Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:13])([CH3:12])[C:10]#N)[CH:6]=[CH:7][CH:8]=1.[H-].C([Al+]CC(C)C)C(C)C.[OH:24]S(O)(=O)=O>C1COCC1.CCCCCCC.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:13])([CH3:12])[CH:10]=[O:24])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(C)(C)C#N)c1
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COc1cccc(C(C)(C)C=O)c1
Temperature: 25 °C

Procedure:
To a ice cold stirred solution of 2-(3-methoxyphenyl)-2-methylpropanenitrile (27.7 g, 158 mmoles) in 250 mL of THF was added dropwise diisobutylaluminum hydride in heptane (202 mL, 1.0M solution). The mixture was allowed to warm to room temperature overnight. After cooling, a solution of concentrated H2SO4 (21.5 mL) in 85 mL of water was cautiously added in small portions. The resulting mixture was partitioned between Et2O and water, the aqueous layer further extracted, and the combined organic extracts dried over Na2SO4, filtered, and evaporated to give 2-(3-methoxyphenyl)-2-methylpropanal, 21.7 g, as an oil.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]([CH2:11][NH2:12])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[C:13]([OH:22])(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16]>O>[CH2:1]1[CH2:2][CH2:3][C:4]([CH2:11][NH2:12])([CH2:7][C:8]([OH:10])=[O:9])[CH2:5][CH2:6]1.[C:13]([O-:22])(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16]
Reactant: O=C(O)c1ccccc1O
Agent: NCC1(CC(=O)O)CCCCC1
Solvent: O
Product: O=C([O-])c1ccccc1O
Temperature: 40 °C
Reaction time: 6 h

Procedure:
A solution of 20 kg of gabapentin in 140 liters of water is heated at 40° C. and added with 16.1 kg of salicylic acid. The suspension is stirred for 6 hours at 40° C., then cooled to 20° C., centrifuged and dried under vacuum at approx. 50° C. 34.5 kg (95.5% on theoretical) of 99.65% gabapentin salicylate are obtained, melting point 116° C. The elemental analysis (found C, 62.28%; H, 7.53%; N, 4.44%; calculated C, 62.12%; H, 7.49%; N, 4.53%) confirms the nature of the salt, which is suspended in 130 liters of absolute ethanol at 20° C., added with 15.9 kg of N-ethyl-diisopropylamine, then stirred at 20° C. for four hours, cooled to 8-10° C. and centrifuged, washing in centrifuge with approx. 20 liters of absolute ethanol. Drying affords 15.4 kg of gabapentin (86.68% yield), which can be further purified by suspension in 400 liters of ethanol containing 10% by weight of water and heating for some minutes, under stirring, at approx. 40° C. After standing at room temperature for four-five hours, the mixture is cooled to 0° C. and after, a further 4-5 hours at this temperature, is centrifuged and dried. The resulting pure gabapentin (87% yield) has content in salicylic acid lower than 100 ppm and in lactam lower than 0.1%.
Reaction SMILES: C1CO[C:3]2([CH:12]([CH2:13][C:14]([OH:16])=[O:15])[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[O:17][CH3:18])[CH2:4]2)[O:2]1.Cl>CC(C)=O>[CH3:18][O:17][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][CH:12]([CH2:13][C:14]([OH:16])=[O:15])[C:3](=[O:2])[CH2:4]2
Reactant: COc1cccc2c1CC(CC(=O)O)C1(C2)OCCO1
Agent: Cl
Solvent: CC(C)=O
Product: COc1cccc2c1CC(CC(=O)O)C(=O)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.9 %

