Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C@H:10]([C@@H:12]1[C@@H:16]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C@@H:15]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C@H:14]([N:33]2[CH:38]=[CH:37][C:36](=[O:39])[N:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:34]2=[O:49])[O:13]1)[OH:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:50]([O:57][C:58]([NH:60][C@H:61]([C:71](=[O:77])[NH:72][CH2:73][CH2:74][CH:75]=O)[CH2:62][CH2:63][C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])=[O:59])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.O1CCCC1>[Si:18]([O:17][C@H:16]1[C@@H:15]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[C@H:14]([N:33]2[CH:38]=[CH:37][C:36](=[O:39])[N:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:34]2=[O:49])[O:13][CH:12]1[C@H:10]([OH:11])[C@@H:2]([C:3]([O:5][C:6]([CH3:7])([CH3:9])[CH3:8])=[O:4])[NH:1][CH2:75][CH2:74][CH2:73][NH:72][C:71](=[O:77])[C@H:61]([CH2:62][CH2:63][C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[NH:60][C:58](=[O:59])[O:57][CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCC=O
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3O[C@H]([C@H](O)[C@H](N)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc4ccccc4)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Yield: 82.5 %

Procedure:
By using an analogous procedure to that described for Example 1, a solution of tert-butyl (2S,3R)-2-amino-3-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl-(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-tetrahydro-2-furanyl]-3-hydroxypropanoate (100 mg, 0.139 mmol, obtained from Reference Example 6), tert-butyl (4S)-4-{[(benzyloxy)carbonyl]amino}-5-oxo-5-[(3-oxopropyl)amino]pentanoate (60 mg, 0.152 mmol, obtained from Reference Example 26), acetic acid (2 drops), and sodium triacetoxyborohydride (59 mg, 0.277 mmol) in anhydrous tetrahydrofuran (4 ml) was stirred under nitrogen at room temperature for 3.5 hours. The product was purified by chromatography (flash column, silica gel, 4% methanol in methylene chloride) to provide tert-butyl (5S,12S)-12-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-[3-(tert-butoxy)-3-oxopropyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (126 mg, 83%) as a white amorphous solid.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[N:12]=[C:6]2[CH:7]=[C:8]([NH2:11])[CH:9]=[CH:10][N:5]2[N:4]=1.[CH2:14]([O:16][C:17]([C:19]1[CH:20]=[N:21][N:22]([CH3:27])[C:23]=1[C:24](O)=[O:25])=[O:18])[CH3:15].CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:1][N:2]([CH3:13])[C:3]1[N:12]=[C:6]2[CH:7]=[C:8]([NH:11][C:24]([C:23]3[N:22]([CH3:27])[N:21]=[CH:20][C:19]=3[C:17]([O:16][CH2:14][CH3:15])=[O:18])=[O:25])[CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Reactant: CN(C)c1nc2cc(N)ccn2n1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N(C)C)nc2c1
Yield: 89.3 %

Procedure:
A mixture of N2,N2-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-2,7-diamine (700 mg, 3.95 mmol), 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (812 mg, 4.1 mmol), propylphosphonic anhydride (50% in ethyl acetate, 5.82 ml, 9.88 mmol) and diisopropylethylamine (2.07 ml, 11.9 mmol) in tetrahydrofurane (40 ml) is refluxed for 18 hours under nitrogen atmosphere. The solvent is evaporated and the residue triturated with sat. aqueous sodium hydrogencarbonate solution. The solid is collected by filtration, washed with water and dried affording ethyl 5-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylate (1.26 g, 89.3%) as a light brown solid. Mp.: 193-5° C. MS: m/z=358.4 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([F:16])([F:14])[F:15])=[CH:10][CH:11]=2)[N+:6]([O-:25])=[CH:5][CH:4]=1
Reactant: COc1ccnc2cc(C(F)(F)F)ccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cc[n+]([O-])c2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 15 mL of a chloroform solution containing 1.06 g of 4-methoxy-7-trifluoromethylquinoline, 1.36 g of m-chloroperbenzoic acid was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was added with 20 mL of an aqueous saturated sodium hydrogen carbonate solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain a yellow solid, 4-methoxy-7-trifluoromethylquinoline N-oxide.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[CH:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C>O1CCCC1>[C:9]([C:2]1[N:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1)#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=Cc1nc(Br)cs1
Reactant: C#CCCCCCCCCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCC#Cc1csc(C=O)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 3.7 %

