Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:14])[NH:10][C:11](=[O:13])[CH:12]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18](=[O:22])[CH:19]=[N+]=[N-])[CH3:16]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[CH:19]([C:18]([O:17][CH2:15][CH3:16])=[O:22])[CH:12]2[C:11](=[O:13])[NH:10][C:9]3=[O:14])=[CH:6][CH:7]=1
Reactant: O=C1C=C(c2ccc(Br)cc2)C(=O)N1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1C2C(=O)NC(=O)C21c1ccc(Br)cc1
Yield: 57.3 %

Procedure:
To a solution of 3-(4-bromophenyl)-1H-pyrrole-2,5-dione (3.45 g, 13.74 mmol) obtained in Step 1 of Intermediate IX, in toluene (50 mL) was added ethyldiazoacetate (4.27 mL, 41.23 mmol). The reaction mixture was heated to reflux for 18 h. After completion of the reaction as confirmed by TLC, solvent was removed in vacuo to afford crude product which was purified by column chromatography (silica gel, 4:6 EtOAc:Pet. ether) to afford the title compound as a yellow solid (2.66 g, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:26]1([CH2:31][CH2:32][NH2:33])[CH:30]=[CH:29][N:28]=[CH:27]1.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:33][CH2:32][CH2:31][N:26]1[CH:30]=[CH:29][N:28]=[CH:27]1)=[O:13])=[CH:5]2
Reactant: NCCn1ccnc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCn1ccnc1)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 4 h

Procedure:
A mixture of 1.8 g of 5-chloroindole-2-carboxylic acid in 50 ml of tetrahydrofuran was treated with 1.5 g of 1,1'-carbonyldiimidazole and allowed to stand at room temperature for 4 hours. A solution of 1.15 g of 1H-imidazole-1-ethanamine in 25 ml of tetrahydrofuran was added and the reaction mixture was heated at reflux temperature for 3 hours, treated with 10 ml of water and again heated for one hour and then concentrated to remove the solvent. The residue was shaken with 5 ml of 1N sodium hydroxide and 300 ml of dichloromethane and the layers were separated. The organic layer was washed with water, dried over magnesium sulfate and concentrated to recover the desired compound, mp 167°-169° C.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17]3[C:20](=O)[C:19](=[O:22])[C:18]=3[O:23]C)[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH2:34])=[CH:28][CH:27]=1>CO.C(Cl)(Cl)Cl>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17]3[C:18](=[O:23])[C:19](=[O:22])[C:20]=3[NH:34][CH2:33][CH2:32][C:29]3[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=3)[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: COc1c(NC2CCCC(c3csc(NC(=N)N)n3)C2)c(=O)c1=O
Reactant: NCCc1ccc(Cl)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: N=C(N)Nc1nc(C2CCCC(Nc3c(NCCc4ccc(Cl)cc4)c(=O)c3=O)C2)cs1
Reaction time: 5 h

Procedure:
To a solution of 1-[3-(2-guanidinothiazol-4-yl)cyclohexylamino]-2-methoxycyclobutene-3,4-dione (0.19 g.) in 35 ml. of methanol/chloroform (50:50 v/v) was added 2-(p-chlorophenyl)ethylamine (0.18 g.) and the resulting mixture allowed to stand at room temperature for 5 hours. After heating under reflux for 2.5 hours the reaction mixture was cooled and the precipitated buff-coloured solid collected to give 1-[3-(2-guanidinothiazol-4-yl)cyclohexylamino]-2-[2-(p-chlorophenyl)ethylamino]cyclobutene-3,4-dione. The n.m.r. spectrum in d6 dimethylsulphoxide included resonances at 1.2 (m), 1.8 (m), 2.5 (t), 3.7 (m), 6.24 (s), 6.78 (br s).
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([NH:13][C:14](=[O:26])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][C:22]([F:25])([F:24])[F:23])[C:10]([C:27]3[NH:31][C:30]4[CH:32]=[CH:33][C:34]([CH2:36][N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)=[CH:35][C:29]=4[N:28]=3)=[N:9]2)=CC=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[N:37]1([CH2:36][C:34]2[CH:33]=[CH:32][C:30]3[NH:31][C:27]([C:10]4[C:11]([NH:13][C:14](=[O:26])[C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=5[O:21][C:22]([F:23])([F:24])[F:25])=[CH:12][NH:8][N:9]=4)=[N:28][C:29]=3[CH:35]=2)[CH2:38][CH2:39][O:40][CH2:41][CH2:42]1
Reactant: COc1ccc(Cn2cc(NC(=O)c3ccccc3OC(F)(F)F)c(-c3nc4cc(CN5CCOCC5)ccc4[nH]3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1ccccc1OC(F)(F)F
Temperature: 140 °C
Yield: 29.9 %

