Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24](O)=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Cl.[Cl:28][CH2:29][CH2:30][CH2:31][NH:32][CH3:33].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:28][CH2:29][CH2:30][CH2:31][N:32]([CH3:33])[C:24]([C:23]1[CH:22]=[N:21][N:18]2[CH:19]=[CH:20][C:15]([N:11]3[CH2:12][CH2:13][CH2:14][C@@H:10]3[C:4]3[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:16][C:17]=12)=[O:25]
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Reactant: CNCCCCl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)N(C)CCCCl)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.5 %

Procedure:
To a suspension of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation B, 200 mg, 0.56 mmol) and 3-chloro-N-methylpropan-1-amine hydrochloride (177 mg, 1.23 mmol) in DMF (4 mL) was added N-methylmorpholine (0.25 mL, 2.30 mmol), followed by HATU (234 mg, 0.616 mmol). The reaction was stirred at ambient temperature for 18 hours, then diluted with H2O (10 mL), and extracted EtOAc (2×20 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4), filtered, and concentrated. The crude product was purified by reverse-phase column chromatography, eluting with 5 to 60% acetonitrile/water to yield the desired product as a white foamy solid (129 mg, 52% yield). MS (apci) m/z=447.0 (M+H).
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[CH:5]1([S:8](Cl)(=[O:10])=[O:9])[CH2:7][CH2:6]1.[Cl-]>N1C=CC=CC=1>[CH:5]1([S:8]([O:4][CH:2]([CH3:3])[CH3:1])(=[O:10])=[O:9])[CH2:7][CH2:6]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(C)O
Agent: [Cl-]
Solvent: c1ccncc1
Product: CC(C)OS(=O)(=O)C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
IPA (11 L) was added to pyridine (1850 g; 1890 mL) at 20° C. with stirring for 1 hour. The solution was cooled to between −10° C. and 2° C. and cyclopropane sulfonic chloride (1100 g) was added dropwise followed by stirring at this temperature for 70 hours. NMR analysis showed 85% of sulfonic chloride was consumed in the reaction. The reaction was cooled to 0° C. and NaOH (312 g) in water (600 mL) was added dropwise. The resultant product was concentrated to dryness and 45° C. and diluted with EtOAc (2750 mL), MTBE (1375 mL). The solution was stirred for 10 minutes and filtered. Heptane (1375 mL) was added, filtered and the filtrate was concentrated to dryness giving 1080 g of product as a red liquid (84% yield). 1H NMR (CDCl3, 400 MHz): δ 4.86 (m, 1H), 2.83 (m, 1H), 1.33 (d, 6H), 0.98-1.10 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][C:10]2[S:11][C:12]([S:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:35]1(/[CH:41]=[CH:42]/[C:43](Cl)=[O:44])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][C:10]2[S:11][C:12]([S:15]([N:18]3[CH2:23][CH2:22][N:21]([C:43](=[O:44])/[CH:42]=[CH:41]/[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:20][CH2:19]3)(=[O:16])=[O:17])=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)/C=C/c1ccccc1
Reactant: O=C(NCc1ccc(S(=O)(=O)N2CCNCC2)s1)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccc(S(=O)(=O)N2CCN(C(=O)/C=C/c3ccccc3)CC2)s1)c1ccc(Cl)cc1
Yield: 21 %

Procedure:
To a stirred solution of 1 (36 mg, 0.09 mmol) and iPr2NEt (32 μl, 0.189 mmol) in CHCl3 (2 mL) was added [(2E)-3-phenylprop-2-enoyl]chloride (15 mg, 0.09 mmol). After 4 h the reaction mixture was washed with HCl (1 N) and sat. NaCl solution, and dried over MgSO4. The solvent was evaporated and the residue was filtered through silica gel using AcOEt/MeOH 1% as eluent to afford 159 as white solid (10 mg, 20%). M/Z APCI: 531.2 (M+1), 529.1 (M−1). Anal. HPLC: rt.=6.18 min (method a).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N+:8]([O-])=[C:7]([CH3:13])[CH:6]=[CH:5]2.C1(C)C=CC(S([Cl:23])(=O)=O)=CC=1.CCCCCC.C(OCC)(=O)C>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:13][Cl:23])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cc(Cl)ccc2[n+]1[O-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Solvent: CCCCCC
Product: ClCc1ccc2cc(Cl)ccc2n1
Temperature: 100 °C
Yield: 54.1 %

