Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([N:17]1[C:29]2[CH:28]=[CH:27][C:26]([CH:30]=O)=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16]>C(O)C>[C:1]1([N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=[CH:30][C:26]2[CH:27]=[CH:28][C:29]3[N:17]([CH2:15][CH3:16])[C:18]4[C:23]([C:24]=3[CH:25]=2)=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Reactant: NN(c1ccccc1)c1ccccc1
Solvent: CCO
Product: CCn1c2ccccc2c2cc(C=NN(c3ccccc3)c3ccccc3)ccc21

Procedure:
1,1-diphenylhydrazine and N-ethylcarbazole-3-carbaldehyde were reacted in ethanol at room temperature to obtain N-ethylcarbazole-3-carbaldehyde diphenylhydrazone with melting point of 160.2°-160.5° C., and 60 parts of this hydrazone compound and 100 parts of a polyester (Vylon 200 by Toyobo Co., Ltd.) were dissolved in 450 parts of tetrahydrofuran to prepare a coating solution. Then selenium was vacuum evaporated on a 10 μm thick aluminum foil laminated on a 75 μm thick polyester film to form a charge generating layer with thickness of approximately 0.3 μm, and to this layer was applied the above-said coating solution by a film applicator and dried to form a 20 μm thick charge transporting layer. In this way, there was obtained a double-layer type electrophotographic plate.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH:17]=1>CO.O1CCCC1>[CH3:1][C:2]1([CH3:30])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)(=[O:23])=[O:24])[CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)N3CCCC3)c1)N2
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(S(=O)(=O)N2CCCC2)c1
Yield: 64.4 %

Procedure:
To a stirred solution of methyl 3,3-dimethyl-2-(3-(pyrrolidin-1-ylsulfonyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (57 mg, 0.133 mmol) in methanol/tetrahydrofuran (2 mL/mL) was added 1M aqueous solution (2.0 mL, 2.0 mmol), LC-MS indicated that 2005467-009-01 was consumed. The mixture was concentrated and the residue was dissolved in water. The aqueous layer was basified to pH=4 with 1M hydrochloric acid solution. The precipitated solid was filtered, and dried to give 35.5 mg of 3,3-dimethyl-2-(3-(pyrrolidin-1-ylsulfonyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid. Yield: 64.4%. MS (ESI+APCI) M+1=415.1.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[C:29]([CH3:37])[CH:28]=4)[CH:24]=[C:23]([CH3:38])[N:22]=3)[CH:18]=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:38][C:23]1[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=3)[N:20]=2)[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[C:29]([CH3:37])[CH:28]=2)[CH:24]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)cc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)cc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)n2)n1
Temperature: 23 °C
Reaction time: 16 h
Yield: 33.5 %

Procedure:
To N-tert-butyl-3-[6′-methyl-4′-(3-methyl-4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonamide (Example 438) (0.300 g, 0.556 mmol) was added TFA (5 mL) and the reaction mixture was stirred at 23° C. for 16 h. The mixture was partitioned between EtOAc and saturated NaHCO3 solution, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a crude product which was triturated with diethyl ether to give the title compound as an off-white solid (0.090 g, 33%). MS (ISP) 484.1 [(M+H)+]; mp>250° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[O:3]1.Br[CH2:18][CH2:19][OH:20].C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:10]=[C:11]([NH:12][CH2:18][CH2:19][OH:20])[CH:13]=[CH:14][CH:15]=2)[O:5]1
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Reactant: OCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC1(C)OB(c2cccc(NCCO)c2)OC1(C)C
Temperature: 25 °C
Yield: 29 %

Procedure:
A mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (219 mg, 1.00 mmol), 2-bromoethanol (82.7 μL, 1.10 mmol) and N,N-diisopropylethylamine (261 μL, 1.50 mmol) in toluene (2 mL) was refluxed for 22 hours. After cooling to room temperature, the mixture was concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane=2:1→1:1) to afford desired product (76.3 mg, 29.0%) as colorless oil.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH3:4].[Br:6][C:7]1[CH:8]=[C:9]([O:17][C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=2[Cl:29])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:10]([NH:13][C:14]([NH2:16])=[S:15])=[N:11][CH:12]=1.C(N(CC)CC)C>C(O)C>[Br:6][C:7]1[CH:8]=[C:9]([O:17][C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=2[Cl:29])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:10]([NH:13][C:14]2[S:15][CH:2]=[C:3]([CH3:4])[N:16]=2)=[N:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(Cl)c(Oc2cc(Br)cnc2NC(N)=S)c1
Reactant: CC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1ccc(Cl)c(Oc2cc(Br)cnc2Nc2nc(C)cs2)c1
Yield: 88.1 %

