Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[Cl:35][C:36]1[N:40]([CH:41]([CH3:43])[CH3:42])[N:39]=[CH:38][C:37]=1[NH2:44].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:35][C:36]1[N:40]([CH:41]([CH3:43])[CH3:42])[N:39]=[CH:38][C:37]=1[NH:44][C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[C:6]=2[N:7]=1
Reactant: CC(C)n1ncc(N)c1Cl
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5CCCC5)c34)cc2o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Nc5cnn(C(C)C)c5Cl)nc(OC5CCCC5)c34)cc2o1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a degassed mixture of 6-(2-chloro-4-(cyclopentyloxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), 5-chloro-1-isopropyl-1H-pyrazol-4-amine (1.3 equiv) and cesium carbonate (3 equiv) in 1,4-dioxane (0.06 M) was added palladium acetate (0.1 equiv) and 2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (0.3 equiv). The reaction was stirred at 100° C. for 2 h. Upon completion, the reaction mixture was cooled to room temperature, and concentrated. The residue was purified by silica gel chromatography (1-2% MeOH in DCM) to afford the desired product as a yellow solid, which was used in next step without further purification. MS (ESI) m/z 622.2 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][Si](C(C)(C)C)(C)C)=[CH:17][C:16]=2[O:29][Si](C(C)(C)C)(C)C)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:44](Cl)(=[O:47])[CH2:45][CH3:46]>ClC(Cl)C.CN(C)C1C=CN=CC=1>[CH2:1]([N:8]([C@H:9]1[CH2:10][CH2:11][C@@H:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[OH:29])[CH2:13][CH2:14]1)[C:44](=[O:47])[CH2:45][CH3:46])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](NCc3ccccc3)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(=O)N(Cc1ccccc1)[C@H]1CC[C@@H](c2ccc(O)cc2O)CC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
cis-N-Benzyl-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl] amine (0.084 g) was dissolved in dichloroethane (7 ml), and triethylamine (0.045 ml) and 4-dimethylaminopyridine (catalytic) added. Propionyl chloride (0.028 ml) was then added, and the mixture stirred at room temperature for 60 hr. The reaction mixture was partitioned between dichloromethane (10 ml) and saturated aqueous sodium hydrogen carbonate (10 ml). The aqueous layer was extracted with dichloromethane (2×10 ml) and the combined organic extracts washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was dissolved with stirring in dichloroethane (16 ml) and heated with a mixture of water (10 ml), methanol (5 ml) and trifluoroacetic acid (10 ml) at 80° C. for 17 hr. Toluene (25 ml) was then added and the mixture concentrated in vacuo. Methanol (25 ml) was then added and the mixture again concentrated in vacuo. Purification via flash chromatography (SiO2, ethyl acetate/petroleum ether) afforded the title compound (0.021 g, 37%) as a colourless solid. Rf 0.20 (ethyl acetate/petroleum ether, 1:1, v/v); m/s(ES+) 354.17 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH2:17][CH3:18])=[O:8]
Reactant: Cc1ccc(Cl)cc1C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(Cl)ccc1C
Temperature: 25 °C

Procedure:
5-chloro-2-methylbenzoic acid (5.04 g, 29.5 mmol) was dissolved in 100 mL ethanol in a 250 mL round bottom flask fitted with a water condenser. 0.5 mL concentrated sulfuric acid was added and the solution heated to reflux. The solution was heated for 48 h and cooled to ambient temperature. The ethanol was removed under reduced pressure. The resultant oil was taken up in 300 mL diethyl ether and washed with saturated aqueous sodium bicarbonate (2×300 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to yield 5.12 (87%) of ethyl 5-chloro-2-methylbenzoate as a clear oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][N:41]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:40]5[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][N:41]=5)=[CH:27][CH:28]=4)[CH2:21][CH2:22]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Reactant: Clc1cccnc1Br
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: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ncccc5Cl)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 35.7 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 2-bromo-3-chloropyridine (294 mg, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (193 mg, 36%) as a black oily substance.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=O)C.C[Al](C)C.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:18][N:17]([CH3:19])[CH2:16][CH2:15][N:14]1[CH2:13][CH2:12][C:7]2[NH:8][CH:9]=[C:10]([CH3:11])[C:6]=2[C:4]1=[O:3]
Reactant: CCOC(=O)c1c(C)c[nH]c1CCNCCN(C)C
Agent: C[Al](C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c[nH]c2c1C(=O)N(CCN(C)C)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.4 %

