Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:14][C:13]=2[C:12]2[N:23](COCC[Si](C)(C)C)[N:24]=[C:25]([NH:26][CH:27]3[CH2:32][CH2:31][N:30]([S:33]([CH3:36])(=[O:35])=[O:34])[CH2:29][CH2:28]3)[C:11]=2[N:10]=1.FC1C=CC=C(F)C=1C1C2C=C(C(OC)=O)C=CC=2C2=NN(COCC[Si](C)(C)C)C(NC3CCN(S(C)(=O)=O)CC3)=C2N=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:23][N:24]=[C:25]([NH:26][CH:27]3[CH2:28][CH2:29][N:30]([S:33]([CH3:36])(=[O:35])=[O:34])[CH2:31][CH2:32]3)[C:11]=2[N:10]=1
Reactant: COC(=O)c1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(NC3CCN(S(C)(=O)=O)CC3)nn(COCC[Si](C)(C)C)c12
Agent: COC(=O)c1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(NC3CCN(S(C)(=O)=O)CC3)n(COCC[Si](C)(C)C)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(NC3CCN(S(C)(=O)=O)CC3)n[nH]c12
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A 25 ml round-bottomed flask equipped with a magnetic stirrer is charged with 46 mg of the mixture of methyl 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carboxylate and methyl 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinoline-7-carboxylate obtained in step 9 in 5 ml of DCM. After cooling to 0° C. using an ice bath, 0.5 ml of TFA are added and the mixture is stirred at RT for 18 h. It is concentrated under RP and the solid obtained is taken up in 20 ml of water and extracted with three times 20 ml of AcOEt. The organic phase is dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with DCM and then with a mixture of DCM/AcOEt (50/50 by vol.), to give 12 mg of methyl 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carboxylate (yellow solid). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.67 (m, 2 H) 2.11 (m, 2 H) 2.88 (s, 3 H) 2.92 (m, 2 H) 3.56 (m, 2 H) 3.80 (m, 1 H) 3.87 (s, 3 H) 6.16 (d, J=7.7 Hz, 1 H) 7.37 (m, 2 H) 7.71 (m, 1 H) 8.23 (broad s, 1 H) 8.42 (broad d, J=8.5 Hz, 1 H) 8.54 (d, J=8.5 Hz, 1 H) 13.01 (s, 1 H). LC-MS-DAD-ELSD: 516 (+)=(M+H)(+).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[C:11](Cl)[CH:10]=[CH:9][C:8]=1[C:14](=[O:25])[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=1[F:24])C.[OH-].[Na+].Cl.[CH2:30]([OH:32])C>C(OCC)(=O)C>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][NH:15][C:14]([C:8]2[CH:9]=[CH:10][C:11]([O:32][CH3:30])=[CH:12][C:7]=2[O:6][CH2:5][C:4]([OH:3])=[O:26])=[O:25])=[C:18]([F:24])[CH:19]=1
Reactant: CCO
Reactant: CCOC(=O)COc1cc(Cl)ccc1C(=O)NCc1ccc(Br)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)NCc2ccc(Br)cc2F)c(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
A solution of [2-(4-bromo-2-fluoro-benzylcarbamoyl)-5-chloro-phenoxy]-acetic acid ethyl ester (1.23 g, 2.8 mmol) in ethanol (16 mL, 0.18 M) was cooled to 0° C. and treated with aq NaOH (1.25 M, 7.0 mL, 8.7 mmol). After stirring for 2.5 h, the solution was warmed to room temperature and stirred an additional 24 h. Next, the solution was acidified to pH 1–2 with 2 N HCl, diluted with ethyl acetate and washed with saturated aq NaCl. The organic layer was dried over Na2SO4, filtered and concentrated to give (2-(4-bromo-2-fluoro-benzylcarbamoyl)-5-methoxy-phenoxy]-acetic acid as a white solid (1.03 g, 89%): mp 203–204° C.; Rf 0.10 (10% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 9.02 (br t, J=5.9 Hz, 1 H), 7.84, (d, J=8.2 Hz. 1 H), 7.50, (br d, J=8.7 Hz, 1 H), 7.48–7.29 (m, 2 H), 6.69–6.80 (m, 2 H), 4.87 (s, 2 H), 4.49 (d, J=5.8 Hz, 2 H), 3.79 (s, 3 H). ESI-LC/MS m/z calcd for C17H15BrFNO5: 411.0; found 412.0 (M+1)−. Anal. calcd for C17H15BrFNO5: C, 49.53; H, 3.67; N, 3.40. Found C, 49.48; H, 3.68; N, 3.39.