Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[N-:11]=[N+:12]=[N-:13].[Na+].O>CS(C)=O.[N-]=[N+]=[N-].[Na+]>[N:11]([CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4])=[N+:12]=[N-:13]
Reactant: O[C@H](CCl)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NC[C@@H](O)c1ccccc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 96.8 %

Procedure:
(S)-α-(Chloromethyl)benzenemethanol (2.38 g) in dry DMSO (50 ml) was treated with sodium azide (1.48 g) with stirring then heated at 60° C. for 24 h. More sodium azide (74 mg) was added and heating continued at 80° C. for a further 24 h. The reaction mixture was cooled, poured into water and extracted into ethyl acetate, which was washed with water (3×) then brine and dried (MgSO4). The solvent was evaporated to give the sub-title compound (2.40 g) as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].Cl[C:8]1[N:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1.C(Cl)Cl.CO>CS(C)=O>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:11]2[N:10]=[N:9][C:8]([N:1]3[CH2:5][CH2:4][NH:3][C:2]3=[O:6])=[CH:13][CH:12]=2)=[CH:15][CH:16]=1)#[N:21]
Reactant: N#Cc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: O=C1NCCN1
Solvent: CS(C)=O
Solvent: CO
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccc(N3CCNC3=O)nn2)cc1

Procedure:
Prepared from imidazolidin-2-one and 3-chloro-6-(4-cyano-phenyl)-pyridazine in dimethylsulphoxide Rf value: 0.30 (silica gel; methylene chloride/methanol=19:1)
Reaction SMILES: [CH:1]12[CH:16]=[CH:15][CH:5]([O:6][N:7]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3][CH2:2]2.[H][H]>[Ni]>[OH:6][C@@H:5]1[CH2:4][CH2:3][CH2:2][C@H:1]([NH:7][C:8](=[O:9])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1OC2C=CC1CCC2
Reactant: [H][H]
Agent: [Ni]
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H](O)CC1

Procedure:
A Parr bottle was charged with Raney Nickel (ca. 1 g). The catalyst was washed with ethanol and suspended in ethanol (30 mL). The starting material, 23A (1.0 g, 4.44 mmol) was added and the reaction pressurized with hydrogen. After hours, TLC analysis suggests good conversion to desired product. The reaction was flushed with nitrogen and filtered through a pad of magnesium sulfate. The filter cake was rinsed well with ethanol. The ethanol solution was evaporated. The isolated material was dissolved in tetrahydrofuran to give a cloudy solution. The liquid was passed through a PTFE filter and then evaporated. The crude product was crystallized from ether-hexanes. The crystalline material was filtered off and rinsed with hexanes. Residual solvent was removed under vacuum to give 23B (780 mg, 3.40 mmol, 77% yield) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.76 (d, 1H, J=7.6 Hz); 4.36 (d, 1H, J=4.0 Hz); 3.51-3.73 (m, 1H); 3.37 (br. s, 1H); 1.69-1.91 (m, 2H); 1.45-1.66 (m, 5H); 1.37 (s, 9H); 1.06-1.34 (m, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][NH:9][CH2:10][CH2:11][NH:12][CH3:13].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH3:8][N:9]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH2:10][CH2:11][NH:12][CH3:13]
Reactant: CNCCNC
Reactant: Fc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CNCCN(C)c1ccccn1
Yield: 98 %

Procedure:
A mixture of 2-fluoropyridine (0.485 g, 5 mmol), N,N′-dimethyl-1,2-ethanediamine (1.32 g, 15 mmol) and sodium carbonate (1.59 g, 15 mmol) in 1,4-dioxane (5 mL) was heated under reflux overnight. The mixture was filtered and the filtrate was concentrated. The residue was co-evaporated with 1,4-dioxane (×2), and then dried to give the desired product (810 mg, 98%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CN(C=O)C.C(N(C(C)C)C(C)C)C.[NH2:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27]([NH:29][CH3:30])=[O:28]>O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:23][C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=2)[C:27]([NH:29][CH3:30])=[O:28])[N:7]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: CNC(=O)c1cccc(N)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cccc(Nc2ncnc(Cl)n2)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 19.5 %

