Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])/[CH:10]=[N:11]/[S@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:27][C:28]1[CH:33]=[C:32]([CH2:34]Br)[CH:31]=[CH:30][C:29]=1[F:36]>>[Br:27][C:28]1[CH:33]=[C:32]([CH2:34][C@H:10]([NH:11][S@:12]([C:14]([CH3:15])([CH3:16])[CH3:17])=[O:13])[C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22])[CH:31]=[CH:30][C:29]=1[F:36]
Reactant: Fc1ccc(CBr)cc1Br
Reactant: CC(C)(C)[S@](=O)/N=C/[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Product: CC(C)(C)[S@](=O)N[C@@H](Cc1ccc(F)c(Br)c1)[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C

Procedure:
The title compound was prepared from (S,E)-N—((S)-2,3-bis(tert-butyldimethylsilyloxy)propylidene)-2-methylpropane-2-sulfinamide and 2-bromo-4-(bromomethyl)-1-fluorobenzene using a method analogous to that described in Examples 509 and 510.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=3)[NH2:14])[O:10][C:3]=12.[O:18]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.[Cl-].[Na+].O>[O:18]([C:25]1[CH:26]=[CH:27][C:28]([O:31][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=4)[NH2:14])[O:10][C:3]=23)=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: Nc1cccc(-c2cc3nccc(Cl)c3o2)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cccc(-c2cc3nccc(Oc4ccc(Oc5ccccc5)cc4)c3o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
To a 10-mL microwave vial was added 3-(7-chlorofuro[3,2-b]pyridin-2-yl)aniline (88.20 mg; 0.36 mmol), 4-phenoxyphenol (100.68 mg; 0.54 mmol), and cesium carbonate (352.35 mg, 1.08 mmol). The reagents were suspended in DMF (5.00 ml) and run in the microwave reactor at 160° C. for 2 hours. The reaction mixture was cooled to room temperature. Water and brine were added to the reaction mixture which was then extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude mixture was purified using Biotage column chromatography (20-100% EtOAc/Hexanes) to afford the title compound as a white solid (111.70 mg, 79%). HPLC (method F): 91%, RT=3.949 min. MS: m/z=395 [M+H]+, RT=3.80 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11](=O)[NH:12][CH:13]([C:30]2[C:35]([Cl:36])=[N:34][CH:33]=[CH:32][N:31]=2)[C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:21]3)=[CH:16][CH:15]=2)[CH2:7][CH2:6]1)=[O:4].O=P(Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:31]3[CH:32]=[CH:33][N:34]=[C:35]([Cl:36])[C:30]3=[C:13]([C:14]3[CH:23]=[C:22]4[C:17]([CH:18]=[CH:19][C:20]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[N:21]4)=[CH:16][CH:15]=3)[N:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)NC(c2ccc3ccc(-c4ccccc4)nc3c2)c2nccnc2Cl)CC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@H](c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn32)CC1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
A CH2Cl2 solution (2 mL) of trans-4-{[(3-chloropyrazin-2-yl)-(2-phenyl-quinolin-7-yl)-methyl]-carbamoyl}-cyclohexanecarboxylic acid methyl ester (2.3 g, 4.5 mmol) in a round bottom flask equipped with a condenser was charged with POCl3 (15 mL) and stirred at 80° C. for 72 h. The reaction mixture was concentrated in vacuo to a foam, cooled to 0° C., and charged with cold 2M NH3 in isopropanol to basic pH. The mixture was concentrated in vacuo to solids and partitioned between EtOAc and water. The organic layer was washed with water (1×), brine (1×), dried over Na2SO4, filtered, and concentrated to a brown oil. The resulting residue was purified by silica gel chromatography (CH2Cl2 to 1%˜7N1NH3 in MeOH/CH2Cl2) to provide the desired product as a yellow solid; 1H NMR (CDCl3, 400 MHz) δ 1.62-1.73 (m, 2H), 1.92-2.02 (m, 2H), 2.15-2.27 (m, 4H), 2.44-2.60 (m, 1H), 2.99-3.08 (m, 1H), 3.72 (s, 3H), 7.39 (d, 1H, J=5.2 Hz), 7.45-7.50 (m, 1H), 7.51-7.57 (m, 2H), 7.61 (d, 1H, J=5.2 Hz), 7.85-7.93 (m, 3H), 8.19 (d, 2H, J=7.6 Hz), 8.27 (d, 1H, J=8.4 Hz), 8.50 (s, 1H); MS (ES+): m/z 496.9 [MH+]; HPLC: tR=3.6 min (Micromass Platform II, nonpolar—5 min).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[NH2:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=2)[CH2:20][CH2:19][N:18]=1>C1(C)C=CC=CC=1>[CH3:28][O:27][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[C:17]1=[N:16][CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11](=[O:13])[N:18]1[CH2:19][CH2:20]2
Reactant: COc1ccc2c(c1)CCN=C2N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc2n(c1=O)CCc1cc(OC)ccc1-2
Reaction time: 0.17 h
Yield: 69 %

