Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH3:13])([OH:12])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.Br[C:15]1[CH:16]=[C:17]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH:18]=[N:19][C:20]=1[C:21]#[N:22].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:21]([C:20]1[N:19]=[CH:18][C:17]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[CH:16][C:15]=1[NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([OH:12])([CH3:13])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1)#[N:22]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Br)c1
Reactant: CC1(O)CCCc2nc(N)ccc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Nc2ccc3c(n2)CCCC3(C)O)c1
Temperature: 80 °C

Procedure:
A mixture of 2-amino-5-methyl-5,6,7,8-tetrahydroquinolin-5-ol (45.4 mg, 0.255 mmol), tert-butyl (1S,2R)-2-(5-bromo-6-cyanopyridin-3-ylamino)cyclohexylcarbamate (PrepEx 1.1) (111 mg, 0.280 mmol), Xantphos (15 mg, 0.025 mmol), tris(dibenzylideneacetone)dipalladium(0) (12 mg, 0.013 mmol), and cesium carbonate (207 mg, 0.637 mmol) in 1,4-dioxane (10 ml) under an argon atmosphere was heated at 80° C. in an oil bath for 2.25 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (10 mL). The layers were separated, and the organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (1-5% methanol/dichloromethane, linear gradient) to give tert-butyl (1S,2R)-2-(6-cyano-5-(5-hydroxy-5-methyl-5,6,7,8-tetrahydroquinolin-2-ylamino)pyridin-3-ylamino)cyclohexylcarbamate. MS ESI calc'd. for C27H37N6O3 [M+H]+ 493. found 493.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([F:10])[C:3]=1[F:11].P(Br)(Br)[Br:13]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:13])=[C:4]([F:10])[C:3]=1[F:11]
Reactant: OCc1ccc(Br)c(F)c1F
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Fc1c(Br)ccc(CBr)c1F
Temperature: 10 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
To a solution of (4-bromo-2,3-difluorophenyl)methanol (500 mg, 2.242 mmol) in DCM (10 mL) stirred under N2 at 0° C. was added PBr3 (0.634 mL, 6.73 mmol) in one charge. The reaction mixture was stirred at 10° C. for 2 h. Then the solution was concentrated and distributed between DCM and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA=10:1, Rf 0.6) to yield light yellow oil of 1-bromo-4-(bromomethyl)-2,3-difluorobenzene (330 mg, 1.154 mmol, 51.5% yield): 1H NMR (400 MHz, CDCl3) δ 7.30 (ddd, J=2.0, 6.0, 8.2 Hz, 1H), 7.11-7.03 (m, 1H), 4.46 (s, 2H).
Reaction SMILES: [Cl-].[Li+].[BH4-].[Na+].C[O:6][C:7](=O)[C@H:8]([CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.C(O)C>[CH2:13]([O:12][C:10]([NH:9][C@H:8]([CH2:7][OH:6])[CH2:20][Si:21]([CH3:22])([CH3:23])[CH3:24])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)[C@H](C[Si](C)(C)C)NC(=O)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)C[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium chloride (0.64 g, 15 mmol) and sodium borohydride (0.57 g, 15 mmol) and then ethanol (22 ml) are added to a solution of example 74A (2.32 g, 7.5 mmol) in THF (14 ml). The mixture is stirred at RT overnight. For the workup, the mixture is adjusted to pH 4 with a citric acid solution (10% in water) while cooling with ice water, then diluted with 200 ml of water and extracted three times with dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is separated by means of HPLC (Method 41) and the suitable fractions are concentrated in vacuo. The title compound is obtained as an oil (1.24 g, 59% of theory).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH2:12][CH3:13])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[OH:28].[Cl-].[NH4+]>CN(C)C=O>[F:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[O:28][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH2:12][CH3:13])[N:5]=[CH:4][N:3]=1
Reactant: Oc1cccc(F)c1F
Reactant: CCC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC#CCOc1cc(Oc2cccc(F)c2F)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 88.1 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-pentynyloxy)pyrimidine, 0.21 g of potassium carbonate, and 0.16 g of 2,3-difluorophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.26 g of 4-(2,3-difluorophenoxy)-6-(2-pentynyloxy)pyrimidine (the present compound (60)).
Reaction SMILES: C(OC([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[H-].CC(C1C=C(C(C)(C)CC)C=CC=1OCC(O)=O)(C)CC.[I-].C(Br)C1C=CC=CC=1.C(I)C.[H-].[Na+].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>[O-2].[O-2].[Mn+4].CN(C=O)C.C1COCC1>[NH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:6]1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [Mn+4]
Agent: BrCc1ccccc1
Agent: CCC(C)(C)c1ccc(OCC(=O)O)c(C(C)(C)CC)c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCI
Product: c1ccc2[nH]ccc2c1

