Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[S:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[CH3:15][N:16]1[C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=[N:17]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[CH3:15][N:16]1[C:20]([C:2]2[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[S:5][C:6]=2[C:7]([F:10])([F:9])[F:8])=[CH:19][CH:18]=[N:17]1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)c(C(F)(F)F)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)c(C(F)(F)F)s1
Temperature: 70 °C
Reaction time: 12 h
Yield: 77.6 %

Procedure:
A mixture of methyl 4-bromo-5-(trifluoromethyl)-2-thiophenecarboxylate (0.8 g, 40% purity, 1.11 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.299 g, 1.434 mmol), tetrakis (0.128 g, 0.11 mmol) and K2CO3 (0.459 g, 3.32 mmol) in dioxane/H2O (5 mL/1 mL) was heated to 70° C. in a sealed tube. After 12 h, the reaction mixture was concentrated under vacuum and purified on silica (EtOAc/Hex, 40-60%) to afford the title compound (0.25 g, 70%) as a light yellow solid: LC-MS (ES) m/z 291 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:10](Cl)(=[O:12])[CH3:11].[Cl-].[Al+3].[Cl-].[Cl-]>>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:10](=[O:12])[CH3:11])=[C:4]([OH:9])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(O)cc1Br
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1cc(C)c(Br)cc1O
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
To 3-bromo-4-methylphenol (2 g, 10.69 mmol) was added acetyl chloride (0.80 ml, 11.23 mmol). The mixture was heated at 60° C. for one hour, cooled and aluminium chloride (1.426 g, 10.69 mmol) was added. The mixture was heated at 180° C. for 40 minutes, cooled and quenched by stirring with 5N HCl (20 ml) for 20 minutes. The solid was filtered to yield the title compound as a brown solid. 2.45 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][NH:30][CH3:31]>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:30]([CH3:31])[CH3:29])=[O:24])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: CNC
Solvent: CCO
Product: CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 93.4 %

Procedure:
A solution of ethyl 5{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]4-cyclohexylbutyl)-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (1.00 g, 2.53 mmol) in ethanol (8 ml) was cooled to 0° C. and treated dropwise with dimethylamine (5.6M in ethanol, 4.50 ml, 25.3 mmol). The solution was stirred for 17 hours being allowed to warm up to room temperature over this time. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane:ethyl acetate (4:1) to afford the title compound as a yellow oil (0.93 g).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[OH:7][C:8]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:9]=1[CH:10]=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH3:6][O:5][C:3]([C:2]1[O:7][C:8]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:9]=2[CH:10]=1)=[O:4]
Reactant: COc1ccc(C=O)c(O)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(OC)cc2o1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of methyl bromoacetate (1.53 g, 10 mmol), 2-hydroxy-4-methoxybenzaldehyde (1.52 g, 10 mmol) and Cs2CO3 (6.5 g, 20 mmol) in DMF (100 mL) was stirred vigorously at 50° C. for 3 hrs and then at 150° C. for 5 min. The reaction was cooled, diluted with ethyl acetate and washed with water. The organic phase was dried and concentrated to give essentially pure 6-methoxy-benzofuran-2-carboxylic acid methyl ester as a solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([Br:11])[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:6]=2[C:5](=[O:16])[NH:4][C:3]1=[O:17].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.Cl[CH2:32][C:33]1[C:38]([C:39]#[N:40])=[CH:37][CH:36]=[CH:35][N:34]=1>O>[C:39]([C:38]1[C:33]([CH2:32][N:4]2[C:5](=[O:16])[C:6]3[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:8]([Br:11])=[N:9][C:10]=3[N:2]([CH3:1])[C:3]2=[O:17])=[N:34][CH:35]=[CH:36][CH:37]=1)#[N:40]
Reactant: CC#CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Reactant: N#Cc1cccnc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC#CCn1c(Br)nc2c1c(=O)n(Cc1ncccc1C#N)c(=O)n2C
Temperature: 70 °C
Reaction time: 19 h