Procedure:
Diethyl ethoxymethylenemalonate (10.72 g., 0.0496 mole) was added to a stirred mixture at 25° of 1-amino-3,4-dihydro-6-methoxyisoquinoline (8.75 g., 0.0496 mole) in toluene (330 ml.). Stirring was continued for 10 minutes after which the temperature of the resulting yellow solution was raised to the reflux point during ten minutes. The solution was refluxed for 5 minutes and cooled to give ethyl 6,7-dihydro-9-methoxy-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate, m.p. 158°-160° C. Successive recrystallizations from ethyl acetate and ethanol gave off-white flocculent needles: 10.3 g. (69% yield), m.p. 173°-175°.
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9](Br)=[C:8]4[CH:7]=[CH:6][C:5]3=[C:4](Br)[CH:3]=1.[CH3:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](B(O)O)=[CH:23][CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([C:2]2[C:15]3[C:16]4=[C:17]5[C:12](=[CH:13][CH:14]=3)[CH:11]=[CH:10][C:9]([C:24]3[C:25]6[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=6)[C:21]([CH3:20])=[CH:22][CH:23]=3)=[C:8]5[CH:7]=[CH:6][C:5]4=[C:4]([C:2]3[C:15]4[C:16](=[CH:17][CH:12]=[CH:13][CH:14]=4)[C:5]([CH3:6])=[CH:4][CH:3]=3)[CH:3]=2)=[CH:23][CH:22]=1
Reactant: Brc1ccc2ccc3c(Br)cc(Br)c4ccc1c2c34
Reactant: Cc1ccc(B(O)O)c2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3ccc4c(-c5ccc(C)c6ccccc56)cc(-c5ccc(C)c6ccccc56)c5ccc2c3c45)c2ccccc12
Temperature: 130 °C
Reaction time: 9 h
Yield: 133.9 %

