Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[C:7]1[CH:15]=[C:14]([NH:16][C:17](=[O:39])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:54]1[C:59](=[O:60])[CH2:58][CH2:57][C:55]1=[O:56])=[N+](C)C)C.CCN(C(C)C)C(C)C>C1COCC1>[O:56]=[C:55]1[CH2:57][CH2:58][C:59](=[O:60])[N:54]1[O:11][C:10](=[O:12])[C:9]1[CH:8]=[C:7]([CH:15]=[C:14]([NH:16][C:17](=[O:39])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:13]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:40]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)Nc1cc(C(=O)O)cc(C(=O)OC(C)(C)C)c1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)Nc1cc(C(=O)ON2C(=O)CCC2=O)cc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C

Procedure:
5-(15-tert-Butoxycarbonyl-pentadecanoylamino)-isophthalic acid mono-tert-butyl ester (140 mg, 0.25 mmol) was dissolved in dry THF (3.5 ml). TSTU (95 mg, 0.30 mmol) and DIPEA (70 ul, 0.30 mmol) were added. The mixture was stirred at RT under nitrogen over the week-end. The reaction mixture was almost dry. EtOAc was added and the precipitate was removed by filtration. The filtrate was extracted with 0.1 N HCl (2×), brine (1×), dried (Na2SO4) and concentrated to give the title compound as a syrup containing a trace of an impurity in a quantitative yield (0.165 mg).
Reaction SMILES: [O:1]=[C:2]1[O:6][C@H:5]([C:7](Cl)=[O:8])[CH2:4][CH2:3]1.[CH2:10]([Mg]Br)[CH3:11]>C1COCC1>[C:7]([C@H:5]1[O:6][C:2](=[O:1])[CH2:3][CH2:4]1)(=[O:8])[CH2:10][CH3:11]
Reactant: O=C1CC[C@@H](C(=O)Cl)O1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(=O)[C@@H]1CCC(=O)O1
Temperature: -78 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
To a solution of (2S)-5-oxotetrahydrofuran-2-carbonyl chloride (compound 28b, 70 g, 473 mmol) in dry THF (400 mL) was added ethylmagnesium bromide (173 mL, 520 mmol, 3M in THF) slowly at −78° C. under N2. After addition, the reaction mixture was stirred at −78° C. for another 2 hours. The mixture was then quenched with saturated NH4Cl solution and extracted with EtOAc (500 mL) twice. The combined organic layers were concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 1:7 to 1:3 EtOAc in petroleum ether) to afford 35 g of (5S)-5-propanoyltetrahydrofuran-2-one (compound 28c) as a light yellow oil.
Reaction SMILES: [CH:1]([C:3]1[NH:4][CH:5]=[CH:6][CH:7]=1)=[O:2].[OH-].[K+].CS(C)=O.[Br:14][CH2:15][CH2:16]Br>O>[Br:14][CH2:15][CH2:16][N:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[CH:1]=[O:2]
Reactant: O=Cc1ccc[nH]1
Reactant: BrCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1cccn1CCBr

Procedure:
A mixture of 2-formylpyrrole (1 g), potassium hydroxide (2.3 g) and dry DMSO (20 mL) was stirred under nitrogen atmosphere. 1,2-dibromoethane (7.9 g) was added dropwise at 20–25° C. and stirred till the reaction is complete. Water (50 mL) was added and the reaction mixture was extracted with diethyl ether (3×50 mL). The combined organic layer was washed with water (30 mL), followed by brine (30 mL) and was dried over Na2SO4. The solvent was evaporated and the compound obtained was purified by column chromatography (silica gel 100–200) using ethyl acetate: hexane (2:8) as an eluent to obtain the title compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([CH:15]([CH2:20][CH2:21][CH2:22][CH3:23])[C:16]([O:18][CH3:19])=[O:17])[CH3:14].[CH2:24]=[O:25]>C1COCC1>[CH2:13]([C:15]([CH2:24][OH:25])([CH2:20][CH2:21][CH2:22][CH3:23])[C:16]([O:18][CH3:19])=[O:17])[CH3:14]
Reactant: C=O
Reactant: CCCCC(CC)C(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCC(CC)(CO)C(=O)OC
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
47 ml (0.334 mol) of diisopropylamine are added dropwise at 20° C. to a solution of 118 ml (0.319 mol) of n-butyllithium (2.7 M in heptane) in 118 ml of THF, and the mixture is stirred at 20° C. for 30 min. Within approx. 15 min, 48 g (0.304 mol) of methyl 2-ethylhexanoate are added dropwise at −20° C., and the mixture is stirred at −20° C. for 30 min and subsequently admixed with 27 g (0.90 mol) of paraformaldehyde. After 30 min at −20° C., the mixture is stirred at 0° C. for a further 2 h. After the solvent has been removed at 20° C. and 20 mbar (approx. 250 ml), 100 ml of MTBE and 200 ml of saturated aqueous solution of ammonium chloride are added to the oily residue and the mixture is stirred at RT for 2 h. The organic phase is removed, the aqueous phase is re-extracted 1× with 100 ml of MTBE and the combined organic phases are concentrated on a rotary evaporator. The crude product (97% conversion based on methyl 2-ethylhexanoate) can be purified by distillation to obtain methyl 2-ethyl-2-hydroxymethylhexanoate (b.p.: 100° C., 6 mbar) in 91% yield with a purity of >99%.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[O:18]C(=O)[NH:16][CH:15]3[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:33])([F:32])[CH:29]([F:31])[F:30])[CH:22]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[NH2:16][CH:15]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:32])([F:33])[CH:29]([F:30])[F:31])[CH:22]=1)[CH:14]([C:11]1[CH:10]=[CH:9][C:8]([O:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:13][CH:12]=1)[OH:18]
Reactant: O=C1NC(Cc2cccc(OC(F)(F)C(F)F)c2)C(c2ccc(Oc3ccccc3)cc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2ccccc2)cc1
Yield: 87.3 %