Procedure:
2,4-Dichloro-1,3,5-triazine (6.99 g, 46.6 mmol) was dissolved in DMF (56.5 mL, 46.6 mmol) and the solution was cooled to 0° C. To this solution was added N-ethyl-N-isopropylpropan-2-amine (8.93 mL, 51.3 mmol) followed by the portionwise addition of 3-amino-N-methylbenzamide (7.00 g, 46.6 mmol). The resulting reaction mixture was allowed to slowly warm to room temperature and stirred for 4 hours. Water (about 800 mL) was added to the reaction mixture. A small amount of solid precipitated out of the solution at which point 100 mL of CH2Cl2 was added. The product was filtered off through a coarse Buchner funnel with the aid of water. After drying under vacuum, batch #1 of 3-(4-chloro-1,3,5-triazin-2-ylamino)-N-methylbenzamide was obtained (7.15 g, 58% yield) as a yellow solid. The filtrate was extracted with CH2Cl2 (3×100 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated, providing an additional batch of material (2.4 g, 20%) as yellow solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[S:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=O)=O.CN(C)C=O.[N-:32]=[N+:33]=[N-:34].[Na+]>O>[N:32]([CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[S:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N+:33]=[N-:34]
Reactant: CCOC(=O)CSC(CCCCOS(C)(=O)=O)CCCc1cccnc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CSC(CCCCN=[N+]=[N-])CCCc1cccnc1

Procedure:
A mixture of 0.12 g (0.3 mmol) ethyl 8-methylsulfonyloxy-4-[3-(3-pyridyl)propyl]-3-thia-octanoate, 1,5 ml dimethylformamide and 0.062 g (0.95 mmol) sodium azide is heated at 60° for 18 h. The mixture is then poured into water and extracted with ether. The organic phase is washed with water, saturated brine, dried, filtered and evaporated to give ethyl 8-azido-4-[3-(3-pyridyl)propyl]-3-thia-octanoate; IR (CH2Cl2): 2099, 1732 cm-1.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]2[O:19][C:13]3=[C:14]([NH2:18])[N:15]=[CH:16][CH:17]=[C:12]3[CH:11]=2)[N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=12.C1C(=O)N([I:27])C(=O)C1.O>CN(C=O)C>[N:1]1[CH:2]=[C:3]([C:10]2[O:19][C:13]3=[C:14]([NH2:18])[N:15]=[CH:16][C:17]([I:27])=[C:12]3[CH:11]=2)[N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=12
Reactant: Nc1nccc2cc(-c3cnc4cnccn34)oc12
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc(I)c2cc(-c3cnc4cnccn34)oc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.3 %

Procedure:
2-(Imidazo[1,2-a]pyrazin-3-yl)furo[2,3-c]pyridin-7-amine (0.018 g, 0.072 mmol) was dissolved in DMF (1 mL). NIS (0.024 g, 0.11 mmol) was added and the mixture was brought to 40° C. After 4 h, the reaction was cooled to room temperature. Water was added and the resulting solid was filtered off. The solid was dissolved in 2:1 methanol:DCM (−30 mL). To this solution was added aqueous sodium thiosulfate (0.5 mL) and the mixture was then concentrated. Purification by ISCO chromatography (0 to 20% methanol:DCM) afforded 0.018 g (67%) of the title compound as an off-white solid. 1H NMR (400 MHz, CD3OD): δ 9.21 (dd, J=1.4, 4.7 Hz, 1 H), 9.17 (d, J=1.5 Hz, 1 H), 8.50 (s, 1 H), 8.14 (d, J=4.8 Hz, 1 H), 7.97 (s, 1 H), 7.27 (s, 1 H); MS (ESI): 378.14 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:14][N:15]([CH3:17])[CH3:16])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH2:18]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)[CH2:19][CH2:20][CH2:21][CH3:22]>>[CH3:17][N:15]([CH3:16])[CH2:14][C@H:2]([NH:1][S:29]([C:26]1[CH:27]=[CH:28][C:23]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:24][CH:25]=1)(=[O:31])=[O:30])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: CCCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Product: CCCCCc1ccc(S(=O)(=O)N[C@H](CC(=O)OCc2ccccc2)CN(C)C)cc1
Yield: 25 %

