Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[N:5]=[C:4]([N:12]2C(C)=CC=C2C)[CH:3]=1.Cl.NO.[OH-].[K+]>C(O)C.O>[NH2:12][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[N:5]=1
Reactant: Cc1cc(CC(C)C)nc(-n2c(C)ccc2C)c1
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1cc(N)nc(CC(C)C)c1

Procedure:
By analogy to Example 56, Step B, 4-methyl-6-(2-methylpropyl)-2-(2,5-dimethylpyrrol-1-yl)pyridine was treated with 4.6 equivalents of hydroxylamine hydrochloride and 2.8 equivalents of potassium hydroxide in refluxing ethanol/water to yield 2-amino-4-methyl-6-(2-methylpropyl)pyridine as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[C:9]([Cl:17])=[N:10][CH:11]=[C:12]([CH:16]=1)[C:13]([OH:15])=O.Cl.O1CCOCC1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:7][C:8]1[CH:16]=[C:12]([C:13]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:15])[CH:11]=[N:10][C:9]=1[Cl:17]
Reactant: C1COCCN1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cnc(Cl)c(Cl)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.6 %

Procedure:
Oxalyl chloride (3.2 mL; 36.0 mmol) was added to a solution of 5,6 dichloronicotinic acid (5.76 g; 30.0 mmol) and 4M hydrogen chloride in dioxane (7.5 mL; 30 mmol) in DCM (50 mL). The mixture was stirred at RT for 18 hours, the DCM evaporated in vacuo, the residue azeotroped with toluene (2×15 mL) and added to a solution of morpholine (3.1 mL; 36.0 mmol) and triethylamine (10.0 mL; 72 mmol) in DCM (150 mL). The mixture was stirred at RT for 18 hours, the DCM evaporated in vacuo, and the residue partitioned between water (75 mL) and ethyl acetate (100 mL). The organic layer was washed with brine, dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with 50% ethyl acetate in isohexane, to give the desired compound (7.1 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:18][CH2:19][CH2:20][CH2:21]Br>ClCCl>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][CH2:21][CH2:20][CH2:19][Br:18])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)Nc1cccc(OCCCBr)c1
Reaction time: 24 h

Procedure:
To 3-acetamidophenol (15.1 g) in dichloromethane (500 ml, dry) was added potassium carbonate (20 g) and then 1,3-dibromopropane (30 g). The resulting mixture was heated at reflux for 6 hours and then overnight at room temperature. After an additional 24 hours, the reaction was complete. Solids were filtered from the reaction mixture, and the solution was concentrated to an oil, which was purified to yield 3-(3-acetamidophenoxy)propyl bromide, 13.2 g.
Reaction SMILES: Br[C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[C:4]2[CH:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:5]2=[N:6][CH:7]=1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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.CCOCC>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:8]2[C:5]3=[N:6][CH:7]=[C:2]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:3]([N:20]4[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:24][CH2:25]4)=[C:4]3[CH:10]=[N:9]2)=[CH:17][CH:16]=1
Reactant: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(Br)cnc32)cc1
Reactant: OB(O)c1ccccc1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cnc32)cc1
Temperature: 80 °C
Yield: 88.9 %

