Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](C)(C)C)[S:10][C:3]=12.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[S:10][C:3]=12
Reactant: C[Sn](C)(C)c1cc2nccc(Cl)c2s1
Reactant: Brc1ccccn1
Product: Clc1ccnc2cc(-c3ccccn3)sc12
Yield: 30.5 %

Procedure:
This material was prepared by coupling 7-chloro-2-(trimethylstannyl)thieno[3,2-b]pyridine 39a (0.255 g, 0.77 mmole) with 2-bromopyridine (0.121 g, 0.77 mmole) using tereakis(triphenylphosphine)palladium(0) (0.036 g) as catalyst in a manner as previously described in example 39b to give a white solid (0.058 g, 31%). 1H NMR (300 MHz, CDCl3) δ 8.66 (1H, m), 8.57 (1H, d, J=5.1 Hz), 8.00 (1H, s), 7.83 (3H, m), 7.27 (1H, d, J=5.1 Hz); ESIMS (MH+): 246.95.
Reaction SMILES: [H-].[Na+].[CH:3]1([N:6]2[CH:10]=[N:9][N:8]=[C:7]2[C:11]2[CH:12]=[C:13]([NH:17][C:18]([C:20]3[CH:25]=[C:24]([C:26]4[CH:27]=[N:28][C:29](F)=[CH:30][CH:31]=4)[CH:23]=[CH:22][N:21]=3)=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH2:5][CH2:4]1.[CH:33]1([OH:37])[CH2:36][CH2:35][CH2:34]1>>[CH:33]1([O:37][C:29]2[N:28]=[CH:27][C:26]([C:24]3[CH:23]=[CH:22][N:21]=[C:20]([C:18]([NH:17][C:13]4[CH:14]=[CH:15][CH:16]=[C:11]([C:7]5[N:6]([CH:3]6[CH2:5][CH2:4]6)[CH:10]=[N:9][N:8]=5)[CH:12]=4)=[O:19])[CH:25]=3)=[CH:31][CH:30]=2)[CH2:36][CH2:35][CH2:34]1
Reactant: OC1CCC1
Reactant: O=C(Nc1cccc(-c2nncn2C2CC2)c1)c1cc(-c2ccc(F)nc2)ccn1
Agent: [H-]
Agent: [Na+]
Product: O=C(Nc1cccc(-c2nncn2C2CC2)c1)c1cc(-c2ccc(OC3CCC3)nc2)ccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55 %

Procedure:
Sodium hydride (60% in mineral oil, 15 mg, 0.38 mmol) was added to 0.5 mL of cyclobutanol and the reaction mixture was stirred for 10 minutes at room temperature. (N-(3-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)phenyl)-6-fluoro-3,4′-bipyridine-2′-carboxamide) (24 mg, 0.06 mmol) in cyclobutanol (0.2 mL) was added and the reaction mixture was heated to 90° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, neutralized with 1 M HCl and purified by reverse-phase HPLC to give the product as a white powder (15 mg, 55% yield).
Reaction SMILES: [CH:1]1([C:4]([O:6]CC)=O)[CH2:3][CH2:2]1.[C:9]([O:12][CH2:13][CH3:14])(=[O:11])[CH3:10]>>[CH:1]1([C:4](=[O:6])[CH2:10][C:9]([O:12][CH2:13][CH3:14])=[O:11])[CH2:2][CH2:3]1
Reactant: CCOC(C)=O
Reactant: CCOC(=O)C1CC1
Product: CCOC(=O)CC(=O)C1CC1