Procedure:
6-Chloro-2-methylquinoline N-oxide (1.73 g, 8.1 mmol) was added to a stirring solution of p-toluenesulfonyl chloride (1.7 g, 8.96 mmol) in dichloroethane (80 mL). The reaction mixture was heated to 100° C. overnight under N2, cooled and concentrated, partitioned between 10% K2CO3 /ethyl acetate, dried over MgSO4, and evaporated under reduced pressure to afford a solid. The crude solid was purifed by flash chromatography (4:1 hexane/ethyl acetate) to afford 0.93 g (52%) of pure product as an off white solid.
Reaction SMILES: [CH2:1]([C:8]1[C:13](Br)=[CH:12][N:11]=[C:10]([O:15][CH2:16][C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([C@:24]1([OH:32])[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1)#[CH:23].C(N(CC)CC)C>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.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:23]#[C:22][C@:24]2([OH:32])[CH:29]3[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]3)[CH2:25]2)=[CH:12][N:11]=[C:10]([O:15][CH2:16][C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Reactant: Brc1cnc(OCc2ccco2)nc1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O[C@]1(C#Cc2cnc(OCc3ccco3)nc2Cc2ccccc2)CN2CCC1CC2
Temperature: 90 °C
Reaction time: 4 h
Yield: 47.3 %

Procedure:
A mixture of 50.9 mg of 4-benzyl-2-(2-furylmethoxy)-5-bromopyrimidine, 26.8 mg of (3R)-3-ethynyl-3-quinuclidinol, 8.5 mg of tetrakis(triphenylphosphine)palladium(0), 0.3 mg of cuprous iodide, 61.5 μl of triethylamine and 1 ml of N,N-dimethylformamide was stirred at 90° C. for 4 hours in a nitrogen atmosphere. NH-silica gel was added to the reaction solution and the solvent was removed. The residue was subjected to NH-silica gel column chromatography using 3% methanol/ethyl acetate, to give 29.0 mg of the target compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=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.COCCOC>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:18]=[CH:19][C:20]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[CH:21][CH:22]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Brc1ccccn1
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: COCCOC
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ccccn2)cc1
Yield: 88.3 %

Procedure:
N-(2-t-Butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Method 13; 132 mg, 0.3 mmol), 2-bromopyridine (40 mg, 0.25 mmol), tetrakis(triphenylphosphine)palladium (4 mg, 0.004 mmol), 1,2-dimethyoxyethane (1.5 ml) and a saturated aqueous solution of sodium hydrogen carbonate (1.5 ml) were stirred at 80-85° C. under an atmosphere of argon for 24 hours. The mixture was allowed to cool before being partitioned between ethyl acetate and water. The organics were separated, washed with brine, dried over magnesium sulfate, filtered and evaporated to yield the title compound (86 mg, 74%) which was used in the next reaction without further purification; Mass Spectrum: M+H+ 390.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23][NH2:24])[CH3:20]>>[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23][NH:24][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][N:17]=[CH:18][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])[CH3:20]
Reactant: CCOC(CN)OCC
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: CCOC(CNC(=O)c1ccncc1Nc1ccc(I)cc1F)OCC