Procedure:
Aldehyde IX is prepared from Indol-2-carboxylic acid ethyl ester I in two steps: (1) Reduction with lithium aluminium hydride or other hydride in a suitable solvent such as THF at 0° C. and (2) oxidation with an oxidizing reagent such as manganese dioxide in a solvent such as THF. Aldehyde IX can be alkylated by a suitable alkyl bromide (or iodide), such as benzyl bromide or ethyl iodide in the presence of a strong base such as sodium hydride or KHMDS in a solvent such as DMF to yield indole X. Indole X can be converted to an unsaturated acid XI in two steps: (1) Wittig reaction with a suitable reagent such as trimethyl phosphonoacetate in the presence of a base such as sodium hydride in a solvent such as THF and (2) Hydrolysis by aqueous sodium hydroxide.
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[C:10]([CH3:24])=[C:11]([N+:21]([O-:23])=[O:22])[C:12]([NH:15][C:16]([CH:18]2[CH2:20][CH2:19]2)=[O:17])=[N:13][CH:14]=1.C(N(CC)CC)C.C(O)=O>CCCCCC.C(OCC)(=O)C>[CH:18]1([C:16]([NH:15][C:12]2[C:11]([N+:21]([O-:23])=[O:22])=[C:10]([CH3:24])[CH:9]=[CH:14][N:13]=2)=[O:17])[CH2:19][CH2:20]1
Reactant: Cc1c(Br)cnc(NC(=O)C2CC2)c1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O=CO
Product: Cc1ccnc(NC(=O)C2CC2)c1[N+](=O)[O-]
Yield: 72.3 %

Procedure:
Toluene (60 ml) was added to 3.0 g (10.0 mmol) of 5-bromo-2-cyclopropanecarboxamido-4-methyl-3-nitropyridine, 10% Pd--C (100 mg) and 2.9 g (28.6 mmol) of triethylamine, followed by stirring and heating under reflux. 1.9 g (41.3 mmol) of formic acid was dropwise added to this solution, followed by stirring for 5 hours. The reaction liquid was brought to room temperature and filtered to remove the catalyst. The filtrate was subjected to vacuum concentration. Chloroform (100 ml) and water (100 ml) were added to the residue and the obtained mixture was caused liquid-liquid separation. The aqueous phase was further extracted with chloroform (50 ml) once. The organic phases were combined, dried over anhydrous magnesium sulfate and subjected to vacuum concentration. The residue was purified by silica gel column chromatography: (a n-hexane/ethyl acetate system) to give 1.6 g of the title compound (yield 72%).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([OH:15])=O)=[CH:11][CH:12]=1>>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([Cl:3])=[O:15])=[CH:11][CH:12]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: COc1ccc(C(=O)Cl)cc1
Reaction time: 6 h

Procedure:
25 g of thionyl chloride was added to 5 g of p-methoxybenzoic acid. After the temperature of the mixture was kept at 70° C. for 6 hours under reflux, the mixture was heated under reduced pressure to remove unchanged thionyl chloride. The residue was dissolved in benzene, and after the solution was heated to be condensed, it was cooled to produce precipitate. The precipitate was recrystallized with benzene to obtain p-methoxybenzoyl chloride. 10 mmol of choline chloride was added to 10 mmol of p-methoxybenzoyl chloride. The temperature of the mixture was kept at 120° C. for 5 hours. The residue was separated and purified by subjecting to silica gel chromatography to obtain p-methoxybenzoyl choline chloride.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(=O)C>Br.O>[CH2:21]([C:18]1[CH:19]=[N:20][C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:16][CH:17]=1)[CH3:22]
Reactant: CCc1cnc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CCc1cnc(NC2CCNCC2)nc1
Yield: 92.2 %