Procedure:
A solution of 2.59 g of 1-amino-3-cyclopropyl-3-p-trifluoromethylphenoxy-propane (obtainable by a condensation reaction of ethyl cyclopropanecarboxylate with ethyl acetate to give ethyl 3-cyclopropyl-propan-3-on-1-oate; reduction of the latter to ethyl 3-cyclopropyl-propan-3-ol-1-oate; reaction of the latter with p-trifluoromethylphenol analogously to Example 3, to give ethyl 3-cyclopropyl-3-p-trifluoromethylphenoxy-propanoate; reaction with NH3 to give the amide; and reduction of the latter with LiAlH4) and 1.5 g of benzaldehyde in 25 ml of toluene is boiled for one hour under a water separator. The solution of the resulting 1-benzylideneamino-3-cyclopropyl-3-p-trifluoromethylphenoxy-propane is heated with 5 g of methyl iodide for 12 hours at 150° in a tube and then evaporated. The resulting quaternary salt is boiled for 10 minutes in 90% ethanol. The mixture is again evaporated, the residue is taken up in dilute hydrochloric acid and the benzaldehyde which has been split off is removed by extraction with ether. The acid, aqueous solution is rendered alkaline with sodium hydroxide solution and worked up in the customary manner. 1-Methylamino-3-cyclopropyl-3-p-trifluoromethylphenoxypropane is obtained. Rf 0.22 (A).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:11])(=[O:10])=[O:9])[N:3]=1.C([Li])CCC.Br[C:18]1[S:22][C:21]([C:23]2[N:27]3[N:28]=[C:29]([CH3:37])[CH:30]=[C:31]([CH:32]([CH2:35][CH3:36])[CH2:33][CH3:34])[C:26]3=[N:25][C:24]=2[CH3:38])=[C:20]([CH3:39])[CH:19]=1>[Cl-].[Cl-].[Zn+2].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]>[CH2:33]([CH:32]([C:31]1[C:26]2[N:27]([C:23]([C:21]3[S:22][C:18]([C:2]4[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:11])(=[O:10])=[O:9])[N:3]=4)=[CH:19][C:20]=3[CH3:39])=[C:24]([CH3:38])[N:25]=2)[N:28]=[C:29]([CH3:37])[CH:30]=1)[CH2:35][CH3:36])[CH3:34]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Reactant: CS(=O)(=O)c1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4cccc(S(C)(=O)=O)n4)cc3C)c(C)nc12
Yield: 27.5 %

Procedure:
Using a procedure similar to Example 25, 2-bromo-6-methanesulfonyl-pyridine (0.29 mL, 1.22 mmol), 1.3 M n-Bu-Li (0.82 mL, 1.07 mmol), ZnCl2 (2.14 mL, 1.07 mmol), 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.40 g, 1.02 mmol) and PdCl2(dppf) (0.037 g, 0.051 mmol) furnish the title compound (0.13 g, 0.28 mmol, 27%). 1H NMR (CDCl3), 60.88 (t, J=7.5 Hz, 6H), 1.75-1.93 (m, 4H), 2.18 (s, 3H), 2.50 (s, 3H), 2.52 (s, 3H), 3.30 (s, 3H), 3.30-3.38 (m, 1H), 6.70 (s, 1H), 7.64 (s, 1H), 7.83 (dd, J=7.6, 0.8 Hz, 1H), 7.89 (dd, J=7.9, 0.8 Hz, 1H), 7.93 (dd, J=7.9, 7.6 Hz, 1H). LC/MS (m/z): calcd. for C24H28N4O2S2 (M+H)+: 469.3; found: 469.2.
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH:6]([OH:20])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH3:19])[CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])([CH3:3])[CH3:2].[CH2:21](N(C(C)C)CC1OC1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Na].CS(C1C(C)=CC(O)=CC=1)(=O)=O>C(O)C>[CH2:21]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH:6]([OH:20])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH3:19])[CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:16])=[O:17])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1ccc(S(C)(=O)=O)c(OCC(O)CNC(C)C)c1
Reactant: CC(C)N(Cc1ccccc1)CC1CO1
Agent: Cc1cc(O)ccc1S(C)(=O)=O
Agent: [Na]
Solvent: CCO
Product: Cc1ccc(S(C)(=O)=O)c(OCC(O)CN(Cc2ccccc2)C(C)C)c1