Procedure:
A mixture of N-[1-(4-methoxy-benzyl)-3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2-trifluoromethoxy-benzamide (50 mg) and anisole (25 μl) in trifluoroacetic acid (1 ml) was heated at 140° C. (100 W) for 20 min in a CEM Discover™ microwave synthesiser. The reaction mixture was evaporated and then azeotroped with toluene (2×10 ml). To the crude material was added EtOAc (5 ml) and the mixture neutralised with saturated aqueous sodium hydrogen carbonate. The organic portion was washed with water, dried (MgSO4) and reduced in vacuo. The residue was purified by flash column chromatography [SiO2, CH2Cl2-MeOH (100:0-95:5)] to give N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2-trifluoromethoxy-benzamide (12 mg) as a white solid. (LC/MS: Rt 2.06, [M+H]+ 487).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=O.[CH3:11][NH:12][C:13](=[S:16])[NH:14][NH2:15].P(Cl)(Cl)(Cl)=O>O1CCOCC1>[CH3:11][NH:12][C:13]1[S:16][C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)=[N:15][N:14]=1
Reactant: CNC(=S)NN
Reactant: O=C(O)c1cccc(Cl)c1
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: CNc1nnc(-c2cccc(Cl)c2)s1

Procedure:
A well-stirred mixture of 125 g (0.8 mole) of 3-chlorobenzoic acid and 84 g (0.8 mole) of 4-methylthiosemicarbazide in 700 ml of dioxane was heated until the solution was homogeneous. Phosphorus oxychloride (123 g, 0.8 mole) was added dropwise to the resulting solution at a rate to maintain the dioxane at gentle reflux.
Reaction SMILES: [O:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=[CH:2]1.[NH:9]1[CH2:13][CH2:12][C:11]2([N:18]3[CH:19]=[N:20][CH:21]=[C:17]3[CH2:16][CH2:15][CH2:14]2)[CH2:10]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[O:1]1[C:5]([C:6]([N:9]2[CH2:13][CH2:12][C:11]3([N:18]4[CH:19]=[N:20][CH:21]=[C:17]4[CH2:16][CH2:15][CH2:14]3)[CH2:10]2)=[O:8])=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1cnco1
Reactant: c1ncn2c1CCCC21CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cnco1)N1CCC2(CCCc3cncn32)C1
Temperature: 25 °C

Procedure:
1.5 mmol of oxazole-5-carboxylic acid [118994-90-4] are dissolved in 5 ml of dichloro-methane and the solution is admixed at 0° C. with 1.6 mmol of chlorenamine. The reaction solution is subsequently stirred at room temperature for an hour and then added dropwise at 0° C. to a solution of 1 mmol of 7,8-dihydro-6H-spiro[imidazo[1,5-a]pyridine-5,3′-pyrrolidine] (Example 3a) and 2 mmol of triethylamine in 5 ml of dichloromethane. The reaction mixture is subsequently stirred at room temperature for 3 hours, poured into saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane (3×). The combined organic extracts are washed with brine, dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60 F) on the basis of the Rf value.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C1COCC1>[N:3]1([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)n1ccnc1
Yield: 57.3 %

