Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:12][CH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1csc(C)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1csc(CBr)n1
Temperature: 25 °C
Yield: 31.1 %

Procedure:
A solution of ethyl 2-methyl-4-thiazolecarboxylate [JCS 1946, 87, E. R. H. Jones, F. A. Robinson, M. N. Strachan] (5.0 g, 29.2 mmol) in CCl4 (30 ml) was treated with N-bromosuccinimide (5.2 g, 29.2 mmol) and benzoylperoxide (0.03 g). The reaction was heated to reflux while irradiating with a strong lamp for 21/2 hours. The reaction mixture was allowed to cool to ambient temperature, filtered and evaporated. The residue was purified by chromatography (eluant: CH2Cl2) to obtain ethyl 2-bromomethyl-4-thiazolecarboxylate (2.27 g, 31%).
Reaction SMILES: [C:1]([OH:17])(=[O:16])[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH2:18]1CCN2C(=NCCC2)CC1.CI>C(#N)C>[CH3:18][O:16][C:1](=[O:17])[C:2]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)C(O)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CI
Product: COC(=O)C(O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
90 g (0.394 mol) of benzilic acid are dissolved in 900 mL acetonitrile and at 5° C. 109.6 g (0.72 mol) of DBU are added dropwise. After the addition of 204.4 g (1.44 mol) of methyl iodide, the mixture is stirred for 24 hours at ambient temperature (about 20° C. to 23° C.). The solution is evaporated down to the residue, the residue is taken up in diethyl ether and extracted with water. The organic phase is washed with 5% aqueous sodium carbonate solution and water, dried, and the solvent is distilled off. The product is purified by recrystallization from cyclohexane. Yield: 77.19 g of white crystals (81% of theoretical yield); melting point: 74° C.-76° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@@H:23]2[C@@H:28]([OH:29])[CH2:27]O[CH2:25][CH2:24]2)[C:12]3=[O:30])=[CH:4][CH:3]=1.N[C@H:32]1CCOC[C@@H]1O>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:24][CH2:25][CH2:32][CH2:27][C@@H:28]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1
Reactant: N[C@H]1CCOC[C@@H]1O
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Product: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@H]1CCCC[C@@H]1O

Procedure:
6-[(6-Chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one was prepared by the procedure described for the synthesis of 1,5-anhydro-3-{6-[(6-chloropyridin-3-yl)methyl]-4-oxobenzo[h]quinazolin-3(4H)-yl}-2,3-dideoxy-L-threo-pentitol in Example 2, substituting (1S,2S)-2-aminocyclohexanol for (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(Br)cccc1Br
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1c(Br)cccc1-c1ccccc1

Procedure:
A mixture of the product from Example 114A (2.2 g, 7.5 mmol), phenylboronic acid (919 mg, 7.5 mmol), sodium carbonate (7.55 mL, 2 M aqueous solution, 15.1 mmol) tetrakis(triphenyphosphine)palladium(0) (261 mg, 0.23 mmol) and 50 mL of toluene were refluxed for 16 hours under nitrogen. The reaction was cooled and partitioned between 50 mL of water and 50 mL of ethyl acetate. The aqueous portion was separated and extracted with 2×25 mL of ethyl acetate and the combined organic extracts were washed with 2×25 mL of water and 1×25 mL of brine and dried over sodium sulfate. The organic solution was concentrated and the residue was purified via flash chromatography on a silica gel column (95:5 hexane:ethyl acetate) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.63 (s, 3H) 7.35-7.60 (m, 6H) 7.71-7.79 (m, 2H); MS (DCI+) m/z 308.0 [M+NH4]+.
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21]O)[CH2:17][CH2:16]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:14][CH2:21][CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CCNCC1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: c1ccc(C(OCC2CCNCC2)c2ccccc2)cc1
Yield: 94.3 %