Procedure:
202 g (0.68 mol) of 3-methyl-7-(2-butin-1-yl)-8-bromoxanthine, 188.5 g (1.36 mol) of anhydrous potassium carbonate and 1.68 liters of N-methyl-2-pyrrolidone are initially charged in the reactor and heated to 70° C. Subsequently, 119 g (0.75 mol) of 2-chloromethyl-3-cyanopyridine in 240 ml of N-methyl-2-pyrrolidine (NMP) are added dropwise. The reactor contents are stirred at 70° C. for 19 hours. After the reaction has ended, 2.8 liters of water are added to the reaction mixture and it is cooled to 25° C. The product is filtered off, washed with 2 liters of water and dried at 70° C. in a drying cabinet under inertization.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:16]=[O:17])=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:7][CH:6]=1)=[O:4].[O-:18][Mn](=O)(=O)=O.[K+]>CC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:16]([OH:18])=[O:17])=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCn1cc(C=O)c2ccc(C(=O)OC)cc21
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCn1cc(C(=O)O)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.4 %

Procedure:
1-Ethyl-3-formyl-1H-indole-6-carboxylic acid methyl ester (800 mg, 3.5 mmol), prepared as shown in example 1P, step A, is dissolved in acetone (98 mL). A solution of KMnO4 (655 mg, 4.15 mmol) in H2O (31 mL) is added. The reaction mixture is stirred at room temperature for 90 minutes. Another addition of KMnO4 (108 mg) in H2O (6 mL), followed by stirring for another 45 minutes is required to drive the reaction to completion. The reaction mixture is then quenched with 10% H2O2 (1.5 mL). The mixture is filtered through celite. The filtrate is stripped down under vacuum to roughly ⅓ of the volume. The residue is acidified with 6N HCl, and is extracted into ethyl acetate. The solids isolated from the ethyl acetate layer are triturated with acetone to yield 1-ethyl-1H-indole-3,6-dicarboxylic acid 6-methyl ester (696 mg, 79%) as a light orange solid.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH2:20][S:21]([NH2:24])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1N=CN=C(NC2C=C(CS(N)(=O)=[O:41])C=CC=2)N=1.OC[C@@H]1CCCN1>>[OH:41][CH2:2][C@@H:3]1[CH2:4][CH2:5][CH2:6][N:1]1[C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:15]=[C:16]([CH2:20][S:21]([NH2:24])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[N:8]=1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCCCC3)n2)c1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Agent: OC[C@@H]1CCCN1
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCC[C@H]3CO)n2)c1

Procedure:
B25 was prepared following the general procedure reported for B1 using A1 and (S)-2-(hydroxymethyl)pyrrolidine. MS (ES) C15H20N6O3S requires: 364. found: 365 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])[C:13](O)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][N:22](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:13](=[O:14])[NH:22][CH3:21])[CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)NCc1cc(C(=O)O)cc(Cl)c1F
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1

Procedure:
was prepared according to Scheme C3 (step A) from 3-(tert-butoxycarbonylamino-methyl)-5-chloro-4-fluoro-benzoic acid (125 mg, 0.41 mmol), HATU (235 mg, 0.6 mmol), methylamine (0.25 mL, 2M in THF) and DIPEA (0.29 mL, 1.6 mmol) in DMF (2 mL). MS (LC-MS): 633.0 [2M]+; tR (HPLC conditions c): 4.55 min.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3](=O)[CH2:4][C:5](=O)[CH3:6].[Cl:11][C:12]1[CH:27]=[CH:26][C:15]([O:16][CH2:17][CH2:18][S:19][C:20]2[N:24]=[C:23]([NH2:25])[NH:22][N:21]=2)=[CH:14][CH:13]=1>C(O)(=O)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][CH2:18][S:19][C:20]2[N:24]=[C:23]3[N:25]=[C:5]([CH3:6])[CH:4]=[C:3]([C:2]([F:10])([F:9])[F:1])[N:22]3[N:21]=2)=[CH:26][CH:27]=1
Reactant: Nc1nc(SCCOc2ccc(Cl)cc2)n[nH]1
Reactant: CC(=O)CC(=O)C(F)(F)F
Solvent: CC(=O)O
Product: Cc1cc(C(F)(F)F)n2nc(SCCOc3ccc(Cl)cc3)nc2n1
Temperature: 135 °C
Yield: 64.7 %