Procedure:
A solution of 8.0 g (28.7 mmol) of 2,2-ethylenedioxy-5-methoxy-1,2,3,4-tetrahydronaphthalen-3-ylacetic acid, 80 ml of 3N aqueous hydrochloric acid, and 80 ml of acetone was degassed and heated to 60° under nitrogen then stirred under nitrogen at 60° for 4 hours. The reaction was cooled to room temperature, approximately 50% of the solvent was removed by rotary evaporation, diluted with 100 ml of brine, and extracted with three 100 ml portions of ethyl acetate. The organic layers were combined and washed with two 100 ml portions of brine, dried over anhydrous sodium sulfate, filtered, and concentrated via rotary evaporation to give an orange solid. The orange solid was triturated with 10 ml of ether and filtered to give 4.9 g (73%) of the title compound (f), m.p. 129°-131°.
Reaction SMILES: [C:1]([C:4]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:6](=[O:25])[C:5]=1O)(=O)[CH3:2].[NH:27]([C:29]1[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=1)[NH2:28]>CCO.C1(C)C=CC=CC=1>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:8]2[C:4]3[C:1]([CH3:2])=[N:28][N:27]([C:29]4[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=4)[C:5]=3[C:6](=[O:25])[N:7]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(CN2C(=O)C(O)=C(C(C)=O)C2c2ccc(Cl)cc2)cc1
Reactant: Cn1nccc1NN
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(CN2C(=O)c3c(c(C)nn3-c3ccnn3C)C2c2ccc(Cl)cc2)cc1
Temperature: 115 °C
Reaction time: 20 h
Yield: 85.4 %

Procedure:
To a stirred solution of 4-acetyl-5-(4-chlorophenyl)-3-hydroxy-1-(4-methoxybenzyl)-1H-pyrrol-2(5H)-one (Step 71.2) (3 g, 8.07 mmol) in EtOH (50 mL) and toluene (50 mL) was added 5-hydrazinyl-1-methyl-1H-pyrazole (Step 74.2) (1.941 g, 10.49 mmol) and the resulting mixture was heated up and stirred at 115° C. for 20 hr. The reaction was quenched with a saturated aq. NaHCO3 solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/EtOAc 40-50%) to afford the title product (3.15 g, 6.89 mmol, 85% yield) as yellow solid. tR: 5.60 min (HPLC 1); tR: 1.24 min (LC-MS 2); ESI-MS: 448 [M+H]+ (LC-MS 2); Rf=0.41 (hexane/EtOAc 1:1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([B-](F)(F)F)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[K+].Br[C:16]1[CH:17]=[C:18]([O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[C:19]([Cl:22])=[N:20][CH:21]=1.C(N(CC)CC)C.O>CCO>[Cl:22][C:19]1[N:20]=[CH:21][C:16]([C:7]2[CH:8]=[CH:9][C:4]3[N:3]=[CH:2][S:1][C:5]=3[CH:6]=2)=[CH:17][C:18]=1[O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29]
Reactant: COCCOCOc1cc(Br)cnc1Cl
Reactant: F[B-](F)(F)c1ccc2ncsc2c1
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: COCCOCOc1cc(-c2ccc3ncsc3c2)cnc1Cl
Reaction time: 1 h
Yield: 10.3 %

