Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)/[CH:5]=[N:6]\[OH:7].[ClH:11].OS([O-])(=O)=O.OS(O[O-])(=O)=O.OS(O[O-])(=O)=O.[O-]S([O-])(=O)=O.[K+].[K+].[K+].[K+].[K+]>CN(C=O)C>[OH:7]/[N:6]=[C:5](\[Cl:11])/[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=1
Reactant: O/N=C\c1cccc(Cl)c1
Reactant: Cl
Agent: O=S(=O)(O)O[O-]
Agent: O=S(=O)([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Product: O/N=C(\Cl)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of (E)- and/or (Z)-3-chloro-benzaldehyde oxime (54 g, 347 mmol) in DMF (800 mL) was added HCl (conc., 17 mL) and the mixture cooled to room temperature. Then potassium monopersulfate triple salt (247 g, 400 mmol) and the reaction mixture was stirred at room temperature for 1 h. The mixture was then poured onto ice-water, and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated to afford the title compound (66 g, 100%) which was obtained as a white solid. Mp: 58-60° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][NH:19][C:20]([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:20]([N:19]([CH3:18])[C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:23])([CH3:22])[CH3:21]
Reactant: CNC(C)(C)C
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(C)(C)C

Procedure:
In analogy to the procedure described in Example 47 b), 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid was reacted with N,2-dimethylpropan-2-amine (CAN 94896-77-2) in the presence of TBTU and DIEA to give the title compound as colorless oil; MS (EI): m/e=303.4 [MH+].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)=[N:7][CH:8]=1)#[N:2].[F:19][C:20]([F:36])([F:35])[C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29](O)=[O:30])[N:22]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:29](=[O:30])[C:28]3[CH:32]=[CH:33][CH:34]=[C:26]([C:23]4[N:22]=[C:21]([C:20]([F:36])([F:35])[F:19])[O:25][N:24]=4)[CH:27]=3)[CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)=[N:7][CH:8]=1)#[N:2]
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: COC(=O)C1CN(c2ccc(C#N)cn2)CCN1
Product: COC(=O)C1CN(c2ccc(C#N)cn2)CCN1C(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 73 %

Procedure:
This compound was synthesized from methyl 4-(5-cyanopyridin-2-yl)piperazine-2-carboxylate and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (130 mg, yield 73%). 1H NMR (400 MHz, CDCl3) δ 8.55-8.50 (m, 1H), 8.42 (br s, 1H), 8.24 (m, 1H), 7.73-7.64 (m, 3H), 6.71 (d, J=9.0 Hz, 1H), 4.94 (m, 1H), 4.52-4.41 (m, 1H), 3.78 (s, 3H), 3.75 (m, 2H), 3.69-3.59 (m, 1H), 3.51-3.48 (m, 1H), 3.11-3.04 (m, 1H). MS (ESI) m/z: Calculated for C22H17F3N6O4: 486.13. found: 487.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[OH:19])=O)=[CH:6][C:5]([C:20]2[CH:21]=[N:22][N:23]([CH:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[CH:24]=2)=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O.N>C(O)(=O)C.CN(C=O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]2[N:10]=[C:8]([C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:20]4[CH:21]=[N:22][N:23]([CH:25]5[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]5)[CH:24]=4)[CH:6]=3)[O:19][C:12]=2[CH:13]=1
Reactant: COc1ccc(NC(=O)c2cc(-c3cnn(C4CCN(C)CC4)c3)cnc2N)c(O)c1
Agent: N
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2nc(-c3cc(-c4cnn(C5CCN(C)CC5)c4)cnc3N)oc2c1
Temperature: 200 °C
Yield: 23.7 %

