Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.CS(O[CH2:27][CH2:28][C@H:29]([F:34])[CH2:30][CH2:31][CH2:32][CH3:33])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:34][C@H:29]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:28][CH2:27][O:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: Oc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1
Reactant: CCCC[C@@H](F)CCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC[C@@H](F)CCOc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
A mixture of 1.12 g of 5-hydroxy-2-(4-benzyloxyphenyl)pyrimidine, 1.30 g of 3-(R)-fluoroheptyl methanesulfonate, 1.2 g of potassium carbonate, and 50 ml of DMF was stirred at 80° C. for 4 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and distilled to remove the solvent to obtain a residue weighing 2.12 g. Recrystallization of the residue from ethanol furnished 1.41 g (percent yield: 87.7%) of 5-[3-(R)-fluoroheptyloxy]-2-(4-benzyloxyphenyl)pyrimidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([OH:22])=[CH:17][C:18]=3[NH:19]2)=[CH:11][CH:10]=1)[C:2]1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(OCC[O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][F:48])(=O)=O)=CC=1>CN(C=O)C.O.C(O)(=O)C.[Pd]>[F:48][CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:42][CH2:2][CH2:1][O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([OH:22])=[CH:17][C:18]=3[NH:19]2)=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCF)cc1
Reactant: Oc1ccc2c(c1)[nH]c1cc(OCc3ccccc3)ccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc2c(c1)[nH]c1cc(OCCOCCOCCF)ccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 27 %

Procedure:
To a round bottom flask containing Compound 8 (50 mg, 0.17 mmol) in DMF (1 ml), was added cesium carbonate (56 mg, 0.17 mmol) and 2-(2-(2-fluoroethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (53 mg, 0.17 mmol). The reaction was stirred at rt for 15 h and then diluted with water (15 mL). White precipitate (72 mg) was collected via filtration and dried in vacou. The solid was dissolved in MeOH (10 mL). To the reaction, was added Pd/C (20 mg) and acetic acid (5 drops). The mixture was stirred under hydrogen (1 atm) atmosphere for 20 h and then filtered through a celite plug and concentrated in vacuo. The residue was purified on HPLC to afford CB-26 (20 mg, 0.046 mmol, 27% yield). 1H NMR (400 MHz, CD3CN) δ: 9.03 (br, 1H), 7.81-7.75 (m, 2H), 6.96 (d, J=2.4 Hz, 1H), 6.84 (d, J=2.4 Hz, 1H), 6.76 (dd, J=7.6 Hz, 2.0 Hz, 1H), 6.67 (dd, J=7.6 Hz, 2.0 Hz, 1H), 4.59-4.57 (m, 1H), 4.47-4.45 (m, 1H), 4.17-4.15 (m, 2H), 3.83-3.63 (m, 8H); LRMS for C20H20NO5+H+, calc'd: 431.1. found: 334.1 (M+H+-TFA).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[C:21]([O:25][C:26](=[O:45])[C:27]([CH2:29][N:30]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH2:28])([CH3:24])([CH3:23])[CH3:22].Cl>O1CCCC1>[C:21]([O:25][C:26](=[O:45])[CH:27]([CH2:29][N:30]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:28][C:13]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:22])([CH3:23])[CH3:24]
Reactant: O=C(O)C1CCCC1
Reactant: C=C(CN(Cc1ccccc1)Cc1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(CN(Cc1ccccc1)Cc1ccccc1)CC1(C(=O)O)CCCC1
Temperature: -20 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
To a stirred solution of diisopropylamine (14.98 g, 20.75 ml, 148 mmole) in dry tetrahydrofuran (250 ml) cooled to -30° C. under nitrogen, was added dropwise, n-butyl lithium (59.3 ml of a 2.5M solution, 148 mmole), keeping the temperature below -20° C. The reaction was stirred at -20° C. for 1 hour, then cooled to -30° C. and cyclopentanecarboxylic acid (8.05 g, 7.65 ml, 70.6 mmole) added dropwise in a small amount of dry tetrahydrofuran. The reaction mixture was stirred at 0° C. for two hours, during which time a white precipitate formed. The solution was then cooled to -70° C., and a solution of 2-(dibenzylaminomethyl)-propenoic acid t-butyl ester (23.8 g, 70.6 mmol) in dry tetrahydrofuran (35 ml) was added dropwise. The reaction was left overnight (below -40° C.), and then poured into iced hydrochloric acid (4.2 eq, final pH=2) and the product extracted into diethyl ether. The ether layer was washed with hydrochloric acid, water (2x), dried (Na2SO4) and evaporated to yield the crude product (40 g). This was chromatographed over silica gel (500 g) eluting with dichloromethane containing methanol (0 to 5%) to yield, on evaporation of the pure fractions, 3-(1-carboxycyclopentyl)-2-(dibenzylaminomethyl)propanoic acid t-butyl ester as an oil (18.3 g, 57%). Found: C,74.38; H,8.41; N,2.91. C28H37NO4 requires C,74.47; H,8.26; N,3.10%.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.II.[I:20]([O-])(=O)=O.[Na+]>C(O)(=O)C>[NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([I:20])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: [O-][I+2]([O-])[O-]
Agent: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: N[C@@H](Cc1ccc(I)cc1)C(=O)O
Temperature: 70 °C
Reaction time: 2 h
Yield: 472.8 %