Procedure:
In a reactor fitted with a water trap, a mixture of benzhydrol (3.7 g), 4-piperidinemethanol (2.3 g), camphor-10-sulfonic acid (7.0 g), and toluene (30 mL) was refluxed for 2 hours. After cooling, 35 mL of 1N-aqueous sodium hydroxide was added and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated under reduced pressure to provide 5.3 g of the title compound. Yield 94%. This product was not further purified but directly submitted to the next reaction.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:18])([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])[CH3:7])=[O:5])[CH3:2].CN.Cl.[CH3:22][N:23](C)CCCN=C=NCC>C(Cl)Cl.C(O)C.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4](=[O:5])[C:6]([CH3:18])([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:11]([C:12](=[O:13])[NH:23][CH3:22])[CH:10]=1)[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C(=O)O)c1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1cccc(C(=O)NC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
1.0 g (4.0 mmol) of 3-(1-ethoxycarbonyl-1-methyl-ethoxy)-benzoic acid was dissolved in 50 ml of methylene chloride; then, 1.5 ml (4.0 mmol) of a methylamine-solution in ethanol was added. The reaction mixture was cooled down to 0° C. and 0.91 g (4.8 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 1.50 g (11.9 mmol) of 4-dimethylaminopyridine were added. After stirring for two hours at ambient temperature, it was poured into crashed ice/HCl (1N) and extracted twice with MeCl2. The combined organic phases were washed with water and brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the crude product was purified by flash chromatography (SiO2, MeCl2/MeOH) to give 0.97 g of the title compound in form of colorless needles.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:25]1([CH2:31][CH2:32][S:33][CH:34]([C:38](O)=[O:39])[C:35](O)=[O:36])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[O:11][C:35](=[O:36])[C:34]([S:33][CH2:32][CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:38]([OH:39])[CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)c1cc(C)cc(C)c1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2cc(O)c(SCCc3ccccc3)c(=O)o2)c1

Procedure:
The title compound was prepared by Method A using 3',5'-dimethyl acetophenone (1.75 g, 11.82 mmol), lithium diisopropylamide (1.89 g, 17.73 mmol), chlorotrimethylsilane (2.25 mL, 17.73 mmol), THF (120 mL), and diethyl ester of [(2-phenylethyl)thio]-propanedioic acid (1.00 g, 3.37 mmol). m.p. 155°-157° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.34 (s, 6 H), 2.77 (t, 2 H), 2.99 (t, 2 H), 6.72 (s, 1 H), 7.21 (m, 6 H), 7.41 (s, 2 H), 8.74 (d, 2 H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]([CH3:19])[C:8]2[O:13][C:12]([C:15]#[CH:16])([CH3:14])[CH2:11][CH2:10][C:9]=2[C:17]=1[CH3:18])(=[O:3])[CH3:2].Br[C:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[S:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]([CH3:19])[C:8]2[O:13][C:12]([C:15]#[C:16][C:22]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[S:24][CH:23]=3)([CH3:14])[CH2:11][CH2:10][C:9]=2[C:17]=1[CH3:18])(=[O:3])[CH3:2]
Reactant: Brc1csc2ccccc12
Reactant: C#CC1(C)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C#Cc1csc3ccccc13)O2
Temperature: 95 °C

Procedure:
A mixture of 0.544 g of rac-6-acetyloxy-2-ethynyl-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran, 0.64 g of 3-bromobenzothiophene, 90 mg of triphenylphosphine, 20 mg of cuprous iodide, 2 ml of triethylamine and 40 ml of dimethylformamide was stirred and degased by a stream of argon for 15 minutes. Palladium acetate, 30 mg, was then added and the mixture was heated at 95° C. for 5 hours. The reaction mixture was partitioned between saturated sodium bicarbonate solution and toluene. The organic phase was washed with water, dried and evaporated. The residue was chromatographed over 50 g of silica gel using toluene for elution. The combined clean fractions were crystallized from hexane to give the title compound with m.p. 96°-99°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[N:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13][C:12](=[O:21])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]2[CH2:11][C:12](=[O:21])[CH2:13][CH2:14][N:15]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)N1CCC(=O)C=C1Cc1ccc(Cl)c(Cl)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(=O)CC1Cc1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 34.8 %