Procedure:
According to the method described in example S20a, (R)-benzyl 3-amino-4-(dimethylamino)butanoate (27 mg, 0.086 mmol) was reacted with 4-pentylbenzene-1-sulfonyl chloride to yield the title compound as a white solid (9 mg, 25%). MS ESI 447.3 [M+H]+, calcd for [C24H34N2O4S+H]+ 447.22
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][CH:22]([CH3:32])[CH2:23][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[NH2:25]>>[CH3:21][CH:22]([CH3:32])[CH2:23][CH:24]([NH:25][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: CC(C)CC(N)c1ccccn1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: CC(C)CC(NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)c1ccccn1

Procedure:
In analogy to the procedure described in Example 293, 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (Example 69 b) and 3-methyl-1-(pyridin-2-yl)butan-1-amine (CAN 825647-69-6) were condensed to the title product. MS (EI): m/e=431.4 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O.C(OCC)(=O)C>ClCCl>[NH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C#N)cc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(CCN)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.90 g commercially available [2-(4-Cyano-phenyl)-ethyl]-carbamic acid tert-butyl ester were dissolved in 100 ml dichloromethane. 10 ml trifluoroacetic acid were added and the reaction mixture was stirred at room temperature for one hour. 250 ml ethyl acetate were added and the mixture was washed three times with saturated NaHCO3 solution. The organic layer was dried over MgSO4 and then the solvent was removed in vacuo to obtain 700 mg 4-(2-Amino-ethyl)-benzonitrile as pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2.[N+:17]([O-])([OH:19])=[O:18]>>[Cl:12][C:11]1[C:10]([N+:17]([O-:19])=[O:18])=[C:9]2[C:4](=[CH:3][C:2]=1[Cl:1])[N:5]=[C:6]([O:15][CH3:16])[C:7]([O:13][CH3:14])=[N:8]2
Reactant: COc1nc2cc(Cl)c(Cl)cc2nc1OC
Reactant: O=[N+]([O-])O
Product: COc1nc2cc(Cl)c(Cl)c([N+](=O)[O-])c2nc1OC
Temperature: 10 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
6,7-Dichloro-2,3-dimethoxyquinoxaline (25 g, 0.096 mol) was added, portionwise, to fuming nitric acid (0.113 L) which had been pre-cooled to −5° C. The solution was allowed to warm to 10° C. and stirring continued for 2 hours. The solution was then poured into an ice/water mixture (0.5 L). The slurry was filtered and the solid was washed with water and isopropanol (0.05 L) to give 6,7-dichloro-2,3-dimethoxy-5-nitroquinoxaline(27 g, 92%) as a beige solid. m.p. 184-186° C.
Reaction SMILES: [CH2:1]([C:12]1[O:13][CH2:14][CH2:15][N:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]C.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18]>C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH2:17]([N:19]([CH2:20][CH3:21])[CH2:14][CH2:15][NH:16][C:12](=[O:13])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:18]
Reactant: CCCCCCCCCCCC1=NCCO1
Reactant: CCNCC
Agent: CC(=O)[O-]
Agent: [Zn+2]
Product: CCCCCCCCCCC(=O)NCCN(CC)CC
Yield: 87 %