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:10][C:9]2=[O:23])=[CH:4][C:3]=1[NH:24][CH3:25].[CH:26]12[CH2:31][CH:30]1[C:29](=O)[O:28][C:27]2=[O:33].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C1COCC1.CC(O)=O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]4[N:1]=[C:29]([CH:30]5[CH2:31][CH:26]5[C:27]([OH:28])=[O:33])[N:24]([CH3:25])[C:3]=4[CH:4]=3)[C:9](=[O:23])[CH:10]=2)=[CH:21][CH:20]=1
Reactant: CNc1cc(-n2ccc(OCc3ccc(Cl)cc3)cc2=O)ccc1N
Reactant: O=C1OC(=O)C2CC12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Cn1c(C2CC2C(=O)O)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (2.0 g), 3-oxabicyclo[3.1.0]hexane-2,4-dione (0.662 g) and triethylamine (1.175 ml) in THF (80 ml) was stirred at room temperature overnight. After concentration of the mixture in vacuo, AcOH (80 ml) was added to the residue. The mixture was stirred at 80° C. for 1 h. After concentration of the mixture in vacuo, the mixture was neutralized with saturated NaHCO3 solution at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The resulting solid was washed with IPE and dried to give the title compound (1.67 g) as a brown solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[O:15]2)[S:10][C:9]1=[S:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([CH3:36])[CH:30]=[CH:29][C:28]([S:31]([O:34]C)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[C:25]1([CH3:36])[CH:26]=[CH:27][C:28]([S:31]([O-:34])(=[O:32])=[O:33])=[CH:29][CH:30]=1.[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[O:15]2)[S:10][CH2+:9]1[S:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1C(=C2SC(=S)N(Cc3ccccc3)C2=O)Oc2ccccc21
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: ClC(Cl)Cl
Product: CS[CH2+]1SC(=C2Oc3ccccc3N2C)C(=O)N1Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 120 °C

Procedure:
To a 10 mL flask was added 3-benzyl-5-(3-methyl-3H-benzoxazol-2-ylidene)-2-thioxothiazolidin-4-one (100 mg, 0.28 mmol), anhydrous CHCl3 (2 mL) and methyl p-toluenesulfonate (53 μL, 0.35 mmol). After heating at reflux 10 min, the reaction mixture was heated at 120° C. for 2 h to yield a red oil. The desired intermediate, 3-benzyl-5-(3-methyl-3H-benzoxazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate, was not isolated successfully in previous experiments similar to Example 1 and, thus, the crude reaction mixture was diluted with anhydrous CHCl3 (4 mL) and used without purification in the next step.
Reaction SMILES: [C:1]([CH2:3][CH2:4][S:5][CH2:6][CH2:7]C(O)=O)#[N:2].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:18])C=CC=CC=1.C([N:30]([CH2:33]C)CC)C>C1C=CC=CC=1>[C:1]([CH2:3][CH2:4][S:5][CH2:6][CH2:7][N:30]=[C:33]=[O:18])#[N:2]
Reactant: N#CCCSCCC(=O)O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Solvent: c1ccccc1
Product: N#CCCSCCN=C=O

Procedure:
The reaction of 3-(2-cyanoethylthio)propionic acid and diphenylphosphoryl azide in a solution of triethyl amine and benzene provided a solution comprising 2-(2-cyanoethylthio)ethyl isocyanate (I.R.: 2250 cm-1), which was reacted with 5-fluorouracil to provide 1-[N-[2-(2-cyanoethylthio)ethyl]carbamoyl]-5-fluorouracil substantially in the similar method to that of Example 10.