Procedure:
A 50 mL Schlenk flask was charged with potassium benzo[d]thiazol-6-yltrifluoroborate (0.1929 g, 0.800 mmol), Pd(dppf)C12-DCM adduct (0.0469 g, 0.0641 mmol) and a stirbar. The flask was evacuated to <1 mm Hg and refilled with nitrogen. A degassed solution of 5-bromo-2-chloro-3-((2-methoxyethoxy)methoxy)pyridine (0.1900 g, 0.641 mmol) in 5 mL 1% aqueous EtOH was added, followed by triethylamine (0.262 ml, 1.92 mmol). The flask was fitted with a cold finger, and was heated using a 110° C. oil bath for 12 h. The solution was cooled, and water (10 mL) was added. The mixture was vigorously stirred for 1 h, and poured onto a glass frit. The oily residue was washed with water (2×10 mL), and then dissolved in MeOH (30 mL). The brownish solution was stirred for 30 minutes, and then filtered through a 0.22 μm PTFE membrane. The filtrate was concentrated in vacuo. The sample was purified in one injection using a 30×100 mm Waters Xterra Prep C18 OBD column (A=water; B=2% TFE in ACN; 100 Å pore diameter, 5 μm particle size, spherical shape, PN 186001942; Gradient: 0→5 min@35 mL/min, 40% B; 5→20 min@35 mL/min, linear gradient to 70% B; 20→24.9@35 mL/min, isocratic at 70% B, 25→29.9 min@35 mL/min, step to 100% B; 30→40 min@35 mL/min, step to 40% B; 40 min end). A fraction that eluted from 14.7 to 15.9 minutes was isolated. The solvent was removed in vacuo to afford 6-(6-chloro-5-((2-methoxyethoxy)methoxy)pyridin-3-yl)benzo[d]thiazole (0.0231 g, 10.3% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 3.37 (s, 3H) 3.58-3.61 (m, 2H) 3.91-3.96 (m, 2H) 5.46 (s, 2H) 7.72 (dd, J=8.51, 1.86 Hz, 1H) 7.83 (d, J=2.15 Hz, 1H) 8.15 (dd, J=1.81, 0.44 Hz, 1H) 8.23 (dd, J=8.51, 0.49 Hz, 1H) 8.35 (d, J=2.05 Hz, 1H) 9.06 (br. s., 1H). 13C NMR (101 MHz, chloroform-d) δ ppm 58.97 (s, 1 C) 68.25 (s, 1 C) 71.34 (s, 1 C) 94.14 (s, 1 C) 120.47 (s, 1 C) 122.57 (s, 1 C) 124.10 (s, 1 C) 125.67 (s, 1 C) 134.15 (s, 1 C) 134.78 (s, 1 C) 136.37 (s, 1 C) 140.24 (s, 1 C) 140.68 (s, 1 C) 149.46 (s, 1 C) 153.22 (s, 1 C) 154.95 (br. s., 1 C). HPLC-MS: 2.06 min (>99%@215 nm; 99.2% @254 nm; m/z=351.1, calculated for C16H15ClN2O3S+H+=351.1).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.FC1C(F)=C(C#CC2C=C(C=CC=2)N)C(F)=C(F)N=1.[O:25]=[C:26]([NH:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([C:55]#[C:56][C:57]2[C:62]([F:63])=[C:61]([F:64])[N:60]=[C:59]([F:65])[C:58]=2[F:66])[CH:50]=1)[C@@H:27]([NH:40]C(=O)OC(C)(C)C)[CH2:28][CH2:29][CH2:30][CH2:31][NH:32]C(=O)OC(C)(C)C>N1C=CC=CC=1.Cl>[ClH:3].[ClH:3].[NH2:40][C@@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])[C:26]([NH:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([C:55]#[C:56][C:57]2[C:62]([F:63])=[C:61]([F:64])[N:60]=[C:59]([F:65])[C:58]=2[F:66])[CH:50]=1)=[O:25]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccc(C#Cc2c(F)c(F)nc(F)c2F)c1
Agent: Cl
Agent: Nc1cccc(C#Cc2c(F)c(F)nc(F)c2F)c1
Solvent: c1ccncc1
Product: NCCCC[C@H](N)C(=O)Nc1cccc(C#Cc2c(F)c(F)nc(F)c2F)c1
Temperature: -25 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
L-Boc-Lys(Boc)-OH (0.26 g, 0.75 mmol) was dissolved in 3 mL of pyridine. The solution was cooled to −25° C. and phosphorus oxychloride (0.12 g, 0.75 mmol) was added dropwise with vigorous stirring. After stirring for 15 min. at −25° C., 3-((perfluoropyridin-4-yl)ethynyl)aniline, (13b) (0.10 g, 0.36 mmol) in pyridine (3 mL) was added slowly. The reaction mixture was stirred for 0.5 h at −25° C. and then at room temperature for 10 h. The reaction mixture was quenched with ice/water and extracted with EtOAc. The organic layer was washed with sat. NaHSO4 three times, dried with Na SO4 and was concentrated in vacuo. The crude product was subjected to chromatography with CH2Cl2:CH3CN=1:30 and the product was obtained in 36% yield. (S)-Di-tert-butyl (6-oxo-6-((3-((perfluoropyridin-4-yl)ethynyl)phenyl)amino)hexane-1,5-diyl)dicarbamate (97 mg, 0.16 mmol) was dissolved in gaseous HCl saturated MeOH (4 mL) at 0° C. and the solution was stirred for 10 hours at room temperature. The solvent was evaporated and the product (65 mg, 86%) was purified by recrystallization with isopropanol: 1H-NMR (600 MHz, CD3OD) δ 8.07 (dd, J=1.74 Hz, J=1.68 Hz, 1H), 7.75 (ddd, J=7.98 Hz, J=1.92 Hz, J=1.14 Hz, 1H), 7.48 (dd, J=7.8 Hz, J=7.8 Hz, 1H), 7.43 (ddd, J=7.68 Hz, J=1.32 Hz, J=1.32 Hz, 1H) 4.12 (t, J=6.6 Hz, 1H), 2.97 (t, J=7.56 Hz, 2H), 2.00-2.07 (m, 1H), 1.97-2.00 (m, 1H), 1.74-1.77 (m, 2H), 1.56-1.60 (m, 2H); 13C-NMR (150 MHz, CD3OD) δ 168.7, 144.9 (dm, J=224 Hz), 143.5 (dm, J=262 Hz), 139.7, 130.8, 129.4, 124.2, 123.3, 122.4, 117.9 (m), 106.5 (m), 74.2 (m), 54.9, 40.3, 32.2, 28.2, 23.0; m.p. >250° C. (decomp.)
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[CH:7]([C:12]([O:14]CC3C=CC([N+]([O-])=O)=CC=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[SH:27][C@@H:28]1[CH2:32][N:31]([CH3:33])[C@H:30]([C:34]([N:36]2[CH2:41][CH2:40][N:39]([C:42](=[N:44]C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH3:43])[CH2:38][CH2:37]2)=[O:35])[CH2:29]1>>[C:42]([N:39]1[CH2:40][CH2:41][N:36]([C:34]([C@@H:30]2[CH2:29][C@H:28]([S:27][C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]4[C:7]=3[C:12]([OH:14])=[O:13])[CH2:32][N:31]2[CH3:33])=[O:35])[CH2:37][CH2:38]1)(=[NH:44])[CH3:43]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCN(C(=O)[C@@H]2C[C@H](S)CN2C)CC1
Product: CC(=N)N1CCN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2C)CC1
Yield: 8.5 %