Procedure:
A solution of 4-(5-ethyl-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (4.53 g, 16.3 mmol) in 48% HBr in water (45 mL) and acetic acid (45 mL) was heated to 100° C. After 4 h the solvents were removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (200 mL) with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure to yield 3.1 g (92%) of the title compound which was directly used in the consecutive step. MS (ISP): 207.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30](O)=[O:31])=[CH:20][C:19]=3[CH:33]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.S(Cl)(Cl)=O.[NH2:43][C:44]1[CH:49]=[CH:48][C:47]([S:50][CH2:51][C:52]2[N:53]([CH2:57][CH2:58][CH2:59][C:60]([O:62][CH2:63][CH3:64])=[O:61])[CH:54]=[CH:55][N:56]=2)=[CH:46][CH:45]=1>O1CCCC1.N1C=CC=CC=1.O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:43][C:44]4[CH:49]=[CH:48][C:47]([S:50][CH2:51][C:52]5[N:53]([CH2:57][CH2:58][CH2:59][C:60]([O:62][CH2:63][CH3:64])=[O:61])[CH:54]=[CH:55][N:56]=5)=[CH:46][CH:45]=4)=[O:31])=[CH:20][C:19]=3[CH:33]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCCN3CC(C)C)cc1
Reactant: CCOC(=O)CCCn1ccnc1CSc1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CCCC(=O)OCC)cc2)CCCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylic acid (700 mg) in tetrahydrofuran (10 ml) was added a drop of DMF. Then, after adding thionyl chloride (0.147 ml), the mixture was stirred under nitrogen atmosphere for 1 hour. The resulting solution was slowly added dropwise to a solution of ethyl 4-(2-(((4-aminophenyl)sulfanyl)methyl)imidazol-1-yl)butanoate (544 mg) in pyridine (10 ml) at 0° C. under nitrogen atmosphere. After stirring overnight at room temperature and under nitrogen atmosphere, to the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water and once with saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified with basic silica gel column chromatography (hexane:ethyl acetate=1:1→ethyl acetate), and re-crystallized from hexane-ethyl acetate to give ethyl 4-(2-(((4-(((8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydro-1-benzoazocine-5-yl)carbonyl)amino)phenyl)sulfanyl)-methyl)imidazol-1-yl)butanoate (1.03 g) (Compound 33) as yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:11](=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=2)[N:12]=1.[ClH:20].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:44][CH:45]1[CH2:52][CH:51]2[N:53]([CH3:54])[CH:47]([CH2:48][CH2:49][CH2:50]2)[CH2:46]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[ClH:20].[CH3:54][N:53]1[CH:47]2[CH2:48][CH2:49][CH2:50][CH:51]1[CH2:52][CH:45]([NH:44][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:10]3[O:9][C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[OH:1])=[N:12][C:11]=13)=[O:19])[CH2:46]2
Reactant: O=C(O)c1cccc2oc(-c3ccccc3O)nc12
Reactant: CN1C2CCCC1CC(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4ccccc4O)nc13)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.2 %

Procedure:
A mixture of 2-(2-hydroxyphenyl)benzoxazole-4-carboxylic acid (96 mg, 0.37 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (143 mg, 0.75 mmol), 1-hydroxybenzotriazole (102 mg, 0.75 mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (85 mg, 0.37 mmol) in DMF (5 mL) was stirred at room temperature for 10 min, then triethylamine (0.15 mL, 1.12 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic layers were washed with water (2×50 mL) and brine (2×50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) and recrystallization from acetonitrile to afford the desired product (70 mg, 48%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 10.54 (s, 1H), 8.21 (dd, J=7.8, 1.1 Hz, 1H), 8.09 (dd, J=8.1, 1.6 Hz, 1H), 7.80-7.77 (m, 1H), 7.75 (dd, J=8.1, 0.9 Hz, 1H), 7.57-7.50 (m, 2H), 7.17 (dd, J=8.6, 0.6 Hz, 1H), 7.10-7.05 (m, 1H), 4.70-4.60 (m, 1H), 3.25-3.15 (m, 2H), 2.73-2.69 (m, 2H), 2.56 (s, 3H), 2.15-1.95 (m, 2H), 1.65-1.45 (m, 4H), 1.25-1.10 (m, 2H); MS (ESI+) m/z 392 (M+H).
Reaction SMILES: C(=O)([O-])[O-:2].[Ca+2].C(#N)C.[CH3:9][N:10]([CH3:32])[CH2:11][CH2:12][C:13]1([C:19]2[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[CH:21]=[CH:22][CH:23]=2)SCCCS1>CCCCCC>[CH3:9][N:10]([CH3:32])[CH2:11][CH2:12][C:13]([C:19]1[N:20]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[CH:21]=[CH:22][CH:23]=1)=[O:2]
Reactant: CN(C)CCC1(c2cccn2Cc2ccccc2F)SCCCS1
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC#N
Solvent: CCCCCC
Product: CN(C)CCC(=O)c1cccn1Cc1ccccc1F