Reaction SMILES: [N+:1]1([O-])[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[NH:3][CH:2]=1.CS([Cl:15])(=O)=O>CN(C=O)C>[Cl:15][C:6]1[CH:7]=[CH:8][N:9]=[C:4]2[NH:3][CH:2]=[N:1][C:5]=12
Reactant: [O-][n+]1c[nH]c2ncccc21
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Product: Clc1ccnc2[nH]cnc12
Temperature: 50 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
A 50 mL round bottom flask set up with a reflux condenser under nitrogen atmosphere was charged 4-azabenzimidazole N-oxide (1.2 g, 8.88 mmol) and 11 mL of DMF. This was heated to 50° C. and methanesulfonyl chloride (1.86 ml, 23.98 mmol) was added dropwise via syringe. The resulting mixture was heated to 80° C. and stirred at this temperature for 16 hours. This was cooled to room temperature and quenched with water (approximately 10 mL) and reaction mixture brought to pH 7 by adding 6N NaOH aqueous solution. The reaction was extracted four times with dichloromethane (50 mL). Some product was present in aqueous layer, this was concentrated and residue set aside. The combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep 40 g column, gradient elution 0-10% MeOH:DCM) to afford 7-chloro-3H-imidazo[4,5-b]pyridine (450 mg, 33.0% yield). MS [M+H]=154.2. Calc'd C6H4ClN3=153.56.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=4[F:25])[N:18]([CH3:27])[N:17]=3)[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=4[F:25])[N:18]([CH3:27])[N:17]=3)[N:14]=2)[NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)cc(F)c34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)cc(F)c34)nc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
To a solution of 2-(4,6-difluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide (30 mg, 0.06 mmol) in CH2Cl2 (1.5 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature for 4 h then concentrated. The residue was redissolved in 10:90:0.5 MeOH/CH2Cl2/NH4OH (3 mL) and stirred at room temperature for 3 h then concentrated. The residue was purified by silica gel chromatography with 0% to 5% MeOH/EtOAc to afford 18 mg (82%) of 2-(4,6-difluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide as a light yellow powder. MS (M+Na)+=393; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.83 (s, 1H), 8.99 (s, 1H), 8.40 (s, 1H), 8.27 (d, J=7.9 Hz, 1H), 7.59 (dd, J=9.1, 1.9 Hz, 1H), 7.12-7.23 (m, 1H), 4.16-4.27 (m, 1H), 4.14 (s, 3H), 1.22 (d, J=6.4 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([CH3:15])=[CH:13][N:14]=1)=[O:8].[H-].[Na+].Cl[CH2:22][C:23]1[N:24]=[CH:25][S:26][CH:27]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[C:7](/[N:9]=[C:10]1\[S:11][C:12]([CH3:15])=[CH:13][N:14]\1[CH2:22][C:23]1[N:24]=[CH:25][S:26][CH:27]=1)=[O:8]
Reactant: ClCc1cscn1
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C)s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C)cn1Cc1cscn1
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a solution of Example 79A (2.65 g, 9.4 mmol) in DMF (20 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 0.247 g, 10.3 mmol). The reaction mixture was stirred for 30 min. and then treated with commercially available 4-(chloromethyl)thiazole (1.25 g, 9.4 mmol). The resulting mixture was stirred at room temperature for 18 hr, poured into water (100 mL) and extracted with EtOAc (2×100 mL). The organics were washed with water, brine (2×100 mL), dried over MgSO4 and concentrated. The residue was purified by using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in hexanes) to afford the title compound (2.56 g, 72% yield). 