Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=O)[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[Cl:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:44]([O:46][CH2:47][CH2:48][O:49][NH2:50])=[CH2:45].[NH4+].[Cl-]>C(Cl)Cl>[F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([NH:50][O:49][CH2:48][CH2:47][O:46][CH:44]=[CH2:45])=[O:13])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[Cl:22]
Reactant: C=COCCON
Reactant: O=C(O)c1cc2snnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCl
Product: C=COCCONC(=O)c1cc2snnc2c(F)c1Nc1ccc(Br)cc1Cl
Reaction time: 1 h

Procedure:
To a solution of 4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylic acid (200 mg, 0.46 mmol) in CH2Cl2 (10 mL) was added HOBt (100 mg, 0.74 mmol) and EDCI (132 mg, 0.74 mmol). The mixture was stirred for 1 h and O-(2-(vinyloxy)ethyl)hydroxylamine (76 mg, 0.74 mmol) was added. After stirring for 4 h at ambient temperature, the reaction was treated with saturated NH4Cl (aq.). The resultant mixture was extracted with CH2Cl2 (15 mL×3). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4 filtered, and concentrated in vacuo. The crude product (191 mg) was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[C:4](=[O:17])[CH2:5][C:6](=[O:16])[CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9])[CH3:2].C([BH3-])#N.[Na+]>CC(C)[O-].CC(C)[O-].CC(C)[O-].[Cl-].[Ti+4]>[CH2:18]([N:3]([CH2:1][CH3:2])[C:4](=[O:17])[CH2:5][CH:6]([OH:16])[CH2:7][CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9])[CH3:19]
Reactant: CCN(CC)C(=O)CC(=O)CC(O)c1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Product: CCN(CC)C(=O)CC(O)CC(O)c1ccccc1
Yield: 70.2 %

Procedure:
By carrying out the reaction as in Example 9 but starting from 1.02 g of N,N-diethyl-5-phenyl-5-hydroxy-3-oxopentanamide (3.92 mmol), 1.05 cm3 of titanium chloride triisopropoxide (4.18 mmol) and from 283.9 mg of sodium cyanoborohydride (4.28 mmol), there is obtained, with a yield of 70.2%, 730 mg of N,N-diethyl-5-phenyl-3,5-dihydroxypentanamide for which the syn/anti ratio is equal to 80/20.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.FC(F)(F)C(O)=O.[NH:18]1[CH:22]=[C:21]([C:23]2[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=2)[C:26]#[N:27])[CH:20]=[N:19]1>>[NH:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([N:18]3[CH:22]=[C:21]([C:23]4[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=4)[C:26]#[N:27])[CH:20]=[N:19]3)=[C:3]2[CH:10]=[CH:9]1
Reactant: N#Cc1cccc(-c2cn[nH]c2)c1
Reactant: Brc1ccnc2[nH]ccc12
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(-c2cnn(-c3ccnc4[nH]ccc34)c2)c1
Temperature: 180 °C

Procedure:
A mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine (25.0 mg, 0.000127 mol) and 3-(1H-pyrazol-4-yl)benzonitrile trifluoroacetate (23.6 mg, 0.0000833 mol) was heated at 180° C., neat overnight. The crude residue was purified by HPLC on a C-18 column eluting with a water; ACN gradient containing 0.2% TFA to give the title compound as an amorphous white solid, LC/MS (M+H)+: 286, 1H NMR (DMSO-d6) δ 11.85 (bs, 1H), 9.18 (s, 1H), 8.42 (s, 1H), 8.28 (s, 1H), 8.25 (d, 1H, J=5.0), 8.07 (d, 1H, J=7.0), 7.64 (d, 1H, J=7.0), 7.56 (t, 1H, J=7.0), 7.51 (m, 1H), 7.47 (d, 1H, J=5.0), 7.03 (m, 1H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:12])[CH2:6][NH:7][C:8](=[O:11])[CH2:9][NH2:10])[CH3:3].C(N(CC)CC)C.O.O.[C:22]([O:26][C:27]([NH:29][C@H:30]([C:38](O)=[O:39])[CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].O.ON1C2C=CC=CC=2N=N1.Cl.CN(CCCCN=C=NCC)C>O1CCCC1>[CH2:2]([O:4][C:5](=[O:12])[CH2:6][NH:7][C:8](=[O:11])[CH2:9][NH:10][C:38](=[O:39])[C@H:30]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:28])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Reactant: CCOC(=O)CNC(=O)CN
Agent: CCN=C=NCCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)CNC(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Yield: 90.9 %