Procedure:
A mixed solution of 2 g of 1,3,6-tribromopyrene, 3.4 g of 4-methyl-1-naphthaleneboronic acid, 5.8 g of tripotassium phosphate, 0.88 g of tetrabutylammonium bromide, 61 mg of palladium acetate and 140 ml of deaerated dimethylformamide was heated while stirred under nitrogen gas stream at a temperature of 130° C. for 9 hours. After cooling the mixed solution to room temperature, 500 ml of water was injected thereinto to extract therefrom with 200 ml of dichloromethane. The organic layer was washed twice with 100 ml of water, dried by magnesium sulfate and thereafter concentrated by evaporation. The organic layer was purified by silica gel column chromatography and vacuum dried under a temperature of 70° C. to obtain 1.9 g of 1,3,6-tri(4-methylnaphthalene-1-yl)pyrene as milky-white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[N:31]=[C:30]([C:32](O)=[O:33])[CH:29]=[CH:28][CH:27]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[Cl-].[NH4+]>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:32]([C:30]5[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:24])[F:35])[N:31]=5)=[O:33])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: O=C(O)c1cccc(C(F)(F)F)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1cccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (95 mg, 0.307 mmol) in N,N-dimethylformamide (5 mL) were added 6-(trifluoromethyl)pyridine-2-carboxylic acid (65 mg, 0.337 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (65 mg, 0.337 mmol) and 1-hydroxybenzotriazole (46 mg, 0.337 mmol), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate/diisopropyl ether to give the title compound (126 mg, 85%) as a white powder.
Reaction SMILES: [C:1]([NH:4][C:5]1[NH:6][CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[C:9]=1[C:10]([NH2:12])=[O:11])(=[O:3])[CH3:2].[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1>[C:1]([NH:4][C:5]1[NH:6][CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:28]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([Cl:27])[C:21]=3[Cl:20])(=[O:30])=[O:29])=[CH:15][CH:14]=2)[C:9]=1[C:10]([NH2:12])=[O:11])(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: CC(=O)Nc1[nH]cc(-c2ccc(N)cc2)c1C(N)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1[nH]cc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)cc2)c1C(N)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of 70 mg (0.271 mmol) of 2-acetylamino-4-(4-aminophenyl)-1H-pyrrole-3-carboxamide and 70 mg (0.285 mmol) of 2,3-dichlorobenzene-sulphonyl chloride in 1.5 cm3 of pyridine is stirred at room temperature for 24 hours and then the reaction medium is evaporated to dryness under reduced pressure. The crude product is purified by flash chromatography [eluent; dichloromethane/methanol (97/3 by volume)]. After concentrating under reduced pressure the fractions containing the expected product, 22 mg of 2-acetylamino-4-[4-(2,3-dichlorobenzenesulphonylamino)phenyl]-1H-pyrrole-3-carboxamide are obtained in the form of a beige solid melting at 265° C.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:10]([CH2:12][C:13]1([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[N:26][N:25]4[C:28]([C:31]5[CH:32]=[C:33]([NH:37][C:38]([NH:40][CH2:41][C:42]([F:45])([F:44])[F:43])=[O:39])[CH:34]=[CH:35][CH:36]=5)=[CH:29][N:30]=[C:24]4[CH:23]=3)[CH:19]=[N:18]2)[CH2:16][NH:15][CH2:14]1)#[N:11].C(N(CC)CC)C>CN(C)C=O.CO>[C:10]([CH2:12][C:13]1([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[N:26][N:25]4[C:28]([C:31]5[CH:32]=[C:33]([NH:37][C:38]([NH:40][CH2:41][C:42]([F:44])([F:45])[F:43])=[O:39])[CH:34]=[CH:35][CH:36]=5)=[CH:29][N:30]=[C:24]4[CH:23]=3)[CH:19]=[N:18]2)[CH2:14][N:15]([C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:8])[CH2:16]1)#[N:11]
Reactant: O=C(Cl)N1CCOCC1
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CN(C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Morpholine-4-carbonyl chloride (6.8 mg, 0.045 mmol) was added to a mixture of N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (15.0 mg, 0.0303 mmol) and triethylamine (13 μL, 0.093 mmol) in N,N-dimethylformamide (0.5 mL) and methanol (0.1 mL). The reaction mixture was stirred at r.t. for 2 h. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=609.2.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH:8]1([OH:12])[CH2:11][CH2:10][CH2:9]1.Cl[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]#[N:21]>O>[CH:8]1([O:12][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[C:20]#[N:21])[CH2:11][CH2:10][CH2:9]1
Reactant: OC1CCC1
Reactant: N#Cc1ccncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccncc1OC1CCC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 92.6 %

Procedure:
A mixture of mineral oil free NaH (0.86 g, 21.4 mmol) and DMF (15 ml) was cooled in an ice-bath and cyclobutanol (1.6 ml, 20.5 mmol) was added in one portion. The mixture was slowly warmed to room temperature and was stirred for 45 minutes. The mixture was once again cooled in an ice-bath and 3-chloro-4-cyanopyridine (2.6 g, 18.6 mmol) was added in one portion. The mixture was warmed to room temperature and was stirred for 3 hours. Water (10 ml) was added and the solvent was removed in vacuo. Water (225 ml) was added to the residue and the mixture was extracted with ether (3×100 mL). The combined organic layers were dried over anhydrous MgSO4, treated with charcoal and removed in vacuo to afford 3.0 g (95%) of 3-cyclobutyloxy-4-cyanopyridine as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:10]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=3)=[N:14][N:15]=2)=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O)[CH3:2].[NH:30]1[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH2:31]1.CC(O)=O>C(O)C>[CH2:1]([C:3]1[C:10]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[C:18]([C:26]([F:28])([F:29])[F:27])[CH:17]=3)=[N:14][N:15]=2)=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][N:30]1[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH2:31]1)[CH3:2]
Reactant: CCc1c(C=O)cccc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(Cc2cccc(-c3nnc(-c4ccc(OC(C)C)c(C(F)(F)F)c4)s3)c2CC)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
To a solution of 2-ethyl-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}benzaldehyde (D6) (54 mg) and ethyl 4-piperidinecarboxylate (101 mg) in ethanol (10 mL) stirred at room temperature was added AcOH (0.037 mL). The reaction mixture was stirred at room temperature for 10 min. Then the solvent was removed by evaporation. To the residue was added dichloromethane (DCM) (10 mL) and sodium triacetoxyborohydride (82 mg). Stirring continued for 2 h. Water was added to quench the reaction, and DCM was removed by evaporation. The mixture was extracted by EA for 3 times. The combined organic phases were washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated to afford the crude product ethyl 1-[(2-ethyl-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}phenyl)methyl]-4-piperidinecarboxylate (D7) (72.1 mg). MS (ES): C29H34F3N3O3S requires 561. found 562.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:10]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:19](O)=[O:20].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:51][CH2:52][C:53]1[C:54]([OH:61])=[N:55][C:56]([CH3:60])=[CH:57][C:58]=1[CH3:59]>ClCCl.O>[OH:61][C:54]1[C:53]([CH2:52][NH:51][C:19]([C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]([CH:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH3:12])[C:2]=2[CH3:1])=[O:20])=[C:58]([CH3:59])[CH:57]=[C:56]([CH3:60])[N:55]=1
Reactant: Cc1c(C(=O)O)c2cccnc2n1C(C)c1ccccc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2c(C)n(C(C)c3ccccc3)c3ncccc23)c(O)n1
Yield: 67.5 %