Procedure:
N-(2,2-diethoxyethyl)-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.33 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.5 mmol of 2,2-diethoxy-ethylamine. LC/MS [5.51 min; 474 (M+1)]
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=2[C:13](=[O:16])[CH2:14][CH3:15])[CH2:3][CH2:2]1.[C:17](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH:1]1([C:4]2[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:17])=[O:9])=[CH:6][C:5]=2[C:13](=[O:16])[CH2:14][CH3:15])[CH2:2][CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: CCC(=O)c1cc(C(=O)O)ccc1C1CC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCC(=O)c1cc(C(=O)OC)ccc1C1CC1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 4-cyclopropyl-3-propanoylbenzoic acid (compound 10.6, 500 mg, 2.29 mmol) in N,N-dimethylformamide (20 mL) and potassium carbonate (633 mg, 4.55 mmol). The mixture was cooled to 0-5° C. then iodomethane (157 μL, 2.52 mmol) was added drop-wise. The resulting mixture was stirred for 1 h at 5-10° C., then quenched with water/ice (80 mL). The aqueous phase was extracted with ethyl acetate (2×150 mL) and the combined organic layers were washed with brine (20 mL), sodium carbonate (sat., 20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Obtained 400 mg (75%) of the title compound as a light brown oil.
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:18])=O>C1(C)C=CC=CC=1>[Cl:18][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1
Reactant: COCCCOc1ccnc(CO)c1C
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COCCCOc1ccnc(CCl)c1C
Temperature: 25 °C
Yield: 112.6 %

Procedure:
2-Hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine (5.0 g (23.7 mmol)) was dissolved in toluene (40 ml), and thionyl chloride (4.23 g (35.6 mmol)) was added dropwise thereto so that the temperature did not exceed 25° C. Following stirring at room temperature, disappearance of the raw materials was confirmed by TLC, and 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (6.13 g) was obtained by concentrating under a reduced pressure (yield: 97.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2Cl)[N:3]=1.[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[S:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]2[C:9]([C:8]([NH:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=3[S:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)=[CH:7][CH:6]=[N:5]2)=[CH:10][CH:11]=1
Reactant: Clc1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Solvent: CCO
Product: Cc1ccc(Sc2ccc(O)cc2)c(Nc2ccnc3nc(Cl)ccc23)c1
Temperature: 25 °C

Procedure:
The product from Example 13d (0.67 g, 3.36 mmol) and the product from Example 4c (0.78 g, 3.36 mmol) in 10 mL ethanol were heated under reflux for 5.5 hr. The reaction mixture was cooled to room temperature and the solvent was removed concentrated under vacuum leaving yellow solid that was used without further purification (1.43 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.C1(C)C=CC(S([Cl:37])(=O)=O)=CC=1.O>O1CCCC1>[Cl:37][C:15]1[N:10]2[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:16]([C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)=[C:11]2[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1ccc(-c2nn3ccccc3c2-c2ccncc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2ccncc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 2-(4-fluorophenyl)-3-(4-pyridinyl)-pyrazolo[1,5-a]pyridine (from Example 26, 100 mg, 0.346 mmol) in dry tetrahydrofuran (4 mL) was cooled to about −78° C. under N2 and n-butyllithium in hexanes (2.5 M in hexanes, 0.27 mL, 0.7 mmol) was added dropwise. The mixture was stirred at −78° C. for about 30 min and a solution of p-toluenesulfonyl chloride (0.15 g, 0.76 mmol) in dry tetrahydrofuran (1 mL) was added. The mixture was allowed to warm to room temperature over 30 min and was stirred at room temperature for 1 hour. Water was added and the mixture was poured into a separatory funnel. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried using anhydrous magnesium sulfate, filtered and evaporated. Purification by silica gel chromatography yielded the title compound, 0.087 g (78.6%). 1H NMR (CDCl3): δ 8.65 (d, 2H, J=5.8 Hz), 7.55–7.69 (m, 3H), 7.30 (d, 2H, J=5.8 Hz), 7.11–7.21 (m, 1H), 7.04–7.13 (m, 3H). MS (ES+ve): 326 (25, M+3), 323 (50, M+), 290 (100).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@@H:7]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:8][CH2:9][C:10](O)=[O:11])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.[C:30]1([CH2:36][N:37]2[CH2:42][CH2:41][C:40]3([CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)[CH2:39][CH2:38]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>C1COCC1.C(N(CC)CC)C>[C:17]1([S:14]([NH:13][C@@H:7]([CH2:8][CH2:9][C:10](=[O:11])[N:45]2[CH2:46][CH2:47][C:40]3([CH2:39][CH2:38][N:37]([CH2:36][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:42][CH2:41]3)[CH2:43][CH2:44]2)[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:23])(=[O:15])=[O:16])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(CN2CCC3(CCNCC3)CC2)cc1
Reactant: CC(C)(C)OC(=O)[C@H](CCC(=O)O)NS(=O)(=O)c1ccccc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](CCC(=O)N1CCC2(CCN(Cc3ccccc3)CC2)CC1)NS(=O)(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 6.82 g (19.86 mmol) of the intermediate from Step B in 20 ml dry THF containing 2.8 ml triethylamine was cooled to −10° C. 2.15 g (19.8 mmol) ethyl chloroformate were added dropwise, and the mixture was stirred for ten minutes, while a precipitate was formed spontaneously. A solution of 4.85 g (19.86 mmol) of the intermediate from Example 20, Step D in a mixture of 24 ml dry THF and 5.3 ml triethylamine was added quickly in small portions. It was warmed to room temperature, stirred over night, poured into water, and extracted three times with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, and concentrated under reduced pressure, and the title compound was obtained by chromatography on silica gel with dichloromethane/ethanol 93:7.
Reaction SMILES: CC1N=C(N2CCC(=C)CC2)[C:5]([N+:15]([O-])=[O:16])=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](I)[CH:20]=1.C=C1CCN(C2C([N+]([O-])=O)=CC=CN=2)CC1.[CH2:42]=[C:43]1[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]1>>[Cl:18][C:19]1[CH:20]=[C:21]([C:3]#[C:4][C:5]2[CH2:42][C:43]3([CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]3)[O:16][N:15]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: Clc1cccc(I)c1
Reactant: C=C1CCN(c2nc(C)ccc2[N+](=O)[O-])CC1
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(C#Cc1cccc(Cl)c1)=NO2