Procedure:
A further modification of the procedure for preparing 1-(isopropylamino)-3-[4-(methylsulfonyl)-m-tolyloxy]-2-propanol employing an epihalohydrin derivative of Formula VII containing a hydrogenolyziable blocking group follows. 1-[(N-Benzyl)isopropylamino]-2,3-epoxypropane is reacted with 4-(methylsulfonyl)-m-cresol sodium salt in ethanol to provide 1-[(N-benzyl)isopropylamino]-3-[4-(methylsulfonyl)-m-tolyloxy]-2-propanol.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:10])([CH3:9])[CH2:4][S:5]([NH2:8])(=[O:7])=[O:6].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(Cl)(Cl)Cl>N1C=CC=CC=1>[S:17]([O:1][CH2:2][C:3]([CH3:10])([CH3:9])[CH2:4][S:5]([NH2:8])(=[O:7])=[O:6])([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(CO)CS(N)(=O)=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OCC(C)(C)CS(N)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a solution of 5.0 g of 3-hydroxy-2,2-dimethyl-1-propanesulfonamide in 18 ml of pyridine was added 6.3 g of p-toluenesulfonyl chloride under ice-cooling and stirring. After 2 hours, the reaction mixture was poured into a mixture of 300 ml of chloroform and 100 ml of ice-water. The separated chloroform layer was washed in turn with diluted hydrochloric acid and water, dried over anhydrous magnesium sulfate and distilled under reduced pressure to obtain 8.5 g of 3-tosyloxy-2,2-dimethyl-1-propanesulfonamide.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[N:11]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:18]=2)[C:10](=[O:27])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][CH2:30][CH2:31]Br>>[CH2:1]([N:8]1[C:12](=[O:13])[N:11]([C:14]2[CH:15]=[N:16][N:17]([CH2:19][C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])[CH:18]=2)[C:10](=[O:27])[N:9]1[CH2:31][CH2:30][O:29][CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCBr
Reactant: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]n(Cc3ccccc3)c2=O)cn1
Product: COCCn1c(=O)n(-c2cnn(Cc3c(C)noc3C)c2)c(=O)n1Cc1ccccc1
Yield: 20 %

Procedure:
Prepared as in example 10-91 from 1-benzyl-4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1,2,4-triazolidine-3,5-dione (example 10-91a) and 2-bromoethyl methyl ether. Yield: 20%. MS M+H calculated 425.19; found 425.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.06 μM.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[H-].[Na+].[CH3:17][CH:18]([CH3:30])[C:19]([O:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20]>>[CH3:17][CH:18]([CH3:30])[C:19]([O:21][N:22]([S:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[S:2]([CH3:1])(=[O:4])=[O:3])(=[O:13])=[O:12])[C:23](=[O:24])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:20]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)C(=O)ONC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: CC(C)C(=O)ON(C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O

Procedure:
tert-Butyl [(2-methylpropanoyl)oxy]{[2-(methylsulfonyl)phenyl]sulfonyl}carbamate (45) is prepared from 2-methylsulfonylbenzenesulfonyl chloride, sodium hydride and [(tert-butoxy)carbonyl]amino 2-methylpropanoate according to Scheme 2. (1.2 g, 72%), 1H NMR (250 MHz, DMSO-d6) δ ppm 8.18-8.34 (2H, m), 8.00-8.14 (2H, m), 3.46 (3H, s), 2.86 (1 H, sept, 7.1 Hz), 1.29 (9H, s), 1.21 (6H, d, 7.0 Hz).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1.Cl.[NH:20]1[CH2:24][CH2:23][C@@H:22]([OH:25])[CH2:21]1>CN(C)C=O>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:20]2[CH2:24][CH2:23][C@@H:22]([OH:25])[CH2:21]2)=[CH:13][CH:12]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: O[C@@H]1CCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O[C@@H]1CCN(Cc2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
Diisopropylethylamine (1.57 ml, 9.00 mmol) was added to a solution (15 ml) of 1.50 g (6.00 mmol) of 4-bromobenzyl bromide and 1.11 g (9.00 mmol) of (R)-pyrrolidin-3-ol hydrochloride in dimethylformamide and the mixture was stirred at room temperature for one hr. The solvent was removed by distillation under the reduced pressure. Water and 1 N hydrochloric acid were then added to the residue, and the mixture was washed with ethyl acetate. A 5 N aqueous sodium hydroxide solution and an aqueous sodium hydrogencarbonate solution were added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and was then filtered. The filtrate was concentrated under the reduced pressure to give 1.09 g (yield 71%) of the title compound.
Reaction SMILES: [C:1]([C@@H:3]([N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][O:7][CH2:6]1)#[N:2].CO.C(Cl)Cl.[O-][Mn](=O)(=O)=O.[K+]>N.CO.[Ni]>[NH2:2][CH2:1][C@@H:3]([N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][O:7][CH2:6]1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](C#N)C[C@H]1CCCOC1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [Ni]
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)[C@H](CN)C[C@H]1CCCOC1
Reaction time: 1 h
Yield: 92 %