Procedure:
Undecyloxazoline (53 mmoles), diethylamine (104 mmoles) and 0.9 mmole of zinc acetate are reacted under conditions similar to Example 2 to yield 87 percent of theoretical N-(2-diethylaminoethyl)undecylamide.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]([C:14]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15]2)=[CH:4][C:3]=1Br.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.[F-].[Cs+].CCOC(C)=O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:1][C:2]1[C:3]([C:29]2[CH:30]=[CH:31][C:26]([C:25]([F:36])([F:35])[F:24])=[CH:27][CH:28]=2)=[CH:4][C:5]([C:14]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15]2)=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C1(c2cc(Br)c(N)c(OCC(F)(F)F)c2)CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C1(c2cc(OCC(F)(F)F)c(N)c(-c3ccc(C(F)(F)F)cc3)c2)CCC1
Yield: 73.1 %

Procedure:
A mixture of ethyl 1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (0.32 g, 0.86 mmol), 4-trifluoromethylphenylboronic acid (0.246 g, 1.3 mmol), CsF (0.262 g, 1.7 mmol) and Pd (PPh3)4 (0.1 g, 0.08 mmol) in 10 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 25 mL of EtOAc and 75 mL of water were added. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 1-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate (0.290 g) as a yellow oil.
Reaction SMILES: C1(C[N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:9]2)C=CC=CC=1.[H][H]>[Pd].CO>[F:19][C:16]([F:17])([F:18])[CH2:15][NH:14][CH2:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: [H][H]
Reactant: FC(F)(F)CNCC1CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: FC(F)(F)CNCC1CCNC1
Yield: 53.2 %

Procedure:
A mixture of 7.15 g (26.3 mmole) 1-(phenylmethyl)-N-(2,2,2-trifluoroethyl)-3-pyrrolidinemethanamine 100 ml of methanol and 0.7 g of 20% palladium on carbon was shaken in an atmosphere of hydrogen at about 4.5×105Pa and at room temperature for 24 hours. The catalyst was filtered and the filtrate evaporated under reduced pressure. The residue was distilled under vacuum (63°-65° C., 2.8 mm Hg) to give 2.55 g of N-(2,2,2-trifluoroethyl)-3-pyrrolidinemethanamine.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([CH3:27])[C:25]=1[OH:26])[CH:21]=O>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14](=[O:16])[CH:15]=[CH:21][C:20]2[CH:23]=[C:24]([CH3:27])[C:25]([OH:26])=[C:18]([CH3:17])[CH:19]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Oc2ccccc2)cc1
Reactant: Cc1cc(C=O)cc(C)c1O
Product: Cc1cc(C=CC(=O)c2ccc(Oc3ccccc3)cc2)cc(C)c1O

Procedure:
This compound was synthesized from 4′-phenoxyacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde according to general method 1 described earlier.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11].[CH2:12](Cl)[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14]>CC#N>[CH3:1][C:2]1[N:10]=[C:5]2[N:6]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:14])[CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11]
Reactant: O=C(CCl)c1ccccc1
Reactant: Cc1[nH]c2ncccc2c1C
Solvent: CC#N
Product: Cc1nc2n(CC(=O)c3ccccc3)cccc-2c1C