Procedure:
The title compound was synthesized following the method reported for the compound of Example 3, substituting 2-bromo-6-methylpyridine with 1-chloro-3-iodobenzene and Compound 3c with Compound 2a, with tert-butyl 4-methylenepiperidine-1-carboxylate. After the usual work-up, the crude was purified by automated flash chromatography (SP1®TM -Biotage; gradient Petroleum Ether-EtOAc from 95:5 to 6:4) affording the title product as white solid. Yield: 76.9%.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:49][C:50]1[CH:58]=[C:57]2[C:53]([C:54]([CH:59]3[CH2:63][N:62]([C:64]4[N:69]=[CH:68][CH:67]=[CH:66][N:65]=4)[CH:61]4[CH2:70][CH2:71][NH:72][CH:60]34)=[CH:55][NH:56]2)=[CH:52][CH:51]=1>CN1C(=O)CCC1.C(OCC)C>[C:12]([O:11][C:9](=[O:10])[NH:1][CH:2]([C:6]([N:72]1[CH2:71][CH2:70][CH:61]2[N:62]([C:64]3[N:69]=[CH:68][CH:67]=[CH:66][N:65]=3)[CH2:63][CH:59]([C:54]3[C:53]4[C:57](=[CH:58][C:50]([F:49])=[CH:51][CH:52]=4)[NH:56][CH:55]=3)[CH:60]12)=[O:8])[CH:3]([CH3:4])[CH3:5])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Fc1ccc2c(C3CN(c4ncccn4)C4CCNC34)c[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2c1ncccn1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 87.4 %