Procedure:
To a solution of 2-amino-N-(2-hydroxy-4-methoxy-phenyl)-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridine-3-carboxamide (110 mg) in acetic acid (1.8 ml) was added TFA (1.8 ml). The clear mixture was sealed into a microwave tube. The reaction was heated to 200° C. a 300 W microwave for 20 minutes. The solvents were evaporated. The residue was trituratred in diethyl ether, dried to give a yellow solid. The solid was dissolved in DMF (1.5 ml) and two drops of a 30% aqueous ammonia solution. The precipitate was filtered, washed with Ether and dried at 50° C. for 48 h to afford 3-(6-methoxy-1,3-benzoxazol-2-yl)-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridin-2-amine (25.00 mg). NMR Spectrum: (DMSOd6) 1.93-2.12 (m, 6H), 2.22 (s, 3H), 2.94-2.91 (m, 2H), 3.86 (s, 3H), 4.07-4.16 (m, 1H), 7.03 (dd, 1H), 7.40 (d, 1H), 7.57 (bs, 2H), 7.72 (d, 1H), 7.89 (d, 1H), 8.30 (s, 1H), 8.36 (d, 1H), 8.49 (d, 1H). Mass spectrum: M+H+ 405.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[CH:6]=[CH:5]2.[CH2:16]([CH2:18][NH2:19])[OH:17].C(N(CC)CC)C.CO>>[Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:19]([CH2:18][CH2:16][OH:17])[CH:6]=[CH:5]2
Reactant: NCCO
Reactant: O=c1occc2c([N+](=O)[O-])c(Cl)ccc12
Solvent: CCN(CC)CC
Solvent: CO
Product: O=c1c2ccc(Cl)c([N+](=O)[O-])c2ccn1CCO
Reaction time: 1 h

Procedure:
A microwave vial was charged with 6-chloro-5-nitro-1H-isochromen-1-one (1.0 g, 0.00443 mol), ethanolamine (0.401 mL, 0.00665 mol), triethylamine (1.24 mL, 0.00886 mol) and methanol (30 mL, 0.7 mol) and the reaction was subjected to microwave at 100° C. for 1 hour. The reaction was complete in the sense that all the starting material was consumed but the major product formed was the chloro displacement with the amine. The solvent was removed and the residue purified by flash chromatography to obtain the product as a yellow solid. MS m/z=269.4 (M+H). 1H NMR (400 MHz; CDCl3) δ 8.41 (d, J=8.56 Hz, 1H), 7.52 (d, J=8.56 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 6.31 (d, J=8.56 Hz, 1H), 4.17 (t, J=44.88 Hz, 2H), 3.99 (t, J=5.11 Hz, 2H), 2.55 (bs, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])[C:6]=2[C:5](=[O:17])[NH:4][C:3]1=[O:18].[OH-].[Na+].[CH2:21](Br)[CH3:22]>CO.O>[CH2:21]([N:4]1[C:5](=[O:17])[C:6]2[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:18])[CH3:22]
Reactant: CCBr
Reactant: C=CCCCCn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCCCCn1cnc2c1c(=O)n(CC)c(=O)n2C
Reaction time: 40 h