Procedure:
tert-Butyl 4-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.50 g, 0.995 mmol), phenylboronic acid (0.182 g, 1.49 mmol), Pd(PPh3)4 (0.115 g, 0.0995 mmol) and Cs2CO3 (1.30 g, 3.98 mmol) were placed in dioxane:H2O (8 mL, 3:1). The solution was heated to 80° C. for 6 hours. Ether (50 mL) and H2O (20 mL) were then added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography (DCM:ethyl acetate=5:1) to give tert-butyl 4-(1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.442 g, 89%) as a foam solid. MS ESI (+) m/z 500.4 detected. 1H NMR (400 Hz, DMSO-d6) δ 8.26 (s, 1H), 8.10 (s, 1H), 7.51 (m, 2H), 7.44 (m, 2H), 7.32 (m, 1H), 7.20 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 5.50 (s, 2H), 3.67 (s, 3H), 3.23 (m, 4H), 3.20 (m, 4H).
Reaction SMILES: S1C=CN=C1C1SC=CN=1.ClC1C=CC(OC)=C(NC2S[CH:21]=[C:22]([C:24]3[S:28][C:27]([NH:29]C(=O)C4C=CC=CC=4)=[N:26][C:25]=3[CH3:38])N=2)C=1.ClC(C(=O)C)C(=[O:45])C.NC(N)=S>C(O)C>[C:22]([C:24]1[S:28][C:27]([NH2:29])=[N:26][C:25]=1[CH3:38])(=[O:45])[CH3:21]
Reactant: COc1ccc(Cl)cc1Nc1nc(-c2sc(NC(=O)c3ccccc3)nc2C)cs1
Reactant: CC(=O)C(Cl)C(C)=O
Agent: NC(N)=S
Agent: c1csc(-c2nccs2)n1
Solvent: CCO
Product: CC(=O)c1sc(N)nc1C
Yield: 90 %

Procedure:
An efficient route for the synthesis bithiazole analogs was developed as follows. Efforts began with a synthesis of N-(2-(5-chloro-2-methoxyphenylamino)-4′-methyl-4,5′-bithiazol-2′-yl)benzamide—the putative structure of “Corr-4” corrector 4. This work commenced by treating 3-chloropentane-2,4-dione with thiourea under reflux in absolute ethanol. 5-Acetyl-2-amino-4-methylthiazole (5) was obtained in 90% yield. Surprisingly, attempts to aminoacylate the 2-amino moiety in 5 with benzoyl chloride under various base, solvent and temperature conditions failed to deliver the desired intermediate N-(5-acetyl-4-methyl-thiazol-2-yl)-benzamide (6).
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:24][O:23][C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[NH:4]1)[N:11]=[C:10]([O:15][CH:16]([CH3:18])[CH3:17])[CH:9]=[C:8]3[C:19]([F:22])([F:21])[F:20])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:31](Br)[C:32](=[CH2:34])[CH3:33].O>CN(C=O)C>[CH2:1]([C@@H:3]1[CH2:24][O:23][C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[N:4]1[CH2:33][C:32](=[CH2:31])[CH3:34])[N:11]=[C:10]([O:15][CH:16]([CH3:18])[CH3:17])[CH:9]=[C:8]3[C:19]([F:21])([F:22])[F:20])[CH3:2]
Reactant: C=C(C)CBr
Reactant: CC[C@@H]1COc2c(ccc3nc(OC(C)C)cc(C(F)(F)F)c23)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)CN1c2ccc3nc(OC(C)C)cc(C(F)(F)F)c3c2OC[C@H]1CC
Temperature: 50 °C
Yield: 85.9 %

Procedure:
To a suspension of (R)-3-ethyl-3,4-dihydro-8-isopropoxy-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (0.020 g, 0.059 mmol) and K2CO3 (0.041 g, 0.295 mmol) in 1 mL DMF was added methallyl bromide (0.077 mL, 0.767 mmol) and the reaction mixture was heated to 50° C. for 16 h. The reaction mixture was poured into 25 mL water and extracted with EtOAc (2×25 mL). The extracts were washed with 25 mL each water and brine, dried over MgSO4, filtered and concentrated to a yellow oil. Column chromatography (5–10% EtOAc in hexane gradient) gave 0.020 g (87%) of (R)-3-ethyl-3,4-dihydro-8-isopropoxy-4-methallyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline, a yellow oil. Rf0.7 (9:1 hexane:EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.39 (d, 1H, J=9.0), 7.18 (s, 1H), 7.12 (d, 1H, J=9.0), 5.47 (septet, 1H, J=6.2), 4.91 (s, 2H), 4.33 (dd, ABX, 1H, J=10.6, 2.0), 3.96 (dd, ABX, 1H, J=10.7, 2.6), 3.86 (d, 1H, J=17.0), 3.80 (d, 1H, J=17.0), 3.25–3.20 (m, 1H), 1.79 (s, 3H), 1.65–1.59 (m, 2H), 1.38 (d, 3H, J=6.1), 1.37 (d, 3H, J=6.1), 0.97 (t, 3H, J=7.5).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10]Br)=[CH:4][CH:3]=1.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)=[CH:4][CH:3]=1
Reactant: BrCCOc1ccc(Br)cc1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Brc1ccc(OCCn2cccn2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 104.9 %