Procedure:
To a solution of 289.4 mg (1.47 mmol) of glycyl-glycine ethyl ester hydrochloride in anhydrous tetrahydrofuran (5 mL), 155.9 mg (1.54 mmol) of triethylamine, 451.5 mg (1.47 mmol) of N-t-butoxycarbonyl-β-cyclohexyl-L-alanine dihydrate, 205.3 mg (1.52 mmol) of 1-hydroxybenzotriazole hydrate, and 292.7 mg (1.53 mmol) of 1-[3-(dimethylaminomethyl)propyl]-3-ethylcarbodiimide hydrochloride were added sequentially with stirring under ice cooling. After the mixture was stirred for 1 hour, the reaction mixture was stirred at room temperature for 0.5 hour. The reaction mixture was concentrated under reduced pressure, chloroform (30 mL) was added to the residues, and the solution was washed sequentially with 0.5M hydrochloric acid (3×5 mL), water (3×5 mL) and 5% aqueous sodiumhydrogen carbonate solution (3×5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, whereby 570 mg of a crude product was obtained. The crude product was purified by column chromatography on alumina (alumina 2g, chloroform), to give 552.8 mg of N-t-butoxycarbonyl-β-cyclohexyl-L-alanyl-glycyl-glycine ethyl ester (yield 91%) as a colorless crystalline powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:7]2[CH2:6][CH2:5][NH:4][C:3](=[O:8])[C:2]2([CH3:9])[CH3:1])=[CH:14][CH:13]=1
Reactant: CC1(C)NCCNC1=O
Reactant: COc1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN2CCNC(=O)C2(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 55 %

Procedure:
A mixture of 3,3-dimethyl-piperazin-2-one (Step 108.4) (3.7 g, 28.9 mmol), 4-methoxybenzyl bromide (5.4 mL, 37.6 mmol, 1.3 equiv) and triethylamine (5.2 mL, 37.6 mmol, 1.3 equiv) in DCM (60 mL) was stirred for 48 h at rt. Additional 5.0 mL of 4-methoxybenzyl bromide were added and the mixture was stirred for 72 h at rt, then concentrated. The residue was diluted with DCM/saturated aqueous solution of NaHCO3. The aqueous phase was separated and extracted with DCM. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was triturated in DCM to provide 3.95 g of the title compound as a white solid: ESI-MS: 249.2 [M+H]+; TLC: Rf=0.16 (Hex/EtOAc, 2:3).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:9]=[C:8]([N:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH3:11])[N:7]=[C:6]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[C:5]=1/[CH:23]=[CH:24]/[C@@H:25]([OH:33])[CH2:26][C@@H:27]([OH:32])[CH2:28][C:29](O)=[O:30])[CH3:3].[Mg+2].[Br-].[Br-].Cl.[NH2:38][OH:39].C(=O)(O)[O-].[Na+]>C1COCC1.CO.C(Cl)Cl.CCOC(C)=O.CC#N>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:6]2[C:5](/[CH:23]=[CH:24]/[C@@H:25]([OH:33])[CH2:26][C@@H:27]([OH:32])[CH2:28][C:29]([NH:38][OH:39])=[O:30])=[C:4]([CH:2]([CH3:3])[CH3:1])[N:9]=[C:8]([N:10]([CH3:11])[S:12]([CH3:15])(=[O:13])=[O:14])[N:7]=2)=[CH:17][CH:18]=1
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H](O)C[C@@H](O)CC(=O)O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CC#N
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H](O)C[C@@H](O)CC(=O)NO