Procedure:
To a solution of 28.1 g of mercuric chloride and 10.3 g of calcium carbonate in 150 ml of aqueous 80% acetonitrile is added under nitrogen a solution of 17.0 of 2-(2-dimethylaminoethyl)-2-[1-(o-fluorobenzyl)-2-pyrryl]-1,3-dithiane in 100 ml of aqueous 80% acetonitrile. The reaction mixture is stirred at reflux for 4 hours, the mixture is permitted to cool and filtered through celite. The filter cake is washed with a hexane-dichloromethane mixture and the washed solution is washed successively with a 5M aqueous ammonium acetate solution and water, dried and filtered. The solvents are evaporated off leaving a dark oil which solidifies upon trituration witn n-hexane to give the solid product of 2-(3-dimethylaminopropionyl)-1-(o-fluorobenzyl)pyrrole.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:17][C@H:18]([CH:21]([CH3:23])[CH3:22])[CH2:19][OH:20])=[N:4][C:5]([NH:8][C:9]2[NH:13][C:12]([S:14]([CH3:16])=[O:15])=[N:11][N:10]=2)=[N:6][CH:7]=1.[OH:24]OS([O-])=O.[K+]>CO.O.O>[Br:1][C:2]1[C:3]([NH:17][C@H:18]([CH:21]([CH3:23])[CH3:22])[CH2:19][OH:20])=[N:4][C:5]([NH:8][C:9]2[NH:13][C:12]([S:14]([CH3:16])(=[O:24])=[O:15])=[N:11][N:10]=2)=[N:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: CC(C)[C@H](CO)Nc1nc(Nc2nnc(S(C)=O)[nH]2)ncc1Br
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)[C@H](CO)Nc1nc(Nc2nnc(S(C)(=O)=O)[nH]2)ncc1Br

Procedure:
35 mg (0.086 mmol) of (R)-2-[5-bromo-2-(5-methanesulfinyl-4H-[1,2,4]triazol-3-ylamino)-pyrimidin-4-ylamino]-3-methyl-butan-1-ol is dissolved in 4 ml of MeOH/water (4:1) and stirred with 25 mg of oxone (0.25 mmol) at room temperature. The batch is diluted with water and extracted with ethyl acetate. The organic phase is concentrated by evaporation, and the residue is digested with ethyl acetate. 19 mg (0.045 mmol, 52% of theory) of the product (R)-2-[5-bromo-2-(5-methanesulfonyl-4H-[1,2,4]triazol-3-ylamino)-pyrimidin-4-ylamino]-3-methyl-butan-1-ol is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1.B1([C:26]2[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=2)OCCCO1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: Fc1ccc(-c2noc(-c3cccc(Br)c3)n2)nc1
Reactant: c1cncc(B2OCCCO2)c1
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: ClCCl
Solvent: COCCOC
Product: Fc1ccc(-c2noc(-c3cccc(-c4cccnc4)c3)n2)nc1
Yield: 50.2 %

Procedure:
A mixture of 3-(5-fluoro-pyrid-2-yl)-5-(3-bromophenyl)-1,2,4-oxadiazole (100 mg, 0.313 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (102 mg, 0.624 mmol), and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 50.8 mg, 0.044 mmol), in a solution of ethylene glycol dimethyl ether (2 mL) and 2M sodium carbonate (2 mL) was heated in a sealed vial at 110° C. for 1 hour. The reaction was cooled, diluted with dichloromethane, washed with water and saturated brine, filtered, and concentrated. Silica gel chromatography using a gradient of 50% ethyl acetate in hexane to 100% ethyl acetate afforded 50 mg (50.2%) 3-(5-fluoro-pyrid-2-yl)-5-[3-(3-pyridyl)phenyl]-1,2,4-oxadiazole. 1H-NMR (CDCl3), δ (ppm): 8.91 (d, 1H), 8.69 (d, 1H), 8.64 (d, 1H), 8.49 (s, 1H), 8.28 (m, 2H), 8.00 (m, 1H), 7.84 (dd, 1H), 7.69 (t, 1H), 7.60 (td, 1H), 7.44(dd, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.[CH3:14][N:15]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[N:16]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(=O)OCC>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:8][C:6]1[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=[C:2]([C:18]2[CH:17]=[N:16][N:15]([CH3:14])[CH:19]=2)[N:7]=1
Reactant: CCOC(=O)c1cnc(Cl)nc1C
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(-c2cnn(C)c2)nc1C
Yield: 5.8 %