Procedure:
A suspension of 16.0 g (0.4 mol) of NaH-oil (60%) was washed with hexane to remove the oil and then resuspended in 400 mL of THF. This was then treated dropwise with a solution of 27.23 g (0.4 mol) of imidazole in 150 mL of THF and then refluxed for 1hour. This was then treated dropwise with a solution. of 72.4 g (0.4 mol) of ethyl 2-bromopropanoate in 100 mL of THF and the mixture heated at reflux for 2.5 hours. The mixture was filtered and the solvent removed under reduced pressure. The residue was taken up in Et2O and washed with H2O, then saturated NaCl. Drying over MgSO4 and treatment with charcoal gave the crude product. This was triturated with pentane and the pentane removed under reduced pressure to give 38.56 g (57.3% yield) of the product as an oil. The structure was confirmed by NMR and mass spectroscopy. MS m/z 169 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C=O)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH2:15][N:27]=[N+:28]=[N-:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(C(=O)OC(C)(C)C)CCC2O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)C(CN=[N+]=[N-])C1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-hydroxy-3-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (8.56 mmol, 3.3 g) in DMF (20 mL) was added sodium azide (35.28 mmol, 2.34 g), and the reaction mixture was stirred at 80-90° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with DCM (200 mL), washed with water, and the organic layer was dried and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography by eluting with ethyl acetate in hexanes (1:1) to provide 3-azidomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][NH:13][CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl>[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][N:13]([C:36](=[O:38])[CH3:37])[CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1
Reactant: Clc1ccc2c(c1)CNCc1nnc([C@H]3CC[C@H](c4ccccc4)CC3)n1-2
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3ccccc3)CC2)C1
Reaction time: 19 h

Procedure:
To a solution of trans-8-chloro-1-(4-phenyl-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride (0.090 g, 0.22 mmol) and triethylamine (0.063 ml, 0.46 mmol) in dichloromethane (5 ml) was added acetyl chloride (0.017 ml, 0.24 mmol) at room temperature. After stirring for 19 h the reaction mixture was concentrated in vacuo. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.082 g, 90%) as white solid. MS m/e: 421 (M+H+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:17]=[C:16]([CH3:18])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:5](F)=[N:6][CH:7]=1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[N:31]1[C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([NH2:40])[C:34]=2[CH:33]=[N:32]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:17]=[C:16]([CH3:18])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:5]([NH:40][C:35]2[C:34]3[CH:33]=[N:32][N:31]([CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][O:25]4)[C:39]=3[CH:38]=[CH:37][CH:36]=2)=[N:6][CH:7]=1
Reactant: Nc1cccc2c1cnn2C1CCCCO1
Reactant: Cc1nc(-c2cc(Br)cnc2F)c2ncn(C3CCCCO3)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(-c2cc(Br)cnc2Nc2cccc3c2cnn3C2CCCCO2)c2ncn(C3CCCCO3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 6-(5-bromo-2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.250 g, 0.637 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (0.138 g, 0.637 mmol) in THF (10 mL) was stirred at 0° C. and treated dropwise with lithium bis(trimethylsilyl)amide, 1.0 M solution in THF (1.912 mL, 1.912 mmol) (Aldrich catalog number 225770) and stirred at 0° C. for 30 minutes. The mixture was quenched with water (10 mL), diluted with water (50 mL) and extracted with dichloromethane. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a RediSep®, Teledyne ISCO, Lincoln, Nebr., pre-packed silica gel column (40 g), eluting with a gradient of 5% to 10% 2 M NH3/MeOH in dichloromethane to give N-(5-bromo-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine as yellow crystals. This was treated with dichloromethane (5 mL) and trifluoroacetic acid (5 mL) (Aldrich, St. Louis, Mo.) to give N-(5-bromo-3-(2-methyl-9H-purin-6-yl)pyridin-2-yl)-1H-indazol-4-amine. m/z (ESI, +ve) 421/423 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 13.75 (br. s., 1H); 13.25 (br. s., 1H); 12.85 (br. s., 1H); 8.69 (br. s., 1H); 8.48 (br. s., 1H); 7.99 (br. s., 1H); 7.32 (br. s., 1H); 7.23 (br. s., 1H); 2.93 (s, 3H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH3:6])=[C:2]=[S:3].CN(C)C=O.[NH2:12][C:13]1[S:14][CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19]>O>[CH2:4]([NH:1][C:2](=[S:3])[NH:12][C:13]1[S:14][CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19])[CH2:5][CH3:6]
Reactant: CCCN=C=S
Reactant: COC(=O)c1ccsc1N
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=S)Nc1sccc1C(=O)OC
Temperature: 132.5 °C
Reaction time: 12 h
Yield: 40.7 %