Procedure:
A solution of 4-bromo-2-thiazolecarboxaldehyde (14.8 g), 1-dodecyne (14.1 g), and triethylamine (23.5 g) in dry tetrahydrofuran (85 m) was chilled to 5° C. and degassed under nitrogen. bis(Triphenylphosphine)paIladium (II) chloride (0.54 g) and copper (I) iodide (0.07 g) were added to the mixture, which was degassed, and stirred, under nitrogen, at room temperature for 2.5 hrs. The reaction mixture was heated at 40° C. for 7 hrs, during which time additional amounts of 1-dodecyne (3.9 g), bis(triphenylphosphine)palladium (II) chloride (0.11 g), and copper (I) iodide (0.02 g) were added. The mixture was cooled to room temperature, the precipitate was collected, and the filter cake was wasted with ethyl acetate. The filtrate was diluted with ethyl acetate (300 ml). Water was added in portions, and the organic layer was washed with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was chromatographed on silica gel, eluting with heptane to heptane: 1% ethyl acetate. A portion (1.05 g) of the residue was rechromatographed, eluting with hexane:(0.3 to 1%) ethyl acetate. The appropriate fractions were collected and evaporated to yield 0.79 g (76.5% yield) of product, mp 25.5°-26° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)[CH:7]=1.[B:15]1(B2OCC(C)(C)CO2)[O:20]CC(C)(C)C[O:16]1>>[F:14][C:5]1[CH:4]=[CH:3][C:2]([B:15]([OH:20])[OH:16])=[CH:7][C:6]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][N:9]=1
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Reactant: Fc1ccc(Br)cc1-c1ccncn1
Product: OB(O)c1ccc(F)c(-c2ccncn2)c1

Procedure:
4-(5-Bromo-2-fluorophenyl)pyrimidine (503 mg, 2.0 mmol) was reacted with bis(neopentyl glycolato)diboron (494 mg, 2.2 mmol) using the method of Example 20 to give 4-fluoro-3-(pyrimidin-4-yl)phenylboronic acid as a tan solid: MS (ES+) m/z 219 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.N1C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH2:1]([C:3]1[N:4]([C:33]2[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2]
Reactant: CCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nc(CC)n(-c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h
Yield: 102.8 %

Procedure:
A mixture of 4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (3.0 g), 4-methoxyphenylboronic acid (2.5 g), copper(II) acetate (3.1 g), pyridine (3.1 mL), triethylamine (3.4 mL), molecular sieves 4 A (6.0 g) and dichloromethane (60 mL) was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (4.0 g, 100%) as a pale-yellow liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12])([O-:3])=[O:2].S(=O)(=O)(O)O.[OH-].[NH4+].[CH3:21]O>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([O:13][CH3:21])=[O:12])([O-:3])=[O:2]
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: COC(=O)Cc1ccccc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
To a solution of 2-nitrophenylacetic acid (2.00 kg) in methanol (4 l) at room temperature is added concentrated sulfuric acid (71.0 ml) all at once. The solution is stirred and refluxed for 6 hours, then allowed to stand at room temperature overnight. After cooling in an ice bath to 7°, the solution is adjusted to pH 8 by the addition of concentrated ammonium hydroxide (150 ml), keeping the temperature below 10°. The solution is concentrated in vacuo to a volume of 2 l and is then admixed with dichloromethane (2.5 l). The combined solution is washed with water (2×500 ml) and brine (500 ml), dried over anhydrous magnesium sulfate, and evaporated to yield crude product which is distilled to give methyl 2-nitrophenylacetate, b.p. 116°-131° (0.2 mm Hg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([O:12][CH3:13])[CH:7]=1.C(Cl)Cl>[Pd].CCO>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([O:12][CH3:13])[CH:7]=1
Reactant: COC(=O)C=Cc1ccnc(OC)c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)CCc1ccnc(OC)c1
Yield: 93 %