Procedure:
1-chloropropan-2-one (0.469 g; 5.07 mmol), ethyl 3-(5-bromo-2-thioureidopyridin-3-yloxy)-4-chlorobenzoate (1.680 g, 3.39 mmol), triethylamine (0.671 g, 6.63 mmol), and ethanol (70 mL) were reacted according to the method of Example 10, Step E, to provide the title compound (1.40 g, 77% yield). 1H NMR (d6-DMSO) δ 8.26 (d, 1H), 7.78 (m, 2H), 7.50 (s, 1H), 7.46 (d, 1H), 6.59 (s, 1H), 4.29 (q, 2H), 2.23 (s, 3H), 1.28 (t, 3H); Mass spectrum (apci) m/z=470.1 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:10].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[Cl:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:2][NH:1][S:20]([CH3:19])(=[O:22])=[O:21]
Reactant: CC(C)(C)OC(=O)NC(CN)c1ccccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC(CNS(C)(=O)=O)c1ccccc1Cl

Procedure:
A solution of 330 mg (1.15 mmol) of the compound from Example 113A in 7 ml of pyridine was admixed at RT with 177 μl (2.29 mmol) of methanesulphonyl chloride. After 1 h the volatile constituents were removed on a rotary evaporator. The residue is purified by preparative HPLC [Method 23]. The product fraction was freed from the solvents on a rotary evaporator. Drying of the residue in an HV gave 312 mg (78% of theory) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][OH:11].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.C1(C2C3C(=C(Cl)C=CC=3)CCN=2)C=CC=CC=1>>[F:12][C:13]([F:23])([F:24])[C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:10][OH:11])=[O:19])=[CH:16][CH:15]=1
Reactant: NCCc1ccccc1CO
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: Clc1cccc2c1CCN=C2c1ccccc1
Product: O=C(NCCc1ccccc1CO)c1ccc(C(F)(F)F)cc1

Procedure:
1-Amino-2-(2-hydroxymethylphenyl)ethane and 4-trifluoromethylbenzoyl chloride were successively reacted in the same way as in steps (b) and (c) of Example 12 to afford 1-(4-trifluoromethylbenzoyl)amino-2-(2-hydroxymethylphenyl)ethane having a melting point of 145.8° to 146.3° C. The product was successively reacted in the same way as in steps (d), (e), (f) and (g) of Example 12 to afford 1-(4-trifluoromethylphenyl)isoquinoline-5-acetonitrile having a melting point of 121.9° to 122.6° C.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][S:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)C(=O)C2=CC=CC=C12.O.NN.C(OCC)(=O)C>C(O)C>[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCSc1ccncc1
Agent: NN
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: NCCCCSc1ccncc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
To a suspension of 12.50 g (40 mmol) of 4-(4-phthalimidobutylthio)pyridine in 200 ml of ethanol, 5.82 ml (120 mmol) of hydrazine monohydrate was added, and the mixture was stirred at room temperature for 4 hours. Then, 200 ml of ethyl acetate was added, and the insoluble material was filtered off. The volatile components were distilled off and chloroform was added to the residue. The mixture was washed with saturated saline and dried over potassium carbonate. The solvent was distilled off and 7.30 g of the desired compound were obtained (quantitative yield, yellow oil).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:3]=1[C:4]([NH:6][C@H:7]([CH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29])[CH:16]=[CH:15]2)[C:8]([OH:10])=[O:9])=[O:5].C(OC(N[C@H](CC1C=C2C(=CC=1)NC(C1C(Cl)=CC=CC=1Cl)CC2SC1C=CC=CC=1)C(OC)=O)=O)(C)(C)C.C(OC(N[C@H](CC1C=C2C(=CC=1)N=C(C1C(Cl)=CC=CC=1Cl)C=C2)C(OC)=O)=O)(C)(C)C.N[C@H](CC1C=C2C(=CC=1)N=C(C1C(Cl)=CC=CC=1Cl)C=C2)C(OC)=O>>[Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:3]=1[C:4]([NH:6][C@@H:7]([CH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29])[CH:16]=[CH:15]2)[C:8]([OH:10])=[O:9])=[O:5]
Reactant: O=C(N[C@H](Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)C(=O)O)c1c(Cl)cccc1Cl
Agent: COC(=O)[C@@H](Cc1ccc2c(c1)C(Sc1ccccc1)CC(c1c(Cl)cccc1Cl)N2)NC(=O)OC(C)(C)C
Agent: COC(=O)[C@@H](Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)OC(C)(C)C
Agent: COC(=O)[C@H](N)Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1
Product: O=C(N[C@@H](Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)C(=O)O)c1c(Cl)cccc1Cl