Procedure:
In a sulfonation flask, 2.02 g (0.02 mol) of 1-isothiocynatopropane are added dropwise to 30 ml dimethylformamide and 3.0 g (0.019 mol) of methyl 2-aminothiophene-3-carboxylate. The reaction mixture is then stirred at 130-135° C. for 12 hours and after cooling added to 120 ml of water. The resulting mixture is then extracted three times with ethylacetate and the separeted organic phase dried over sodium sulfate. The solvent is then removed in a water-jet vacuum, giving the crude product as a dark oil, which is purified by column chromatography over silica gel (eluant: tert.butylmethylether/hexane=2:3). 2.0 g of methyl 2-(3-propylthioureido)thiophene-3-carboxylate are obtained in the form of a yellow powder having a melting point of 122-124° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:4][C:3]=1[OH:18].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(O)[C:28]#[CH:29])=[CH:23][CH:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1COCC1>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:18][C:3]3[CH:4]=[C:5]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)[C:6]4[C:11]([C:2]=3[CH:29]=[CH:28]2)=[CH:10][CH:9]=[CH:8][CH:7]=4)=[CH:23][CH:22]=1
Reactant: Oc1cc(N2CCOCC2)c2ccccc2c1Cl
Reactant: C#CC(O)(c1ccccc1)c1ccc(OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C2(c3ccccc3)C=Cc3c(cc(N4CCOCC4)c4ccccc34)O2)cc1
Yield: 16.1 %