Procedure:
Following a procedure similar to that described in Example 1, but using 181 mg of 4-nitrobenzyl (1R, 5R, 6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 220 mg of (2S, 4S)-4-mercapto-2-[4-(N-4-nitrobenzyloxycarbonylacetimidoyl)piperazin-1-ylcarbonyl]-1-methylpyrrolidine (prepared as described in Preparation 44), 20 mg of the title compound were obtained, as a powder.
Reaction SMILES: OC1CON(C([C:9]2[C:17]3[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]([CH:21]([CH3:23])[CH3:22])[C:12]=3[S:11][C:10]=2CC2C3C(=NC=CC=3)NC=2)=O)C1.[Br:34]N1C(=O)CCC1=O.[C:42]([O:45][CH2:46]C)(=[O:44])[CH3:43]>>[Br:34][CH2:9][C:10]1[S:11][C:12]2[N:13]([CH:21]([CH3:23])[CH3:22])[C:14](=[O:20])[N:15]([CH3:19])[C:16](=[O:18])[C:17]=2[C:43]=1[C:42]([O:45][CH3:46])=[O:44]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(C)=O
Reactant: CC(C)n1c(=O)n(C)c(=O)c2c(C(=O)N3CC(O)CO3)c(Cc3c[nH]c4ncccc34)sc21
Product: COC(=O)c1c(CBr)sc2c1c(=O)n(C)c(=O)n2C(C)C
Temperature: 25 °C