Procedure:
To a solution (S)-2-amino-3-phenylpropanoic acid 91 (4.01 g, 24.3 mmol) in acetic acid (22 mL) was added sulfuric acid (2.9 mL, 5.14 mmol), iodine (2.47 g, 4.7 mmol) and sodium iodate (1.02 g, 5.14 mmol). The mixture was heated to 70° C. and allowed to stir at this temperature for 16 h before an additional portion of sodium iodate (1.02 g, 5.14 mmol) was added. The reaction was left for a further 2 h before being concentrated, dissolved in methanol (20 mL) and treated with NaOH (60 mL). The mixture was left to precipitate out of the basic solution overnight and the resulting solid was filtered by vacuum filtration to yield the title compound (7.07 g, 24.3 mmol, 100%) as a pink solid, which had spectral data in agreement with that reported.93 [α]D21 −10.6 (c. 0.3, HCl). Mp 258-260° C. (lit. 261-262° C.)93 1H NMR (CD3OD, 300 MHz): δ 7.71 (d, J=8.4 Hz, 2H, ArH2′ and ArH6′); 7.10 (d, J=8.4 Hz, 2H, ArH3′ and ArH5′); 4.26 (dd, J=6.3, 7.2 Hz, H2); 3.26 (dd, J=5.4, 14.1 Hz, 1H, H3a); 3.04 (dd, J=7.2, 14.4 Hz, 1H, H3b). Mass Spectrum (CI, +ve) m/z 279 (100%), 292 (70%) [M+]. HRMS calcd for C9H11NO2 291.9834 found 291.9568.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].[CH3:13][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])([CH3:16])[CH3:15].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH3:13][C:14]([CH3:16])([S:17]([NH:20][C:7]([C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:9])(=[O:19])=[O:18])[CH3:15]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)S(=O)(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 84.1 %

Procedure:
To a mixture of 3-nitrobenzoic acid (0.37 g, 2.2 mmol), 1,1-dimethylethylsulphonamide (0.3 g, 2.2 mmol) and 4-dimethylaminopyridine (0.27 g, 2.2 mmol) in anhydrous dichloromethane (20 ml), under an atmosphere of nitrogen, was added. 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.42 g, 2.2 mmol). The mixture was stirred at ambient temperature for 22 h. The mixture was extracted with 1M NaOH (50 ml) and the separated aqueous phase acidified using 5M HCl. This was extracted with dichloromethane (5×20 ml), then the combined organic extracts were dried (Na2SO4) and evaporated to dryness. The residue was chromatographed on silica gel using 1% methanol in dichloromethane as the eluant. The title compound (0.53 g, 85%) was isolated as a colourless solid. mp 220° C. 1H NMR (360 MHz, D6-DMSO) δ 1.27 (9H, s), 6.59 (1H, brs), 7.65 (1H, t, J=7.9 Hz), 8.24-8.30 (1H, m), 8.34-8.38 (1H, m), 8.68-8.72 (1H, m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[N+:29](=[CH2:31])=[N-:30]>O1CCCC1.CCOCC>[N+:29](=[CH:31][C:11](=[O:13])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:10])=[N-:30]
Reactant: C=[N+]=[N-]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CCOCC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)C=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.23 h

