Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=O)[N:8]2[CH3:11])=[C:4]([N:14]2[CH:19]3[CH2:20][CH2:21][CH:15]2[CH2:16][O:17][CH2:18]3)[N:3]=1.[NH:22]1[CH2:27][CH2:26][CH:25]([C:28]([OH:31])([CH3:30])[CH3:29])[CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:22]3[CH2:27][CH2:26][CH:25]([C:28]([OH:31])([CH3:30])[CH3:29])[CH2:24][CH2:23]3)[N:8]2[CH3:11])=[C:4]([N:14]2[CH:19]3[CH2:20][CH2:21][CH:15]2[CH2:16][O:17][CH2:18]3)[N:3]=1
Reactant: CC(C)(O)C1CCNCC1
Reactant: Cn1c(C=O)nc2c(N3C4CCC3COC4)nc(Cl)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3C4CCC3COC4)nc(Cl)nc21
Reaction time: 17 h
Yield: 81.4 %

Procedure:
A mixture of 2-chloro-9-methyl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-9H-purine-8-carbaldehyde (500 mg, 1.63 mmol), 2-piperidin-4-ylpropan-2-ol (256 mg, 1.79 mmol) and 4 Å powdered molecular sieves (500 mg) in DCE (11 mL) was stirred for 4 h before the addition of sodium triacetoxyborohydride (690 mg, 3.26 mmol). The resulting mixture was allowed to stir for 17 h then filtered through Celite®, washing with MeOH. The resulting filtrate was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH/DCM. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording the title compound as a pale yellow solid (577 mg, 82%). LCMS (method H): RT 0.30 and 2.00 min [M+H]+ 435.4
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:28])[C:20]([C@H:22]2[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)=[O:21])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]([CH3:28])[C:20]([C@H:22]2[CH2:27][CH2:26][CH2:25][N:24]([C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:23]2)=[O:21])=[CH:17][CH:18]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN(C(=O)[C@H]1CCCNC1)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)[C@H]1CCCN(C(=O)c2ccc(F)cc2)C1)c1ccc(F)cc1
Reaction time: 2 h
Yield: 84.4 %

Procedure:
4-Fluorobenzoyl chloride (47 mL, 0.40 mmol) was added at 0° C. to a solution of (S)-piperidine-3-carboxylic acid (4-fluoro-phenyl)-methyl-amide hydrochloride (0.11 g, 0.40 mmol) and triethylamine (112 mL, 0.80 mmol) in dichloromethane (3 mL), under nitrogen atmosphere. The reaction mixture was kept under stiffing at R.T. for 2 h, the solvent was evaporated and the residue was diluted with water and ethyl acetate. The phases were separated and the organic layer was washed with HCl 1N (10 mL), with Na2CO3 2M (aq.) (10 mL) and with brine (10 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure to give 0.121 g of (S)-1-(4-fluoro-benzoyl)-piperidine-3-carboxylic acid (4-fluoro-phenyl)-methyl-amide as a gummy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[F:11])[C:5](O)=[O:6].S(Cl)([Cl:15])=O>CN(C=O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[F:11])[C:5]([Cl:15])=[O:6]
Reactant: O=C(O)c1cc(Cl)c(F)c(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1cc(Cl)c(F)c(Cl)c1

Procedure:
3,5-dichloro-4-fluorobenzoic acid was refluxed with >1 equivalent of thionyl chloride and one drop of DMF neat or as a solution in CHCl3. The solvent and volatile by-products were removed in vacuo to provide 3,5-dichloro-4-fluorbenzoyl chloride.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH2:31][CH2:32][CH:33]1[CH2:35][CH2:34]1>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:29])[C:15]2[O:14][CH:13]([CH2:12][NH:31][CH2:32][CH:33]3[CH2:35][CH2:34]3)[CH2:17][C:16]=2[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4c(C)cccc4C)c3O2)cc1
Reactant: NCC1CC1
Product: Cc1cccc(C)c1-c1cc(Cl)cc2c1OC(CNCC1CC1)C2

Procedure:
The title compound was prepared (0.058 g, 45%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and (aminomethyl)cyclopropane (0.50 g, 6.77 mmol). mp 203-205° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:12])(=O)=[O:10])=[CH:5][CH:4]=1)=[CH2:2].[Na+].P(Cl)(Cl)(Cl)(Cl)[Cl:15]>C(Cl)(Cl)Cl>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([Cl:15])(=[O:12])=[O:10])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: C=Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: C=Cc1ccc(S(=O)(=O)Cl)cc1
Yield: 80.4 %