Procedure:
(2R)-2-[(2,6-dichlorobenzoyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoic acid 40 can be synthesised according to the same procedure but starting from (D)-p-nitro-Phe-OMe, involving methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-[2-(2,6-dichlorophenyl)-4-(phenylsulfanyl)-1,2,3,4-tetrahydro-6-quinolinyl]propanoate 25a, methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate 26a and methyl (2R)-2-amino-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate 34a (MS (MH+): 375/377/379) as intermediates.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.[Mg].II.C(O[C@H:18]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH2:20][CH2:19]1)(=O)C.Cl>O1CCCC1.[Cu]I>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][C@H:18]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)C1=CCC[C@H]1OC(C)=O
Reactant: COc1cccc(CCl)c1
Agent: [Cu]I
Agent: Cl
Agent: II
Solvent: C1CCOC1
Product: CCOC(=O)C1=CCC[C@H]1Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A tetrahydrofuran (50 ml) solution of 3-methoxybenzyl chloride (14.01 g) was added slowly to a suspension of magnesium (2.18 g) and iodine (a catalytic amount) in tetrahydrofuran (50 ml) at 60° C. over 40 minutes. After 1 hour stirring at the same temperature, the reaction mixture was cooled to the room temperature. An insoluble material was filtered off and the Grignard solution was prepared. The Grignard solution was added slowly to a suspension of ethyl 5(R)-acetoxy-1-cyclopentenecarboxylate (4.50 g) and copper(I) iodide (0.56 g) in tetrahydrofuran (100 ml) over 1 hour at -60° C. After 1 hour stirring at the same temperature, IN-hydrochloric acid (100 ml) was added to the reaction mixture. The mixture was extracted with ethyl acetate The extract was washed with 1N-hydrochloric acid, water, saturated aqueous sodium hydrogencarbonate and brine. Drying (sodium sulfate) and removal of solvent at reduced pressure followed by flash chromatography over 250 g of silica afforded (-)-ethyl 5(S)-(3-methoxybenzyl)-1-cyclopentencarboxylate as a colorless oil (4.73 g).
Reaction SMILES: C([O:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)(=O)C1C=CC=CC=1.C[O-].[Na+].O>CO>[OH:9][N:10]1[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCN(OC(=O)c2ccccc2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(O)CC1
Reaction time: 2 h

Procedure:
A solution of 3.8 g (0.012 mole) 1-benzoyloxy-4-[1,1-dimethylethoxycarbonyl]piperazine in 25 ml methanol-ether (1:1) was added dropwise to a stirred suspension of 0.95 g (0.017 mole) sodium methoxide in 25 ml methanol at room temperature. The mixture was stirred for 2 hours, treated with 50 ml H2O, and evaporated in vacuo. The residue was thoroughly extracted with ether and the extracts were dried (MgSO4), filtered, diluted with hexane, and evaporated to a lower volume to yield 1.9 white, crystalline solid, m.p. 95°-97° C. Calc. for C9H18N2O3 (202.25): C, 53.45; H, 8.97; N, 13.85; O, 23.73. Found: C, 53.26; H, 8.74; N, 13.98; O, 23.96.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8](Br)=[CH:9][CH:10]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:19][C:20]([CH3:24])([CH3:23])[C:21]#[CH:22]>CN(C=O)C.[Cu](I)I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([C:22]#[C:21][C:20]([CH3:24])([CH3:23])[CH3:19])=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(Br)s1
Reactant: C#CC(C)(C)C
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#CC(C)(C)C)s1
Yield: 238.4 %

Procedure:
A mixture of 5-bromo-thiophene-2-carboxylic acid ethyl ester (7 g, 30 mmol), copper iodide (1.2 g, 6 mmol), triethylamine (20 mL) in DMF (100 mL) was degassed in a 350 mL pressure bottle. Then tris(dibenzylideneacetone)dipalladium(0) (2.1 g, 3 mmol) and 3,3-dimethyl-but-1-yne (18.3 mL, 150 mmol) were added and heated at 80 degree for 3 hours. The reaction mixture was filtered on celite and washed with ethyl acetate. The solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and washed with water. After drying and concentration, the crude residue was purified by flash chromatography to yield 16.9 g (95%) of 5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid ethyl ester as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)=[CH:13][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: Fc1ccc(Cn2ccc3cc(Br)ccc32)cc1
Product: Fc1ccc(Cn2ccc3cc(-c4ccccc4)ccc32)cc1