Procedure:
tert-Butyl (S)-1-cyano-2-((R)-tetrahydro-2H-pyran-3-yl)ethyl(methy)carbamate (397 mg, 4:1 mixture of diastereomers at the alpha-amino stereocenter) was dissolved in a solution of 4M NH3 in MeOH (15 mL) and passed through a Raney-nickel cartridge (CatCart®, 50 mm) on an in-line hydrogenation apparatus (H-Cube) with the following settings: ambient temperature (14° C.), flow rate 1.0 mL/min, H2 pressure 30 atm. The solution was recirculated so that the product solution was fed back into the apparatus. After thirty minutes, TLC analysis (1:9 MeOH/CH2Cl2, KMnO4 stain) showed complete conversion of the starting material. After 60 min total reaction time, the solution was evaporated to yield 371 mg (92%) of tert-butyl (S)-1-amino-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-yl(methyl)carbamate as a clear, rose-colored oil. LC-MS (ELSD) m/e 273.6 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:8][CH:7]=1)[CH:2]=[CH2:3]>ClCCl.C(P(C1CCCCC1)(C1CCCCC1)C1CCCCC1)(P(C1CCCCC1)(C1CCCCC1)C1CCCCC1)C1C=CC=CC=1.Cl[Ru]Cl>[Si:14]([O:13][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][O:4][CH2:1][CH:2]=[CH:3][CH2:1][O:4][CH2:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:8][CH:7]=2)=[CH:11][CH:10]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16]
Reactant: C=CCOCc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Agent: Cl[Ru]Cl
Agent: c1ccc(C([PH](C2CCCCC2)(C2CCCCC2)C2CCCCC2)[PH](C2CCCCC2)(C2CCCCC2)C2CCCCC2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1ccc(COCC=CCOCc2ccc(CO[Si](C)(C)C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 57.4 %

Procedure:
Benzylidene-bis(tricyclohexylphosphine)-dichlororuthenium (420 mg, 0.513 mmol, 15 mol %) is added under an argon atmosphere to a solution of 4-allyloxymethyl-1-tert-butyldimethylsilyloxymethyl)-benzene (80, 1.0 g, 3.24 mmol) in 70 mL dry dichloromethane. The reaction mixture is stirred at room temperature for 15 h, and additional catalyst (200 mg) is added and the reaction mixture heated to reflux for 5 h. The solvent is removed in vacuo, and the product purified by column chromatography (petrol ether/ethyl acetate 50:1) to yield 520 mg (0.93 mmol, 55%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[I:11]Cl>Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:11])=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)c1ccccc1N
Reactant: ClI
Agent: Cl
Product: CC(=O)c1cc(I)ccc1N
Temperature: 0 °C