Procedure:
The mixture of 1-bromo-4-(2-bromoethoxy)benzene (1.00 g, 3.57 mmol), pyrazole (0.360 g, 5.36 mmol) and cesium carbonate (1.75 g, 5.36 mmol) in acetonitrile (10 mL) was heated at 80° C. and stirred for 2 hours. The reaction mixture was filtered. The filtrate was concentrated in vacuo to give a white solid, which was purified by silica gel chromatography to give the title compound (1.0 g, 100%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.56 (d, 1H) 7.54 (d, 1H) 7.35 (d, 2H), 6.74 (d, 2H), 6.26 (m, 1H), 4.53 (t, 2H), 4.30 (t, 2H).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29].[N:39]#[C:40]Br.C(=O)(O)[O-].[Na+]>C(O)C>[F:1][C:2]([F:37])([F:38])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:26])[CH3:27])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29])[C:40]#[N:39]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(C#N)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amine (2.0 g) is dissolved in ethanol (20 ml), and thereto are added cyanogen bromide (578 mg) and sodium bicarbonate (928 mg) and the mixture is stirred at room temperature for 2 hours. To reaction mixture is added a saturated aqueous sodium bicarbonate solution and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=10:1→5:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-cyanamide (1.8 g). MS (m/z): 575 [M+H]+
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[CH:3]=1.ClC1C=C(N2[C:22]([C:23]3[CH:28]=[C:27]([O:29][C:30](F)([F:32])[F:31])[CH:26]=[C:25]([F:34])[CH:24]=3)=[CH:21][C:20]([C:35]([OH:37])=[O:36])=N2)C=CC=1F>>[F:34][C:25]1[CH:24]=[C:23]([C:22]2[N:8]([C:4]3[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=3)[N:9]=[C:20]([C:35]([OH:37])=[O:36])[CH:21]=2)[CH:28]=[C:27]([O:29][CH:30]([F:32])[F:31])[CH:26]=1
Reactant: O=C(O)c1cc(-c2cc(F)cc(OC(F)(F)F)c2)n(-c2ccc(F)c(Cl)c2)n1
Reactant: NNc1cccnc1
Agent: Cl
Product: O=C(O)c1cc(-c2cc(F)cc(OC(F)F)c2)n(-c2cccnc2)n1

Procedure:
590 mg (1.01 mmol) of the compound from example 4A is reacted with 161 mg (1.11 mmol) 3-pyridylhydrazine hydrochloride in a manner analogous to the synthesis of the compound from example 8A. Following hydrolysis, 150 mg (43% of theoretical yield) of the title compound is produced.
Reaction SMILES: FC(F)(F)S(O[Si:7]([CH3:18])([CH3:17])[CH:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH3:15])=[C:9]1[CH3:16])(=O)=O.[CH3:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[CH3:31])[C-:27]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:26]=[CH:25]2.[Li+]>CCOCC>[CH3:31][C:30]1[CH:29]=[C:28]2[C:24](=[CH:23][C:22]=1[CH3:21])[CH:25]([Si:7]([CH3:17])([CH3:18])[CH:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH3:15])=[C:9]1[CH3:16])[CH:26]=[C:27]2[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC1=C(C)C([Si](C)(C)OS(=O)(=O)C(F)(F)F)C(C)=C1C
Reactant: Cc1cc2cc[c-](-c3ccccc3)c2cc1C
Agent: [Li+]
Solvent: CCOCC
Product: CC1=C(C)C([Si](C)(C)C2C=C(c3ccccc3)c3cc(C)c(C)cc32)C(C)=C1C
Reaction time: 24 h