Procedure:
A mixture of 1,1,1-trifluoro-2,4-pentanedione (114 mg, 0.739 mmol), 3-{[2-(4-chlorophenoxy)ethyl]sulfanyl}-1H-1,2,4-triazol-5-amine (200 mg, 0.739 mmol), and glacial acetic acid (1.5 mL) was added to a 50 mL RBF with a magnetic stirring bar. The flask was fitted with a condenser and warmed in an oil bath to a gentle reflux at 135° C. The solution was heated for 15 hours. Progress of the reaction was monitored by analytical HPLC with UV detection at 215 and 254 nm. The starting material 3-{[2-(4-chlorophenoxy)ethyl]sulfanyl}-1H-1,2,4-triazol-5-amine elutes with retention time of 6.04 min, and the product elutes with retention time of 7.98 min. The solution was allowed to cool to room temperature and added into stirring ice/water (15 mL) to precipitate the product. Solids were isolated by filtration, rinsed with 20 mL of water, and then dried under reduced pressure. The solid was dissolved in 5 mL of ethanol with gentle warming and allowed to cool. The fine white needles that formed were isolated by filtration, washed with 3 mL of cold ethanol, and dried to afford the title compound as off-white crystals (186 mg, 65% yield). EM (calc.): 388.0; MS (ESI) m/e: 389.0 (M+H)+. 1H NMR (DMSO-d6, 400 MHz) δ ppm: 7.85 (s, 1H), 7.31 (d, 2H), 7.00 (d, 2H), 4.33 (t, 2H), 3.62 (t, 2H), 2.69 (s, 3H). 19F NMR (DMSO-d6, 376 MHz) δ ppm: −67.56 (s).
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.CO.Cl[C:9]1[CH:14]=[C:13]([C:15]([O:17]C)=[O:16])[CH:12]=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]=1.Cl>CC(N(C)C)=O>[CH3:1][O:2][C:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]=1
Reactant: C[O-]
Reactant: COC(=O)c1cc(Cl)nc(-c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)N(C)C
Product: COc1cc(C(=O)O)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
25% NaOMe/methanol solution (92 μL) was added to an MeOH (2 mL) solution of methyl 2-chloro-6-phenylpyridine-4-carboxylate (1100 mg), and stirred at room temperature for 2 hours. Further, 25% NaOMe/methanol solution (92 μL) was added to it, and stirred under heat with refluxing for 2 hours and 30 minutes. DMA (3 mL) was added to it, and stirred overnight at 130° C., then 25% NaOMe/methanol solution (92 μL) was added to it, and stirred at 130° C. for 7 hours. With cooling with ice, diluted hydrochloric acid was added to it, the formed precipitate was taken out through filtration, washed with water, dried, and purified through reversed-phase high-performance liquid chromatography [acetonitrile/water+0.11% trifluoroacetic acid] to obtain the title compound as a white powder.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:24][CH2:25][C:26]3[NH:27][CH:28]=[CH:29][N:30]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[NH:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]=O.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[NH:30]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:25][N:24]([CH2:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][NH:15][C:12]2[CH:11]=[CH:10][C:9]([CH2:8][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])=[CH:14][CH:13]=2)=[CH:22][CH:21]=1)[CH2:36][C:32]1[NH:31][CH:35]=[CH:34][N:33]=1
Reactant: CCCN(CCC)Cc1ccc(NCc2ccc(CNCc3ncc[nH]3)cc2)cc1
Reactant: O=Cc1ncc[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)Cc1ccc(NCc2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The compound (199 mg) obtained in Example 43-1 was dissolved in methanol (6 ml) and then added with 2-imidazole carboxaldehyde (57.1 mg) and sodium cyanoborohydride (65.4 mg). The reaction solution was adjusted to pH 5 with the addition of acetic acid, followed by stirring at room temperature for 14 hours. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then extracted with chloroform. Then, the organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. After the solvent had been distilled off, the residue obtained was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (231 mg) of the subject compound as a yellow solid.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:24][N:25](C(OC(C)(C)C)=O)[CH3:26])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=O)(C)(C)C.Cl>CO.C(OCC)C>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:24][NH:25][CH3:26])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: CN(Cc1ccccc1Sc1ccc2c(ccn2C(=O)OC(C)(C)C)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CNCc1ccccc1Sc1ccc2[nH]ccc2c1
Yield: 10.4 %