Procedure:
A suspension of 3-(2-methoxy-pyridin-4-yl)-acrylic acid methyl ester (1.3 g, 6.72 mmol, 1 eq) and Pd/C, 10% (357 mg, 0.05 eq, 10%) was stirred in a DCM (15 ml)/absolute EtOH (15 ml) solvent mixture under hydrogen atmosphere for 1 hour at room temperature. Palladium was filtered off over a celite pad, the solvent was evaporated and obtained crude was purified by chromatography on BIOTAGE SP1 purification device using 25 g normal phase silica SNAP column and cyclohexane/EtOAc solvent system (gradient 3-30% of EtOAc in 20 column volumes). Solvent from the gathered fractions of appropriate composition was evaporated and obtained was 3-(2-methoxy-pyridin-4-yl)-propionic acid methyl ester (1.22 g, yield=88.2%, purity=95%) in form of transparent colourless oil. MS: [M+H]+=196.14 1H NMR (300 MHz; CDCl3) δ/ppm 2.63(t, J=7.91 Hz, 2H), 2.90 (t, J=7.91 Hz, 2H), 3.68(s, 3H), 3.92 (s, 3H), 6.57 (s, 1H), 6.72 (dd, J=5.33 Hz, J=1.29 Hz, 1H), 8.06 (d, J=5.33 Hz, 1H)
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8](=[O:28])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][CH3:24])[CH:18]=[CH:17][C:16]=2[NH2:27])[CH:10]=1.[CH3:34][N:35]([CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1)[C:36]([C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41](O)=[O:42])=[O:37].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:33][C:2]([F:32])([F:1])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][CH3:24])[CH:18]=[CH:17][C:16]=2[NH:27][C:41](=[O:42])[C:40]2[CH:44]=[CH:45][CH:46]=[C:38]([C:36]([N:35]([CH3:34])[CH2:47][CH2:48][N:49]3[CH2:50][CH2:51][O:52][CH2:53][CH2:54]3)=[O:37])[CH:39]=2)[CH:10]=1)=[O:28]
Reactant: CCCN(CC)c1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCOCC3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-(ethyl(propyl)amino)phenyl)isonicotinamide (150 mg, 0.30 mmol, 1.00 equiv, 90%) in dichloromethane (8 mL), 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid (144 mg, 0.44 mmol, 1.50 equiv, 90%), EDC.HCl (126 mg, 0.66 mmol, 2.00 equiv), 4-dimethylaminopyridine (80 mg, 0.66 mmol, 2.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 100 mL of ethyl acetate. The resulting mixture was washed with 2×20 mL of NH4Cl aq. and 1×20 mL of sodium bicarbonate (10%). The resulting mixture was washed with 1×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (250 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (25% CH3CN up to 39% in 6 min); Detector, Waters2545 UvDector 254&270 nm. 183.7 mg product was obtained. This resulted in 183.7 mg (56%) of N1-(2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(ethyl(propyl)amino)phenyl)-N3-methyl-N3-(2-morpholinoethyl)isophthalamide as a yellow solid. LC-MS (ES, m/z) 731 [M+H]+; H-NMR (300 MHz, DMSO, ppm): 9.83 (s, 1H), 9.52 (t, J=18 Hz, 1H), 8.89 (d, J=3 Hz, 1H), 8.26 (s, 1H), 8.13 (s, 1H), 7.99 (m, 2H), 7.82 (d, 1H), 7.54-7.69 (m, 6H), 6.95-7.54 (m, 2H), 4.60 (s, 2H), 3.85-4.02 (m, 4H), 3.64 (m, 4H), 3.36-3.47 (m, 6H), 3.18 (m, 2H), 2.95 (s, 3H), 1.60 (m, 2H), 1.09-1.13 (m, 3H), 0.87-0.92 (m, 3H).
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([F:43])=[C:21]([C@@:23]23[N:32]=[C:31]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[S:30][CH2:29][C@@H:28]2[CH2:27][C@H:26]([CH2:41]O)[O:25][CH2:24]3)[CH:22]=1)([O-:16])=[O:15].NC1C=CC(F)=C([C@@]23N=C(NC(=O)OC(C)(C)C)SC[C@@H]2[C@@H](OC)COC3)C=1.C(=O)(O)[O-].[Na+]>ClCCl>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([F:43])=[C:21]([C@@:23]23[N:32]=[C:31]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:39])[CH3:37])[S:30][CH2:29][C@@H:28]2[CH2:27][C@H:26]([CH2:41][F:11])[O:25][CH2:24]3)[CH:22]=1)([O-:16])=[O:15]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc([N+](=O)[O-])ccc3F)CO[C@@H](CO)C[C@H]2CS1
Agent: CO[C@H]1COC[C@]2(c3cc(N)ccc3F)N=C(NC(=O)OC(C)(C)C)SC[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc([N+](=O)[O-])ccc3F)CO[C@@H](CF)C[C@H]2CS1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[Bis(2-methoxyethyl)amino]sulfur trifluoride (285 μl) was added dropwise to a solution of tert-butyl [(4aR,6R,8aS)-8a-(5-nitro-2-fluorophenyl)-6-hydroxymethyl-4,4a,5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl]carbamate obtained in Preparation Example 13 (575 mg) in dichloromethane (55 ml) at −78° C. The mixture was stirred overnight with gradual heating to room temperature. A sodium bicarbonate solution was added to the reaction solution, and the aqueous layer was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by NH-silica gel column chromatography to obtain the title compound (240 mg).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[N+:12]([C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:21])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:7](=[O:15])[NH:8]2)=[CH:3][C:2]=1[N:31]1[CH2:32][CH2:33][N:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:29][CH2:30]1)([O-:14])=[O:13]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N3CCN(c4ccccc4)CC3)cc2c1=O
Yield: 66 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 1-phenyl-piperazine according to the GPA affording 28.6 mg (66%) of an orange powder. Rt=4.49 min.
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]=[C:11]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH2:12][NH:13][C:14](=[O:28])[C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[Br:57][C:58]1[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][C:59]=1[C:60](O)=[O:61]>CN(C=O)C.O>[Br:57][C:58]1[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][C:59]=1[C:60]([N:32]1[CH2:31][CH2:30][N:29]([C:11](=[O:10])[CH2:12][NH:13][C:14](=[O:28])[C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:19][CH:20]=2)[CH2:34][CH2:33]1)=[O:61]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Oc2ccccc2)cc1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Br)c(C(=O)N2CCN(C(=O)CNC(=O)c3ccc(Oc4ccccc4)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 84.5 %