Procedure:
To a solution of dimethyl(2,3,4,5-tetramethylcyclopenta-2,4-dien-1-yl)silyl trifluoromethanesulfonate (Compound C, 7.50 g, 22.8 mmol, 1.00 eq.) in ether (25 mL) at −35° C. was added lithium (5,6-dimethyl-1-phenylindenide) (5.53 g, 24.4 mmol, 1.07 eq.). The reaction was stirred for 24 hours, and was then evaporated under vacuum. The residue was extracted with pentane (40 mL, then 2×25 mL) and the extract was filtered. The resulting solution was evaporated under vacuum to give a sticky solid. Yield 9.34 g (103%). 1H NMR(C6D6): δ 7.71 (d, 2H), 7.62 (s, 1H), 7.36 (s, 1H), 7.31 (t, 2H), 7.20 (m, 1H), 6.57 (s, 1H), 3.70, (s, 1H), 2.98 (br s, 1H), 2.23 (s, 3H), 2.17 (s, 3H), 1.97 (s, 3H), 1.95 (s, 3H), 1.84 (s, 6H), −0.04 (s, 3H), −0.32 (s, 3H).
Reaction SMILES: Cl.[O:2]1[C:6]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:5][N:4]=[CH:3]1.[NH:14]=[C:15]=[NH:16].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[O:2]1[C:6]([C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:15]([NH2:16])=[NH:14])=[CH:9][CH:8]=2)=[CH:5][N:4]=[CH:3]1
Reactant: N=C=N
Reactant: Nc1ccc(-c2cnco2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N=C(N)Nc1ccc(-c2cnco2)cc1
Yield: 110.9 %

Procedure:
Hydrochloric acid (4.04 mL, 24.35 mmol) was added to a solution of 4-(oxazol-5-yl)aniline (5 g, 31.22 mmol) and carbodiimide (1.444 g, 34.34 mmol) in ethanol (50 mL). The resulting mixture was heated to reflux for 5 h. The reaction mixture was concentrated under reduced pressure and potassium carbonate (2.59 g, 18.73 mmol) in water (50.00 mL) was added. The formed crystals were filtered off, washed with several portions of potassium carbonate (aq) and dried over night under reduced pressure. The crude solid was slurried in DCM and filtered to give 1-(4-(oxazol-5-yl)phenyl)guanidine (7.00 g, 86%). No further purification. MS (ESI+)/(ESI−) m/z 203/201
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N:21]1([C:26]2[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH3:20][C:13]1([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([N:21]5[CH2:22][CH2:23][CH2:24][CH2:25]5)[CH:27]=4)[N:3]=3)[NH:8][CH:9]=2)=[O:12])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCCC1
Reactant: OB(O)c1cccc(N2CCCC2)c1
Product: CC1(C(=O)c2c[nH]c3ncc(-c4cccc(N5CCCC5)c4)nc23)CCCCCC1

Procedure:
(1-Methyl-cycloheptyl)-[2-(3-pyrrolidin-1-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cycloheptyl)-methanone and 3-(1-pyrrolidinyl)phenylboronic acid following general procedures as described in these Examples. MP 192-193° C., M+H=403.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C@H:11]([OH:22])[C@@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH3:13].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:23]([O:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C@H:11]([OH:22])[C@@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])[CH3:13])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O)CCc1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O)CCc1ccc(F)cc1OCc1ccccc1
Yield: 81.4 %

