Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[C:28]([CH3:35])[CH:27]=1.[N:36]1([CH2:42][CH2:43][OH:44])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]([N:39]2[CH2:40][CH2:41][N:36]([CH2:42][CH2:43][OH:44])[CH2:37][CH2:38]2)=[O:18])[N:8]([C:6]([C:29]2[CH:30]=[CH:31][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH3:19])=[CH:27][C:28]=2[CH3:35])=[O:7])[CH2:12]1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: OCCN1CCNCC1
Reactant: Cc1cc(-c2ccccc2C)ccc1C(=O)O
Product: CON=C1C[C@@H](C(=O)N2CCN(CCO)CC2)N(C(=O)c2ccc(-c3ccccc3C)cc2C)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and 2-(1-piperazinyl)ethanol, the title compound was obtained in 86% purity by HPLC. MS(ESI+): m/z=479.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C@H:6]1[C@H:15]2[CH2:16][CH2:17][N:18]([C:19]([C@H:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]3[NH:27][C:28](=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:20])[C@H:14]2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:7]1.[H-].[Na+].[CH3:38]I.O>CN(C=O)C>[CH3:38][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C@H:6]1[C@H:15]2[CH2:16][CH2:17][N:18]([C:19]([C@H:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]3[NH:27][C:28](=[O:35])[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:20])[C@H:14]2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:7]1
Reactant: CI
Reactant: O=C(N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ncc[nH]3)Nc3ccccc3[C@@H]21)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccnc1[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1NC(=O)c1ccccc1
Reaction time: 1 h
Yield: 62.8 %

Procedure:
To a solution of the compound (119 mg, 0.252 mmol) synthesized in Example 81 in DMF (1 ml) was added sodium hydride (60% in oil, 12.1 mg, 0.30 mmol) under ice-cooling, and the mixture was stirred for 1 hr. Methyl iodide (0.0187 ml, 0.30 mmol) was added dropwise and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous MgSO4, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel and eluted with hexane-ethyl acetate (5:95, v/v) to give the title compound (76.5 mg, 63%) as an amorphous form.
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=[CH2:3].C(N=C=[N:10][CH2:11][CH2:12][CH2:13]N(C)C)C.[NH2:17][C:18]([OH:24])([CH2:22][CH3:23])C(O)=O>O>[CH2:11]([NH:10][C:1](=[O:5])[CH3:2])[CH2:12][CH3:13].[CH2:1]([NH:17][C:18](=[O:24])[CH:22]=[CH2:23])[CH2:2][CH3:3]
Reactant: CCC(N)(O)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Reactant: C=CC(=O)O
Solvent: O
Product: C=CC(=O)NCCC
Product: CCCNC(C)=O

Procedure:
Acrylic acid (20 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (30 g) were dissolved in water (300 mL). Then aminohydroxybutyric acid (2.0 g) was added to the obtained solution and reacted at room temperature for 10 hours. After the completion of the reaction, water was distilled off and the residue was sufficiently washed with hexane (200 mL) in 3 portions. Next, this residue was dissolved in dimethyl-formamide (350 mL), in which N-hydroxysuccinimide (3 g) and N,N′-dicyclohexylcarbodiimide (3 g) had been dissolved, and reacted overnight. After the completion of the reaction, the solvent was distilled off. Ethyl acetate was added to the residue thus obtained and the precipitate thus formed was filtered off. The filtrate was recovered and a fraction containing the target product was taken up by silica gel column chromatography with the use of ethyl acetate as a mobile phase and alumina column chromatography. Next, a half of the solvent was distilled off with an evaporator and recrystallization was carried out by adding a hexane solvent at −20° C. to thereby give the target monomers (N-propylacetamide, N-propyl acrylamide) (yield: 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[N:5]=[C:4]2[CH2:12][CH2:13][CH2:14][C:3]=12.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][OH:24])=[CH:18][CH:17]=1>>[ClH:1].[CH:9]([O:8][C:6]1[N:5]=[C:4]2[CH2:12][CH2:13][CH2:14][C:3]2=[C:2]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][OH:24])=[CH:18][CH:17]=2)[CH:7]=1)([CH3:11])[CH3:10]
Reactant: CC(C)Oc1cc(Cl)c2c(n1)CCC2
Reactant: Nc1ccc(CCO)cc1
Product: CC(C)Oc1cc(Nc2ccc(CCO)cc2)c2c(n1)CCC2
Product: Cl
Yield: 35 %

Procedure:
Following general procedure B1, 4-chloro-2-isopropoxy-6,7-dihydro-5H-cyclopenta[b]pyridine (0.057 g, 0.27 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.056 g, 0.40 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.033 g, 35%) as a white solid. MW=348.87. 1H NMR (DMSO-d6, 300 MHz) δ 13.84 (s, 1H), 9.50 (s, 1H), 7.33 (d, J=8.5 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 6.12 (s, 1H), 4.82-4.67 (m, 1H), 3.64 (t, J=7.0 Hz, 2H), 2.93 (t, J=7.5 Hz, 2H), 2.83-2.69 (m, 4H), 2.15 (quin, J=7.5 Hz, 2H), 1.28 (d, J=6.0 Hz, 6H); APCI MS m/z 313 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[F:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH2:37].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[F:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH:37][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:4][CH:5]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:29]
Reactant: NCc1ccccc1F
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1F)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (50 mg, 0.11 mmol) was combined with 2-fluorobenzylamine (14 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.14 mmol), 1-hydroxybenzotriazole (17 mg, 0.13 mmol), and triethylamine (0.064 ml, 0.46 mmol) in 1 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 30 ml of ethyl acetate, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford 48 mg of the title compound as a colorless solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([O:17][C@H:18]3[CH2:58][N:21]4[C:22](=[O:57])[C@@H:23]([NH:49]C(=O)OC(C)(C)C)[C@H:24]([CH3:48])[CH2:25][CH:26]([CH3:47])[CH2:27][CH2:28][CH:29]=[CH:30][C@@H:31]5[CH2:36][C@@:32]5([C:37](=[O:46])[NH:38][S:39]([C:42]5([CH3:45])[CH2:44][CH2:43]5)(=[O:41])=[O:40])[NH:33][C:34](=[O:35])[C@@H:20]4[CH2:19]3)[CH:14]=[C:13]([C:59]3[CH:64]=[N:63][CH:62]=[CH:61][N:60]=3)[N:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(Cl)Cl.[F:68][C:69]([F:74])([F:73])[C:70]([OH:72])=[O:71]>C1(C)C=CC=CC=1>[F:68][C:69]([F:74])([F:73])[C:70]([OH:72])=[O:71].[NH2:49][C@@H:23]1[C:22](=[O:57])[N:21]2[CH2:58][C@H:18]([O:17][C:15]3[CH:14]=[C:13]([C:59]4[CH:64]=[N:63][CH:62]=[CH:61][N:60]=4)[N:12]=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=4)[CH:16]=3)[CH2:19][C@H:20]2[C:34](=[O:35])[NH:33][C@:32]2([C:37]([NH:38][S:39]([C:42]3([CH3:45])[CH2:44][CH2:43]3)(=[O:40])=[O:41])=[O:46])[CH2:36][C@H:31]2[CH:30]=[CH:29][CH2:28][CH2:27][CH:26]([CH3:47])[CH2:25][C@H:24]1[CH3:48]
Reactant: CC1CCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)[C@@H]2C[C@@H](Oc3cc(-c4ccc(OC(C)C)cc4)nc(-c4cnccn4)c3)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)C1
Agent: CC1CC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)[C@@H]2C[C@@H](Oc3cc(-c4ccc(OC(C)C)cc4)nc(-c4cnccn4)c3)CN2C(=O)[C@@H](N)[C@H](C)C1
Agent: CC1CC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)[C@@H]2C[C@@H](Oc3cc(-c4ccc(OC(C)C)cc4)nc(-c4cnccn4)c3)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)C1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)[C@@H]2C[C@@H](Oc3cc(-c4ccc(OC(C)C)cc4)nc(-c4cnccn4)c3)CN2C(=O)[C@@H](N)[C@H](C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 25 mL round-bottom flask equipped with a stir bar and charged with tert-butyl ((2R,6S,7R,13aS,14aR,16aS,Z)-2-((2-(4-isopropoxyphenyl)-6-(pyrazin-2-yl)pyridin-4-yl)oxy)-7,9-dimethyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate (all material from Step 1) was added CH2Cl2 (1 mL), then trifluoroacetic acid (1.0 mL, 13 mmol). The solution was stirred at room temperature for 2 h. The reaction solution was diluted with toluene (2 mL) and then concentrated in vacuo to afford (2R,6S,7R,13aS,14aR,16aS,Z)-6-amino-2-((2-(4-isopropoxyphenyl)-6-(pyrazin-2-yl)pyridin-4-yl)oxy)-7,9-dimethyl-N-((1-methylcyclopropyl)sulfonyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide trifluoroacetic acid salt as an amber solid residue. MS: MS m/z 800.5 (M++1).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1.[CH2:25]([O:27]CC)C>ClCCCl.CO.C(Cl)Cl.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH3:25][O:27][CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1
Reactant: CCOCC
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CBr)c3c2)c1=O
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CO
Solvent: ClCCl
Solvent: ClCCCl
Product: COCc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-[3-(bromomethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.750 g, 1.79 mmol) in 1,2-dichloroethane is diluted with methanol, treated with silver trifluoromethanesulfonate (0.610 g, 2.37 mmol), stirred overnight at room temperature, and filtered through diatomaceous earth. The resultant filtrate is washed with saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a solid. Column chromatography of the solid using silica gel, and 2% and 5% diethyl ether in methylene chloride solutions gives the title product as a white solid (0.600 g, mp 161-163° C.) which is identified by 1H NMR spectral analysis.