Procedure:
0.91 g of 1-chloro-4-morpholino-2-naphthol are allowed to react with 0.95 g of 1-(p-methoxyphenyl)-1-phenyl-2-propyn-1-ol in 30 ml of THF under reflux for 4 hours in the presence of 0.72 g of p-toluene sulfonic acid. The solution is then neutralized with 30 ml of 1N sodium hydroxide and then extracted twice with 30 ml of toluene. The organic phases are evaporated and then the photochrome is separated by chromatography on an alumina column in eluting with a mixture of ethyl acetate/diisopropyl ether (10/90). 250 mg of 3-(p-methoxyphenyl)-3-phenyl-6-morpholino-[3H]-naphtho-[2,1-b]pyran (compound II) are thus obtained. Its structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([F:13])([F:12])[F:11])=[C:6]([CH:9]=1)[CH2:7]Cl.[CH:14]1([CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:30][CH2:31][N:32]([CH2:7][C:6]4[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[C:10]([F:13])([F:12])[F:11])[CH2:33][CH2:34]3)=[CH:27][CH:28]=2)=[O:22])[CH2:16][CH2:15]1
Reactant: O=C(NCCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: Fc1ccc(C(F)(F)F)c(CCl)c1
Product: O=C(NCCCC1CC1)c1ccc(N2CCN(Cc3cc(F)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 11, making variations only as required to use 5-fluoro-2-trifluoromethylbenzyl chloride in place of 2-trifluoromethylbenzyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-cyclopropylpropyl)amide, the title compound was obtained as a light yellow solid (34% yield). 1H NMR (300 MHz, CDCl3) δ 7.98, 7.88, 7.55-7.65, 7.2, 6.93, 3.68-3.85, 3.50, 2.60, 1.70, 1.25, 0.65, 0.40, 0.09. MS (ES+) m/z 466 (M+1).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.Cl[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]3[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)=[N:21][CH:22]=1)#[N:25]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3ccc(C#N)cn3)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a mixture of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (2 g, 8 mmol, 1 eq.) and 6-chloronicotinonitrile (2.78 g, 20 mmol, 2.5 eq.) in 50 ml DMF was added cesium carbonate (7.82 mg, 24 mmol, 3 eq.). The reaction was stirred at room temperature overnight. The starting material was gone but no right mass was observed. The reaction was then quenched by water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel (DCM/methanol=39:1 to 19:1) to give colorless oil (2.52 g, yield 89%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[NH:9])[NH:7][OH:8])=[C:4]([F:12])[CH:3]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[NH:9])[NH:7][O:8][CH:15]=[CH:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])=[C:4]([F:12])[CH:3]=1
Reactant: N=C(NO)c1ccc(Br)cc1F
Reactant: C#CC(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C=CONC(=N)c1ccc(Br)cc1F
Temperature: 50 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
To a solution of 4-Bromo-2-fluoro-N-hydroxybenzimidamide 24 (800 g, 3.43 mol, 1 eq) and Amberlyst® A21 (20 wt %, 160 g) in PhMe (12 L, 15 vol) was added ethyl propiolate (471 g, 4.8 mol, 1.4 eq) at 10° C. The reaction was stirred at 50° C. overnight and checked by LC-MS (ca 14A % of starting material 24 was left). Reaction was then filtered and the filtrate was concentrated under vacuum, and 1015 g ethyl 3-(4-bromo-2-fluorobenzimidamidooxy)acrylate 25 was obtained as a yellow oil with 84.9% LC purity (yield: 89%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])=[CH:11][CH:12]=1)(=O)=O.[C:29]([C:31]1([OH:39])[CH:36]2[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]2)[CH2:32]1)#[CH:30].C(N(CC)CC)C>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.CN(C)C=O>[CH2:20]([C:8]1[C:7]([C:30]#[C:29][C:31]2([OH:39])[CH:36]3[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]3)[CH2:32]2)=[CH:12][CH:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:9]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=S(=O)(Oc1ccc(-c2ccccc2O)nc1Cc1ccccc1)C(F)(F)F
Reactant: C#CC1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Oc1ccccc1-c1ccc(C#CC2(O)CN3CCC2CC3)c(Cc2ccccc2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
A mixture of 67.0 mg of 2-benzyl-6-(2-hydroxyphenyl)-3-pyridyl trifluoromethane sulfonate, 24.7 mg of 3-ethynyl-3-quinuclidinol, 19.0 mg of tetrakis(triphenylphosphine)palladium(0), 0.1 mg of cuprous iodide, 68.6 μl of triethylamine and 1.5 ml of N,N-dimethylformamide was heated under stirring at 100° C. for 2 hours in a nitrogen atmosphere. NH-silica gel was added to the reaction solution, and the solvent was removed. The residue was subjected to NH-silica gel column chromatography using 3% methanol/ethyl acetate, to give 56.8 mg of the target compound.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(NC(=O)N(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(NC(=O)N(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-(dimethylaminocarbonyl)-amino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [CH2:1]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[Li]CCCC.[C:15]([N:19]=[C:20]=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[CH2:1]([C:5]1[S:6][C:7]([C:20]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])=[CH:8][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1cccs1
Reactant: CC(C)(C)N=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(C(=O)NC(C)(C)C)s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
To 2-iso-butylthiophene (1 g, 7.143 mmol, see step (a) above) in THF (15 mL) was added n-BuLi (1.6 M in hexane, 5.3 mL, 8.48 mmol) at −78° C. and the reaction mixture was stirred at 0° C. for 2 hours. tert-Butyl-isocyanate (897 μL, 7.86 mmol) was then added to the mixture at −78° C. The stirred solution was kept at 0° C. for an additional 2 hours. The reaction mixture was then quenched with H2O (15 mL) and extracted with EtOAc (3×20 mL). The organic layer was dried over MgSO4, concentrated and purified using silica gel column chromatography (10:90 petroleum ether-EtOAc) to give the sub-title compound (1.2 g, 5.01 mmol) as white needles in 70% yield.