Procedure:
A solution of the product of example 8, part b), (1.6 g), N-bromosuccinimide (1 g), and azoisobutyronitrile (10 mg) in ethyl acetate (25 ml) was refluxed for 1 h. The solution was cooled to room temperature, washed successively with dilute sodium hydroxide solution and water, the organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica, eluting with diethyl ether/i-hexane (1:1) to give the sub-title compound as a solid (1.5 g). δ 1HCDCl3 1.62 (6H, d), 3.37 (3H, s), 3.99 (3H, s), 3.60-3.70 (3H, m)
Reaction SMILES: C1CCCCC=1.C([O:14][CH2:15][CH2:16][O:17][CH2:18][P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])C1C=CC=CC=1>C(O)C>[OH:14][CH2:15][CH2:16][O:17][CH2:18][P:19](=[O:26])([O:20][CH2:21][CH3:22])[O:23][CH2:24][CH3:25]
Reactant: CCOP(=O)(COCCOCc1ccccc1)OCC
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCOP(=O)(COCCO)OCC

Procedure:
The method of claim 1 wherein in step (a) a solution of (i) the diethyl ester of hydroxymethylphosphonic acid and (ii) 2-benzyloxyethyl p-toluene sulfonate in ethylene glycol dimethyl ether is added to a slurry of sodium hydride in ethylene glycol dimethyl ether under a nitrogen atmosphere to form diethyl 2-(benzyloxy)ethoxymethylphosphonate as a first intermediate; wherein, in step (b), said first intermediate is dissolved together with cyclohexene in ethanol, paladium on carbon is added to the ethanol solution, and the resulting slurry is heated under nitrogen to form diethyl 2-hydroxyethoxymethylphosphonate as a second intermediate; wherein in step(c), said second intermediate is dissolved in dichloromethane under a nitrogen atmosphere, toluene sulfonyl chloride is added to the dichloromethane solution, and a solution of pyridine in dichloromethane is added to the resulting mixture to form diethyl 2-(phosphonomethoxy)ethyl p-toluene sulfonate as a third intermediate; and wherein in step (d), said third intermediate is dissolved together with the diethyl ester of hydroxymethylphosphonic acid in ethylene glycol dimethyl ether, and a slurry of sodium hydride in ethylene glycol dimethyl ether is added thereto under a nitrogen atmosphere to form tetraethyl ethyleneglycol di-(phosphonomethyl) ether.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]([OH:11])[OH:10])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].O[C:17]([C:20](O)([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(OCC)C.O>O1CCOCC1>[CH3:18][C:17]1([CH3:19])[C:20]([CH3:22])([CH3:21])[O:11][B:9]([C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[C:4]([C:12]([F:15])([F:13])[F:14])[CH:5]=2)[O:10]1
Reactant: CSc1ccc(B(O)O)cc1C(F)(F)F
Reactant: CC(C)(O)C(C)(C)O
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CSc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(F)(F)F

Procedure:
The product of step b) (0.25 g) was heated in dioxan (2 ml) with pinacol (2 equiv) for 3 h. The solution was treated with diethyl ether and water. The organic layer was separated, washed with brine, dried (Na2SO4) and concentrated in vacuo. Yield 85 mg.
Reaction SMILES: N[C:2]1[C:3](SC(C)C)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:12][C:13]([F:17])([F:16])[CH2:14][OH:15].CS(O)(=O)=O.[C:23](ON=O)(C)([CH3:25])[CH3:24].C(=O)(O)[O-].[Na+]>>[CH:23]([C:3]1[C:2]([O:15][CH2:14][C:13]([F:17])([F:16])[F:12])=[CH:7][CH:6]=[CH:5][N:4]=1)([CH3:25])[CH3:24]
Reactant: OCC(F)(F)F
Reactant: CC(C)(C)ON=O
Reactant: CC(C)Sc1ncccc1N
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)c1ncccc1OCC(F)(F)F