Procedure:
To a solution of 2-methyl-1-(1-phenylethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (400 mg, 1.43 mmol) in dichloromethane (30 mL) were added 1-hydroxybenzotriazole (291 mg, 2.15 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (412 mg, 2.15 mmol) and triethylamine (434 mg, 4.30 mmol). The resultant mixture was stirred at room temperature for 30 minutes. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (262 mg, 1.72 mmol) was added and the resultant mixture was stirred at room temperature for 16 hours. Water (50 mL) was added to the mixture. The mixture was extracted with dichloromethane (100 mL×2). The organic layer was concentrated in vacuo to provide crude product which was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to afford N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-1-(1-phenylethyl)-1H-pyrrolo-[2,3-b]pyridine-3-carboxamide (400 mg, 67.6%) as a white solid. LRMS (M+H+) m/z: calcd 414.21. found 414. HPLC purity (214 nm): 94%. 1H NMR (300 MHz, CD3OD): δ 8.22-8.13 (m, 2H), 7.28-7.15 (m, 6H), 6.47-6.45 (m, 1H), 6.09 (s, 1H), 4.50 (s, 2H), 2.42 (s, 3H), 2.39 (s, 3H), 2.23 (s, 3H), 2.02 (d, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([NH:21][CH3:22])[CH2:17][CH2:16]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:16][CH2:17][CH:18]([N:21]([CH3:22])[S:39]([CH3:38])(=[O:41])=[O:40])[CH2:19][CH2:20]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[CH:8]=2)=[CH:29][CH:30]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1)S(C)(=O)=O
Reaction time: 0.17 h

Procedure:
To a solution of 1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}-N-methylpiperidin-4-amine (150 mg, 0.37 mmol) in DCM (3 mL) at room temperature was added triethylamine (56 μL, 0.40 mmol) followed by methanesulfonyl chloride (29 μL, 0.37 mmol) and the solution stirred for 10 minutes. The solution was then loaded directly onto a pre-wetted Biotage 25M column for flash chromatography and eluted with 2-8% MeOH/DCM to yield the title compound as a white solid, 137 mg, 76%. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.47-8.56 (2 H, m), 7.61-7.68 (2 H, m), 7.23-7.35 (2 H, m), 7.03-7.19 (2 H, m), 6.52 (1 H, s), 5.10-5.29 (2 H, m), 4.37 (1 H, d, J=13.39 Hz), 3.90-3.99 (3 H, m), 3.74-3.89 (1 H, m), 3.06-3.19 (1 H, m), 2.93 (3 H, s), 2.68 (3 H, s), 2.58-2.65 (1 H, m), 1.62-1.77 (3 H, m), 1.42-1.59 (1 H, m); m/z (APCI+) for C24H28N5O3FS 486.2 (M+H)+.
Reaction SMILES: Cl.[C:2]1([CH:8]([CH3:11])[CH2:9][NH2:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:19][CH:20]([S:22](Cl)(=[O:24])=[O:23])[CH3:21]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:2]1([CH:8]([CH3:11])[CH2:9][NH:10][S:22]([CH:20]([CH3:21])[CH3:19])(=[O:24])=[O:23])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CN)c1ccccc1
Reactant: CC(C)S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CNS(=O)(=O)C(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.7 %