Procedure:
A solution of 2,3-dimethylpyrrolo[2,3-b]pyridine (146 mg, 1 mmol) and phenacyl chloride (170 mg, 1.1 mmol) in 3 ml CH3CN was refluxed for 4.5 h. The mixture was allowed to cool and the precipitated product filtered off and washed with a small volume of ice cold CCl4 affording 207 mg (69%) pure title compound as the hydrochloride salt.
Reaction SMILES: [C:1]([O:7][C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[CH:23]=3)=[CH:15][CH:14]=2)[O:10][N:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]>C(OCC)(=O)C.[C].[Pd]>[C:1]([O:7][C:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=3)=[CH:17][CH:18]=2)[O:10][N:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Oc1cc(-c2ccc(OCCc3cccc([N+](=O)[O-])c3)cc2)on1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)Oc1cc(-c2ccc(OCCc3cccc(N)c3)cc2)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(4-(2-(3-nitrophenyl)ethoxy)phenyl)-3-isoxazolyl pivalate (100 mg) in ethyl acetate (5 ml), 13 mg of 10% palladium-carbon catalyst was added, and the reaction solution was stirred at room temperature for 1 hour under hydrogen atmosphere. The catalyst was filtered off through Celite, then the filtrate was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (0:100-25:75-30:70)) to afford the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C:18](=[O:20])[CH3:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(OCC)(=O)C.O.CO[CH:30](OC)[N:31]([CH3:33])[CH3:32]>>[CH3:30][N:31]([CH3:33])/[CH:32]=[CH:19]/[C:18]([C:8]1[N:4]2[CH:5]=[CH:6][CH:7]=[C:2]([N:1]=[CH:3][N:4]([CH3:8])[CH3:5])[C:3]2=[N:10][C:9]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:20]
Reactant: CC(=O)c1c(-c2ccc(F)cc2)nc2c(N)cccn12
Reactant: COC(OC)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)C=Nc1cccn2c(C(=O)/C=C/N(C)C)c(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of 1-[8-amino-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl]ethanone (150 mg, 0.56 mmol) in N,N-dimethylformamide dimethyl acetal (5 mL) was heated at reflux for 6 days. The mixture was cooled to room temperature, ethyl acetate and water were added. The phases were separated and the organic layer was washed with brine. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by silica gel chromatography (1:1 acetone:ethyl acetate) gave 130 mg (62%) of N′-[3-[(2E)-3-(dimethylamino)-2-propenoyl]-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-8-yl]-N,N-dimethylimidoformamide as a foam. 1H NMR (CDCl3): δ 9.28 (d, 1H), 8.53 (s, 1H), 7.76 (q, 2H), 7.62 (d, 1H), 7.13 (t, 2H), 6.87 (m, 2H), 5.12 (d, 1H), 2.4–3.3 (m, 12H); MS m/z 380 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:10]Cl)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[N:7]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[NH:20][CH:21]=[CH:22][N:23]=2)[N:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH2:10][N:23]2[CH:22]=[CH:21][N:20]=[C:19]2[C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[N:14]=2)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[N:7]=1
Reactant: COc1cnc(CCl)c(Cl)n1
Reactant: Fc1cccc(-c2ncc[nH]2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cnc(Cn2ccnc2-c2cccc(F)n2)c(Cl)n1
Temperature: 45 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
A mixture of 3-chloro-2-chloromethyl-5-methoxy-pyrazine (350 mg, 1.81 mmol), 2-fluoro-6-(1H-imidazol-2-yl)-pyridine (266 mg, 1.63 mmol) and K2CO3 (750 mg, 5.43 mmol) in DMF (10 mL) is stirred at 45° C. for 16 hours. On cooling, the reaction is quenched with saturated NH4Cl (3 mL) and extracted with DCM (3×20 mL). The combined organic layers are dried and solvent removed. PTLC (silica gel) separation (10% MeOH in DCM) gives 370 mg of 3-chloro-2-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-methoxy-pyrazine as an oil. 1H NMR (CDCl3) 8.08–8.14 (m, 1H), 7.98(s, 1H), 7.81 (dd, 1H), 7.20 (s, 1H), 7.07 (s, 1H), 6.80 (dd, 1H), 6.02 (s, 2H), 3.98 (s, 3H) F. Synthesis of 2-[2-(6-Fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-methoxy-3-pyridin-2-yl-pyrazine (Compound 7)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([C:24]4[N:25]=[N:26][N:27]([CH:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH:28]=4)[CH:23]=[C:18]3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH2:35])[CH:10]=1.N1C=CC=CC=1.[CH2:42]([S:44](Cl)(=[O:46])=[O:45])[CH3:43]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([C:24]4[N:25]=[N:26][N:27]([CH:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[CH:28]=4)[CH:23]=[C:18]3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:35][S:44]([CH2:42][CH3:43])(=[O:46])=[O:45])[CH:10]=1
Reactant: Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(C5CCOCC5)nn4)cnc32)c1
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(C5CCOCC5)nn4)cnc32)c1
Yield: 42 %