Procedure:
20 g of 3-methyl-7-(hex-5-enyl)-xanthine (see Example 22) are added to a solution of approximately 3.3 g of NaOH in 70 ml of methanol/water (1:1) and 9 g of ethyl bromide are added thereto. The mixture is kept at 40° C. under a nitrogen atmosphere for 40 hours. The solvent is then removed under reduced pressure, the residue dissolved in diethyl ether and the pH of the solution is adjusted with aqueous sodium hydroxide solution to a pH-value of 13.5 to remove unreacted 3-methyl-7-(hex-5-enyl)-xanthine. 1-Ethyl-3-methyl-7-(hex-5-enyl)-xanthine recovered from the ether phase is subsequently subjected to column chromatography using silica gel with methylene chloride/acetone (8:2) as eluent followed by distillation under reduced pressure and is obtained as a colourless oil. Yield: 11.2 g (81.3% of theory relative to reacted starting material) of the title compound, nD20 =1.5415.
Reaction SMILES: [Mg+2].[Cl-].[Cl-].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.[N-]=[N+]=[N-].[Na+].N1(C(=O)C2NC=NC=2N(C)C1=O)C.SC(CS)CO.C[O:48][C@H:49]1[O:54][C@H:53]([CH2:55][OH:56])[C@@H:52]([OH:57])[C@H:51]([OH:58])[C@@H:50]1[OH:59]>C(O)C(N)(CO)CO>[OH:48][C@H:49]1[O:54][C@H:53]([CH2:55][OH:56])[C@@H:52]([OH:57])[C@H:51]([OH:58])[C@@H:50]1[OH:59]
Reactant: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Agent: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: NC(CO)(CO)CO
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Product: OC[C@H]1O[C@H](O)[C@@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A reaction mixture (100 mL, 100 mM Tris, pH 7.5, 10 mM MgCl2, 10 mM MnCl2, 5 mM EDTA, 5 ThM NaN3, 1 mm ATPe 0.01 mM theophylline and 0.03 mM 2, 3-dimercaptopropanol) containing α-methyl-D-mannopyranoside (0.4 g, 20 M), Man-1-P (about 1.5 g, about 50 mM), PEP (1.0 g, 42.7 HM), GDP (30 mg, 1 mM), dried yeast cells (0.4 g), pyruvate kinase PK (300 U), recombinant α1,2-ManT (1.2 U) and inorganic pyrophosphatase (2 U) was slightly stirred at room temperature for 72 hours, then centrifuged. The supernatant was lyophilized and extracted with methanol. After removal of the methanol, the product was purified by silica gel column chromatography (CHCl :CH3OH:H2O=6: 3:0.5, v/v/v) to afford Manα1, 2ManαOMe (Compound 3) (96 mg) in 38 percent overall yield based on consumed α-methyl-D-mannopyranoside. 1H NMR (D2O) δ3.41 (s, 3H), 3.60-3.80 (m, 6H), 3.86 (dd, 1H, J=3.5, 10 Hz), 3.88 (dd, 1H, J=3.5, 10 Hz), 3.90 (d, 1H, d, J=1.5 Hz), 3.92 (d, 1H, J=l Hz), 3.97 (dd, 1H, J=2, 3.5 Hz), 4.08 (dd, 2H, J=2, 3.5 Hz), 5.02 (d, 1H, d, J=2 Hz), 5 .04 (d, 1H, J=2.0 Hz). 13C {1H} NMR (D2O) δ54.90, 61.01, 61.24, 66.98, 67.03, 70.02, 70.29, 70.37, 72.63, 73.40, 78.62, 99.40, 102.43. HRMS calculated for C13H24O11Na+ (M+Na+) 379.1216, found 379.1220.
Reaction SMILES: [F:1][C:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][CH:5]([C:33]1[NH:37][CH:36]=[N:35][N:34]=1)[CH2:6][CH:7]([O:29]C(=O)C)[CH:8]([NH:16][C:17]([C:19]1[CH:28]=[N:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1)=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:9]([CH:8]([NH:16][C:17]([C:19]1[CH:28]=[N:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1)=[O:18])[CH:7]([OH:29])[CH2:6][CH:5]([C:33]1[NH:37][CH:36]=[N:35][N:34]=1)[CH2:4][CH2:3][C:2]([F:1])([CH3:39])[CH3:38])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)OC(CC(CCC(C)(C)F)c1nnc[nH]1)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)c1nnc[nH]1
Reaction time: 5 h
Yield: 86.6 %

Procedure:
To a solution of acetic acid 6-fluoro-6-methyl-1-{2-phenyl-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-3-(4H-[1,2,4]triazol-3-yl)-heptyl ester (575 mg, 1.08 mmol) in methanol (10 mL) was added potassium carbonate (276 mg, 2.00 mmol), stirred for 5 hours, and concentrated. The crude product was dissolved in ethyl acetate and water. The organic layer was then washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated. Chromatography on silica gel gave the title compound (459 mg, 87%).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH2:15]Br)=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH2:15][N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1
Reactant: BrCc1ccc(-c2nc3ccc(Br)cc3o2)cc1
Reactant: C1CCNCC1
Solvent: C1CCOC1
Product: Brc1ccc2nc(-c3ccc(CN4CCCCC4)cc3)oc2c1