Procedure:
A reactor vessel is charged with 3-amino-2-isopropylthiopyridine (3.0 g, 18 mmol), 2,2,2-trifluoroethanol (21 g, 210 mmol), and methanesulfonic acid (1.7 g, 18 mmol). The solution is heated to the range 65° C. to 70° C. and then t-butylnitrite (2.2 g of a 90% solution, 19 mmol) is added drop-wise to the vessel while maintaining the temperature at 65° C. to 70° C. After nitrogen evolution ceases, the solution is cooled, neutralized with aqueous saturated sodium bicarbonate solution and then extracted with MTBE. The solvent is removed by evaporation to obtain 2-isopropyl-3-(2,2,2-trifluoroethoxy)pyridine as a crude oil (4.22 g, crude yield 94%).
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][N:16]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[N+:38]([C:41]1[CH:48]=[CH:47][C:44]([CH2:45]Br)=[CH:43][CH:42]=1)([O-:40])=[O:39]>C(Cl)(Cl)Cl>[C:24]([CH2:23][N:16]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][N:9]([CH2:8][C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2])[CH2:22][CH2:21][CH2:20][N:19]([CH2:45][C:44]2[CH:47]=[CH:48][C:41]([N+:38]([O-:40])=[O:39])=[CH:42][CH:43]=2)[CH2:18][CH2:17]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)CN1CCCNCCN(CC(=O)OC(C)(C)C)CCCNCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CN1CCCN(Cc2ccc([N+](=O)[O-])cc2)CCN(CC(=O)OC(C)(C)C)CCCNCC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 77.9 %

Procedure:
To a solution of compound (5) (1.27 g, 2.96 mmol) in dry CHCl3 (50 ml) were added triethylamine (1.21 ml, 0.90 g, 8.88 mmol) and 4-nitrobenzyl bromide (0.64 g, 2.96 mmol). After stirring at an ambient temperature for 10 hours, the solvent was removed under reduced pressure, and the residue was purified through column chromatography on alumina (basic). Extraction with a mixture of ethyl acetate and methanol (10:2) gave a purified clear oil, which was then solidified to obtain compound (7) (1.30 g, 78% yield). 1H NMR (500 MHz, CDCl3): δ 8.11-8.10 (dd, 2H), 7.55-7.53 (dd, 2H), 3.56 (s, 2H), 3.24 (s, 2H), 3.20-3.06 (m, 6H), 3.01 (brs, 2H), 2.70-2.58 (m, 4H), 2.54-2.42 (m, 4H), 2.39 (brs, 2H), 1.93 (brs, 2H), 1.75 (brs, 2H), 1.39-1.36 (dd, 18H); 13C NMR (125 MHz, CDCl3): δ 171.3, 170.5, 147.0, 146.6, 130.1, 123.3, 81.9, 81.2, 58.1, 56.4, 55.8, 54.9, 53.1, 51.6, 51.5, 51.2, 49.6, 48.5, 46.1, 28.0, 25.1, 22.7; HRMS (FAB) calculated for C29H50N5O6: 564.3761 [(M+H)+], measured value: 564.3757 [(M+H)+].
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[C@H:50]12[CH2:56][C@H:53]([NH:54][CH2:55]1)[CH2:52][N:51]2C(OC(C)(C)C)=O.C(O)(=O)C>CS(C)=O>[C@H:50]12[CH2:56][C@H:53]([NH:54][CH2:55]1)[CH2:52][N:51]2[CH2:46][C:42]1[CH:41]=[C:40]([C:35]2[C:36]([F:39])=[CH:37][CH:38]=[C:33]([CH2:32][NH:31][C:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([C:21]([NH:20][CH2:19][C:10]4[C:11]([NH:12][CH:13]5[CH2:18][CH2:17][O:16][CH2:15][CH2:14]5)=[C:6]5[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]5=[N:8][C:9]=4[CH2:48][CH3:49])=[O:22])[N:24]=3)=[O:30])[CH:34]=2)[CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(C=O)c3)c2)n1
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4C[C@@H]5C[C@H]4CN5)c3)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.3 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]-2,6-pyridinedicarboxamide (50.0 mg. 0.075 mmol) was diluted in DMSO (1.5 mL) and dispensed into a 1 dram vial containing 1,1-dimethylethyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.226 mmol) and acetic acid (4.52 mg, 0.075 mmol) and fitted magnetic stir bar. The resulting solution was stirred at room temperature for 4 h. MP-B(OAc)3H (0.753 mmol, 176 mg) was added and the solution was stirred for another 12 h. The polymer reagent was filtered off and to the filtrate was added MeOH (2.0 mL) and 1 drop of concentrated HCl. This solution was heated at 60° C.° for 12 h. Purification was completed via a Gilson HPLC (basic conditions) to afford 10.26 mg (18.4%) of the title compound. LC-MS m/z 746 (M+H)+, 0.69 min (ret time).
Reaction SMILES: [I-].[Na+].[C:3]([NH:6][CH2:7][CH2:8][NH:9][C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]=[C:12]([NH:22][C:23](=[O:26])[CH2:24]Cl)[CH:11]=1)(=[O:5])[CH3:4].[Cl:27][C:28]1[CH:40]=[CH:39][CH:38]=[CH:37][C:29]=1[O:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>C1COCC1.C(#N)C>[C:3]([NH:6][CH2:7][CH2:8][NH:9][C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]=[C:12]([NH:22][C:23](=[O:26])[CH2:24][N:34]2[CH2:33][CH2:32][CH:31]([O:30][C:29]3[CH:37]=[CH:38][CH:39]=[CH:40][C:28]=3[Cl:27])[CH2:36][CH2:35]2)[CH:11]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)NCCNc1cc(NC(=O)CCl)nc(-c2ccccc2)n1
Reactant: Clc1ccccc1OC1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(=O)NCCNc1cc(NC(=O)CN2CCC(Oc3ccccc3Cl)CC2)nc(-c2ccccc2)n1