Procedure:
A stirred solution of 2-[2-(2-dimethylamino-ethylamino)-ethyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (267 mg, 1 mmol) in 5 ml of toluene was added dropwise with 2M trimethyl aluminum in toluene (1 ml, 2 mmol) under an argon atmosphere. The mixture was stirred for 1 hour at room temperature and heated to reflux for another 4 hours. The reaction mixture was cooled down to or in an ice-water bath, added with 1N hydrochloric acid (10 ml) and cold water (10 ml). The mixture was adjusted to pH12 with 10% aqueous sodium hydroxide solution and extracted with dichloromethane (25 ml×5). The combined organic extracts were filtered through a pad of Celite. The filtrate was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 5-(2-dimethylamino-ethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (242 mg, 97%) as a brown oil which was used as such.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O:11][C:12](=O)[C:13]([C:26]#[N:27])=[CH:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([Br:25])[CH:16]=1)C>>[NH2:1][C:2]1[CH:3]=[C:4]2[C:5]([C:14]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([Br:25])[CH:16]=3)=[C:13]([C:26]#[N:27])[C:12](=[O:11])[O:8]2)=[CH:6][CH:7]=1
Reactant: Nc1cccc(O)c1
Reactant: CCOC(=O)C(C#N)=Cc1cc(Br)c(OC)c(OC)c1
Product: COc1cc(-c2c(C#N)c(=O)oc3cc(N)ccc23)cc(Br)c1OC
Yield: 7 %

Procedure:
The title compound was prepared from 3-aminophenol and 3-(3-bromo-4,5-dimethoxyphenyl)-2-cyano-acrylic acid ethyl ester by a procedure similar to that described for Example 16 in 7% yield. 1H NMR (CDCl3): 7.20-7.16 (m, 2H), 6.96 (d, J=2.1 Hz, 1H), 6.59-6.55 (m, 2H), 4.63 (brs, 2H), 3.96 (s, 3H), 3.92 (s, 3H).
Reaction SMILES: BrBr.[F:3][C:4]1[CH:9]=[C:8]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)=O)[CH:7]=[CH:6][N:5]=1.[CH3:20][S:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[S:27])=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[F:3][C:4]1[CH:9]=[C:8]([C:10]2[S:27][C:26]([C:25]3[CH:29]=[CH:30][C:22]([S:21][CH3:20])=[CH:23][CH:24]=3)=[N:28][C:11]=2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CSc1ccc(C(N)=S)cc1
Reactant: Cc1cccc(C(=O)Cc2ccnc(F)c2)c1
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CSc1ccc(-c2nc(-c3cccc(C)c3)c(-c3ccnc(F)c3)s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
Bromine (2.7 mL, 52 mmol) was added to a solution of 2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone (12 g, 53 mmol) in acetic acid (90 mL) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated. This residue was dissolved in N,N-dimethylformamide (60 mL), 4-(methylthio)thiobenzamide (9.6 g, 52 mmol) was added and the mixture was stirred at room temperature for 15 hours. A saturated aqueous solution of sodium hydrogencarbonate (100 mL) was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 4:1) to obtain 4.7 g (yield 23%) of the title compound.
Reaction SMILES: [C:1]([N:8]([CH2:19][C:20]1[CH:21]=[C:22]([N+:45]([O-])=O)[CH:23]=[C:24]([CH2:26][N:27]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:28]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[NH:29])[CH:25]=1)[C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[NH:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CO.[Pd]>[C:38]([N:27]([CH2:26][C:24]1[CH:23]=[C:22]([CH:21]=[C:20]([CH2:19][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[NH:10])[CH:25]=1)[NH2:45])[C:28]([NH:30][C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[NH:29])([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]
Reactant: CC(C)(C)OC(=O)NC(=N)N(Cc1cc(CN(C(=N)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc([N+](=O)[O-])c1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(=N)N(Cc1cc(N)cc(CN(C(=N)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
3,5-bis-(N,N′-bis-Boc-guanidinyl)methyl nitrobenzene (4.52 g, 6.86 mmol) was dissolved in 50 ml absolute methanol, and catalytic amount of Pd/C was added into this mixture. The mixture was stirred at room temperature under hydrogen atmosphere for four hours. The solvent was removed to give the title compound as a light yellow solid (100%).
Reaction SMILES: [C:1]([N:8]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:9][C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].OS([O-])(=O)=O.[K+]>CCOCC.O>[C:1]([N:8]([CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)[CH2:9][CH:10]=[O:11])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)C1CCCCC1
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N(CC=O)C1CCCCC1
Reaction time: 0.25 h