Procedure:
(3S,4S)-1-(2-hydroxy-4-fluorophenyl)-4-tert-butyldimethylsilyloxy-3-pentanol (0.94 g) was treated with benzyl bromide (0.48 ml) and potassium carbonate (0.53 g) in DMF (5 ml) at room temperature for 2 hr. The mixture was diluted with EtOAc and washed with water twice, dried and evaporated. The residual oil (1.43 g) was chromatographed over silica gel (30 g), eluting with a mixture of hexane and EtOAc (40:1) to give a second crop of colorless oil of (3S,4S)-1-(2-benzyloxy-4-fluorophenyl)-4-tert-butyldimethylsilyloxy-3-pentanol (0.79 g, total yield 81.4%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([CH:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]3[N:22]=[C:21]([N:23]4[C:27]5[CH:28]=[CH:29][CH:30]=[C:31](I)[C:26]=5[N:25]=[N:24]4)[CH:20]=[CH:19][N:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[S:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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.CCO>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([CH:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]3[N:22]=[C:21]([N:23]4[C:27]5[CH:28]=[CH:29][CH:30]=[C:31]([C:35]6[CH:36]=[CH:37][S:33][CH:34]=6)[C:26]=5[N:25]=[N:24]4)[CH:20]=[CH:19][N:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:4][CH2:3]1
Reactant: OB(O)c1ccsc1
Reactant: O=C(C1CCC(Nc2nccc(-n3nnc4c(I)cccc43)n2)CC1)N1CCC(O)CC1
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(C1CCC(Nc2nccc(-n3nnc4c(-c5ccsc5)cccc43)n2)CC1)N1CCC(O)CC1
Temperature: 110 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
A mixture of (4-hydroxy-piperidin-1-yl)-{4-[4-(4-iodobenzotriazol-1-yl)-pyrimidin-2-yl-amino]-cyclohexyl}-methanone (274 mg) and 3-thiopheneboronic acid (67 mg) was placed in a screw cap pressure flask, and Na2CO3 (2 M aq, 0.7 mL, degassed), toluene (5 mL, degassed) and EtOH (5 mL), added. To this was added Pd(PPh3)4 (20 mg), the flask sealed, and the mixture stirred overnight at 110° C. The reaction mixture was then cooled to RT, diluted in water, extracted in DCM, washed with water and brine, dried over Na2SO4, and the solvent stripped to yield a crude solid (0.25 g). The crude product was chromatographed on silica, and eluted with 0-70% Magic Base/DCM, titurated in Et2O, filtered, and evaporated to yield (4-hydroxy-piperidin-1-yl)-{4-[4-(4-thiophen-3-ylbenzotriazol-1-yl)-pyrimidin-2-ylamino]-cyclohexyl}-methanone (Compound 6, 201 mg). mp=233-234° C.; M+H=504.
Reaction SMILES: C(C1C=C(O)C(=CC=1)O)(C)(C)C.[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH:15]=[CH:14]1.[CH2:20]([NH2:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C=CC1C=CC=CC=1>[CH2:20]([NH:38][C:13](=[O:19])/[CH:14]=[CH:15]\[C:16]([OH:18])=[O:17])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: O=C1C=CC(=O)O1
Agent: CC(C)(C)c1ccc(O)c(O)c1
Solvent: C=Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCNC(=O)/C=C\C(=O)O
Temperature: 85 °C

Procedure:
In a 21-4-necked glass reaction flask, supplied with dispersion wheel (circumference of 8 cm), reflux cooler, nitrogen supply pipe, thermometer and dosage device, 91.9 gr. of styrene =0.88 moles (purity >99%, stabilized with 0.005% 4-tert-butylcatechol), 79.2 gr of maleic acid anhydride =0.808 moles (purity >99%) and 215.2 gr. distilled stearyl amine =0.8 mole (Arneen 18 D , the Akzo Nobel company) are heated while stirring to a temperature of 85° C., until a clear solution of the reaction product, maleic acid monostearyl amide in styrene is formed.
Reaction SMILES: [N+:1]1([O-:8])[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[Si]([C:13]#[N:14])(C)(C)C.CN(C)C(Cl)=O.O>C(Cl)Cl>[C:13]([C:2]1[CH:3]=[C:4]([CH3:7])[CH:5]=[CH:6][N+:1]=1[O-:8])#[N:14]
Reactant: Cc1cc[n+]([O-])cc1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1cc[n+]([O-])c(C#N)c1
Reaction time: 0.08 h

