° C. The reaction mixture was stirred for three hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and a saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure to give 5.94 g of 2-nitro-4-(trifluoromethylthio)phenol.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.Br[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[O:20][CH3:21].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>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:1]1[CH2:6][CH2:5][N:4]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[O:20][CH3:21])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2
Reactant: c1ccc2c(c1)NCCO2
Reactant: COc1cc(C#N)ccc1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COc1cc(C#N)ccc1N1CCOc2ccccc21
Temperature: 100 °C
Yield: 80.4 %

Procedure:
A mixture of 3,4-dihydro-2H-benzo[b][1,4]oxazine (500 mg, 3.69 mmol), 4-bromo-3-methoxybenzonitrile (784 mg, 3.69 mmol), Pd2(dba)3 (271 mg, 0.295 mmol), Xantphos (342 mg, 0.591 mmol) and sodium-tert-butoxide (590 mg, 6.14 mmol) in toluene (10 mL) was degassed for 10 minutes. The reaction mixture was heated at 100° C. for 1 h under microwave conditions. After completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material which was purified by combi flash column chromatography (column size: 24 g; elution: 5% ethyl acetate in hexane) to obtain 4-(2H-benzo[b][1,4]oxazin-4(3H)-yl)-3-methoxybenzonitrile (790 mg, 80.2%) as yellow solid. m/z (ESI) 266.0 (M+H)+.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:44]=[CH:43][C:8]([CH2:9][N:10]([CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])[C:11](=[O:34])[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:33])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[C:29]([F:32])([F:31])[F:30])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)=[NH:4].CCN(C(C)C)C(C)C.[CH3:54][C:55]1[CH:63]=[CH:62][C:58]([C:59](Cl)=O)=[CH:57][CH:56]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.C(Cl)Cl>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:19]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([C:11]([N:10]([CH2:35][C:36]([OH:38])=[O:37])[CH2:9][C:8]3[CH:7]=[CH:6][C:5]([C:3]4[N:4]=[C:54]([C:55]5[CH:63]=[CH:62][C:58]([CH3:59])=[CH:57][CH:56]=5)[O:1][N:2]=4)=[CH:44][CH:43]=3)=[O:34])=[CH:13][CH:14]=2)=[O:33])=[C:22]([C:29]([F:32])([F:30])[F:31])[CH:23]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(C(=N)NO)cc3)cc2)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(-c4noc(-c5ccc(C)cc5)n4)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
Prepared using General Procedures 20 and 8: To a stirring solution of tert-butyl 2-(N-(4-(N-hydroxycarbamimidoyl)benzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-33 (128 mg, 0.21 mmol) and DIEA (0.058 mL, 0.31 mmol) in dioxane (4 mL) was added a solution of 4-methylbenzoyl chloride (0.028 mL, 0.21 mmol) in dioxane (1 mL). After stirring at room temperature for 1 h, the reaction mixture was heated to 120° C. for 2 h. The reaction mixture was allowed to cool to room temperature, diluted with DCM (4 mL), shaken with NaHCO3 (10 mL), split through a hydrophobic frit and evaporated. The crude material was purified by column chromatography (EA/isohexanes). The isolated material was dissolved in DCM (2 mL) and TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 2 h then evaporated and re-slurried from acetonitrile (6 mL) to afford 77 mg (56%) of 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(p-tolyl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetic acid 355 as a white solid. LCMS-ESI (m/z) calculated for C35H29F3N4O6: 658; found 659 [M+H]+, tR=7.97 min (Method 9). 1H NMR (400 MHz, DMSO) δ 12.81 (s, 1H), 10.34 (s, 1H), 8.10 (d, J=6.1 Hz, 2H), 8.09-8.05 (m, 2H), 7.70-7.56 (m, 3H), 7.53-7.41 (m, 4H), 7.38 (d, J=8.0 Hz, 2H), 7.26-7.14 (m, 2H), 4.76 (s, 1H), 4.68 (s, 1H), 4.04 (s, 1H), 3.97 (s, 1H), 3.91-3.79 (m, 5H), 2.45 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:26][CH3:27])[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCNC2)CC1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN1CCC[C@@H](CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C