Procedure:
A solution of 40 g (0.119 mole) of BOC-CYCLOHEXYLGLYCINE, O,N-DIMETHYLHYDROXAMIDE in 550 ml Et2O was cooled in ice and 148 ml (0.148 mole) of a 1M solution of LiAlH4 in Et2O added over 0.5 hour. After an additional 15 minutes, the mixture was treated cautiously with 28 g of KHSO4 in 100 ml H2O. The mixture was filtered through Celite and washed with 10% citric acid and saturated NaHCO3. After drying the solvent was removed under reduced pressure to give the crude BOC-CYCLOHEXYLGLYCINAL. The material was used immediately in the following reaction. ##STR175##
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][CH:29]=1)[C:15]([NH:17][C:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:20])[CH3:19])=[O:16])(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]>CN(C=O)C>[Si:40]([O:39][CH2:38][CH2:37][N:5]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][CH:29]=1)[C:15]([NH:17][C:18]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([CH3:20])[CH3:19])=[O:16])[S:2]([CH3:1])(=[O:3])=[O:4])([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]
Reactant: CC(C)(NC(=O)c1cccc(-c2ccncc2NS(C)(=O)=O)c1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)c1cccc(-c2ccncc2N(CCO[Si](C)(C)C(C)(C)C)S(C)(=O)=O)c1)c1ccccc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a mixture containing 3-(3-(methylsulfonamido)pyridin-4-yl)-N-(2-phenylpropan-2-yl)benzamide (0.20 g, 0.50 mmol), potassium carbonate (0.30 g, 2.0 mmol) and DMF (1.6 mL) was added (2-bromoethoxy)(tert-butyl)dimethylsilane (0.10 mL, 0.50 mmol) in a steady stream via syringe. The mixture was stirred at 80° C. for 4 h, cooled to room temperature, filtered, concentrated and purified on silica gel (0-10% methanol/dichloromethane, 60 min gradient) to afford 3-(3-(N-(2-(tert-butyldimethylsilyloxy)ethyl)methylsulfonamido) pyridin-4-yl)-N-(2-phenylpropan-2-yl)benzamide as a brown oil. 1H NMR (500 MHz, DMSO-D6) δ ppm 8.75 (s, 1H), 8.64 (d, J=4.88 Hz, 1H), 8.35 (s, 1H), 7.96 (s, 1H), 7.91 (d, J=7.94 Hz, 1H), 7.77 (d, J=7.93 Hz, 1H), 7.52-7.60 (m, 2H), 7.40 (d, J=7.32 Hz, 2H), 7.28 (t, J=7.63 Hz, 2H), 7.17 (t, J=7.32 Hz, 1H), 3.42-3.50 (m, 1H), 3.25 (s, 3H), 3.03 (s, 1H), 1.64-1.71 (m, 6H), 0.71-0.78 (m, 9H), −0.12-−0.06 (m, 6H). LCMS: retention time: 2.497 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters-Sunfire, 5u, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 568 (MH+).
Reaction SMILES: C([Mg]Br)(C)C.[OH:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][CH2:14][CH2:15][C:16]2([C:29](OCC)=[O:30])[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)[CH2:9][CH2:8]1>O>[OH:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:14][CH2:15][C:16]3([CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:17]3)[C:29]2=[O:30])[CH2:9][CH2:8]1
Reactant: CCOC(=O)C1(CCN[C@H]2CC[C@@H](O)CC2)CCCN(C(=O)OC(C)(C)C)C1
Agent: CC(C)[Mg]Br
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC2(CCN([C@H]3CC[C@@H](O)CC3)C2=O)C1
Reaction time: 1 h