Procedure:
Intermediate 9 (0.176 mol) in THF (880 ml) was stirred under a N2 flow, and cooled to −78° C. L-selectride (0.264 mol) was added dropwise at −78° C. The reaction mixture was stirred for 1 hour, then poured out into water. DIPE was added. The organic layer was separated, washed with an aqueous NaHCO3 solution, with an aqueous NaCl solution, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 90/10). The desired fractions were collected and the solvent was evaporated, yielding 20.2 g (34.8%) of (±)-ethyl 2-[(3,4-dichlorophenyl)methyl]-4-oxo-1-piperidinecarboxylate (intermediate 10).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.I[CH2:19][CH3:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH2:19][CH3:20])[CH2:14][CH2:13]2)[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: FC(F)(F)c1cc(Cl)cc(N2CCNCC2)c1
Reactant: CCI
Product: CCN1CCN(c2cc(Cl)cc(C(F)(F)F)c2)CC1

Procedure:
Beginning with 1-(3-Chloro-5-trifluoromethyl-phenyl)-piperazine and iodoethane, the title compound was recovered by the procedure described in Example 2. MS m/z (rel. intensity, 70 eV)) 292 (M+, bp), 277 (88), 234 (33), 206 (55), 179 (49).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:21][OH:22])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][C:32]=1O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:21][O:22][C:38]1[CH:37]=[C:34]([C:35]#[N:36])[CH:33]=[CH:32][C:31]=1[O:30][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)CC(=O)OCc1ccccc1
Reactant: N#Cc1ccc(OCc2ccccc2)c(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](COc1cc(C#N)ccc1OCc1ccccc1)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.8 g (15.5 mmol) of benzyl (3R)-3-t-butoxycarbonylamino-4-hydroxybutanoate was dissolved in 100 ml of tetrahydrofuran. 2.9 g (12.9 mmol) of 4-benzyloxy-3-hydroxybenzonitrile, 4.1 g (15.5 mmol) of triphenylphosphine and 6.7 g (15.5 mmol) of diethyl azodicarboxylate were added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[C@@H:12]1[CH2:14][C@H:13]1[CH2:15]O.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:48]1(=[O:58])[NH:52][C:51](=[O:53])[C:50]2=[CH:54][CH:55]=[CH:56][CH:57]=[C:49]12>O1CCCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[C@@H:12]1[CH2:14][C@H:13]1[CH2:15][N:52]1[C:48](=[O:58])[C:49]2[C:50](=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:51]1=[O:53]
Reactant: Cn1cc2c([C@@H]3C[C@H]3CO)c(F)ccc2n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cn1cc2c([C@@H]3C[C@H]3CN3C(=O)c4ccccc4C3=O)c(F)ccc2n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of trans-[2-(5-fluoro-2-methyl-2H-indazol-4-yl)cyclopropyl]methanol (500 mg, 2.27 mmol) in tetrahydrofuran (22 mL) were added a solution (40%, 1.24 mL, 2.72 mmol) of diethyl azodicarboxylate in toluene, triphenylphosphine (774 mg, 2.95 mmol) and phthalimide (434 mg, 2.95 mmol), and the mixture was stirred under nitrogen atmosphere at room temperature for 1.5 hr. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane=10/90→40/60) to give trans-2-{[2-(5-fluoro-2-methyl-2H-indazol-4-yl)cyclopropyl]methyl}-1H-isoindole-1,3(2H)-dione as a crudely purified product (893 mg).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH2:19][CH3:20])[C:13]([OH:15])=O)([O-])=O.CN(C=O)C.[F:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][C:33]=1[F:34])[NH2:30]>>[NH2:7][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH2:19][CH3:20])[C:13]([NH:30][C:29]1[CH:31]=[CH:32][C:33]([F:34])=[C:27]([F:26])[CH:28]=1)=[O:15]
Reactant: CCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1ccc(F)c(F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: CCc1ccc(C(=O)Nc2ccc(F)c(F)c2)cc1N
Yield: 89.8 %