Procedure:
The title compound was prepared from 5-bromo-1-(4-fluorobenzyl)-1H-indole (Step 1 of Example 27) and benzeneboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil. Mass spectrum (ESI, [M+H]+) m/z 302. 1HNMR (300 MHz, DMSO-d6): δ 7.81 (s, 1H), 7.63 (d, 2H, J=8.3 Hz), 7.56-7.51 (m, 2H), 7.45-7.37 (m, 3H), 7.30-7.22 (m, 3H), 7.20-7.08 (m, 2H), 6.54 (d, 1H, J=6.0 Hz), and 5.43 ppm (s, 2H).
Reaction SMILES: C(OC([CH2:11][NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][CH2:24][N:25]=2)=[CH:17][CH:16]=1)=O)C1C=CC=CC=1>CO.[Pd]>[CH3:11][NH:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][CH2:24][N:25]=2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN=C1c1ccc(CCNCC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CNCCc1ccc(C2=NCCN2C(=O)OC(C)(C)C)cc1
Reaction time: 2 h

Procedure:
A suspension of 4.0 g (9.14 mmol) of tert.-butyl 2-{4-[2-(benzyl-oxycarbonylmethylamino)ethyl]phenyl}4,5-dihydroimidazole-1-carboxylate and 0.4 g of palladium/10% carbon in 80 ml of methanol was hydrogenated in an autoclave for two hours. The catalyst was then filtered off and the filtrate was evaporated to dryness. The crude product obtained in this manner was immediately reacted further without additional purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[N:8]([N:12]=[C:13]([NH:15][C:16]4[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=4)[N:14]=3)[CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1.[CH:26]1(Br)[CH2:30][CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[CH:26]1([N:1]2[CH:5]=[C:4]([C:6]3[C:7]4[N:8]([N:12]=[C:13]([NH:15][C:16]5[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=5)[N:14]=4)[CH:9]=[CH:10][CH:11]=3)[CH:3]=[N:2]2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COC(=O)c1ccc(Nc2nc3c(-c4cn[nH]c4)cccn3n2)cc1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Nc2nc3c(-c4cnn(C5CCCC5)c4)cccn3n2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
A suspension of methyl 4-(8-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoate (43 mg, 0.13 mmol, 1 equiv), cyclopentyl bromide (41 μL, 0.38 mmol, 3.0 equiv) and cesium carbonate (126 mg, 0.383 mmol, 3.0 equiv) in N,N-dimethylformamide (1 mL) was heated at 100° C. After 2 h, the reaction mixture was diluted with ethyl acetate, and the resulting solution was washed with saturated aqueous sodium chloride solution. The collected organic was concentrated. Purification of the resulting residue by flash column chromatography (20% ethyl acetate in dichloromethane) afforded a white solid (23.5 mg, 45% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1 H), 8.74-8.55 (m, 2 H), 8.32 (s, 1 H), 7.91 (dd, J=13.9, 8.1 Hz, 3 H), 7.85 (d, J=8.9 Hz, 2 H), 7.10 (t, J=7.0 Hz, 1 H), 4.81 (s, 1 H), 3.82 (s, 3 H), 2.25-2.11 (m, 2), 2.11-1.93 (m, 2 H), 1.85 (d, J=3.5 Hz, 2 H), 1.77-1.63 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][NH:13][CH3:14]>C1COCC1>[Cl:1][C:2]1[C:7]([S:8]([N:13]([CH3:14])[CH3:12])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CNC
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1cccnc1Cl
Reaction time: 10 h

Procedure:
2-Chloro-3-pyridinesulfonyl chloride in THF (10 mL) was treated with a 2.0M solution of dimethylamine in THF (8 mL, 16 mmol). After stirring for 10 hours, the mixture was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The organics were concentrated under reduced pressure and the residue was purified by flash chromatography (30% ethyl acetate in hexanes) to provide the title compound.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].OS(O)(=O)=O.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=1)[C:15]#[N:16]>>[F:11][C:12]1[C:13]([N+:1]([O-:4])=[O:2])=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=1)[C:15]#[N:16]
Reactant: N#Cc1cc(F)cc(F)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: N#Cc1cc(F)cc(F)c1[N+](=O)[O-]
Reaction time: 3 h
Yield: 95.4 %