1H NMR (300 MHz, DMSO-D6) δ ppm 2.28 (s, 3H), 3.77 (s, 3H), 5.50 (s, 2H), 7.10 (d, J=8.7 Hz, 1H), 7.31 (d, J=1.6 Hz, 1H), 7.38-7.52 (m, 2H), 7.63 (dd, J=14.5, 2.6 Hz, 1H), 9.09 (d, J=2.0 Hz, 1H). MS (DCI) m/z 398 (M+H)+; MS (DCI) m/z 380 (M+H)+. Anal. Calculated for C16H14ClN3O2S2: C, 50.59; H, 3.71; N, 11.06. Found: C, 50.57; H, 3.02; N, 11.03.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:9]#[CH:10].[Cl-:11].[Al+3].[Cl-].[Cl-]>>[Cl:11][CH:9]=[CH:10][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: [Cl-]
Reactant: C#C
Reactant: CCCCCC(=O)Cl
Agent: [Al+3]
Product: CCCCCC(=O)C=CCl
Yield: 94 %

Procedure:
This compound is prepared according to the procedure of Price and Pappalardo [C. C. Price and J. A. Pappalardo, Org. Syn., 32, 27 (1952)] from hexanoyl chloride, acetylene, and aluminum chloride in 94% yield, bp 51°-52° C. (0.1 mm); λ max 1680, 1595, 941 cm-1.
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH3:34][C:35]([O:38][C:39]([N:41]1[C@H:44]([C:45]([OH:47])=[O:46])[CH2:43][CH2:42]1)=[O:40])([CH3:37])[CH3:36].CCN(C(C)C)C(C)C.O[N:58]=[C:59]([NH2:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>C(Cl)Cl.O>[C:59](=[NH:58])([NH:66][O:46][C:45]([C@@H:44]1[CH2:43][CH2:42][N:41]1[C:39]([O:38][C:35]([CH3:34])([CH3:36])[CH3:37])=[O:40])=[O:47])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: NC(=NO)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)ONC(=N)c1ccccc1
Reaction time: 2 h

Procedure:
PyBOP (2.53 g, 4.85 mmol) was added to a 0° C. solution of Boc-L-azetidine-2-carboxylic acid (650 mg, 3.23 mmol) and DIPEA (1.66 mL, 9.69 mmol) in DCM (14 mL) and the rxn mixture was stirred at rt for 20 min, before N′-hydroxybenzimidamide (440 mg, 3.23 mmol) was added and stirring continued at rt for 2 h. To the rxn mixture was added H2O and the mixture extracted with DCM (2×). The combined org. extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to yield (S)-tert-butyl 2-((benzimidamidooxy)carbonyl)azetidine-1-carboxylate B-1-1 which was used further without purification.
Reaction SMILES: [CH:1]([C:4]([CH3:6])=[O:5])([CH3:3])[CH3:2].[C:7](=O)([O:11]CC)[O:8][CH2:9][CH3:10].[H-].[Na+].Cl>C1C=CC=CC=1.CO.CN(C)P(=O)(N(C)C)N(C)C>[CH2:9]([O:8][C:7](=[O:11])[CH2:6][C:4](=[O:5])[CH:1]([CH3:3])[CH3:2])[CH3:10]
Reactant: CC(=O)C(C)C
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CO
Product: CCOC(=O)CC(=O)C(C)C
Temperature: 30 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
10 g of methyl isopropyl ketone were added to a solution of 400 cc of benzene, 850 cc of diethyl carbonate, 200 cc of hexamethyl phosphoric acid triamide and 60 g of sodium hydride (80% in paraffin oil), and the reaction mixture was heated to 70° to 80° C. After the reaction had started, the reaction mixture was cooled to approximately 30° C, and a solution of 76 g of methyl isopropyl ketone in 200 cc of benzene was added dropwise over a period of 2 hours at that temperature. After the reaction mixture had stood overnight, methanol was carefully added to it with cooling, followed by acidification with aqueous hydrochloric acid. The reaction mixture was then treated as described in Example 1.1. The yield was 81% of 3-keto-4-methyl valeric acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:19])([C@@H:16]([OH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(OCC)(=O)C.ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:19])([C@@H:16]([O:18][S:28]([CH3:27])(=[O:30])=[O:29])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](O)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](OS(C)(=O)=O)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a mixture of ethyl acetate (2 ml) and dichloromethane (0.5 ml) was dissolved (2S,3S)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol (58 mg). To the solution were added, under ice-cooling, triethylamine (66 μl) and methanesulfonyl chloride (37 μl). The mixture was stirred for two hours at room temperature. To the reaction mixture was added ethyl acetate (30 ml), which was washed with water, dried (anhydrous magnesium sulfate) and concentrated to afford (2S,3S)-2-(2,4-difluorophenyl)-3-methanesulfonyloxy-1-(1H -1,2,4-triazol-1-yl)-2-butanol as an oily product . This product was dissolved in methanol (2 ml), to which was added, under ice-cooling, 28% sodium methyl ate (116 μl), and the mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added dichloromethane (30 ml), which was washed with water and dried (anhydrous magnesium sulfate), followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel chromatography (eluent: ethyl acetate-dichloromethane=4:1 ), followed by crystallization from hexane to afford (2S,3R)-2-(2,4-difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyl oxirane (42 mg) as colorless needles. m.p. 89°-90° C. [α]D23 =+7.8° (c=1.0 in MeOH)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]([CH:23]([CH3:25])[CH3:24])[CH3:22])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:26])[C:4]=1[CH2:27][CH2:28][C:29](O)=[O:30])[CH3:2].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:74]([NH:81][CH2:82][CH2:83][NH2:84])([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75]>CN(C=O)C>[C:77]([O:76][C:74](=[O:75])[NH:81][CH2:82][CH2:83][NH:84][C:29](=[O:30])[CH2:28][CH2:27][C:4]1[C:5]([CH3:26])=[CH:6][C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]([CH:23]([CH3:25])[CH3:24])[CH3:22])[CH:15]=3)[O:11][N:10]=2)=[CH:8][C:3]=1[CH2:1][CH3:2])([CH3:78])([CH3:79])[CH3:80]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(C)C(C)C)c3)n2)cc(C)c1CCC(=O)O
Reactant: CC(C)(C)OC(=O)NCCN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(C)C(C)C)c3)n2)cc(C)c1CCC(=O)NCCNC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a solution of 3-(2-ethyl-4-{5-[2-(isopropyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenyl)-propionic acid (41 mg, 0.097 mmol) and DIPEA (38 mg, 0.291 mmol) in DMF (3 mL) is added PyBOP (56 mg, 0.107 mmol) at 0° C. The mixture is stirred for 15 min at 0° C. before N-BOC-ethylenediamine (17 mg, 0.107 mmol) is added and stirring is continued for 1 h at 0° C. The reaction is quenched with 2 mL water, and the mixture is diluted in sat. aq. NaHCO3-solution, and extracted three times with diethyl ether. The combined org. extracts are dried over MgSO4, filtered and dried to give crude {2-[3-(2-ethyl-4-{5-[2-(isopropyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenyl)-propionylamino]-ethyl}-carbamic acid tert-butyl ester (44 mg). This material is dissolved in 4 N HCl in dioxane (5 mL) and the mixture is stirred at rt for 18 h. The solvent is evaporated and the crude product is purified on prep. TLC plates with DCM containing 6% of 7 N NH3 in methanol to give N-(2-amino-ethyl)-3-(2-ethyl-4-{5-[2-(isopropyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenyl)-propionamide (23 mg) as a yellow solid; LC-MS: tR=0.72 min; [M+1]+=465.32.