Procedure:
Sodium iodide (19 mg; 0.13 mmol) was added to a solution of chloroacetamide 6 (40 mg; 0.12 mmol), piperidine 7.6 (31 mg; 0.15 mmol) and DIPEA (30 μL; 0.17 mmol) in 3:1 acetonitrile:THF (2 mL). After 22 h the reaction was filtered through a short plug of silica gel with THF as a wash. The solution was concentrated in vacuo then purified on silica gel (20 mL) with 10:1 EtOAc:i-PrOH yielding a hard white foam (59.2 mg; 98%). LC (method B) tR=12.9 min; 1H NMR (200 MHz, CDCl3) δ 9.51 (s, 1H), 8.37 (m, 2H), 7.47 (m, 3H), 7.38 (m, 1H), 7.31-7.14 (m, 2H), 7.02-6.86 (m, 2H), 6.72 (brs, 1H), 5.69 (brt, J=5.6 Hz, 1H), 4.48 (m, 1H), 3.67 (m, 2H), 3.53 (m, 2H), 3.19 (s, 2H), 2.90 (m, 2H), 2.56 (m, 2H), 2.20-2.00 (m, 4H), 1.86 (s, 3H). ESIMS 523.0/525.0 (100/42) [MH+], 262 (58), 198 (75).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)C.ClC1C=CC(C2N(C(C3CCCCC3)C(O)=O)C3C=C(F)C([F:66])=CC=3N=2)=CC=1.NC1C=CC(C(OC)=O)=CC=1F>CN(C)C1C=CN=CC=1>[CH3:1][O:3][C:4](=[O:39])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[C:7]([F:66])[CH:6]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: CN(C)c1ccncc1
Agent: COC(=O)c1ccc(N)c(F)c1
Product: COC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(F)c1

Procedure:
This compound was prepared in analogy to example 22, intermediate d, from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid, methyl 4-amino-3-fluorobenzoate and using 4-(dimethylamino)pyridine as base.