Procedure:
To a vigorously stirred solution of [(t-butyloxy)carbonyl]-L-alanine (15.14 g, 80 mmol) and N-methylmorpholine (8.80 ml, 80 mmol) in 80 ml of dry tetrahydrofuran at -15° C. under argon was added a solution of isobutyl chloroformate (10.37 ml, 80 mmol) in 10 ml tetrahydrofuran, maintaining the reaction temperature below -12° C. After the addition was complete, the reaction mixture was stirred for 14 minutes and then diluted with 250 ml of anhydrous ether (prechilled to -20° C.) and quickly filtered. Approximately one-fourth of the filtrate was transferred to a separatory funnel (the remainder kept chilled) and added rapidly to a gently stirred, chilled (0° C.) solution of diazomethane (160 mmol, generated from 23.54 g of N-methyl-N'-nitro-N-nitrosoguanidine). Additional chilled portions were transferred to the separatory funnel until the entire solution had been added (over approximately 10 minutes). The resulting solution was stirred for 2 hours, warming gradually to room temperature, then purged with nitrogen for 1 hour, washed with chilled half-saturated sodium bicarbonate (2×100 ml) and water (3×50 ml), dried (sodium sulfate) and evaporated to a yellow semi-crystalline residue. Two recrystallizations from ethyl acetate-petroleum ether yielded yellow plates, 10.29 g, melting point 99°-102° C., plus an additional crop of 1.33 g, melting point 97.5°-101° C. A portion was recrystallized once more giving the analytical sample, melting point 102°-103° C.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][S:11][C:10](=S)[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1[O:17]C1C.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([C@H:8]1[CH2:12][S:11][C:10](=[O:17])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C1N[C@@H](Cc2ccccc2)CS1
Reactant: CC1CO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1N[C@@H](Cc2ccccc2)CS1
Reaction time: 2 h

Procedure:
To a solution of (4S)-4-benzyl-1,3-thiazolidine-2-thione (38 g) in dichloromethane (350 mL) cooled to 0° C., propylene oxide (12.7 mL) and trifluoroacetic acid (14 mL) were added. After stirring the reaction mixture for 2 hours, the solvents were evaporated under reduced pressure to obtain a residue which was purified by column chromatography over silica gel using 20% ethyl acetate in hexane as eluant to afford the title compound (0.9 g). Mass (m/z): 194.18
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:15])=[O:14].[C:17](OCC)(=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][C:17]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[CH:4][C:3]=1[S:13](=[O:14])(=[O:15])[NH2:16])=[O:24])[CH3:23]
Reactant: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)CC(=O)Nc1ccc(NS(C)(=O)=O)cc1S(N)(=O)=O
Temperature: 160 °C
Yield: 71.2 %

Procedure:
To 2-amino-5-methanesulfonylamino-benzenesulfonamide (Example 17d, 175 mg, 0.66 mmol) was added diethyl malonate (297 mg, 1.66 mmol) and heated at 160° C. for 60 min. After cooling down to 25° C., a 1:1 mixture of ethyl acetate/hexanes (5 mL) was added, upon which as a white solid precipitated out. The solid was collected by vacuum filtration, washed twice with a 1:1 mixture of ethyl acetate/hexanes, and dried under high vacuum to afford the desired product, N-(4-methanesulfonylamino-2-sulfamoyl-phenyl)-malonamic acid ethyl ester (179 mg, 0.47 mmol, 72% yield) as an off-white solid. 1H NMR (400 MHz, CD3OD) δ: 1.32 (t, 3H, J=7.0 Hz), 3.00 (s, 3H), 3.60 (s, 2H), 4.25 (quartet, 2H, J=6.8 Hz), 7.44 (dd, 1H, J1=3.2 Hz, J2=8.4 Hz), 7.87 (d, 1H, J=5.6 Hz), 7.92 (d, 1H, J=8.4 Hz). LC-MS (ESI+) calcd for C12H17N3O7S2 379.05. found 380.1 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:26])[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(OC(C)C)(C)C.CCCCCC>>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14](=[O:15])[C:13]([N:10]2[CH2:11][CH2:12][CH:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:28][CH:27]=3)[CH2:8][CH2:9]2)=[O:26])=[CH:18][CH:19]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: CC(C)OC(C)C
Solvent: CCCCCC
Product: Nc1ccc(NC(=O)C(=O)N2CCC(Cc3ccc(F)cc3)CC2)cc1