Procedure:
20.6 g (0.1 mole) of sodium 4-vinylbenzenesulfonate was added to 200 ml of chloroform, and with stirring, 27.1 g (0.13 mole) of phosphorus pentachloride was gradually added at 5° C. After the addition, the mixture was stirred further for 1 hour. Chloroform was removed, and the product was washed with water and purified with ether to afford 16.3 g (yield 80.5%) of 4-vinylbenzenesulfonyl chloride. The resulting 4-vinylbenzenesulfonyl chloride was dissolved in 200 ml of toluene, and 14.8 g (0.08 mole) of p-aminodiphenylamine and 8 g of triethylamine were gradually added to the resulting solution. The mixture was stirred at 0° C. for 2 hours. The resulting precipitate was separated to afford 23.4 g (yield 83%) of N-(4-anilino)-phenyl-4-vinylbenzenesulfonamide having a melting point of 135° C.
Reaction SMILES: [CH3:1][CH:2]([S:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[CH2:22]([N:24]=[C:25]=[S:26])[CH3:23].O>CN(C=O)C>[CH2:22]([NH:24][C:25](=[S:26])[O:13][CH2:12][CH2:11][O:10][C:9]1[CH:14]=[CH:15][C:6]([S:5][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:7][CH:8]=1)[CH3:23]
Reactant: CCC(C)Sc1ccc(OCCO)cc1
Reactant: CCN=C=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=S)OCCOc1ccc(SC(C)CC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the above alcohol (2.16 g, 10.0 mmol) and potassium carbonate (1.66 g, 12.0 mmol) in 10 ml of DMF is cooled to 5° and ethyl isothiocyanate (1.10 ml, 12.0 mmol) in 10 ml of DMF is added dropwise. After addition is complete, the mixture is allowed to warm to RT and is stirred at RT overnight. Water is added and the aqueous phase is extracted with ether. The combined organic layers are washed with water and brine, dried, and the solvent removed, and the residue is purified by column chromatography to give O-2-[4-(1-methylpropylthio)phenoxy]ethyl N-ethylthiocarbamate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:26])[CH:3]=1.[CH3:27][N:28]1[C:32](=[O:33])[CH:31]([CH3:34])[NH:30][C:29]1=[O:35]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:30]5[CH:31]([CH3:34])[C:32](=[O:33])[N:28]([CH3:27])[C:29]5=[O:35])=[CH:3][C:4]=4[F:26])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Reactant: CC1NC(=O)N(C)C1=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)N(C)C(=O)C3C)cc2F)CC1
Yield: 27.5 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (167 mg) described in Preparation Example 121 and 3,5-dimethylimidazolidine-2,4-dione (51 mg) described in Preparation Example 217 and by the reaction and treatment in the same manner as in Example 536, the title compound (51 mg) was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.[CH3:8][C:9]1[N:14]=[C:13]([SH:15])[N:12]=[C:11]([OH:16])[CH:10]=1.C(N(CC)CC)C>C(O)C>[CH3:8][C:9]1[N:14]=[C:13]([S:15][CH2:2][C:3]2[CH:7]=[CH:6][S:5][CH:4]=2)[N:12]=[C:11]([OH:16])[CH:10]=1
Reactant: BrCc1ccsc1
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2ccsc2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 19.7 %

Procedure:
A mixture of 3-(bromomethyl)thiophene (360 mg, 2.0 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (242 mg, 1.7 mmol), and triethylamine (280 μL, 2.0 mmol) in absolute ethanol (10 mL) was stirred at room temperature for 2 days. The solid residue was removed by filtration. The filtrate was recovered and evaporated under reduced pressure. The solid product was suspended in water (20 mL). The solid material was recovered by filtration, washed with water (2×15 mL) and hexanes (3×15 mL), and dried in vacuo, affording the title compound (80 mg, 20% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 4.39 (s, 2H), 6.02 (s (br), 1H), 7.12 (dd, 1H, J=1.3 Hz, 3.5 Hz), 7.47 (m, 2H); M+239; HPLC purity: 96.1%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1.Br.[OH-].[Na+]>C(O)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(-c3ccc(F)cc3)csc2c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc2c(-c3ccc(F)cc3)csc2c1
Yield: 70.6 %