Procedure:
Into a 250 mL round-bottom flask, was placed a solution of 1-(2-aminophenyl)ethanone (11 g, 81.48 mmol, 1.00 equiv) in 1N HCl (300 mL). This was followed by the addition of a solution of ICl (14.5 g, 89.51 mmol, 1.10 equiv) in 2N HCl (50 mL) dropwise with stirring at 0° C. The reaction mixture was stirred for 2 h at room temperature in a water/ice bath. The solid were collected by filtration and then washed with 200 mL of ethyl acetate: MeOH (10:1). The title compound was obtained as a brown solid.
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10](O)=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1>C1COCC1>[O:1]1[C:5]2[C:6]([CH2:10][OH:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc2c1OCC2
Solvent: C1CCOC1
Product: OCc1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
Added BH3 (1M in THF, 9 mL) to a solution of 2,3-dihydro-1-benzofuran-7-carboxylic acid (481 mg, 2.93 mmol) in THF (7 mL) drop wise at 0° C., thereto, the mixture was stirred at room temperature overnight. Extracted with ethyl acetate twice, and washed the organic phase with brine and dried with anhydrous Na2SO4, concentrated to give the title compound (340 mg, 77%). 1H NMR (400 MHz, CDCl3): δ 2.09 (1H, s), 3.22 (2H, t, J=8.8 Hz), 4.61 (2H, t, J=8.8 Hz), 4.67 (2H, s), 6.83 (1H, t, J=7.6 Hz), 7.08 (1H, d, J=7.2 Hz), 7.14 (1H, d, J=7.2 Hz).
Reaction SMILES: [N+]([O-])([O-])=O.[Na+].[CH3:6][C:7]1([CH3:19])[C:16]2[C:11](=[CH:12][C:13](N)=[CH:14][CH:15]=2)[C:10](=[O:18])[CH2:9][CH2:8]1.[BrH:20]>S(=O)(=O)(O)O.C(O)(=O)C.O.[Cu]Br>[CH3:6][C:7]1([CH3:19])[C:16]2[C:11](=[CH:12][C:13]([Br:20])=[CH:14][CH:15]=2)[C:10](=[O:18])[CH2:9][CH2:8]1
Reactant: Br
Reactant: CC1(C)CCC(=O)c2cc(N)ccc21
Agent: [Cu]Br
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)CCC(=O)c2cc(Br)ccc21
Temperature: 10 °C

Procedure:
To a cooled (10° C.) stirred solution of sodium nitrate (2.18 g, 13.92 mmol) in concentrated sulfuric acid (28.4 mL) and glacial acetic acid (26.27 mL) [prepared by adding sodium nitrate to cooled (10° C.) concentrated sulfuric acid, heating to dissolve, recooling and then adding glacial acetic acid] was added a solution of 4,4-dimethyl-7-amino-1-tetralone (XII) (5.0 g, 26.46 mmol) in glacial acetic acid (89 mL) over 10 mintues. The resulting solution was added slowly (over 10 minutes) to a heated (60° C.) solution of copper (I) bromide (16.66 g) in concentrated hydrobromic acid (159 mL). The mixture was warmed to 90° C. for 10 minutes, cooled, diluted with water (250 mL) and extracted with ethyl acetate (2×200 mL). The combined organic phases were concentrated in vacuo and the residue chromatographed on silica gel (eluted with 3% ethyl acetate in hexane) to give 1.95 g (Y: 29%) of the title compound; 1H-NMR (CDCl3): δ8.13 (d,J=2.3 Hz, 1H), 7.62 (dd, J=8.5, 2.3 Hz, 1H), 7.31 (d, J=8.5 Hz, 1H), 2.73 (t, J=7.0 Hz, 2H), 2.01 (t, J=7.0 HZ, 2H), 1.38 (s, 6H); MS (DCI) m/e: 253 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([OH:11])[CH:10]=1)[CH:6]=[O:7])#[CH:2].N1C=CN=C1.Cl[Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20].O>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[CH:10]=1)[CH:6]=[O:7])#[CH:2]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: C#Cc1cc(O)cc(C=O)c1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C#Cc1cc(C=O)cc(O[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.0 g of 3-ethynyl-5-hydroxybenzaldehyde [CAS No. 871345-34-5] in 20 ml of DMF there were added 1.87 g of imidazole and 4.4 ml of chlorotriisopropylsilane. The mixture was stirred overnight at room temperature. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with ice-cooled 1N hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (3.92 g) as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][N:16]([C:17]4[N:22]=[C:21]([N:23]5[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)[CH:20]=[CH:19][CH:18]=4)[C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1.Cl>O1CCOCC1>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][N:16]([C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([N:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[N:22]=4)[C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCNCC3)n2)n1
Yield: 55 %