Procedure:
Prepared according to the procedure described for Example 1 using oxalyl chloride (2.0 mL, 22.93 mmol), 3-nitro-4-ethylbenzoic acid from Example 17, Step A (3.85 g, 19.74 mmol), DMF (1.0 mL, 12.92 mmol), and 3,4-difluoroaniline (4.0 mL, 40.34 mmol) to afford the product (4.9 g); m.p. 108-110° C. after trituration in hexane.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][NH:16][C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1.[F:17][C:18]1[CH:23]=[C:22]([CH:24]2[CH2:27][O:26][CH2:25]2)[CH:21]=[C:20](F)[N:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:17][C:18]1[N:19]=[C:20]([N:16]2[C:10]3[CH:9]=[C:8]([C:6]4[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=4)[N:13]=[CH:12][C:11]=3[CH:14]=[N:15]2)[CH:21]=[C:22]([CH:24]2[CH2:27][O:26][CH2:25]2)[CH:23]=1
Reactant: Fc1cc(C2COC2)cc(F)n1
Reactant: Cc1cncc(-c2cc3[nH]ncc3cn2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cc(C3COC3)cc(F)n2)n1
Temperature: 25 °C
Yield: 37.3 %

Procedure:
To a mixture of 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine (0.468 mmol; 98.9 mg) and 2,6-difluoro-4-(oxetan-3-yl)pyridine (0.468 mmol; 80.1 mg) in DMF (5 mL) was added Cesium carbonate (0.562 mmol; 183 mg). The resulting mixture was stirred at room temperature. The mixture was filtered. The filtrate was partitioned between EtOAc and water. The organic layer was concentrated. The residue was purified on silica eluted with 0 to 6% MeOH in DCM to afford 1-[6-fluoro-4-(oxetan-3-yl)-2-pyridyl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine as a white solid (63.2 mg, 31%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(C)=O>[CH2:13]([N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Ic1cnn(Cc2ccccc2)c1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
To a stirred suspension of 4-iodo-1H-pyrazole (1.50 g, 7.73 mmol) and potassium carbonate (2.67 g, 19.3 mmol) in acetone was added benzyl bromide (0.96 mL, 8.07 mmol) and the reaction was refluxed for 3 h. After cooling to room temperature the mixture was concentrated onto silica gel in vacuo and eluted through a short silica plug (sequential elution-hexane, 10% diethyl ether in hexanes) to provide the title compound as a white solid (2.12 g, 97% yield).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C>[N:19]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)=[N+:20]=[N-:21]
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1-c1ccc(CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4'-bromomethylbiphenyl-2-carboxylate (5.0 g, 16.4 mmol) in DMF (40 ml) was added sodium azide (2.7 g, 41 mmol). The mixture was stirred overnight at room temperature, filtered, and the filtrate was partitioned between water and ethyl acetate (100 ml). The aqueous phase was extracted once more with ethyl acetate (100 ml) and the combined organic phase was washed with water (3×100 ml) and saturated aqueous sodium chloride (100 ml) before being dried (MgSO4), filtered and concentrated to an oily residue (3.9 g) which was used in the subsequent reaction without further purification: NMR (200 MHz; CDCl3,TMS) δ: 7.9-7.2 (m,8H), 4.37 (s,2H), and 3.60 (s,3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:43])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[C:33]([CH2:34][O:35]C3CCCCO3)=[CH:32][N:31]=[N:30]2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:35][CH2:34][C:33]1[N:29]([C:25]2[CH:24]=[C:23]([C:22]3[CH2:21][C:20](=[O:43])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:16])([F:18])[F:17])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)[N:30]=[N:31][CH:32]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-methyl-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M46) (0.90 g, 1.46 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (400 mg, 66%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[N+](C1C=CC([O:19][C:20]([N:22]2[CH2:25][CH:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][N:28]=3)[CH2:23]2)=O)=CC=1)([O-])=O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([NH:3][C:20]([N:22]2[CH2:23][CH:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][N:28]=3)[CH2:25]2)=[O:19])[N:5]=1
Reactant: Nc1cccnn1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(Oc2ccc(Br)cn2)C1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1cccnn1)N1CC(Oc2ccc(Br)cn2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.1 %