Procedure:
200 mg (545 μmol) 6-bromo-2-(4-bromomethyl-phenyl)-benzoxazole and 100 mg (1174 μmol) piperidine are stirred for 20 min in 4 ml THF at RT, the solv. is eliminated by rotary evaporation in vacuo. The residue is dissolved in ether and extracted with water, the org. phase is dried on magnesium sulphate and the solv. is eliminated completely in vacuo.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:15]([CH3:17])=[CH2:16])([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH2:4][N:3]1[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:35][CH2:36][Cl:37]>C1COCC1>[Cl:37][CH2:36][CH2:35][CH:7]([C:6]1([C:15]([CH3:17])=[CH2:16])[CH2:5][CH2:4][N:3]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:2]1=[O:1])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: C=C(C)C1(CC(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Reactant: ClCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)C1(C(CCCl)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A cold (-78° C.) solution of tert-butyl 2-oxo-1-(2-phenylethyl)-3-(propen-2-yl)-3-pyrrolidineacetate (prepared similarly to that described in EXAMPLE 1, step 3; 5.52 g, 16.1 mmol) in dry THF (100 mL) is treated with the dropwise addition of LDA (9.66 mL, 19.3 mmol, 2.0N). The solution is stirred for 30 min, and then treated with the dropwise addition of 1-bromo-2-chloroethane (1.61 mL, 19.3 mmol). The solution is maintained at -78° C. for 5 hours and then allowed to slowly warm to room temperature under N2 overnight. The solution is quenched with saturated NH4Cl (10 mL) and diluted with H2O (25 mL). The product is extracted with EtOAc (3×100 mL), dried over anhydrous MgSO4, filtered, and concentrated to give 6.6 g of a brown oil. The oil is purified by silica gel chromatography (275 g SG; 10% EtOAc/hexane) to provide 5.07 g (78%) of the title compound as a clear, yellow oil:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1.[C:11](O)(=O)[CH2:12][CH:13]([CH3:15])[CH3:14].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[Cl-].[Ca+2]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[C:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[N:8]([CH3:9])[C:6]=2[CH:7]=1
Reactant: CC(C)CC(=O)O
Reactant: CNc1cc(Br)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Ca+2]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Cc1nc2ccc(Br)cc2n1C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-N1-methylbenzene-1,2-diamine (159 mg), isovaleric acid (0.087 ml) and N,N-diisopropylethylamine (0.41 ml) in DMF (2 ml) was added HATU (316 mg) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 3 h. After evaporation of the mixture, the residue was purified by NH silica gel column chromatography (hexane/EtOAc). The resulting residue was stirred in AcOH (2.0 ml) at 80° C. for 1 h. After evaporation, the residue was purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (156 mg) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][NH:14][C:15]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[O:16])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O)=[O:24].C([O-])([O-])=O.[K+].[K+].[Br-]>COCCOCCOC.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>[CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][NH:14][C:15]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[O:16])[O:10][N:9]=2)=[CH:4][CH:3]=1)=[O:24]
Reactant: O=C(NCC1CC(c2ccc(Br)cc2)=NO1)c1ccc(Cl)s1
Reactant: O=Cc1ccccc1B(O)O
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: [Br-]
Solvent: COCCOCCOC
Solvent: O
Product: O=Cc1ccccc1-c1ccc(C2=NOC(CNC(=O)c3ccc(Cl)s3)C2)cc1