Procedure:
To a solution of 2-phenyl-propylamine HCl salt (1.0 g, 5.8 mmol), DMAP (35 mg, 0.3 mmol) and Et3N (1.77 g, 17.5 mmol) in DCM (25 mL) was added propane-2-sulfonyl chloride (1.25 g, 8.7 mmol) dropwise at 0° C. The mixture was stirred at r.t. for 16 h, and was then concentrated under vacuum. The residue was partitioned between EtOAc (100 mL) and H2O (10 mL). The organic layer was separated and washed with brine (10 mL), dried over anhydrous Na2SO4, filtrated and concentrated to give an oil residue. This residue was purified with silica gel column (Hexane/EtOAc=2/1 to 1/1) to obtain the desired product (1.2 g, 86%) as a pale yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.30-7.32 (m, 2H), 7.18-7.24 (m, 3H), 3.90-3.94 (m, 1H), 3.30-3.35 (m, 1H), 3.18-3.22 (m, 1H), 2.99-3.04 (m, 1H), 2.91-2.95 (m, 1H), 1.27 (d, 3H, J=7.2 Hz), 1.25 (d, H, J=7.8 Hz), 1.22 (d, 1H, J=7.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].Cl.C1C(O)=CC=CC=1C.[N:19]#[C:20][NH2:21].[OH-].[Na+]>CCOCC>[ClH:1].[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH:4][C:20]([NH2:21])=[NH:19]
Reactant: N#CN
Reactant: Nc1c(Cl)cccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: Cc1cccc(O)c1
Product: N=C(N)Nc1c(Cl)cccc1Cl

Procedure:
To 51 g (0.315 mole) of 2,6-dichloroaniline is added 0.4 moles of ethereal HCl and 200 l of m-cresol. The mixture is then stirred and heated on a steam bath to drive off the ether and excess hydrogen chloride. To the resultant mixture is then added 13.3 g (0.315 mole) of cyanamide then heated for 2 hours on a steam bath. The reaction mixture is then cooled, added to 150 ml of conc. sodium hydroxide solution, cooled and extracted with 2 liters of ether. The ether layer is washed with 2×1 liter of water, dried over sodium sulfate, charcoaled and evaporated. The residue is triturated with hexane and the precipitate is filtered off and washed with ether and dried to obtain 2,6-dichlorophenylguanidine hydrochloride.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH:3]([CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH2:11]1)[CH2:4]/[C:5](=[N:7]/[OH:8])/[NH2:6].CCN(C(C)C)C(C)C.[F:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1>C(Cl)Cl>[F:37][C:38]1[CH:46]=[CH:45][C:41]([C:42]([NH:6]/[C:5](=[N:7]\[OH:8])/[CH2:4][CH:3]([CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=3)[CH2:11]2)[C:2]([F:1])([F:26])[F:27])=[O:43])=[CH:40][CH:39]=1
Reactant: N/C(CC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F)=N\O
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N/C(CC(CN1CCCC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F)=N\O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
In a 10 mL round-bottomed flask, (Z)-4,4,4-trifluoro-N′-hydroxy-3-((3-(3-(trifluoromethyl)phenyl)-piperidin-1-yl)methyl)butanimidamide (120 mg, 302 μmol) and DIEA (117 mg, 158 μl, 906 μmol) were combined with CH2Cl2 (2.00 ml) to give a colorless solution. 4-Fluorobenzoyl chloride (47.9 mg, 302 μmol) in CH2Cl2 (1 ml) was added drop-wise and the resulting mixture was stirred at room temperature overnight. The crude reaction mixture was concentrated in vacuo to afford 120 mg (38%) of (Z)-4-fluoro-N-(4,4,4-trifluoro-1-(hydroxyimino)-3-((3-(3-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)butyl)benzamide and used as is. MH+=520.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([Br:11])=[CH:6][C:3]=1[CH2:4]Br.CC[N:14](CC)CC>N.CO.C(Cl)Cl>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([Br:11])=[CH:6][C:3]=1[CH2:4][NH2:14]
Reactant: CCN(CC)CC
Reactant: Fc1cc(Br)c(CBr)cc1Br
Agent: N
Solvent: ClCCl
Solvent: CO
Product: NCc1cc(Br)c(F)cc1Br

Procedure:
A solution of 2,5-dibromo-4-fluorobenzyl bromide (0.350 g, 1 mmol) in 7M NH3/MeOH was heated in a sealed tube at 100° C. for 2 h. The reaction mixture was cooled and concentrated to give a white solid which was dissolved in CH2Cl2 and treated with Et3N (1 mL) then concentrated. The resulting residue was triturated with ethyl acetate (25 mL), filtered and concentrated to give the title compound (0.291 g) as a pale yellow oil. HRMS (M+H) calcd for C7H7Br2FN: 283.94; found: 283.93.