Procedure:
To an ice-bath cooled solution of sodium hydride (60 wt % in mineral oil, (0.946 g, 23.6 mmol) in DMF (21 mL) under nitrogen atmosphere was added (dropwise) a solution of 3-aminopyridazine (1.24 g, 13.01 mmol) in DMF (21 mL). After several minute a solution of 3-(5-bromo-pyridin-2-yloxy)-azetidine-1-carboxylic acid 4-nitro-phenyl ester (Example 10, step 3; 4.66 g, 11.83 mmol) in DMF (17 mL) was added. After 5 min the cooling bath was removed and reaction allowed to warm to ambient temperature and stir for 1.5 hr. Saturated sodium bicarbonate solution (500 mL) was added and the mixture was extracted with EtOAc (4×400 mL). Combined organic phases were washed with sat sodium chloride solution (500 mL), dried over sodium sulphate and filtered. The filtrate solvents were removed in vacuo to afford a crude product that was triturated with diethyl ether to afford the title compound (3.32 g, 80%) as a colourless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)[CH:5]=[CH:6][CH:7]=1.[C:16]1([CH:22]2[CH2:26][CH2:25][NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:24]2[CH2:25][CH2:26][CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23]2)=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnoc1-c1cccc(F)c1
Reactant: c1ccc(C2CCNC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cnoc1-c1cccc(F)c1)N1CCC(c2ccccc2)C1
Temperature: 25 °C

Procedure:
5-(3-fluorophenyl)-isoxazole-4-carboxylic acid (47.8 mg, 0.231 mmol), 3-phenylpyrrolidine (40 mg, 0.271 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (92.6 mg, 0.288 mmol) and diisopropylethylamine (49.7 mg, 0.384 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature over night. Solvent was evaporated in vacuo (0.5-1.0 mL) and the residue was taken up in dichloromethane (1 mL), filtered and purified by normal-phase chromatography (20-50% EtOAc:petroleum ether). The combined fractions were partitioned between H2O/acetic acid (pH 4) and ethyl acetate. The organic fractions were washed with H2O/brine and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C20H17FN2O2: 336.1274, found 336.1277.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].S([O-])(=O)(=O)C.[CH2:22]([O:24][C:25](=[O:48])[CH2:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34](=[O:46])[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH:36]=2)[CH:31]=[CH:30][C:29]=1O)[CH3:23]>>[CH2:22]([O:24][C:25](=[O:48])[CH2:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34](=[O:46])[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH:36]=2)[CH:31]=[CH:30][C:29]=1[O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=1)[CH3:23]
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1O
Reactant: CC(=O)c1ccc(CCCCCCO)cc1
Agent: CS(=O)(=O)[O-]
Product: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1OCCCCCCc1ccc(C(C)=O)cc1
Yield: 80.3 %

Procedure:
In a manner analogous to Example 92B, 2.85 g of 6-(4-acetylphenyl)hexanol were converted into its mesylate and reacted with 1.78 g of 5-[3-(ethoxycarbonyl)benzoyl]-2-hydroxybenzenepropanoic acid ethyl ester to provide 2.21 g of the desired title product as a pale yellow oil.