Procedure:
DIPEA (85.5 mg, 0.114 mL, 0.66 mmol) was added to a stirred solution of N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenoxy-benzamide (60 mg, 0.176 mmol) in DMF (2 mL). HOBT (21.89 mg, 0.16 mmol) and EDCI.HCl (70.5 mg, 0.36 mmol) were then added at room temperature. After 2 minutes, 2-Bromo-5-methoxy benzoic acid (33.9 mg, 0.15 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then diluted with cold water, and the resulting precipitate was filtered, washed with water then hexane and dried to afford 70 mg (86.5% yield) of N-{2-[4-(2-Bromo-5-methoxy-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-4-phenoxy-benzamide as a pale yellow solid. LCMS Purity: 95.76%, HPLC Purity: 96.07%. 1H NMR (CDCl3): δ 8.5 (bs, 1H), 7.9 (d, 2H), 7.5 (m, 1H), 7.4 (m, 2H), 7.2 (m, 1H), 6.9 (m, 5H), 4.2 (m, 2H), 3.8 (s, 3H), 3.5 (m, 6H), 3.2 (m, 2H), 2.1 (s, 1H), 2.0 (m, 1H), 1.3 (s, 3H), 0.8 (m, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].[CH3:7][N:8]([CH3:13])[S:9](Cl)(=[O:11])=[O:10]>COCCOC>[CH3:7][N:8]([CH3:13])[S:9]([O:5][CH2:4][CH2:3][O:6][S:9](=[O:11])(=[O:10])[N:8]([CH3:13])[CH3:7])(=[O:11])=[O:10]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CN(C)S(=O)(=O)OCCOS(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 57% oil dispersion of sodium hydride (8.45 g.; 0.20 mol.) is added to a solution of ethylene glycol (3.1 g.; 0.05 mol.) in 1,2-dimethoxyethane (100 ml.). The resulting suspension is stirred at room temperature for 2 hours and then cooled to +4° C. N,N-dimethylsulfamoyl chloride, 25.8 g. (0.18 mol.), is dissolved in 1,2-dimethoxyethane (400 ml.) and added dropwise to the solution with stirring. The reaction mixture is stirred at +4° C for an additional 24 hours. A precipitate forms which is filtered off and the filtrate is concentrated. The residue is partitioned between heptane and methanol, and the methanol solution is concentrated to a syrup which crystallizes from ethyl acetate to yield 1,2-bis-O-(N,N-dimethylsulfamyl)-1,2-ethanediol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[C:11]([CH:16]=1)[C:12]([O:14]C)=[O:13]>[OH-].[Na+].O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[C:11]([CH:16]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1-c1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2ccc(Cc3c(C)c(OC)c(OC)c(OC)c3OC)cc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.3 %