Procedure:
The title compound is prepared from 2-[4-(4-fluoro-benzyl)-piperidin-1-yl]-N-(4-nitro-phenyl)-2-oxo-acetamide (Example 93) according to the method described in Example 11. Melting Point: 141-143° C. (diisopropylether-hexane).
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][C@H:12]2[CH2:15][C@@H:14]([C:16]3[N:20]4[CH:21]=[CH:22][N:23]=[C:24]([Cl:25])[C:19]4=[CH:18][N:17]=3)[CH2:13]2)(=O)=O)=CC=1.C1(C)C=CC(S([O:36][CH2:37][C@H:38]2[CH2:41][C@H:40]([C:42]3[N:46]4[CH:47]=[CH:48][N:49]=[C:50]([Cl:51])[C:45]4=[CH:44][N:43]=3)[CH2:39]2)(=O)=O)=CC=1.[N+:53]([C:56]1[CH:64]=[CH:63][C:59]([C:60](Cl)=[O:61])=[CH:58][CH:57]=1)([O-:55])=[O:54]>>[N+:53]([C:56]1[CH:57]=[CH:58][C:59]([C:60]([O:10][CH2:11][C@H:12]2[CH2:13][C@@H:14]([C:16]3[N:20]4[CH:21]=[CH:22][N:23]=[C:24]([Cl:25])[C:19]4=[CH:18][N:17]=3)[CH2:15]2)=[O:61])=[CH:63][CH:64]=1)([O-:55])=[O:54].[N+:53]([C:56]1[CH:57]=[CH:58][C:59]([C:60]([O:36][CH2:37][C@H:38]2[CH2:39][C@H:40]([C:42]3[N:46]4[CH:47]=[CH:48][N:49]=[C:50]([Cl:51])[C:45]4=[CH:44][N:43]=3)[CH2:41]2)=[O:61])=[CH:63][CH:64]=1)([O-:55])=[O:54]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@@H](c3ncc4c(Cl)nccn43)C2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](c3ncc4c(Cl)nccn43)C2)cc1
Product: O=C(OC[C@H]1C[C@@H](c2ncc3c(Cl)nccn32)C1)c1ccc([N+](=O)[O-])cc1
Product: O=C(OC[C@H]1C[C@H](c2ncc3c(Cl)nccn32)C1)c1ccc([N+](=O)[O-])cc1

Procedure:
cis-3-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyl 4-nitrobenzoate and trans-3-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyl 4-nitrobenzoate were prepared according to the general procedure for the preparation for cis-3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyl toluene-4-sulfonate and trans-3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyl toluene-4-sulfonate, except 4-nitrobenzoyl chloride was used instead of p-toluenesulfonic anhydride.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:26]=[CH:25][C:10]3[N:11]=[C:12]([N:14]4[CH2:19][CH2:18][CH:17]([O:20][CH2:21][C@@H:22]([NH2:24])[CH3:23])[CH2:16][CH2:15]4)[O:13][C:9]=3[CH:8]=2)[CH2:4][CH2:3]1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1.O>[CH:2]1([CH2:5][O:6][C:7]2[CH:26]=[CH:25][C:10]3[N:11]=[C:12]([N:14]4[CH2:19][CH2:18][CH:17]([O:20][CH2:21][C@@H:22]([NH:24][C:27](=[O:29])[CH3:28])[CH3:23])[CH2:16][CH2:15]4)[O:13][C:9]=3[CH:8]=2)[CH2:4][CH2:3]1
Reactant: C[C@H](N)COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N[C@@H](C)COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S)-1-({1-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]piperidin-4-yl}oxy)propan-2-amine monohydrochloride (17.6 g) in pyridine (85 mL) was added acetic anhydride (12.6 mL) at room temperature, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water, 1M hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was recrystallized from hexane/ethyl acetate to give the title compound (12.0 g) as white crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]([B-](F)(F)F)=[CH2:12].[K+].C(N(CC)CC)C>C(O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:11]=[CH2:12])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: C=C[B-](F)(F)F
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: C=Cc1ccc([N+](=O)[O-])cn1
Temperature: 120 °C

Procedure:
To a 20 ml, microwave tube was added 2-bromo-5-nitropyridine (0.20 g, 0.98 mmol), potassium vinyltrifluoroborate (145 mg, 1.1 mmol), PdCl2(dppf)-CH2Cl2 complex (40 mg, 0.049 mmol), and a stir bar. The tube was sealed, and ethanol (6 mL) and triethylamine (0.41 mL, 3.0 mmol) was added via syringe. The mixture was purged three times with nitrogen and then heated to 120° C. for 30 minutes. LC at that point showed mostly product. The reaction was diluted with DCM, adsorbed onto silica gel, and purified by silica gel flash chromatography (Hexane:EtOAc). LC-MS (IE, m/z): 151 [M+1]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]3[N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[N:18]=[C:19]([CH3:20])[C:14]3=[C:13]([CH2:27][N:28]3[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][CH2:30][C:29]3([CH3:37])[CH3:36])[CH:12]=2)=[CH:7][CH:6]=1.C1COCC1.[CH2:43]([N:45]=[C:46]=[O:47])[CH3:44].CCN(C(C)C)C(C)C>O>[CH2:43]([NH:45][C:46]([N:31]1[CH2:30][C:29]([CH3:37])([CH3:36])[N:28]([CH2:27][C:13]2[CH:12]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][CH:9]=3)[N:16]=[C:15]3[N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[N:18]=[C:19]([CH3:20])[C:14]=23)[CH2:33][C:32]1([CH3:35])[CH3:34])=[O:47])[CH3:44]
Reactant: COCOc1ccc(-c2cc(CN3CC(C)(C)NCC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)cc1
Reactant: CCN=C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCNC(=O)N1CC(C)(C)N(Cc2cc(-c3ccc(OCOC)cc3)nc3c2c(C)nn3C2CCCCO2)CC1(C)C
Yield: 98.3 %