Procedure:
29.96 g 3-(4-Fluoro-phenyl)-6-methoxy-benzo[b]thiophene in 230 ml acetic acid were treated with 130 ml (62% aq) HBr at 125° C. for 4 h. The solution was added slowly to a cooled solution of 210 g NaOH in 600 ml water, the pH was adjusted to 8-9, and the inorganic phase was extracted with EtOAc. The combined organic phases were washed with brine and dried with Na2SO4. Column chromatography on silica gel with hexane:EtOAc 4.1 yielded 20.0 g (73%) 3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-ol as light brown solid, MS: 244(M).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:3]=1[C:17]#[N:18].C(O[CH:22](OCC)[N:23]([CH3:25])[CH3:24])C>C1(C)C=CC=CC=1>[C:17]([C:3]1[C:4]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[N:5][NH:6][C:2]=1[N:1]=[CH:22][N:23]([CH3:25])[CH3:24])#[N:18]
Reactant: COc1ccc(CNc2n[nH]c(N)c2C#N)cc1
Reactant: CCOC(OCC)N(C)C
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2n[nH]c(N=CN(C)C)c2C#N)cc1
Temperature: 5 °C

Procedure:
A mixture of 6.08 g (25 mmol) of 5-amino-4-cyano-3-(4-methoxy-benzylamino)-pyrazole, 5.14 ml (30 mmol) of N,N-dimethylformamide diethyl acetal and 90 ml of toluene is heated under reflux for 3 hours. The reaction mixture is then cooled to approx. 5° C. and filtered and the filter residue is washed with toluene, yielding the title compound; m.p. 147-148° C.
Reaction SMILES: C[C@H:2](N(C)C)[C@H:3]([OH:10])C1C=CC=CC=1.CCN(CC)CC.[CH:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:22][C:23]#[CH:24].C(=O)C>C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Zn+2].C1(C)C=CC=CC=1>[C:25]1(/[CH:21]=[CH:22]/[C:23]#[C:24][C@@H:3]([OH:10])[CH3:2])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C#CC=Cc1ccccc1
Reactant: C[C@@H]([C@H](O)c1ccccc1)N(C)C
Agent: CC=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[C@H](O)C#C/C=C/c1ccccc1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
A flask containing Zn(OTf)2 (Zinc triflate purchased from Fluka was found to give the best results, other vendor's proved inefficient; 557 mg, 1.50 mmol) and (−)—N-methylephedrine (275 mg, 1.50 mmol) was added toluene (1.5 mL) and Et3N (209 μL, 1.50 mmol) at 23° C. under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at 23° C. before but-1-en-3-ynyl-benzene (192 μL, 1.50 mmol) was added in one portion. After stirring for 15 min at 23° C., the reaction was cooled to 0° C., then acetaldehyde (168 μL, 30.0 mmol) was added at the same temperature in one portion. The resulting mixture was warmed to 23° C. and stirred for 35 h, then quenched by the addition of saturated aqueous NH4Cl (3 mL). The mixture was poured into a separatory funnel and diluted with EtOAc (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×3 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue via flash chromatography (0→20% EtOAc/hexanes) afforded compound 7 (106 mg, 41%, 72% ee; the ee was determined after making the acetate ester) as a pale yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([F:14])=[C:12]([NH2:15])[CH:11]=[CH:10][N:9]=1.[Cl-].[NH4+]>>[F:14][C:13]1[C:8]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[N:9][CH:10]=[CH:11][C:12]=1[NH2:15]
Reactant: C1COCCN1
Reactant: Nc1ccnc(Cl)c1F
Agent: [Cl-]
Agent: [NH4+]
Product: Nc1ccnc(N2CCOCC2)c1F

Procedure:
Morpholine (3 ml) was added to 2-chloro-3-fluoropyridin-4-amine (133 mg) obtained in the 2nd step, followed by microwave irradiation (Initiator™, 180° C., 20 minutes, 2.45 GHz, 0-240 W). A saturated ammonium chloride aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layers were washed with a saturated ammonium chloride aqueous solution and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. A light brown solid of 3-fluoro-2-morpholinopyridin-4-amine (153 mg) was thus obtained.
Reaction SMILES: [I:1]I.[NH2:3][C:4]1[CH:5]=[N:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[NH2:3][C:4]1[C:5]([I:1])=[N:6][C:7]([C:10]([F:13])([F:11])[F:12])=[CH:8][CH:9]=1
Reactant: II
Reactant: Nc1ccc(C(F)(F)F)nc1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1ccc(C(F)(F)F)nc1I
Yield: 65.8 %