Procedure:
By a procedure similar to Lova-HA, rosuvastatin (68 mg, 0.15 mmol, in the lactone form) was treated with MgBr2 (54 mg, 0.29 mmol), hydroxylamine hydrochloride (87 mg, 1.25 mmol), and sodium bicarbonate (99 mg, 1.18 mmol) in anhydrous THF/MeOH (7:3, 647 L) at ambient temperature for 6 h to give Rosuva-HA (37 mg, 51%). The purity was 97% as shown by HPLC analysis on an HC—C18 column (Agilent, 4.6×250 mm, 5 am), tR=13.8 min (gradients of 25-80% aqueous CH3CN in 30 min). C22H29FN4O6S; colorless oil; [α]24D=−1.1 (EtOAc, c=1.0); TLC (CH2Cl2/McOH (9:1)) Rf=0.35; IR νmax (neat) 3326, 2925, 2853, 1737, 1660, 1604, 1546, 1510, 1437, 1381, 1336, 1230, 1153, 1069, 965, 901, 845, 776 cm1; 1H NMR (DMSO-d6, 400 MHz) δ 10.32 (1H, br s), 8.70 (1H, br s), 7.71-7.74 (2H, m), 7.30 (2H, t, J=8.8 Hz), 6.50 (1H, dd, J=1.2, 16.2 Hz), 5.54 (1H, dd, J=5.6, 16.2 Hz), 4.94 (1H, d, J=4.4 Hz), 4.70 (1H, d, J=4.8 Hz), 4.19-4.22 (1H, m), 3.88 (1H, br s), 3.55 (3H, s), 3.41-3.48 (4H, m), 2.05 (2H, d, J=6.4 Hz), 1.48-1.56 (1H, m), 1.37-1.43 (1H, m), 1.22 (6H, d, J=6.8 Hz) ppm; 13C NMR (DMSO-d6, 100 MHz) δ 174.8, 167.9, 164.3, 163.3, 161.8, 157.3, 141.7, 134.9, 134.8, 132.6, 132.5, 122.2, 121.9, 115.6, 115.4, 69.1, 65.6, 44.6, 42.0, 41.2, 33.7, 31.7, 22.0 (2×) ppm; ESI-HRMS (negative mode) calcd. for C33H35FN3O5: 572.2561. found: m/z 572.2562 [M−H]−.
Reaction SMILES: IC1C(O)=NC2CCN(C(=O)C(F)(F)F)CC(C)C=2C=1.C(Br)C=C.[CH2:25]([O:28][C:29]1[C:30]([I:47])=[CH:31][C:32]2[CH:38]([CH3:39])[CH2:37][N:36](C(=O)C(F)(F)F)[CH2:35][CH2:34][C:33]=2[N:46]=1)[CH:26]=[CH2:27].C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.CO.C(Cl)(Cl)Cl>[CH2:25]([O:28][C:29]1[C:30]([I:47])=[CH:31][C:32]2[CH:38]([CH3:39])[CH2:37][NH:36][CH2:35][CH2:34][C:33]=2[N:46]=1)[CH:26]=[CH2:27]
Reactant: C=CCOc1nc2c(cc1I)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: CC1CN(C(=O)C(F)(F)F)CCc2nc(O)c(I)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C=CCBr
Solvent: ClC(Cl)Cl
Product: C=CCOc1nc2c(cc1I)C(C)CNCC2
Temperature: 25 °C
Reaction time: 96 h
Yield: 49.7 %

Procedure:
A mixture of 3-iodo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol (615 mg, 1.54 mmol), allyl bromide (1.33 ml, 15.4 mmol), Ag2CO3 (504 mg, 1.83 mmol) and CHCl3 (35 ml) was stirred under exclusion of light for 4 d at ambient temperature. The reaction mixture was diluted with EtOAc (100 ml) and filtered. The filtrate was concentrated in vacuo and purified by column chromatography rendering 445 mg (66%) of 2-(allyloxy)-3-iodo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 7.82 (2×s, 1H), 6.18 (dddd, 1H), 5.48 (m, 1H), 5.27 (m, 1H), 4.87 (m, 2H), 4.16-3.01 (m, 7H), 1.32 (2× d, 3H) ppm. A mixture of 2-(allyloxy)-3-iodo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (145 mg, 329 μmol), K2CO3 (150 mg) and MeOH (6 ml) was heated for 1 h at 60° C. The reaction mixture was concentrated in vacuo and purified by column chromatography to give 56.3 mg (50%) of 2-(allyloxy)-3-iodo-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 7.78 (s, 1H), 6.08 (dddd, 1H), 5.46 (ddd, 1H), 5.25 (ddd, 1H), 4.86 (m, 2H), 3.20-3.02 (m, 5H), 2.98 (m, 1H), 2.78 (m, 1H), 1.33 (d, 3H) ppm.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=2)[CH:13]=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[C:22]=1[C:23]([NH2:25])=[O:24].OS([O-])=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[C:12]([C:13]3[NH:25][C:23](=[O:24])[C:22]4[C:21](=[CH:29][C:28]([O:30][CH3:31])=[CH:27][C:26]=4[O:32][CH3:33])[N:20]=3)[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: COc1cc(C=O)cc(N2CCN(C(C)C)CC2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)cc(N2CCN(C(C)C)CC2)c1
Temperature: 120 °C
Reaction time: 20 h
Yield: 79.1 %