Procedure:
N-(3,4-Dichlorophenyl)-4-[(3R)-piperidin-3-ylmethyl]piperazine-1-carboxamide (0.30 g), bromoethane (0.12 ml) and potassium carbonate (0.56 g) was refluxed in acetone (70 ml) for 18 hours. The reaction mixture was allowed to cool to room temperature then filtered. The filtrate was concentrated in vacuo and the resulting oil separated between ethyl acetate (100 ml) and water (100 ml). The ethyl acetate layer was separated, dried over magnesium sulphate, filtered then concentrated in vacuo onto silica gel (5 g). The resulting powder was subjected to chromatography on silica gel (50 g) using a gradient of 100% dichloromethane through to 20% methanolic ammonia in dichloromethane to give the title compound (24.9 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14]CC[Si](C)(C)C)[C:4]=1[CH2:21][CH:22]=[C:23]([CH3:29])[CH2:24][O:25][P:26]([OH:28])[OH:27].CCN(C(C)C)C(C)C.C/C(/[O:46][Si](C)(C)C)=N\[Si](C)(C)C.C1C=C(SSC2N=CC=CC=2)N=CC=1>O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([OH:14])[C:4]=1[CH2:21][CH:22]=[C:23]([CH3:29])[CH2:24][O:25][P:26](=[O:46])([OH:28])[OH:27]
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)COP(O)O)C(=O)OC2
Reactant: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: COc1c(C)c2c(c(O)c1CC=C(C)COP(=O)(O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of phosphorous acid mono-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}ester (27 mg, 0.06 mmol) in dioxane (1 mL) was stirred with DIEA (21 μL, 0.12 mmol) and N,O-bis(trimethylsilyl)acetamide (29 μL, 0.12 mmol) at room temperature for 3 hours. To the reaction solution was added 2,2′-dipyridyldisulfide (16 mg, 0.072 mmol) and the mixture was allowed to stir for an additional 2 hours at room temperature. The reaction mixture was diluted by addition of H2O and the solution was stirred for 2 more hours when it was concentrated. The residue was dissolved in a solution of 10% TFA/CH2Cl2 and stirred at room temperature for 9 hours. The reaction mixture was dried under reduced pressure and the product was purified by reverse-phase HPLC to provide the desired product as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.87 (s, 3H), 2.16 (s, 3H), 3.47 (d, 2H, J=7 Hz), 3.79 (s, 3H), 4.28 (d, 2H, J=6 Hz), 5.26 (s, 2H), 5.50-5.61 (m, 1H); 31P (121.4 MHz, CD3OD) δ 0.50; MS (m/z) 357 [M−H]−.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13](COCC[Si](C)(C)C)[CH:12]=2)=[O:10])[CH3:7])[CH2:3]1.C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[OH:1][C@@H:2]1[CH2:3][C@H:4]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[NH:13][CH:12]=2)=[O:10])[CH3:7])[CH2:5]1
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@@H](O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: CC(NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@@H](O)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(cis-3-hydroxy-cyclobutyl)-ethyl]-amide (60 mg, 0.11 mmol) in CH2Cl2 (2 mL) was added TFA (1 mL, 13.0 mmol). The bright yellow-orange reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was redissolved in CH2Cl2 (2 mL) and ethylene diamine (0.4 mL, 6.0 mmol) was added. The reaction mixture was stirred at room temperature for 1 h then quenched with water and diluted with CH2Cl2. A very fine precipitate formed which was collected via filtration. This solid was taken up in MeOH/CH2Cl2 (200 mL) and filtered again, rinsing with MeOH/CH2Cl2. The filtrate was concentrated and triturated with EtOAc/MeOH to afford 28 mg (62%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(cis-3-hydroxy-cyclobutyl)-ethyl]-amide as a light yellow solid. MS: (M+H)+=409; 1H NMR (DMSO-d6,300 MHz): δ (ppm) 9.08 (s, 1H), 8.37-8.48 (m, 2H), 7.96 (d, J=8.7 Hz, 1H), 7.70 (dd, J=9.8, 1.9 Hz, 1H), 7.18 (td, J=9.1, 2.3 Hz, 1H), 4.92 (br. s., 1H), 4.14 (s, 3H), 4.04-4.13 (m, 1H), 3.87 (br. s., 1H), 2.14-2.34 (m, 2H), 1.78-1.93 (m, 1H), 1.58 (quin, J=9.8 Hz, 2H), 1.19 (d, J=6.8 Hz, 3H).