Procedure:
A solution of tert-butyl 4-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]piperazine-1-carboxylate (60 mg, 0.1270 mmol) in 1,4-dioxane; 1.0 mL and hydrogen chloride (4 mol/L) in 1,4-dioxane (2.0 mL, 8.0 mmol) was stirred at RT 18 h. The reaction was concentrated and submitted for reverse phase HPLC to give 123 (26 mg) in 32% yield. MS (ESI) m/z: 373.2. 1H NMR (400 MHz, DMSO) δ 9.59 (s, 1H), 9.46 (s, 1H), 9.31 (s, 1H), 8.66 (s, 1H), 8.62 (s, 1H), 7.77 (t, J=8.1 Hz, 1H), 7.27 (d, J=7.7 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 3.67-3.60 (m, 4H), 2.96-2.89 (m, 4H), 2.63 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-])=O)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:15])[N:3]=1>[Pd].CO>[NH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[C:4]([CH3:15])[N:3]=[C:2]2[CH3:1]
Reactant: Cc1cc2c([N+](=O)[O-])cccc2c(C)n1
Agent: [Pd]
Solvent: CO
Product: Cc1cc2c(N)cccc2c(C)n1

Procedure:
A solution of D3 (2.01 g, 9.94 mM) and 10% palladium on charcoal (1 g) in methanol was hydrogenated at atmospheric pressure for 1 h. The catalyst was filtered off and the filtrate concentrated under reduced pressure to afford the product as a cream coloured solid.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([CH:20]3[CH2:25][CH2:24][N:23]([S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.[CH3:38][NH:39][CH3:40]>C1COCC1>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([CH:20]3[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][N:39]([CH3:40])[CH3:38])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: CNC
Reactant: C=CS(=O)(=O)N1CCC(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(C2CCN(S(=O)(=O)CCN(C)C)CC2)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[1-(vinylsulfonyl)-4-piperidinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (59 mg, 0.11 mmol) and 40% aqueous dimethylamine (5 mL) in THF (25 mL) was stirred at room temperature for 15 min. The solvent was removed under vacuum and the residue was diluted with water to give 63 mg (99% yield) of N-[2-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperidinyl}sulfonyl)ethyl]-N,N-dimethylamine: 1H NMR (CDCl3) δ 7.99 (d, J=7.9 Hz, 1H), 7.55 (t, JHF=53.6 Hz, 1H), 7.39 (t, J=8.3 Hz, 1H), 6.85 (d, J=7.9 Hz, 1H), 4.06 (s, 3H), 4.02-3.89 (m, 6H), 3.85-3.78 (m, 4H), 3.14-3.11 (m, 2H), 2.97 (dt, J=12.2, 2.6 Hz, 2H), 2.84-2.77 (m, 3H), 2.28 (s, 6H), 2.17 (br dd, J=13.2, 2.6 Hz, 2H), 2.00 (ddd, J=25.1, 11.8, 4.1 Hz, 2H).
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]([NH:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[S:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[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]([OH:25])=[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]([NH:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[S:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(NC(=S)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(NC(=S)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-cyclohexylaminothiocarbonylamino-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: COC(COCCCCCCCCCCCCCCCCCC)CS.[CH3:26][O:27][CH:28]([CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:29][OH:30].[CH:51]1[CH:56]=[CH:55][C:54]([S:57](Cl)(=[O:59])=[O:58])=[CH:53][CH:52]=1>N1C=CC=CC=1>[C:54]1([S:57]([O:30][CH2:29][CH:28]([O:27][CH3:26])[CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])(=[O:59])=[O:58])[CH:55]=[CH:56][CH:51]=[CH:52][CH:53]=1
Reactant: CCCCCCCCCCCCCCCCCCOCC(CO)OC
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CCCCCCCCCCCCCCCCCCOCC(CS)OC
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCOCC(COS(=O)(=O)c1ccccc1)OC

Procedure:
The 2-methoxy-3-octadecyloxy-1-propanethiol used as starting material is prepared in the following manner: 2-methoxy-3-octadecyloxy-1-propanol is reacted with benzenesulfochloride in anhydrous pyridine to give 2-methoxy-3-octadecyloxy-1-propanol benzene-sulfonate, (oil). This is then reacted with thiorea in butanol to give the isothiuronium salt which is saponified with potassium hydroxide solution and the thiol liberated with hydrochloric acid.