Reaction SMILES: O=[C:2]1[CH2:10][CH2:9][CH:8]2[CH:4]([CH2:5][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]2)[CH2:3]1.[NH3:18].CO.[BH4-].[Na+]>CCO.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[NH2:18][CH:2]1[CH2:10][CH2:9][CH:8]2[CH:4]([CH2:5][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC2CCC(=O)CC2C1
Reactant: N
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2CCC(N)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 5-oxohexahydro-1H-isoindole-2(3H)-carboxylate (11.97 g, 50 mmol) in EtOH (100 mL) were added a solution of NH3 in MeOH (7 M, 100 mL, 700 mmol) and Ti(OiPr)4 (28.42 g, 100 mmol). After addition, the reaction mixture was stirred at rt overnight and NaBH4 (3.78 g, 100 mmol) was added portionwise, then the resulting mixture was stirred at rt for another 5 h. The reaction was quenched with water (100 mL), stirred at rt for 1 h and filtered. The filter cake was washed with DCM (100 mL×3) and the filtrate was concentrated in vacuo. The residue was dissolved in a mixture of EtOAc (100 mL) and water (100 mL), and extracted with EtOAc (250 mL×3). The combined organic phases were washed with brine (250 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound as brown oil (12.02 g, 100%).
Reaction SMILES: [I:1][C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])[CH:3]=1.[H-].[Na+].[CH3:18]I>C1COCC1>[I:1][C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([C:11]([CH3:15])([CH3:14])[CH2:12][O:13][CH3:18])[CH:3]=1
Reactant: CI
Reactant: CC(C)(CO)n1cc(I)c2cncnc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC(C)(C)n1cc(I)c2cncnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
An anhydrous THF (100 mL) solution of 2-(5-Iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methyl-propan-1-ol (Preparation 22) (32 g, 100.91 mmol) was added slowly to a suspension of NaH (60% in paraffin oil, 2.98 g, 121.13 mmol) in anhydrous THF (200 mL) at 00° C. under nitrogen. The mixture was warmed to room temperature and stirred for another 30 minutes and again cooled to 00° C. and methyl iodide (19 mL, 302.82 mmol) was added drop wise. The reaction mixture was stirred at room temperature for 2 hours, quenched with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulphate and evaporated to dryness in vacuo. The crude material was purified by column chromatography on silica (100-200 mesh, gradient of hexane:EtOAc 100:0 to 70:30) to afford the title compound as a yellow sticky solid in 22% yield, 7.5 g.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:8][CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1.N.C[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C[C:24]1C=CC=C[N:25]=1>>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[CH3:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.[C:24]([C:21]1[CH:22]=[N:17][CH:18]=[CH:19][CH:20]=1)#[N:25]
Reactant: Cc1ccccn1
Reactant: CN1CCCCC1
Agent: CC1CCCNC1
Agent: N
Solvent: Cc1cccnc1
Product: N#Cc1cccnc1

Procedure:
2.0 cc of 80% PV3MO12Ox.20% SiO2 catalyst of Example 1 was placed in the microreactor and equilibrated at 405° C., then a gaseous mixture of 0.82 3-methylpyridine:0.18 3-methylpiperidine:7.5 NH3 :19.9 air was fed through the reactor using a contact time of 6.4 seconds. Conversion of the methylpiperidine was 100 percent and conversion of the methylpyridine was 93 percent. For each mole of combined 3-methylpiperidine plus 3-methylpyridine fed was obtained 0.853 mole of 3-cyanopyridine. If it be assumed that all of the converted 3-methylpyridine formed 3-cyanopyridine, the minimum selectivity of 3-methylpiperidine to 3-cyanopyridine was 50 percent.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]3[C:13]([O:16][CH2:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:14][O:15][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:24]([C:26]1([C:32]([O:34][CH3:35])=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=O.C(C1(C(OC)=O)CCC1)=O>>[CH:1]1([O:6][C:7]2[C:12]3[C:13]([O:16][CH2:17][CH:18]4[CH2:19][CH2:20][N:21]([CH2:24][C:26]5([C:32]([O:34][CH3:35])=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[CH2:22][CH2:23]4)=[N:14][O:15][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1(C=O)CCOCC1
Reactant: c1cc(OC2CCCC2)c2c(OCC3CCNCC3)noc2c1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(OC5CCCC5)c34)CC2)CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using 4-(cyclopentyloxy)-3-(piperidin-4-ylmethoxy)-1,2-benzisoxazole (EXAMPLE 24, Step 2) and methyl 4-formyltetrahydro-2H-pyran-4-carboxylate (EXAMPLE 18, Step 1) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][O:27][Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C=O)C.[CH2:43](Br)[C:44]#[CH:45]>CCOCC>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:45][C:44]#[CH:43])[C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][O:27][Si:28]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:35]([CH3:37])[CH3:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CO[Si](C(C)C)(C(C)C)C(C)C)[nH]c2c1
Reactant: C#CCBr
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C#CCn1c(-c2ccccc2CO[Si](C(C)C)(C(C)C)C(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To an ice cooled solution of methyl 3-cyclohexyl-2-(2-{[(triisopropylsilyl)oxy]methyl}phenyl)-1H-indole-6-carboxylate in DMF (0.13 M) NaH (2 eq.) was added. After 20 min. propargyl bromide (80% solution in toluene) (1.5 eq.) was added and the mixture stirred at 0° C. for 1 h, diluted with Et2O, washed with sat aq. NH4Cl and brine. The organic phase was dried over Na2SO4 and evaporated in vacuo. The residual material was subjected to flash chromatography (PE:EtOAc, 20:1). After evaporation of the solvents the product was obtained as yellow oil (67%). MS (ES+): 558.7 (M+H+).
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[F:5][C:6]([F:12])([F:11])[C:7](OC)=[O:8]>>[CH2:1]([NH:4][C:7](=[O:8])[C:6]([F:12])([F:11])[F:5])[C:2]#[CH:3]
Reactant: C#CCN
Reactant: COC(=O)C(F)(F)F
Product: C#CCNC(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
Propargyl amine (4.00 g, 72.62 mmol, 1.00 equiv.) was added dropwise to methyl trifluoroacetate (11.16 g, 87.15 mmol, 1.20 equiv.) at 0° C. The reaction mixture was stirred at 0° C. for 2 h and then concentrated under reduced pressure to remove methanol. The product was purified by vacuum distillation yielding propargyltrifluoroacetamide as a colorless liquid (9.59 g, 87%). The structure was confirmed by 1H- and 19F-NMR.