Procedure:
Aryl bromide (Example 1, 200 mg, 0.50 mmol), 2-formylphenylboronic acid (90 mg, 0.60 mmol) and K2CO3 (106 mg, 1.0 mmol) were diluted with diglyme (5 mL) and water (1 mL). The mixture was degassed for 3-5 min, then treated with Pd(PPh3)4 (58 mg, 0.05 mmol) and heated to 120° C. until all starting bromide was consumed as determined by HPLC. The resulting mixture was diluted with water, filtered and the remaining solids purified by silica gel chromatography (0-10% Ethyl acetate/dichloromethane) affording the desired biphenyl aldehyde as a white solid. MS found for C22H17ClN2O3S as (M+H)+ 425.4, 427.4.
Reaction SMILES: C([NH:8][CH2:9][CH2:10][N:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][CH2:21][CH2:22][S:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:19])[CH3:12])(OC(C)(C)C)=O.Cl>C1COCC1.O1CCOCC1>[NH2:8][CH2:9][CH2:10][N:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][CH2:21][CH2:22][S:23][C:24]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:19])[CH3:12]
Reactant: CN(CCCCCC(=O)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CN(CCN)CCCCCC(=O)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Boc-NH—(CH2)2—N(CH3)—(CH2)5—CONH—(CH2)2-STrt (62.8 mg, 0.11 mmol) was dissolved in THF (6 ml) and HCl in dioxane (130 μl, 4 M solution) was added. The reaction mixture was stirred for 12 h at RT. 200 μl HCl in dioxane was added and the solvent was removed in vacuo. The residue was purified by RP-HPLC to give H2N—(CH2)2—N(CH3)—(CH2)5—CONH—(CH2)2-STrt and not consumed starting material Boc-NH—(CH2)2—N(CH3)—(CH2)5—CONH—(CH2)2-STrt.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][N:17]3[C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][N:22]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][N:17]3[C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][N:22]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)ccn12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)c1cnc2cc(C3CCN(C(=O)OC(C)(C)C)CC3)ccn12
Reaction time: 6 h

Procedure:
H2(balloon) was introduced to a stirred mixture of Pd(OH)2/C (0.055 g) and ethyl 7-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridine-3-carboxylate (89) (0.55 g, 1.48 mmol) in MeOH (5 mL). After 6 hours, the mixture was filtered through a pad of Celite and the solvent was evaporated to give the crude product. The residue was purified over silica using EtOAc and hexanes to give ethyl 7-(1-(tert-butoxycarbonyl)piperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxylate (90). 1H NMR (400 MHz, CD2Cl2) δ 9.27 (d, J=7.2 Hz, 1H), 8.27 (s, 1H), 7.64 (s, 1H), 7.04 (dd, J=1.6, 7.2 Hz, 1H), 4.43 (q, J=7.2 Hz, 2H), 4.31 (m, 2H), 2.87 (m, 1H), 2.83 (m, 2H), 1.95 (m, 2H), 1.67 (m, 2H), 1.49 (s, 9H), 1.43 (t, J=7.2 Hz, 3H). MS m/z 374.2 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].[CH3:16][O:17][C:18](=[O:22])[CH:19](Br)[CH3:20]>CN(C=O)C.CC(=O)OCC>[CH3:16][O:17][C:18](=[O:22])[CH:19]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:20]
Reactant: COC(=O)C(C)Br
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)Oc1ccccc1C=O
Temperature: 120 °C
Reaction time: 0.75 h
Yield: 91.5 %

Procedure:
A mixture of 2-hydroxy-benzaldehyde (1 g; 8.19 mmol; 1 eq.), K2CO3 (3.4 g; 24.6 mmol; 3 eq.) and 2-bromo-propionic acid methyl ester (3.42 g; 20.5 mmol; 2.5 eq.) in DMF (50 mL) was stirred at 120° C. for 45 minutes then diluted with EA. The solution was washed with water (3×) then brine, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (15% to 33% EA in cyclohexane) afforded the title compound (1.56 g, 91%) as a colourless oil. HPLC (max plot) 96.3%; Rt 3.18 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.I[C:11]1[CH:19]=[C:18]2[C:14]([C:15](/[CH:28]=[CH:29]/[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:16][N:17]2[CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:13][CH:12]=1>O1CCOCC1.C(OCC)(=O)C.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>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([C:11]2[CH:19]=[C:18]3[C:14]([C:15](/[CH:28]=[CH:29]/[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:16][N:17]3[CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:26])[CH3:27])=[CH:13][CH:12]=2)=[CH:7][N:6]=1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccccc2)c2ccc(I)cc21
Reactant: COc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3c(/C=C/c4ccccc4)nn(COCC[Si](C)(C)C)c3c2)cn1
Yield: 40.1 %