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([N:18]2[CH:22]=[C:21]([C:23]([OH:25])=O)[N:20]=[N:19]2)[CH:14]=[C:15]([F:17])[CH:16]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:48][CH2:49][C:50]([N:52]1[CH2:57][CH2:56][CH:55]([O:58][C:59]2[CH:60]=[N:61][CH:62]=[C:63]([Cl:65])[CH:64]=2)[CH2:54][CH2:53]1)=[O:51]>CN(C=O)C.O>[Cl:65][C:63]1[CH:64]=[C:59]([O:58][CH:55]2[CH2:54][CH2:53][N:52]([C:50](=[O:51])[CH2:49][NH:48][C:23]([C:21]3[N:20]=[N:19][N:18]([C:13]4[CH:14]=[C:15]([F:17])[CH:16]=[C:11]([F:10])[CH:12]=4)[CH:22]=3)=[O:25])[CH2:57][CH2:56]2)[CH:60]=[N:61][CH:62]=1
Reactant: O=C(O)c1cn(-c2cc(F)cc(F)c2)nn1
Reactant: NCC(=O)N1CCC(Oc2cncc(Cl)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cncc(Cl)c2)CC1)c1cn(-c2cc(F)cc(F)c2)nn1
Reaction time: 0.03 h
Yield: 54.4 %

Procedure:
DIPEA (149.2 mg, 1.15 mmol) was added to a stirred solution of 1-(3,5-difluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid (65 mg, 0.28 mmol) in DMF (2 mL) followed by HOBt (43 mg, 0.31 mmol) and EDCI (110 mg, 0.57 mmol). After 2 minutes of stirring, 2-amino-1-[4-(5-chloro-pyridin-3-yloxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (88.4 mg, 0.28 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was added and the precipitate was collected. The crude solid was purified by recrystallisation from a mixture of DCM and hexane to afford 95 mg (54.4% Yield) of 1-(3,5-difluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid {2-[4-(5-chloro-pyridin-3-yloxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 477.12, 98.45%. 1H NMR (300 MHz, DMSO-d6): δ 9.5 (s, 1H), 8.5 (t, 1H), 8.3 (d, 1H), 8.2 (d, 1H), 7.9 (d, 2H), 7.75 (t, 1H), 7.58-7.5 (m, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 4.0-3.8 (m, 1H), 3.8-3.6 (m, 1H), 3.4 (m, 1H), 3.2 (m, 1H), 2.1-1.9 (m, 2H), 1.9-1.5 (m, 2H).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:9]([C:16]#[N:17])=[C:10]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:5]2=[N:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[C:8]1[C:9]([C:16]#[N:17])=[C:10]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:5]2[N:6]([C:2]([C:30]3[CH:29]=[N:28][C:27]([F:26])=[CH:32][CH:31]=3)=[CH:3][N:4]=2)[CH:7]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: CC(C)COc1c(C#N)c(-c2ccc(Cl)cc2Cl)cn2c(Br)cnc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)COc1c(C#N)c(-c2ccc(Cl)cc2Cl)cn2c(-c3ccc(F)nc3)cnc12
Temperature: 150 °C
Yield: 56 %

Procedure:
In a sealed tube, a mixture of 3-bromo-6-(2,4-dichloro-phenyl)-8-isobutoxy-imidazo[1,2-a]pyridine-7-carbonitrile (115 mg, 0.25 mmol), 2-fluoro-5-pyridine-boronic acid (38.4 mg, 0.27 mmol), PdCl2(PPh3)2 (8.7 mg, 0.01 mmol) and Na2CO3 (2.0 M solution in water, 0.43 mL) in DME (1 mL) was heated at 150° C. for 17 min in a microwave oven. The reaction mixture was cooled to RT, diluted in AcOEt (20 mL) and washed with water (2×10 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to dryness. The remaining residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, hexane/TBME 95:5→7:3) to yield the title compound (64 mg, 0.14 mmol, 56%) as a white solid. MS: 455 [M+1]+; HPLC: AtRet=3.14; TLC: RF 0.34 (hexane/TBME 1:1).