Procedure:
To a solution of 290 mg 6-(4-Methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-4-(2,2,5,5-tetramethyl-piperazin-1-ylmethyl)-1H-pyrazolo[3,4-b]pyridine in 3 ml abs. THF were added 41 mg ethyl isocyanate and 75 mg Hünig's base. After 16 h at rt water was added, and the pH was adjusted to neutral. The mixture was extracted with ethyl acetate twice and the combined organic layers were dried and concentrated in vacuo. 325 mg of the title compound were obtained, which were subjected to the subsequent reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[C:35]1[CH:36]=[N:37][CH:38]=[N:39][CH:40]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[N:37]1[CH:36]=[C:35]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:13]3[O:14][C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=4)=[N:11][N:12]=3)=[CH:16][CH:17]=2)[CH:40]=[N:39][CH:38]=1
Reactant: Brc1cncnc1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(C(F)(F)F)c3)o2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: FC(F)(F)c1cccc(Nc2nnc(-c3ccc(Oc4cncnc4)cc3)o2)c1
Temperature: 80 °C
Yield: 43.6 %

Procedure:
4-(5-{[3-(trifluoromethyl)-phenyl]amino}-1,3,4-oxadiazol-2-yl)phenol (160.6 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (149.6 mg, 0.75 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 10 min, then 5-bromopyrimidine (119.2 mg, 0.75 mmol) was added, followed by anhydrous K2CO3 (69.1 mg, 0.5 mmol). Then the vial was capped and microwaved at 200° C. for 20 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing the product, were partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated NaHCO3. EtOAc layer was washed with brine, dried over anhydrous Na2SO4 and filtered. Solvent was removed in vacuo to give the title product as a beige solid (87.0 mg). Yield 43.5%.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S(O[C:13]1[CH2:14][CH2:15][N:16]([C:19]2[CH:20]=[CH:21][C:22]3[N:23]([C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][N:27]=3)[N:24]=2)[CH2:17][CH:18]=1)(=O)=O.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)O1>COCCOC.O.CCOC(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>[F:29][C:28]([F:31])([F:30])[C:25]1[N:23]2[N:24]=[C:19]([N:16]3[CH2:17][CH:18]=[C:13]([C:42]4[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=4)[CH2:14][CH2:15]3)[CH:20]=[CH:21][C:22]2=[N:27][N:26]=1
Reactant: O=S(=O)(OC1=CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1)C(F)(F)F
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: FC(F)(F)c1nnc2ccc(N3CC=C(c4cccnc4)CC3)nn12
Temperature: 80 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
Sodium carbonate (114 mg, 1.08 mmol) was added to 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (150 mg, 0.36 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (81 mg, 0.40 mmol) in a mixture of DME (2 mL) and water (0.5 mL). The mixture was bubbled with nitrogen for 10 minutes then tetrakis(triphenylphosphine)palladium(0) (20.77 mg, 0.02 mmol) was added and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (3 mL) and water (2 mL). The organic layer was separated and dried, and the solvent was evaporated to give crude product. Purification by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM, gave 1′-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-1′,2′,3′,6′-tetrahydro-3,4′-bipyridine (100 mg, 80%).
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH3:12]>>[C:1]1(=[O:6])[NH:12][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: N
Reactant: O=C1OC(=O)c2ccccc21
Product: O=C1NC(=O)c2ccccc21

Procedure:
U.S. Pat. No. 2,668,326 describes a method of reacting phthalic anhydride and ammonia batchwise and washing the off-gases from the reaction with water or a high-boiling hydrocarbon as the solvent. It is advantageous to recycle the wash fluid, resulting in accumulation of suspended phthalimide. This suspension is also used for cooling and quenching the hot reaction mixture.