Procedure:
(2-Mercapto-benzyl)-methyl-carbamic acid tert-butyl ester (1.85 g, 7.30 mmol) in dry toluene (15 mL) is placed in an Emrys Optimizer EXP 20 mL tube. Tris(dibenzylideneacetone) dipalladium (334 mg, 0.37 mmol), bis(2-diphenylphosphinophenyl)ether (197 mg, 0.37 mmol), tert-butyl-5-bromoindole-1-carboxylate (2.38 g, 8.03 mmol) and potassium tert-butoxide (860 mg, 7.67 mmol) are added. The reaction vessel is sealed and subjected to microwave heating at 160° C. for 15 minutes. Upon cooling the mixture is poured onto a plug of silica and the product is eluted with ethyl acetate-heptane (1:4). 0.67 g (20%) of 5-{2-[(tert-butoxycarbonyl-methyl-amino)-methyl]-phenylsulfanyl}-indole-1-carboxylic acid tert-butyl ester is isolated and used in the next step whithout further purification. 5-{2-[(tert-butoxycarbonyl-methyl-amino)-methyl]-phenylsulfanyl}-indole-1-carboxylic acid tert-butyl ester (0.67 g, 1.43 mmol) in methanol (15 mL) and diethyl ether saturated with hydrochloric acid (15 mL) is stirred at room temperature for 1 hour and concentrated in vacuo. Ice/water is added to the remanence and 28% aqueous NaOH is added until pH 9. The aqueous fraction is extracted with ethyl acetate (3×15 mL). Combined organic fractions are dried with MgSO4 and concentrated in vacuo. The product is purified by silica gel chromatography eluting with ethyl acetate-triethyl amine (100:4) followed by ethyl acetate-ethanol-triethyl amine (100:5:5). Upon evaporation of the volatiles, 40 mg (10%) of [2-(1H-indol-5-ylsulfanyl)-benzyl]-methyl-amine is isolated.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10]([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([NH:31][C:32]1[C:33]([S:41][CH3:42])=[N:34][C:35]([CH3:40])=[CH:36][C:37]=1[S:38][CH3:39])=[O:30]>CN(C=O)C.O>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10]([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:28][C:29]([NH:31][C:32]2[C:33]([S:41][CH3:42])=[N:34][C:35]([CH3:40])=[CH:36][C:37]=2[S:38][CH3:39])=[O:30])[CH2:17][CH2:16]1)(=[O:12])=[O:11]
Reactant: O=S(=O)(CCN1CCNCC1)c1nc2ccccc2[nH]1
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCS(=O)(=O)c2nc3ccccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63.8 %

Procedure:
To a solution of 1-[2-(benzimidazol-2-ylsulfonyl)ethyl]piperazine (17 mg, 0.058 mmol) in DMF (0.1 ml) were added potassium carbonate (16.0 mg, 0.116 mmol) and 2-bromo-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide (18.6 mg, 0.058 mmol), and the mixture was stirred at room temperature for 6 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel preparative thin layer chromatography (developing solvent; chloroform:sat. ammonia methanol=5:1) to provide 19.8 mg (yield 64%) of the desired compound as pale yellow oil. IR (neat) cm−1: 3345, 1672, 1565, 1420, 1124. 1H-NMR (CD3OD) δ: 2.43 (3H, s), 2.47 (3H, s), 2.48 (3H, s), 3.00 (2H, br. d, J=12.9 Hz), 3.12 (2H, t, J=10.7 Hz), 3.34 (2H, s), 3.58-3.78 (8H, m), 6.85 (1H, s), 7.12-7.18 (2H, m), 7.43-7.48 (2H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1I)[CH2:8][C:9]([F:12])([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>CCCCCCC.CCOC(C)=O>[C:1]([O:5][C:6](=[O:20])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[Cl:21])[CH2:8][C:9]([F:12])([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CC(F)(F)F)c1cnccc1I
Reactant: OB(O)c1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N(CC(F)(F)F)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-(2,2,2-trifluoro-ethyl)-carbamic acid tert-butyl ester and 2-chlorophenylboronic acid (CAS RN 1679-18-1) and using a gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic purification. Colorless oil (69%). MS (ESI): m/z=403.012 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH2:10][NH:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Cs+].Cl[C:19]1[N:24]=[C:23]([NH2:25])[N:22]2[N:26]=[C:27]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)[N:28]=[C:21]2[CH:20]=1>CS(C)=O>[CH2:1]([N:8]1[CH2:15][CH2:14][CH:13]2[CH2:12][N:11]([C:19]3[N:24]=[C:23]([NH2:25])[N:22]4[N:26]=[C:27]([C:29]5[O:30][CH:31]=[CH:32][CH:33]=5)[N:28]=[C:21]4[CH:20]=3)[CH2:10][CH:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CCC3CNCC32)cc1
Reactant: Nc1nc(Cl)cc2nc(-c3ccco3)nn12
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: Nc1nc(N2CC3CCN(Cc4ccccc4)C3C2)cc2nc(-c3ccco3)nn12
Temperature: 120 °C
Reaction time: 18 h