Procedure:
To a solution of 3-(4-isopropylpiperazin-1-yl)-5-methoxybenzaldehyde (1.23 g, 4.68 mmol) in N,N-dimethylacetamide (20 mL) was added 2-amino-4,6-dimethoxybenzamide (0.59 g, 3.00 mmol), NaHSO3 (58.5 wt %, 0.87 g, 4.80 mmol) and p-toluenesulfonic acid monohydrate (1.82 g, 9.60 mmol). The reaction mixture was stirred at 120° C. for 20 h under nitrogen. After that time the reaction was cooled to rt and concentrated under reduced pressure. The residue was diluted with saturated Na2CO3 solution to adjust the pH to 12. The precipitated solids were collected by filtration, washed with water and dried under vacuum. The product was purified by flash column chromatography (silica gel, 86:10:4 dichloromethane/ethyl acetate/methanol followed by 86:10:4 dichloromethane/ethyl acetate/7 N NH3 in methanol) and prep. HPLC to give 2-(3-(4-isopropylpiperazin-1-yl)-5-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (1.04 g, 50%) as a white solid: mp 212-213° C.; 1H NMR (400 MHz, DMSO-d6): δ 11.99 (s, 1H), 7.36 (s, 1H), 7.20 (s, 1H), 6.76 (d, J=2.34 Hz, 1H), 6.60 (t, J=1.95 Hz, 1H), 6.53 (d, J=1.95 Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.81 (s, 3H), 3.22 (t, J=4.29 Hz, 4H), 2.68 (quin, J=6.54 Hz, 1H), 2.58 (t, J=4.68 Hz, 4H), 1.01 (d, J=6.63 Hz, 6H); ESI MS m/z 437 [M−H]−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.[OH-].[Na+].C[O:13][N:14]=O.S(=O)(=O)(O)O.N([O-])=O.[Na+]>CO.O>[N:14](=[C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:8]#[N:9])[OH:13]
Reactant: CON=O
Reactant: N#CCc1cccnc1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#CC(=NO)c1cccnc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-pyridylacetonitrile (47.2 g, 400 mmol) was dissolved in a solution of sodium hydroxide (16 g, 400 mmol) in methanol (100 ml). Methylnitrite, generated by dropping a solution of concentrated sulphuric acid (12.8 ml) and water (26 ml) to a solution of sodium nitrite (33.2 g, 480 mmol) in water (20 ml) and methanol (20 ml), was bobled through the 3-pyridylacetonitrile solution at 0° C. The reaction mixture was stirred at 0° C. for 1 h and the precipitate collected by filtration. The precipitate was washed with a little methanol to give the wanted product in 70% (41.1 g) yield. M+ : 147.
Reaction SMILES: Cl.[F:2][CH:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])[CH2:4][O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8][CH2:7]1.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]2[N:27]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][O:31]3)[N:28]=[CH:29][C:22]=12.C(=O)([O-])[O-].[Na+].[Na+]>CC(O)C>[F:2][CH:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])[CH2:4][O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:21]2[N:26]=[CH:25][N:24]=[C:23]3[N:27]([CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][O:31]4)[N:28]=[CH:29][C:22]=23)[CH2:8][CH2:7]1
Reactant: Clc1ncnc2c1cnn2C1CCCCO1
Reactant: N[C@H]1CC[C@H](OCC(F)c2ccccc2F)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: Fc1ccccc1C(F)CO[C@H]1CC[C@H](Nc2ncnc3c2cnn3C2CCCCO2)CC1
Temperature: 80 °C