Procedure:
To a solution containing Boc-Val-OH (106 mg, 0.48 mmol) in anhydrous NMP (3 mL) was cooled to 0° C. HATU (185 mg, 0.48 mmol) and DIPEA (67 mg, 0.52 mmol) were added followed by the addition of crude 71 (150 mg, 0.46 mmol) in anhydrous NMP (3 mL). After 2.5 h, the reaction mixture was diluted with diethyl ether and washed successively with water, aqueous NaHCO3, water, and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (1:1 hexanes/EtOAc) to afford 210 mg (86%) of 72 as a white-colored foam. Mass spectrum, m/z [523] (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]#[C:5][CH2:6][OH:7].[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].O>O1CCCC1>[Si:9]([O:7][CH2:6][C:5]#[C:4][CH2:3][OH:8])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: OCC#CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC#CCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
60% Sodium hydride (1.39 g) was suspended in tetrahydrofuran (50 mL), and the suspension was cooled to 0° C., a solution of but-2-yne-1,4-diol (3.0 g) in tetrahydrofuran (20 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hr. tert-Butyldimethylsilyl chloride (5.26 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 24 hrs. Water was added to the reaction mixture and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=100:0→80:20) to give the title compound (1.48 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([O:22][CH2:23][CH3:24])[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[O:11])=[C:4]([F:25])[CH:3]=1.[OH:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.[CH2:36]([O:38][C:39](=[O:42])[CH2:40]Br)[CH3:37].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:36]([O:38][C:39](=[O:42])[CH2:40][O:26][C:27]1[CH:28]=[C:29]([C:2]2[CH:7]=[C:6]([F:8])[C:5]([CH:9]([C:10](=[O:11])[NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=3)[O:22][CH2:23][CH3:24])=[C:4]([F:25])[CH:3]=2)[CH:30]=[CH:31][CH:32]=1)[CH3:37]
Reactant: CCOC(=O)CBr
Reactant: OB(O)c1cccc(O)c1
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(-c2cc(F)c(C(OCC)C(=O)NCc3ccc(C#N)cc3)c(F)c2)c1

Procedure:
In analogy to example 247.1, (RS)-2-(4-bromo-2,6-difluoro-phenyl)-N-(4-cyano-benzyl)-2-ethoxy-acetamide (example 248.1) was reacted with 3-hydroxyphenylboronic acid. The product of this reaction was alkylated with ethylbromoacetate and cesiumcarbonate in DMF (analogous to example 16.4) to give (RS)-{4′-[(4-cyano-benzylcarbamoyl)-ethoxy-methyl]-3′,5′-difluoro-biphenyl-3-yloxy}-acetic acid ethyl ester. Colorless oil. MS 509.1 ([M+H]+)
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH:3]([C:5]1[C:14]2[CH2:13][O:12][CH2:11][N:10]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:9]=2[N:8]=[C:7]([CH3:24])[N:6]=1)[OH:4].[CH3:27][N:28]=[C:29]=[O:30].CN(C1C=CC=CN=1)C>ClCCl>[F:26][C:2]([F:25])([F:1])[CH:3]([O:4][C:29](=[O:30])[NH:28][CH3:27])[C:5]1[C:14]2[CH2:13][O:12][CH2:11][N:10]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:9]=2[N:8]=[C:7]([CH3:24])[N:6]=1
Reactant: CN=C=O
Reactant: Cc1cc(C)c(N2COCc3c(C(O)C(F)(F)F)nc(C)nc32)c(C)c1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CNC(=O)OC(c1nc(C)nc2c1COCN2c1c(C)cc(C)cc1C)C(F)(F)F

Procedure:
A mixture of 2,2,2-trifluoro-1-[7-methyl-1-(2,4,6-trimethyl-phenyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-5yl]-ethanol (26 mg), methyl isocyanate (0.12 ml), dimethylaminopyridine (27 mg) in dichloromethane (2 ml) was heated at reflux for 2 hrs. The mixture was quenched with water and extracted with chloroform. The organic layer was separated, dried and concentrated to give the crude material which was purified by silica gel column chromatography using chloroform as eluent to give 21 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: COCCOCCBr
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 95 °C
Reaction time: 18 h

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (500 mg, 2.58 mmol), 1-(2-bromo-ethoxy)-2-methoxy-ethane (566 mg, 3.09 mmol) and Cs2CO3 (840 mg, 2.58 mmol) in DMF (5 mL) was stirred at 95° C. for 18 h. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated to afford the title compound as an oil. (MH+=297.1, 1H-NMR in CDCl3: 7.77 (m, 1 or 2H) 4.31 (t, 2H); 3.85 (t, 2H); 3.54 (m, 2H); 3.48 (m, 2H); 3.35 (s, 3H); 1.31 (s, 12H)).