Procedure:
iso-Propylmagnesium bromide (1.0 M in THF, 1.5 mL) was slowly added to a solution of 1-tert-butyl 3-ethyl 3-{2-[(cis-4-hydroxycyclohexyl)amino]ethyl}piperidine-1,3-dicarboxylate (0.15 g, 0.38 mmol) at 0° C. and the mixture was stirred at this temperature for 1 h. The reaction was then poured into cold water and extracted with ethyl acetate, dried and concentrated to give the desired product (0.11 g, 85%). LC-MS: 353.2 (M+H)+, 297.1 (M+H-56)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6](Br)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)CCC.[Cl-].[Li+].[F-].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:15][N:16]=2)[CH:7]=1
Reactant: Cc1cc(Br)cc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [F-]
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccccn2)cc(-c2ccccn2)c1

Procedure:
A tridentate ligand, 3,5-di(2-pyridyl)toluene was synthesized as follows. Specifically, 3,5-dibromotoluene (6.9 g; 20 mmol), 2-tri-n-butylstannylpyridine (26.9 g; 73 mmol), bis(triphenylphosphine)palladium dichloride (1.55 g; 2.2 mmol), and lithium chloride (11.7 g; 276 mmol) were added to 130 ml of toluene and the mixture was refluxed for 2 days. After cooling, 50 ml of saturated potassium fluoride solution was added. The precipitated solid was separated by filtration, washed with a small amount of cooled toluene (20 ml×3), and vacuum dried. The obtained solid was placed to a mixed solution of dichloromethane and NaHCO3, and washed well. The organic layer was separated, was dried over MgSO4 powder, and then the solvent was removed by evaporation. Next, the solid was recrystallized from dichloromethane to obtain 2.2 g of grey solid of 3,5-di(2-pyridyl)toluene of interest.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]3[N:15]=[C:16]([CH3:19])[C:17](I)=[C:13]3[N:12]=[C:11]([N:20]3[CH2:24][CH2:23][CH2:22][C@H:21]3[CH2:25][OH:26])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>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.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]3[N:15]=[C:16]([CH3:19])[C:17]([C:32]4[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=4)=[C:13]3[N:12]=[C:11]([N:20]3[CH2:24][CH2:23][CH2:22][C@H:21]3[CH2:25][OH:26])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1nn2c(-c3ccc(F)c(F)c3)cc(N3CCC[C@H]3CO)nc2c1I
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(C)nn3c(-c4ccc(F)c(F)c4)cc(N4CCC[C@H]4CO)nc23)cc1
Temperature: 85 °C
Reaction time: 6 h
Yield: 97.7 %

Procedure:
(S)-(1-(7-(3,4-Difluorophenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)methanol (62 mg), 4-methoxyphenylboronic acid (27 mg) and tetrakis(triphenylphosphine)palladium (10 mg) are added to toluene (8 mL), ethanol (3 mL) and 1 N NaHCO3 aqueous solution (1.5 mL) and stirred for 6 hours under argon atmosphere at 85° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure, concentrated and purified by column chromatography to yield the target compound (58 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[C-:10]#[N:11].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][C:10]#[N:11])[CH:7]=[CH:8][CH:9]=1
Reactant: Clc1cccc(CBr)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: N#CCc1cccc(Cl)c1
Temperature: 25 °C
Yield: 86.9 %