Procedure:
A mixture of 0.52 g trans-4-[2-fluoro-2-(2-fluorophenyl)ethoxy]-cyclohexanamine hydrochloride, 0.46 g of 4-chloro-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine, and 1 g of powdered sodium carbonate in 25 mL of 2-propanol was heated to 80° C. under nitrogen overnight. The mixture was cooled, filtered and the solid washed with 3×50 mL portions of 10% methanol in chloroform. The combined extracts were concentrated under reduced pressure. Chromatography over silica gel eluting with a gradient of 50%-100% ethyl acetate in hexane gave 0.82 g of product as a white solid: MS (m+1)=458.4.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[N:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][C:54]=2[C:56]([OH:58])=O)[CH:49]=[CH:48][CH:47]=1.[NH2:59][C:60]1[CH:61]=[CH:62][CH:63]=[C:64]2[C:69]=1[N:68]=[CH:67][CH:66]=[CH:65]2>C(Cl)Cl.O>[N:68]1[C:69]2[C:64](=[CH:63][CH:62]=[CH:61][C:60]=2[NH:59][C:56]([C:54]2[CH:53]=[CH:52][CH:51]=[C:50]3[C:55]=2[N:46]=[CH:47][CH:48]=[CH:49]3)=[O:58])[CH:65]=[CH:66][CH:67]=1
Reactant: O=C(O)c1cccc2cccnc12
Reactant: Nc1cccc2cccnc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1cccc2cccnc12)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
(Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (192 mg; 0.43 mmol), 1-hydroxybenzotriazole monohydrate (79 mg; 0.59 mmol) and triethylamine (0.200 ml; 1.44 mmol) are added to a solution of quinoline-8-carboxylic acid (50 mg; 0.29 mmol) dissolved in 5 ml of dry CH2Cl2. After stirring for 30 minutes at ambient temperature, 8-aminoquinoline (84 mg; 0.58 mmol) is added and the mixture is stirred for 4 hours 30 minutes at ambient temperature. Water (10 ml) is added and the product is extracted with CH2Cl2 (3×10 ml). The volume is reduced and the product is purified by silica gel chromatography, eluted with CH2Cl2/CH3OH (0 to 2%, v/v) then the solvent is evaporated under reduced pressure and the fractions containing a high proportion of products are repurified by silica gel chromatography, eluted with CH2Cl2/CH3OH (99.5/0.5; v/v). 24 is obtained after evaporation of the solvent in the form of a white powder (83 mg; 0.28 mmol, yield=96%). NMR-1H (250 MHz, CDCl3) δ, ppm: 15.13 (s, 1H); 9.25 (dd, 3J (H, H)=4.0 Hz, 4J (H, H)=2.0 Hz, 1H); 9.19 (dd, 3J (H, H)=7.5 Hz, 4J (H, H)=1.5 Hz, 1H); 9.00 (m, 2H); 8.32 (dd, 3J (H, H)=8.0 Hz, 4J (H, H)=2.0 Hz, 1H); 8.19 (dd, 3J (H, H)=8.0 Hz, 4J (H, H)=1.5 Hz, 1H); 8.01 (dd, 3J (H, H)=8.0 Hz, 4J (H, H)=1.5 Hz, 1H); 7.74 (dd, 3J (H, H)=7.5 and 8.0 Hz, 1H); 7.60 (m, 3H); 7.48 (dd, 3J (H, H)=4.5 and 8.0 Hz, 1H). NMR-13C (63 MHz, CDCl3) δ, ppm: 164.28; 149.48; 148.57; 145.60; 140.12; 137.59; 136.65; 136.18; 134.02; 132.10; 129.85; 128.41; 128.28; 127.50; 126.63; 121.75; 121.34; 121.12; 118.18. MS (CID, NH3): m/z=300 (MH+). UV/vis [DMSO/20 mM Tris-HCl pH=7.4 containing 150 mM NaCl (8/2, v/v)]: λ nm (ε M−1 cm−1)=261 (13,300, shoulder), 274 (14,800), 294 (12,200).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].C[O-].[Na+].[F:15][C:16]([F:30])([F:29])[C:17]1[CH:18]=[C:19]([CH2:23][NH:24][C:25](=[O:28])[CH2:26]Cl)[CH:20]=[CH:21][CH:22]=1.C(O)(=O)C>CO.O>[OH:10][C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:26]=1[C:25]([NH:24][CH2:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:29])[F:30])[CH:18]=1)=[O:28]
Reactant: O=C(CCl)NCc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccccc1S
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1sc2ccccc2c1O
Temperature: 25 °C
Yield: 75.2 %