Procedure:
2-Benzyl-2,7-diazabicyclo[3.3.0]octane (1.2 mmol; see U.S. Pat. No. 5,071,999) was dissolved in 2 mL of DMSO along with 7-chloro-2-furan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidin-5-ylamine (0.25 mmol; see U.S. Pat. No. 6,222,035 B1) and CsF (0.3 mmol). The reaction mixture was stirred at 120° C. for 18 hours. It was then cooled to room temperature and purified by preparative HPLC to afford the title compound. 1H NMR (400 Hz, DMSO-d6) 7.60 (d, J=1.0 Hz, 1H), 7.28 (br s, 2H), 7.22 (d, J=3.6 Hz, 1H), 7.0-7.2 (m, 5H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H) 5.4 (s, 1H), 3.8 (br s, 2H), 2.2-3.2 (m, 10H). MS: m/z: 402 [M+H]+.
Reaction SMILES: [C:1]12([C:8]3[C:13](Cl)=[N:12][N:11]4[C:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[N:16][N:17]=[C:10]4[CH:9]=3)[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[CH3:24][N:25]1[C:29]([CH2:30][OH:31])=[N:28][CH:27]=[N:26]1.[H-].[Na+].O>CN(C)C=O>[C:1]12([C:8]3[C:13]([O:31][CH2:30][C:29]4[N:25]([CH3:24])[N:26]=[CH:27][N:28]=4)=[N:12][N:11]4[C:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[N:16][N:17]=[C:10]4[CH:9]=3)[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: Cn1ncnc1CO
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1C12CCC(CC1)C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nn2c(-c3ccccc3)nnc2cc1C12CCC(CC1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7-(bicyclo[2.2.1]hept-1-yl)-6-chloro-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (0.125 g, 0.39 mM) and (2-methyl-2H-1,2,4-triazol-3-yl)methanol (0.08 g, 0.47 mM; prepared using the conditions described in EP-A-421210) in N,N-dimethylformamide (20 ml) was added sodium hydride (0.015 g of a 60% dispersion in oil, 0.47 mM eq) and the reaction mixture was stirred at room temperature for 3 hours. Water was added until the solution became cloudy and after stirring for a further 15 minutes a solid was collected by filtration. This solid was recrystallised from ethyl acetate-dichloromethane to give the required product (0.048 g, m.p.=244-246° C.). 1H NMR (360 MHz, DMSO) δ1.39 (2H, m), 1.67-1.84 (8H, m), 2.30 (1H, m), 3.93 (3H, s), 5.70 (2H, s), 7.52-7.62 (3H, m), 8.00 (1H, s), 8.35 (1H, s), 8.38 (2H, m); (Regiochemistry was established using nOe data). MS (ES+) m/e 402 [MH]+. Anal. Found C, 65.71; H, 5.65; N, 24.07. C22H23N7O requires C, 65.82; H, 5.77; N, 24.42%.
Reaction SMILES: Br[C:2]1[C:3]([O:23][CH3:24])=[C:4]([CH:10]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([NH2:21])=[C:15]3[C:14]([CH3:22])=[N:13]2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[CH:25]1([B-](F)(F)F)[CH2:27][CH2:26]1.[K+].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>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>[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([CH:25]2[CH2:27][CH2:26]2)[C:3]([O:23][CH3:24])=[C:4]([CH:10]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([NH2:21])=[C:15]3[C:14]([CH3:22])=[N:13]2)[CH3:11])[CH:5]=1
Reactant: F[B-](F)(F)C1CC1
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CC1
Temperature: 110 °C
Yield: 8 %

Procedure:
To a microwave vial was added 1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (15 mg, 0.037 mmol, from peak 1 from Example 167, step 4), potassium cyclopropyltrifluoroborate (8 mg, 0.06 mmol, from Frontier Scientific, item # C10298), potassium phosphate (23 mg, 0.11 mmol), and tetrakis(triphenylphosphine)palladium (4.2 mg, 0.0036 mmol) and then toluene (0.3 mL)/water (0.1 mL). The vial was sealed and degassed with N2 three times. The reaction was heat at 110° C. for 20 h. The crude was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (1.1 mg, 8%). The product was isolated as a single enantiomer. LCMS calculated for C19H23ClN5O (M+H)+: m/z=372.2; Found: 372.2.