Procedure:
To a solution of 2′,4′-difluoro-5-(6-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-[1,1′-biphenyl]-3-amine (65 mg, 0.136 mmol) in DCM was added pyridine (21 mg, 2.72 mmol, 2.0 eq.) followed by ethanesulfonyl chloride (21 mg, 0.164 mmol, 1.2 eq.). After completion of the reaction the solvent was distilled off and the crude product was purified by preparative HPLC to give the product in 42% yield (30 mg). 1H NMR (300 MHz, DMSO): δ 10.4 (s, 1H) 9.04 (s, 1H), 8.99-8.98 (d, 1H), 8.90 (d, 1H), 8.63-8.61 (d, 1H) 7.95 (d, 1H), 7.76-7.70 (m, 2H), 7.49 (m, 2H), 7.35 (d, 1H), 4.82 (m, 1H), 3.95 (d, 2H), 3.58-3.55 (t, 2H), 3.36-3.28 (m, 2H), 2.12 (m, 2H), 1.29-1.24 (t, 3H), 1.08-1.06 (t, 2H); LC-MS (ESI): Calculated mass: 565.5; Observed mass: 565.9 [M+H]+ (rt: 1.44 min).
Reaction SMILES: [CH2:1]([NH:5][CH3:6])[CH2:2][CH2:3][CH3:4].[Br:7][CH2:8][C:9](Br)=[O:10]>CCOCC.O>[Br:7][CH2:8][C:9]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH3:6])=[O:10]
Reactant: CCCCNC
Reactant: O=C(Br)CBr
Solvent: CCOCC
Solvent: O
Product: CCCCN(C)C(=O)CBr
Reaction time: 0.5 h

Procedure:
26 g of butylmethylamine in solution in 120 ml of ether were added to a solution, cooled down to −20° C., of 11.9 ml of bromo-acetyl bromide in 180 ml of ether. The temperature was returned to 20° C. and the mixture was stirred for 30 minutes, diluted with water and extracted with ether. The extracts were evaporated to dryness under reduced pressure. The 27.4 g of residue were distilled under reduced pressure (0.05 mbar) at 79° C. to 83° C. to obtain 19.36 g of the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([NH2:25])=[O:24])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[C:9]([C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16])[CH:8]=3.[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[F:33].C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:26][C:27]1[CH:28]=[C:29]([C:2]2[CH:3]=[C:4]([C:23]([NH2:25])=[O:24])[C:5]3[NH:6][C:7]4[C:12]([C:13]=3[CH:14]=2)=[CH:11][CH:10]=[C:9]([C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[CH:8]=4)[CH:30]=[CH:31][C:32]=1[F:33]
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1cc(-c2ccc(F)c(Cl)c2)cc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Temperature: 160 °C
Yield: 17.7 %

Procedure:
3-Bromo-7-(morpholine-4-carbonyl)-9H-carbazole-1-carboxamide (33 mg, 0.075 mmol, Example 144A) was dissolved in MeOH (0.6 mL) and added into a microwave vial containing 3-chloro-4-fluorophenylboronic acid (55.7 mg, 0.32 mmol), followed by addition of Na2CO3 (0.12 mL of a 2M aq. solution) and PdCl2(dppf)-CH2Cl2 (6.12 mg, 7.50 μmol) and Toluene (1.2 mL). The vial was sealed and heated in a BIOTAGE® microwave reactor for 15 minutes at 160° C. The reaction mixture was evaporated to dryness, dissolved in DMF+isopropanol and purified by preparative HPLC. Product containing fractions were combined and evaporated to dryness to give 6.0 mg 3-(3-chloro-4-fluorophenyl)-7-(morpholine-4-carbonyl)-9H-carbazole-1-carboxamide. HPLC retention time 4.72 min. (SUPELCO® Ascentis Express 4.6×50 mm 2.7 um C18, 2 ml/min, 0 to 100% B in 8 minutes, then 100% B for 1 minute. Solvent A: 5% CH3CN—95% H2O—10 mM NH4OAc; Solvent B: 95% CH3CN—5% H2O—10 mM NH4OAc). MS (ESI) m/e+=452 [M+H]+.