Reaction SMILES: [CH2:1]([Li])CCC.[Br-].C1(C([PH3+])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:27][C:28]1[C:33]([OH:34])=[C:32]([CH2:35][OH:36])[C:31]([CH:37]=O)=[CH:30][N:29]=1>O1CCCC1>[CH3:27][C:28]1[C:33]([OH:34])=[C:32]([CH2:35][OH:36])[C:31]([CH:37]=[CH2:1])=[CH:30][N:29]=1
Reactant: Cc1ncc(C=O)c(CO)c1O
Reactant: [Li]CCCC
Agent: [Br-]
Agent: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: C=Cc1cnc(C)c(O)c1CO
Reaction time: 1 h

Procedure:
67 Ml. of n-butyl lithium (1.9 M in n-hexane) was run into a stirred suspension of triphenylmethylphosphonium bromide (42.7 g., 0.12 M) at room temperature in tetrahydrofuran (300 ml.) under nitrogen. To this stirred solution a solution of the 3,4α-di-O-isopropylidine derivative of 2-methyl-3-hydroxy-4-hydroxymethyl-5-formylpyridine (24.7 gm. 0.119 M) in tetrahydrofuran (300 ml.) was added dropwise over 1 hour. The reaction was aged 1 hour at room temperature and then refluxed for 4 hours.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15]2[CH:16]=[CH:17][C:18]3[O:27][CH2:26][CH2:25][N:24]4[C:20](=[N:21][C:22]([C:28]5[N:29]([CH:33]([CH3:35])[CH3:34])[N:30]=[CH:31][N:32]=5)=[CH:23]4)[C:19]=3[CH:36]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:33]([N:29]1[C:28]([C:22]2[N:21]=[C:20]3[N:24]([CH2:25][CH2:26][O:27][C:18]4[CH:17]=[CH:16][C:15]([S:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[CH:36][C:19]=43)[CH:23]=2)=[N:32][CH:31]=[N:30]1)([CH3:35])[CH3:34]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(SC3CCN(C(=O)OC(C)(C)C)CC3)ccc1OCC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(SC3CCNCC3)ccc1OCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
An ice-cooled solution of 4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidine-1-carboxylic acid tertbutyl ester (0.722 g) in DCM (10 mL) was treated with TFA (2 mL) and stirred at RT for 2 h. Volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (C18, gradient 20-50% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3/MeOH affording 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-9-(piperidin-4-ylsulfanyl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (0.368 g). LCMS: RT 2.08/2.14 min [M+H]+ 411.2
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].I[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC=CC=1)([O-])=O>[Cu]>[I:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([N:4]([C:1](=[O:3])[CH3:2])[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:13][CH:14]=2)=[CH:19][CH:20]=1
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Reactant: CC(=O)Nc1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)N(c1ccccc1)c1ccc(-c2ccc(I)cc2)cc1
Yield: 64.9 %

Procedure:
20.0 g (0.15 mol) of acetanilide, 65.0 g (0.16 mol) of 4,4'-diiodobiphenyl, 22.1 g (0.16 mol) of anhydrous potassium carbonate, 2.16 g (0.034 mol) of copper powder, and 35 ml of nitrobenzene were mixed. The reaction mixture was then allowed to undergo reaction at a temperature of 190° C. to 205° C. for 10 hours. The reaction product was then extracted with 200 ml of toluene. The insoluble contents were then removed by filtration. The filtrate was then concentrated to dryness. The concentrate was then purified by column chromatography (carrier: silica gel; elute: 6/1 mixture of toluene and ethyl acetate) to obtain 40.2 g (yield: 64.8%) of N-(4'-iodo-4-biphenylyl)acetanilide. The melting point of the product was from 135.0° C. to 136.0 ° C.
Reaction SMILES: BrP(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2:22][C:23]1[C:24]([C:40]([OH:42])=O)=[N:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35](=[O:39])[N:36]([CH3:38])[CH3:37])=[CH:31][CH:30]=2)=[CH:27][N:28]=1.[O:43]1[CH:47]=[CH:46][CH:45]=[C:44]1[C:48]([NH:50][NH2:51])=O.CCN(C(C)C)C(C)C>C(#N)C>[NH2:22][C:23]1[N:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([N:36]([CH3:37])[CH3:38])=[O:39])=[CH:33][CH:34]=2)=[N:25][C:24]=1[C:40]1[O:42][C:48]([C:44]2[O:43][CH:47]=[CH:46][CH:45]=2)=[N:50][N:51]=1
Reactant: NNC(=O)c1ccco1
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)O)n2)cc1
Agent: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccco4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
Dibromo(triphenyl)phosphorane was added to a solution of 3-amino-6-[4-(dimethylcarbamoyl)phenyl]pyrazine-2-carboxylic acid (100 mg, 0.35 mmol) and furan 2-carbohydrazide (44.1 mg, 0.35 mmol) in acetonitrile (3.0 mL) at room temperature. Bright yellow solution observed. The resulting solution was stirred at room temperature for 30 min. After this time, DIPEA (304 μL, 1.75 mmol) was added dropwise and the reaction mixture stirred at room temperature for 30 min. The reaction mixture was filtered to leave a yellow solid. The solid was purified by reverse phase preparative HPLC [Waters Sunfire C18, mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. Product fractions were freeze dried to give the product as a yellow solid (67.6 mg, 51% yield); 1H NMR (400.0 MHz, DMSO) d 2.97 (m, 6H), 6.87 (m, 1H), 7.54-7.56 (m, 3H), 7.57 (br s, 2H), 8.15 (m, 3H) and 8.98 (1H, s) ppm; MS (ES+) 377.17