Procedure:
To a solution of methyl thiosalicylate (0.67 g; 0.004M) in 20 ml of methanol is added solid sodium methoxide (0.65 g; 0.012M; 3 eqv.) followed by N-[(3-trifluoromethylphenyl)methyl]-chloroacetamide (1.0 g; 0.004M) and the mixture is refluxed under a nitrogen atmosphere for 30 minutes. The mixture is cooled to room temperature and added to a solution of 1.5 ml of glacial acetic acid in 25 ml of water and cooled to 0° C. The cream colored solid is collected, washed with 50% methanol-water, air dried, and recrystallized from nitromethane to give 1.05 g (78% yield) of the title compound; m.p. 139°-141° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([CH3:11])[C:8]([OH:10])=O)[CH2:2]1.Cl.CN(C)CCCN=C=NCC.[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[N:30]1[C:38]2[C:33](=[CH:34][C:35]([C:39]3[N:43]=[CH:42][N:41]([C:44]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:40]=3)=[CH:36][CH:37]=2)[C:32]([C:63]2[CH:64]=[C:65]([NH2:69])[CH:66]=[CH:67][CH:68]=2)=[N:31]1.CN(C)C=O>ClCCl>[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[N:30]1[C:38]2[C:33](=[CH:34][C:35]([C:39]3[N:43]=[CH:42][N:41]([C:44]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[N:40]=3)=[CH:36][CH:37]=2)[C:32]([C:63]2[CH:64]=[C:65]([NH:69][C:8](=[O:10])[CH:7]([CH:3]3[CH2:4][CH2:5][CH2:6][NH:1][CH2:2]3)[CH3:11])[CH:66]=[CH:67][CH:68]=2)=[N:31]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: CC(C(=O)O)C1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)C1CCCNC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-piperidyl propanoic acid (0.125 g, 0.796 mmol) in 7 mL of dichloromethane was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.190 g, 0.99 mmol). After 10 min at room temperature, 3-{1-perhydro-2H-pyran-2-yl -5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.200 g, 0.59 mmol) was then added as a solid followed by 2 mL of dimethyl formamide. The reaction mixture was stirred at room temperature overnight. The completion of the reaction mixture was achieved after reacting an additional equivalent of reagents and stirring at room temperature for 24 hours. The crude mixture was partitioned between water and dichloromethane. The crude was not purified (yield not calculated). ES-MS (m/z) 742 [M+H]+.
Reaction SMILES: C(O[B:5]1[O:9][C:8]([CH3:11])([CH3:10])[C:7]([CH3:13])([CH3:12])[O:6]1)(C)C.C([Li])CCC.[F:19][C:20]1[CH:21]=[C:22]([CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:26][C:24]1[CH:23]=[C:22]([CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:21]=[C:20]([F:19])[C:25]=1[B:5]1[O:6][C:7]([CH3:12])([CH3:13])[C:8]([CH3:10])([CH3:11])[O:9]1
Reactant: Fc1cc(F)cc(C2CCOCC2)c1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Product: CC1(C)OB(c2c(F)cc(C3CCOCC3)cc2F)OC1(C)C
Yield: 100 %

Procedure:
Method 3 was followed using 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.2 equiv.), butyllithium (1.1 equiv.) and 4-(3,5-difluorophenyl)tetrahydro-2H-pyran (1.0 equiv.) to give 2-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in 100% yield. 1H NMR (400 MHz, <cdcl3>) δ ppm 1.16-1.19 (m, 12 H), 1.65-1.74 (m, 4 H), 2.60-2.75 (m, 1 H), 3.37-3.51 (m, 2 H), 4.01 (dt, J=11.54, 3.42 Hz, 2 H), 6.67 (d, J=8.22 Hz, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>C(#N)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: CN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CN1CCN(C(=O)c2ccc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 25 %

Procedure:
To a toluene solution (300 ml) at −78° C. in which 2,5-dibromopyridine (4.7 g) was dissolved, n-butyl lithium hexane solution (1.6 M) was added dropwise, followed by stirring at −78° C. for 3 hours. To the reaction mixture, dry ice (ca. 50 g) was added, and followed by further stirring at room temperature for 10 hours. Water (100 ml) was added, and the aqueous layer washed with ethyl acetate (100 ml×2) was neutralized with 5M−HCl aqueous solution under ice cooling, and the resulting precipitate was filtered and dried, to obtain 5-bromo-pyridine-2-carboxylic acid as a colorless powder (2.0 g, 50%). Then, 5-bromo-pyridine-2-carboxylic acid (202 mg), N-methylpiperazine (124 μl), WSCI (230 mg), HOBt (149 mg) and triethylamine (140 μl) were dissolved in acetonitrile (10 ml), followed by stirring at room temperature for 10 hours. To the reaction mixture, water (10 ml) was added, followed by extraction with ethyl acetate (10 ml). The organic layer was washed with saturated aqueous sodium chloride solution, followed by drying over sodium sulfate. After filtering off the sodium sulfate, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by amino silica gel column chromatography (dichloromethane), to obtain (5-bromo-pyridin-2-yl)-(4-methyl-piperazin-1-yl)-methanone as a yellow oil (70 mg, 25%).