Procedure:
1.56 g (6.17 mmol) of iodine is added, in several portions, to a mixture, stirred under argon at 20° C., of 1 g (6.17 mmol) of 3-amino-6-trifluoromethylpyridine and 1.25 g (6.17 mmol) of silver sulfate in 40 mL of ethanol. Stirring is maintained for 18 hours. The insoluble matter is removed by filtration and is washed with ethanol, the filtrate is concentrated at reduced pressure, and the residue is taken up in 100 mL of dichloromethane. The organic phase is washed successively with 20 mL of 5% aqueous solution of sodium hydroxide, 40 mL of water and 20 mL of saturated aqueous solution of sodium chloride, dried over sodium sulfate, concentrated at reduced pressure, and then purified by chromatography on a silica column (eluents: heptane-ethyl acetate). In this way we isolate 1.17 g of the expected product, which is used as it is in the rest of the synthesis.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[CH3:32][N:33]1CCO[CH2:35][CH2:34]1.CNCC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:34]([N:33]([CH3:32])[C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:29])[F:30])[O:14][N:13]=2)=[CH:10][CH:11]=1)[CH3:35]
Reactant: CN1CCOCC1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CCNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCN(C)C(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 47.8 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.031 mL, 0.278 mmol), N-methylethanamine (4.93 mg, 0.083 mmol), and HATU (31.7 mg, 0.083 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=12.2 min) to give (R/S)-N-ethyl-2-hydroxy-N-methyl-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (11 mg, 0.022 mmol, 47.7% yield): LCMS=473.2 [M+H]+; 1H NMR (mixture of rotamers, 400 MHz, methanol-d4) δ ppm 8.16-8.27 (2H, m), 7.48-7.75 (7 H, m), 5.54 (1 H, s), 5.51 (1 H, s), 3.35-3.55 (2 H, m), 2.96 (3 H, s), 2.91 (3 H, s), 1.11 (3 H, t, J=7.15 Hz), 0.92 (3 H, t, J=7.04 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].C([Li])CCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.[Cl-].[NH4+]>C1COCC1.C(OCC)C>[C:10]([O:9][C:8]([NH:7][C:2]1[C:3]([B:20]([OH:25])[OH:21])=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ncccc1B(O)O
Temperature: -6 °C

Procedure:
Under a nitrogen atmosphere, a solution of tert-butyl N-(2-pyridyl)carbamate (15.71 g, 80.9 mmol) and N,N,N′N′-tetramethylethylenediamine (TMEDA, 25.3 g, 218 mmol) in THF (400 mL) was cooled to −78° C. n-Butyllithium (81 mL of a 2.5 M solution in hexanes) was added dropwise over a period of 20 minutes. The solution was stirred for ten minutes, and then the addition funnel was rinsed with additional THF (20 mL). The solution was warmed to −6° C., stirred for two hours, and cooled again to −78° C. Triisopropyl borate (57.7 g, 307 mmol) was added over a period of ten minutes. The resulting solution was warmed to 0° C. and then poured into saturated aqueous ammonium chloride (500 mL). A yellow solid formed and was stirred with diethyl ether (300 mL), isolated by filtration, washed with diethyl ether and water, and air-dried overnight to provide 2-tert-butoxycarbonylamino-3-pyridylboronic acid as a yellow solid.
Reaction SMILES: CNC1N=C(C2C=CC=CN=2)C=C(C2C=NC=C([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)C=2)C=1.Br[C:33]1[CH:34]=[C:35]([C:39]2[CH:44]=[C:43]([C:45]([OH:48])([CH3:47])[CH3:46])[N:42]=[C:41]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=3)[CH:40]=2)[CH:36]=[N:37][CH:38]=1>>[NH:29]1[CH2:28][CH2:27][CH:26]([N:24]2[CH:25]=[C:21]([C:33]3[CH:34]=[C:35]([C:39]4[CH:44]=[C:43]([C:45]([OH:48])([CH3:47])[CH3:46])[N:42]=[C:41]([C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=5)[CH:40]=4)[CH:36]=[N:37][CH:38]=3)[CH:22]=[N:23]2)[CH2:31][CH2:30]1
Reactant: CNc1cc(-c2cncc(-c3cnn(C4CCNCC4)c3)c2)cc(-c2ccccn2)n1
Reactant: CC(C)(O)c1cc(-c2cncc(Br)c2)cc(-c2ccccn2)n1
Product: CC(C)(O)c1cc(-c2cncc(-c3cnn(C4CCNCC4)c3)c2)cc(-c2ccccn2)n1