Procedure:
To a solution of 4-picoline-N-oxide (20 g) in CH2Cl2 (360 mL) was added TMSCN (26.5 mL), stirred 5 minutes, added dimethyl carbamyl chloride (16.6 mL) was added slowly dropwise. The mixture was stirred at RT overnight, poured onto 400 mL H2O, and 40 g NaCO3. Separation of layers and evaporation of CH2Cl2 gave 17.25 g of 2-Cyano-4-methylpyridine-N-oxide, recrystallized from hexane, m.p. 95°-98° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1.N1[CH:20]=[CH:19][CH:18]=[CH:17]C=1>C(OCC#[C-])(=O)C.[Cu+].O>[C:2]([O:7][CH2:20][CH2:19][C:18]#[C:17][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:9][CH:10]=1)(=[O:1])[CH3:3]
Reactant: Ic1ccc(OC2CCCCO2)cc1
Reactant: c1ccncc1
Agent: [Cu+]
Agent: [C-]#CCOC(C)=O
Solvent: O
Product: CC(=O)OCCC#Cc1ccc(OC2CCCCO2)cc1

Procedure:
20 Grams of p-tetrahydropyranyloxyiodobenzene and 70 ml of anhydrous pyridine containing 11.3 g of copper (I) 3-acetyloxy-1-propyn-1-ide were refluxed for 6 hours under an atmosphere of argon gas. After the reaction was finished the reaction mixture was poured into water and the whole mixture was extracted with chloroform. The chloroform layer was washed with water, dried and the solvent was removed by evaporation. The residue thus obtained was purified by means of a silica gel column chromatography (eluent: chloroform: n-hexane=1:1) to yield 8 g of 4-[4-(2-tetrahydropyranyloxy)phenyl]-3-butynyl acetate in the form of colorless oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH2:18]([O:25][C@H:26]([C@H:28]([N:36]1[CH:40]=[C:39]([C:41]([NH2:43])=[O:42])[N:38]=[CH:37]1)[CH2:29][CH2:30]OS(C)(=O)=O)[CH3:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH2:18]([O:25][C@H:26]([C@H:28]([N:36]1[CH:40]=[C:39]([C:41]([NH2:43])=[O:42])[N:38]=[CH:37]1)[CH2:29][CH2:30][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)[CH3:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[C@H](OCc1ccccc1)[C@@H](CCOS(C)(=O)=O)n1cnc(C(N)=O)c1
Reactant: Oc1ccc2ncccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](OCc1ccccc1)[C@@H](CCOc1ccc2ncccc2c1)n1cnc(C(N)=O)c1
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
Under N2, to a solution of 6-hydroxyquinoline (43 mg, 0.296 mmol) in DMF (3 ml) was added potassium carbonate (82 mg, 0.593 mmol) at room temperature. The reaction mixture was stirred for 30 minutes. 1-[(2S,3R)-2-benzyloxy-5-methanesulfonyloxy-3-pentyl]imidazole-4-carboxamide was added and the resulting mixture was stirred for 6 h at 70° C. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried (sodium sulfate) and evaporated in vacuo. The residue was purified by silica gel (8 g) chromatography eluting with chloroform/methanol (100:1 to 30:1) to give 1-[(2S,3R)-2-benzyloxy-5-(6-quinolyloxy)-3-pentyl]imidazole-4-carboxamide (1) (62.5 mg, 48.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([N:9]=[C:10]([NH2:12])[N:11]=2)[CH:8]=1.[C:13](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:14]>ClCCl>[N:12]([C:10]1[N:11]=[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][N:7]2[N:9]=1)=[C:13]=[S:14]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: COc1ccc2nc(N)nn2c1
Solvent: ClCCl
Product: COc1ccc2nc(N=C=S)nn2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
To 6-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-amine (0.3 g, 1.8 mmol) in dichloromethane (15 mL) was added 1,1′-thiocarbonyldi-2(1H)-pyridone (0.51 g, 2.2 mmol). The reaction was stirred at room temperature overnight, concentrated in vacuo and purified via flash chromatography yielding 2-isothiocyanato-6-methoxy-[1,2,4]triazolo[1,5-a]pyridine (166 mg, 0.8 mmol, 44% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 8.03 (1 H, d, J=2.20 Hz), 7.54 (1 H, d, J=9.88 Hz), 7.34 (1 H, dd, J=9.51, 2.56 Hz), 3.88 (3 H, s).