Procedure:
Potassium nitrate (6.56 g, 64.8 mmol) was added to concentrated H2SO4 (33.7 ml, 633 mmol) at 0° C., followed by slow addition of 3,5-difluorobenzonitrile (4.4 g, 31.6 mmol). The suspension was stirred at this temperature for an additional 3 hours and quenched with ice water (500 ml). The resulting solid was collected by filtration and dried to give the title compound (5.55 g, 95%) as a white solid. 1H NMR (400 MHz, CDCl3) 7.43 (m, 1H), 7.35 (m, 1H).
Reaction SMILES: [N+]([O-])(O)=O.[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[CH:20]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([CH3:30])[NH:23][C:22]([CH3:31])=[C:21]1[C:32]([O:34][CH3:35])=[O:33].N([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[CH3:30][C:24]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:20]([C:12]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7][CH2:6][Br:5])[C:21]([C:32]([O:34][CH3:35])=[O:33])=[C:22]([CH3:31])[N:23]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1OCCCCBr
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: O=[N+]([O-])O
Product: COC(=O)c1c(C)nc(C)c(C(=O)OC)c1-c1cc([N+](=O)[O-])ccc1OCCCCBr
Yield: 52.2 %

Procedure:
To 140 ml of 50% dioxane-water solution was added 12.8 ml conc. nitric acid (d=1.40), and suspended therein 20 g of dimethyl 4[(4-bromobutoxy)-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate while maintaining the system at 5° to 10° C. under ice cooling. After adding 5.6 g of sodium nitrite, the reaction mixture was vigorously stirred and then filtered. The filtrate obtained was adjusted to pH8 with a saturated aqueous solution of sodium bicarbonate and extracted with chloroform. After washing with water, the organic layer was dried over anhydrous magnesium sulfate and the solvent distilled off. The resultant residue was recrystallized from ethyl acetate--ether to yield 10.4 g of dimethyl 2,6-dimethyl-4-[(4-bromobutoxy)-5-nitrophenyl]pyridine-3,5-dicarboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][CH2:19][NH:20][C:21](=[O:26])[C:22]([C:24]#[N:25])=[CH2:23])[CH:14]=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:27]([O:30][CH2:31][C:32]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][C:35]([F:47])=[CH:34][C:33]=1[N:48]1[C:60](=[O:61])[C:59]2[S:58][C:57]3[CH2:56][CH2:55][CH2:54][CH2:53][C:52]=3[C:51]=2[CH:50]=[N:49]1)(=[O:29])[CH3:28].[F-].[K+]>C(#N)C.O.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:24]([C:22](=[CH2:23])[C:21]([NH:20][CH2:19][CH2:18][O:17][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:10][C:4]2[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([C:37]3[CH:36]=[C:35]([F:47])[CH:34]=[C:33]([N:48]4[C:60](=[O:61])[C:59]5[S:58][C:57]6[CH2:56][CH2:55][CH2:54][CH2:53][C:52]=6[C:51]=5[CH:50]=[N:49]4)[C:32]=3[CH2:31][O:30][C:27](=[O:29])[CH3:28])[CH:3]=2)[N:16]=1)=[O:26])#[N:25]
Reactant: C=C(C#N)C(=O)NCCOc1cccc(Nc2cc(Br)cn(C)c2=O)n1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1-n1ncc2c3c(sc2c1=O)CCCC3
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [F-]
Solvent: O
Solvent: CC#N
Product: C=C(C#N)C(=O)NCCOc1cccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3COC(C)=O)cn(C)c2=O)n1
Temperature: 75 °C
Reaction time: 3 h
Yield: 15.7 %

Procedure:
A mixture of 117a (300 mg, 0.72 mmol), (4-fluoro-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-triene-5-yl}-6-(tetra-methyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 108c (430 mg, 0.86 mmol), Pd(dppf)Cl2 (52 mg, 0.072 mmol), KF (125 mg, 2.16 mmol) in acetonitrile (10 mL) and H2O (2 mL) was stirred at 75° C. for 3 h under nitrogen. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (PE/EA=1/3) to give 2-cyano-N-[2-[[6-[[5-[5-fluoro-2-(acetoxymethyl)-3-(4-oxo-6,7,8,9-tetrahydrobenzothiopheno[2,3-d]pyridazin-3-yl)phenyl]-1-methyl-2-oxo-3-pyridyl]amino]-2-pyridyl]oxy]ethyl]prop-2-enamide 117b (80 mg, 15%) as white solid. ESI-LCMS: m/z=709.8