Procedure:
is prepared analogously to Methyl-[5″-(1-piperidin-4-yl-1H-pyrazol-4-yl)-[2,2′;4′,3″]terpyridin-6′-yl]-amine (Example 2.183) by replacing (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-methyl-amine (Example 2.1; step 1) with 2-(5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-propan-2-ol (Example 2.80; step2)
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][C@@H:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8]2)=[CH:4][CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].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.C(O)C>[C:13]1([C@@H:9]2[O:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:19]=[CH:20][C:2]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:22]([F:33])([F:32])[F:21])=[CH:3][CH:4]=3)[CH2:8]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccc(CN2CCO[C@@H](c3ccccc3)C2)cc1
Reactant: OB(O)c1ccccc1C(F)(F)F
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: FC(F)(F)c1ccccc1-c1ccc(CN2CCO[C@@H](c3ccccc3)C2)cc1
Temperature: 120 °C
Yield: 69.6 %

Procedure:
106 mg of (S)-4-(4-Bromo-benzyl)-2-phenyl-morpholine was combined with 91 mg of 2-(Trifluoromethyl)phenyl boronic acid, 18 mg of tetrakis(triphenylphosphine)palladium(0), 1.1 mL of 2M sodium carbonate solution, 2.9 mL toluene and 1.4 mL ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography eluting in a 10 to 40% ethyl acetate/hexanes gradient. The product fractions were pooled and concentrated to afford 88.3 mg of product. ES MS (+) m/z 398.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH:27]([C:28]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)C(Cc1ccc(OC)c(CO)c1)C(=O)OC
Reactant: O=C=Nc1ccccc1
Product: COC(=O)C(Cc1ccc(OC)c(COC(=O)Nc2ccccc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)-4-methoxybenzyl]malonate and phenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[CH3:14].C(Cl)(Cl)Cl>>[F:13][C:11]1[CH:12]=[C:7]([F:6])[C:8]([CH3:14])=[CH:9][C:10]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccc(F)cc1F
Solvent: ClC(Cl)Cl
Product: Cc1cc(S(=O)(=O)Cl)c(F)cc1F
Reaction time: 2 h
Yield: 75.1 %

Procedure:
Chlorosulfonic acid (5.2 mL, 0.078 mol) was added dropwise to a solution of 2,4-difluorotoluene (4.00 g, 0.0312 mol) in chloroform (75 mL, 0.94 mol). The reaction was stirred 2 hours. Additional chlorosulfonic acid (3.1 mL, 0.047 mol) was added and stirring was continued for 18 hours. The reaction was evaporated to an oil and poured onto ice. The mixture was extracted two times with ethyl ether. The combined organic phase was dried over magnesium sulfate and treated with activated carbon. The mixture was filtered through diatomaceous earth and the filtrate was evaporated to give 5.31 g of light brown oil.
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([Si:2]([CH3:12])([CH3:11])[CH3:1])=[CH:4][CH:5]=2)=[CH:16][CH:15]=1
Reactant: C[Si](C)(C)c1ccc(C=O)cc1
Reactant: NCCc1ccc(F)cc1
Product: C[Si](C)(C)c1ccc(CNCCc2ccc(F)cc2)cc1

Procedure:
[2-(4-fluoro-phenyl)-ethyl]-(4-trimethylsilanyl-benzyl)-amine was prepared in analogy to example 1 from 4-trimethylsilanyl-benzaldehyde and 2-(4-fluoro-phenyl)-ethylamine. MS (ISP): 302.2 (100) (M+H)+. 1H NMR (CDCl3, 300 MHz): δ 7.47 (d, 2H), 7.27 (d, 2H), 7.15 (dd, 2H), 6.97 (dt, 2H) 3.79 (s, 2H), 2.75-3.00 (m, 4H), 0.26 (s, 9H).