Procedure:
Ethyl 2-chloro-4-methylpyrimidine-5-carboxylate (1.0 g, 5.0 mmol), 1-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.24 g, 6.0 mmol), K3PO4 (3.18 mg, 15.0 mmol) and Pd(dppf)Cl2 (100 mg) in dioxane (15 mL) and H2O (3 mL) were heated at 120° C. for 18 h under N2. Silica gel chromatography (PE:EA=3:1 to 1:1) gave the title compound (72 mg, yield: 32.0%). 1H NMR (CDCl3, 400 MHz) δ 9.08 (s, 1H), 8.22 (s, 1H), 8.15 (s, 1H), 4.40 (q, J=7.2 Hz, 2H), 3.98 (s, 3H), 2.82 (s, 3H), 1.42 (t, J=7.2 Hz, 3H). LCMS: 247.1 (M+1)+.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:16][CH2:17]OC)[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH3:14])[C:8](=[O:15])[CH2:7]1)=[O:5])C.[F:20][C:21]([F:31])([F:30])[O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.[Cl-].C[Al+]C.O>C1(C)C=CC=CC=1.CCCCCC>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:4](=[O:5])[N:27]([C:26]3[CH:28]=[CH:29][C:23]([O:22][C:21]([F:20])([F:30])[F:31])=[CH:24][CH:25]=3)[CH2:17][CH2:16]2)[CH2:7][C:8]1=[O:15])[CH2:13][CH3:14]
Reactant: CCCN1CCC(CCOC)(C(=O)OCC)CC1=O
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CCCN1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25.7 %

Procedure:
4-(2-Methoxy-ethyl)-2-oxo-1-propyl-piperidine-4-carboxylic acid ethyl ester (0.205 g) and 4-(trifluormethoxy)aniline (0.268 g) were dissolved in toluene (15 ml) under an argon atmosphere at RT. Dimethylaluminium chloride in hexane (1 molar in hexane, 3.02 ml) was added and the mixture was refluxed over night. The reaction mixture was then cooled to RT, water (1 ml) was added and the mixture was stirred at RT for 15 minutes. The solvent was removed in vacuo, the residue adsorbed on silica gel and purified by flash chromatography on silica gel (eluents: AcOEt/CH2Cl2, gradient from 0 to 50% then with AcOEt/heptane: 70%) to give the desired material (0.072 g) as a viscous light yellow oil. MS (ESI): 371.2 (MH−).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]([CH3:26])[CH:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([F:14])[C:8]=1[F:15].[BH4-].[Li+].O.C(OCC)(=O)C>C1COCC1>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([S:16]([CH:6]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[C:9]([F:14])[C:8]=2[F:15])[CH:5]([CH3:26])[CH2:4][CH2:3][OH:2])(=[O:17])=[O:18])=[CH:24][CH:23]=1
Reactant: COC(=O)CC(C)C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(CCO)C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(4-Chloro-benzenesulfonyl)-3-methyl-4-(2,3,6-trifluoro-phenyl)-butyric acid methyl ester (0.79 g, 1.88 mmol) was dissolved in 10 mL of THF and lithium borohydride (0.5 g, excess) was added. The reaction mixture was stirred at room temperature overnight. 50 mL of water and 50 mL of EtOAc were added. The organic layer washed with brine (50 mL), dried over Na2SO4 and concentrated. The residue was used in next step without further purification (0.71 g, 96%). 1H NMR (CDCl3 400 MHz) δ 7.61 (m, 2H), 7.36 (m, 2H), 7.06 (m, 1H), 6.82 (m, 0.5H), 6.60 (m, 0.5H), 4.79 (m, 0.5H), 4.56 (m, 0.5H), 3.85 (m, 1H), 3.68 (m, 1H), 3.12 (m, 1H), 2.39 (m, 0.5H), 1.95 (m, 0.5H), 1.57 (m, 0.5H), 1.46 (dd, J=4.4 and 5.9 Hz, 1.5H), 1.32 (m, 0.5H), 0.92 (dd, J=7.3 and 9.5 Hz, 1.5H).