Procedure:
The experimental procedure was followed by the method of Bruno P. Imbimbo et al [J. Med. Chem. 2005, 48, 5707-7520]. A solution of 3-chlorobenzylbromide (5 g, 24.3 mmol) and sodium cyanide (1.3 g, 26.8 mmol) in ethanol (50 ml) was heated to 80° C. for 2 hours. After resulting solution was cooled to room temperature and concentrated under reduced pressure. The residue was suspended in water and organic layer was extracted with ethyl acetate. The solution was evaporated and crude compound was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to yield 2-(3-chlorophenyl)acetonitrile (3.2 g, 87% yield) as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][S:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[CH3:20]I>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][S:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([O:12][CH3:20])=[O:11]
Reactant: COc1cccc(CSc2ncccc2C(=O)O)c1
Reactant: CI
Solvent: CC#N
Product: COC(=O)c1cccnc1SCc1cccc(OC)c1
Yield: 91.7 %

Procedure:
A suspension of 7.15 g (0.026 mole) of 2-(3-methoxybenzylthio)nicotinic acid in 75 ml of dry acetonitrile was treated with 3.95 g (0.026 mole) of 1,8-diazabicyclo[5,4,0]-under-7-ene (DBU). A solution formed and 4.26 g (0.030 mole) of methyl iodide was added over one minute. After keeping the reaction mixture at room temperature for 24 hours, the solution was evaporated in vacuo. The residue was partitioned between 100 ml of ether and 50 ml of water. The ether layer was washed with 50 ml of H2O, dried, and evaporated to a small volume. The addition of hexane with cooling yielded 6.9 g (92% of theory) of methyl 2-(3-methoxybenzylthio)nicotinate; m.p. 69°-70° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].C([O:24][C:25](=[O:55])[C@@H:26]([NH:34][C:35]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([N:47]2[CH2:52][CH2:51][CH:50]([CH:53]=O)[CH2:49][CH2:48]2)(=[O:46])=[O:45])=[CH:40][CH:39]=1)=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)C1C=CC=CC=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[OH:4][C@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[CH2:2][NH:1][CH2:53][CH:50]1[CH2:51][CH2:52][N:47]([S:44]([C:41]2[CH:42]=[CH:43][C:38]([NH:37][C:35]([NH:34][C@@H:26]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:25]([OH:55])=[O:24])=[O:36])=[CH:39][CH:40]=2)(=[O:46])=[O:45])[CH2:48][CH2:49]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: O=CC1CCN(S(=O)(=O)c2ccc(NC(=O)N[C@@H](Cc3ccccc3)C(=O)OCc3ccccc3)cc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCC2CCN(S(=O)(=O)c3ccc(NC(=O)N[C@@H](Cc4ccccc4)C(=O)O)cc3)CC2)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.4 %

Procedure:
A solution of N-[5-(2-amino-1-{R}-hydroxyethyl)-2-hydroxyphenyl]-methane-sulfonamide (0.320 g, 1.3 mmol), (2S)-2-{3-[4-(4-formyl-piperidine-1-sulfonyl)-phenyl]-ureido}-3-phenyl-propionic acid benzyl ester (1.3 mmol) and glacial acetic acid (0.074 g, 1.3 mmol) in 5 mL methanol was stirred for 1 hour over 4A molecular sieves. In one portion sodium cyanoborohydride (0.086 g, 1.3 mmol) was added and the mixture stirred overnight at ambient temperature. The sieves were filtered and the filtrate was preabsorbed on silica gel. The solids were purified by flash chromatography (CH2Cl2—CH3OH, 19:1). to give 0.12 g of the product.