Procedure:
Methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(3-methoxyphenyl)benzoate (1.23 g, 2.6394 mmol) was dissolved in a mixed solution of a 1N aqueous solution of sodium hydroxide (20 ml) and 1,4-dioxane (40 ml) followed by stirring at room temperature for 16 hours. The reaction solution was diluted with water (200 ml), washed with ether, acidified with concentrated hydrochloric acid and extracted with ether. The extract was washed with water and dried and the solvent was evaporated therefrom to give the title compound (1.03 g, 2.2787 mmol, 85%).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[C:5]([F:13])[CH:4]=1)#[N:2].[OH-].[K+]>C(O)C.O>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[C:5]([F:13])[CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(C#N)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(C(=O)O)c(F)c1
Yield: 82.2 %

Procedure:
Dissolve methyl 4-cyano-2-fluoro-benzoate (2.9 g, 16.2 mmol) in absolute ethanol (100 mL). Add potassium hydroxide (4.5 g, 80.2 mmol) and stir the milky white mixture for 1.5 h. Dilute the mixture with water (125 mL) and wash with diethyl ether (50 mL). Collect the aqueous layer and concentrate in vacuo until solids start to appear in the flask, then adjust the mixture to pH 1 with concentrated HCl. Extract the aqueous mixture with diethyl ether (3×500 mL). Combine the organic extracts and concentrate in vacuo to obtain the desired intermediate as a white solid (2.2 g, 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[CH2:9]([Sn](CCCC)(CCCC)CCCC)[CH:10]=[CH2:11].[Cl-].[Li+].C(N(CC)C(C)C)(C)C.[F-].[K+]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:11]([C:5]1[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1)[CH:10]=[CH2:9]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: Nc1cnc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C=CCc1cnc(N)cn1
Temperature: 120 °C
Reaction time: 0.75 h
Yield: 48.7 %

Procedure:
A mixture of 2-amino-5-bromopyrazine (1.00 g, 5.746 mmol), tetrakis(triphenylphosphine)palladium(0) (132 mg, 0.114 mmol), allyltri-n-butyltin (2.2 mL, 7.096 mmol), lithium chloride (875.0 mg, 20.64 mmol) and N,N-diisopropylethylamine (2.6 mL, 14.93 mmol) in N,N-dimethylformamide (29 mL) was stirred at 120° C. for 45 min. The reaction mixture was cooled to 25° C. and then treated with a saturated aqueous potassium fluoride solution (20 mL). The mixture was stirred for 3 h, treated with a solution of water and a saturated aqueous sodium chloride solution, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 1/1 hexanes/ethyl acetate) afforded 5-allyl-pyrazin-2-ylamine (378.2 mg, 48.7%) as a yellow solid: LRMS for C7H9N3 (M+H)+ at m/z=136.