Procedure:
A solution of 5-bromo-2-methoxypyridine (2.00 g, 6.10 mmol), hexanethylditin (1.15 g, 6.10 mmol), and Pd(PPh3)4 (0.28 g, 0.24 mmol) in degassed dioxane (10 ml) was refluxed under for 16 h. 6-Iodo-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (2.90 g, 6.10 mmol) was added to above mixture, followed by Pd(PPh3)4 (0.35 g 0.31 mmol). The reaction mixture was refluxed for 16 h. The mixture was then diluted with ethyl acetate (150 ml), and washed with brine (30 ml). The organics were dried over MgSO4, then concentrated under reduced pressure. Purification by silica gel chromatography gave 6-(2-methoxypyridin-5-yl)-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole as a yellow solid (1.12 g, 40%). 1H NMR (300 MHz, CDCl3) δ 8.51 (d, 1H, J=2.5 Hz), 8.50 (d, 1H, J=9.1 Hz), 7.93 (dd, 1H, J=2.5, 8.6 Hz), 7.69 (s,1H), 7.69–7.28 (m, 8H), 6.89 (d, 1H, J=8.6 Hz), 5.83 (s, 2H), 4.03 (s, 3H), 3.64 (t, 2H, J=8.3 Hz), 0.93 (t, 2H, J=8.3 Hz), −0.03 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:13][C@H:14]([C:21](C)(C)[O:22][SiH2]C(C)(C)C)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[F-].C([NH3+])(C)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:13][C@@H:14]([CH2:15][CH2:16][C:17]([F:18])([F:19])[F:20])[CH2:21][OH:22])[C:9]([F:12])([F:11])[F:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@H](CCC(F)(F)F)NC(c1ccc(Br)cc1)C(F)(F)F
Agent: CC(C)(C)[NH3+]
Agent: [F-]
Solvent: C1CCOC1
Product: OC[C@H](CCC(F)(F)F)N[C@@H](c1ccc(Br)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 4 h

Procedure:
n-BuLi (2.5 M in hexanes, 21.4 mL) was added dropwise to a stirred solution of 1,4-dibromobenzene (12.6 g) in dry diethyl ether (80 mL) at −30° C. and the reaction mixture was stirred for 30 minutes. A solution of (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-5,5,5-trifluoro-N-[(1E)-2,2,2-trifluoroethylidene]pentan-2-amine (3.75 g, 10.7 mmol) in dry diethyl ether (30 mL) was then added dropwise and the reaction mixture was allowed to warm to ambient temperature and stirred for 16 hours. The reaction mixture was then quenched with 100 mL of water. The organic phase was washed with brine, dried with magnesium sulfate, and filtered. The filtrate was concentrated by rotary evaporation to yield crude product which was purified by silica gel chromatography using 1% ethyl acetate in hexanes as eluant to yield (S)-[1-(4-bromophenyl)-2,2,2-trifluoro-ethyl]-[1-(tert-butyl-dimethyl-silanyloxymethyl)-4,4,4-trifluoro-butyl]-amine (1.8 g). (S)-[1-(4-Bromophenyl)-2,2,2-trifluoro-ethyl]-[1-(tert-butyl-dimethyl-silanyloxymethyl)-4,4,4-trifluoro-butyl]-amine was dissolved in THF (50 mL) and chilled to 0° C. and tert-butylammonium fluoride (10.6 mL, 1 M THF solution) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred for 4 hours. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride and then ethyl acetate was added and the mixture vigorously shaken. The organic layer was separated and washed two times with brine, dried with magnesium sulfate and filtered. The solvent was removed by rotary evaporation to yield a residue which was purified on SiO2 using a gradient of 20-25% ethyl acetate in hexanes as eluant to yield (2S)-2-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]amino}-5,5,5-trifluoropentan-1-ol.