Reaction SMILES: [Na].C(O)(=[S:4])C.Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].[OH-].[Na+].Cl>CO>[SH:4][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23]
Reactant: CC(O)=S
Reactant: OCCCCCCCCCCCCCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: OCCCCCCCCCCCCCCCCS
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.3 %

Procedure:
Under inert atmosphere 365 mg of sodium metal suspension (40% in mineral oil) were added dropwise to 20 ml of dry methanol at 0° C. After completion of addition the reaction mixture was stirred for 10 min at RT followed by addition of 0.45 ml (6.30 mmole) of thioacetic acid. After additional 10 min of stirring 3 ml degassed methanolic solution of 1.0 gr (3.11 mmole) of 16-bromohexadecan-1-ol were added. The resulted mixture was refluxed for 15 hrs, allowed to cool to RT and 20 ml of degassed 1.0 M NaOH aqueous solution were injected. The reaction completion required additional 3 hr of reflux. Resulted reaction mixture was cooled with ice bath and poured, with stirring, into a vessel containing 200 ml of ice water. This mixture was titrated to pH=7 by 1.0 M HCl and extracted with 300 ml of ether. The organic layer was separated, washed with 3×1 50 ml of water, 150 ml of saturated NaCl aqueous solution and dried over sodium sulfate. After ether removal material was dissolved in minimum amount of dicloromethane and purified by silica gel chromatography (100% dicloromethane as eluent). 600 mg (70% yield) of the desired product were obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:28])[C:7]([CH2:19][CH2:20][O:21][CH2:22][CH2:23]OCCI)(CCOCCOCCI)[C:8]#[N:9])[CH3:4]>O1CCCC1>[C:8]([CH:7]([C:6]([O:5][CH2:3][CH3:4])=[O:28])[CH2:19][CH2:20][O:21][CH:22]([O:21][CH2:20][CH2:19][CH:7]([C:6]([O:5][CH2:3][CH3:4])=[O:28])[C:8]#[N:9])[CH3:23])#[N:9]
Reactant: CCOC(=O)C(C#N)(CCOCCOCCI)CCOCCOCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)CCOC(C)OCCC(C#N)C(=O)OCC
Yield: 200 %

Procedure:
0.19 g (4 mmol) of sodium hydride was added to 20 ml of dry tetrahydrofuran, and to this solution was added dropwise, while refluxing under heating, a solution formed by dissolving 0.6 g (1 mmol) of bis(8-iodo-3,6-dioxaoctyl)cyanoacetic acid ethyl ester obtained in the above-said preparation process and 0.34 g (1 mmol) of bis(3-cyano-3-carboethoxypropoxy)ethane in 20 ml of tetrahydrofuran, by using a specific dropping apparatus for the high dilution reactions (an apparatus designed to dilute the dropping solution with the refluxing solvent) over the period of 24 hours. After completion of said dropwise addition, reflux was continued for further 12 hours. After neutralizing the solution with dilute hydrochloric acid, tetrahydrofuran was distilled off and the residue was extracted with ether. Then ether was distilled off and the resultant oily residue was separated by basic alumina-packed column chromatography by using benzene-tetrahydrofuran (2:1) as eluent, obtaining 0.17 g of tricyanotricarboxylic acid triethyl ester (yield: 25%). The property analyses of this compound gave the following results.
Reaction SMILES: [CH3:1][C@:2]([NH:26]C(=O)OC(C)(C)C)([C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]([CH3:25])[CH2:18][CH2:19][O:20]3)=[N:12][CH:13]=1)=[O:6])[CH2:3][CH3:4].C(O)(C(F)(F)F)=O>ClCCl>[CH3:25][CH:17]1[C:16]2[C:21](=[CH:22][CH:23]=[CH:24][C:15]=2[O:14][C:11]2[N:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C@:2]([CH3:1])([CH2:3][CH3:4])[NH2:26])=[CH:9][N:10]=2)[O:20][CH2:19][CH2:18]1
Reactant: CC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)Nc1cnc(Oc2cccc3c2C(C)CCO3)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@](C)(N)C(=O)Nc1cnc(Oc2cccc3c2C(C)CCO3)nc1
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a solution of 1,1-dimethylethyl {(1R)-1-methyl-1-[({2-[(4-methyl-3,4-dihydro-2H-chromen-5-yl)oxy]-5-pyrimidinyl}amino)carbonyl]propyl}carbamate (Intermediate 218, 100 mg, 0.219 mmol) in dry Dichloromethane (5 mL), cooled to 0° C., TFA (1 mL, 12.98 mmol) was added dropwise. The reaction mixture was stirred at that temperature for 3 hours, then it was allowed to reach the room temperature and stirred at that temperature for 2 hours. Volatiles were evaporated and the residue was diluted with DCM (10 mL) and washed with an aqueous saturated solution of NaHCO3 (10 mL). The organic layer was separated, dried (Na2SO4), filtered and evaporated to afford the title compound (78 mg) as white solid that was used in the next step without further purification.