Procedure:
To a solution of (4RS,5SR)-5-(4-(phenyloxy)phenyl)-4-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)-1,3-oxazolidin-2-one (3.7 g, 8.02 mmol) in ethanol (10 ml) was added 8N aqueous sodium hydroxide solution (5.0 ml, 40 mmol), and the mixture was heated under reflux for 4 hrs. The reaction solution was concentrated, diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave (1RS,2SR)-2-amino-1-(4-(phenyloxy)phenyl)-3-(3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)-1-propanol (3.05 g, 87%).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[Cl:5][C:6]1[N:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.BrBr.O>C(O)(=O)C>[Cl:5][C:6]1[N:11]=[C:10]2[S:1][C:2]([NH2:3])=[N:12][C:9]2=[CH:8][CH:7]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc2ccc(Cl)nc2s1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To glacial acetic acid (125 mL) pre-cooled to 5° C. were added potassium thiocyanate (93 g, 961 mmol) and 6-chloropyridin-3-amine (Q-1) (15 g, 117 mmol). The mixture was placed in a freezing mixture of ice and salt and stirred, while 10 mL of bromine in glacial acetic acid (30 mL) was added from an addition funnel at such a rate that the temperature never rose beyond 0° C. After all the bromine had been added, the solution was stirred for an additional 2 h at 0° C. and at room temperature overnight. Water (60 mL) was added quickly, and the slurry maintained at 90° C. was filtered hot. The orange filter cake was placed in the reaction flask. Glacial acetic acid (60 mL) was added to the flask. The mixture in the flask was maintained at 85° C. was filtered hot once again. The combined filtrates were cooled and neutralized with concentrated ammonia solution to pH 6. A precipitate was collected as the title compound (19 g). MS (m/z): 186 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:21]Br)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][C:32]([CH3:43])([CH3:42])[CH2:33][C:34]1[CH:35]=[C:36]([CH2:40][OH:41])[CH:37]=[CH:38][CH:39]=1.[I-].[Na+].CCN(C(C)C)C(C)C>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:21][NH:31][C:32]([CH3:43])([CH3:42])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][OH:41])[CH:35]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(N)Cc1cccc(CO)c1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(Cc1cccc(CO)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (R)-8-(benzyloxy)-5-(2-bromo-1-(tert-butyldimethylsilyloxy)ethyl)quinolin-2 (1H)-one (0.518 g) and (3-(2-amino-2-methylpropyl)phenyl)methanol (0.19 g) (example 275, step c) and sodium iodide (0.159 g) and Hunig's Base (0.555 mL) in acetonitrile (3 mL) was heated at reflux under nitrogen for 2 days. Further (3-(2-amino-2-methylpropyl)phenyl)methanol (0.19 g) and Hunig's Base (0.185 mL) were added and heating at reflux continued for 1 day. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and brine, the organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography eluting with 3% methanol and 1% triethylamine in dichloromethane. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.44 g.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15].[F:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:21]=3[F:20])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15]
Reactant: CCCNC(=O)c1nnc2c(I)c(F)ccc2c1N
Reactant: COc1cccc(B(O)O)c1F
Product: CCCNC(=O)c1nnc2c(-c3cccc(OC)c3F)c(F)ccc2c1N
Yield: 28.9 %

Procedure:
Using method A, 4-amino-7-fluoro-8-iodo-N-propyl-cinnoline-3-carboxamide (250 mg, 0.67 mmol) and (2-fluoro-3-methoxyphenyl)boronic acid (193.4 mg, 1.136 mmol) were reacted to afford the title compound (72.0 mg, 29% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 8.49 (bs, 1H), 7.94 (d×d, J=4.9 Hz, J=9.2 Hz, 1H), 7.55 (t, J=8.5 Hz, 1H), 7.21 (m, 1H), 7.03-7.10(m, 2H), 3.94 (s, 3H), 3.44 (q, J=6.7 Hz, J=13.4 Hz, 2H), 1.64 (apparent sextet, J=7.3 Hz, 2H), 0.98 (t, J=7.3 Hz, 3H). MS APCI, m/z=373 (M+H) HPLC 2.72 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])=[N:6][CH:7]=1.C[OH:25]>>[C:8](=[O:9])=[O:25].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:12]([Cl:14])([Cl:13])[Cl:15])=[O:9])=[N:6][CH:7]=1
Reactant: CO
Agent: O=C(NC(Nc1ccc(Cl)cc1)C(Cl)(Cl)Cl)c1ccc(Br)cn1
Product: O=C=O

Procedure:
Compound 34 has identical NMR as Compound 29, but has an (−) optical rotation. Compound 34 was obtained from chiral HPLC separation (Chiralpak IA 30% MeOH, CO2 at 100 barr) of Compound 29 above: and collect the first eluting peak (−) enantiomer: [α]=−121° (c 0.69 in CHCl3). 1H NMR (300 MHz, CDCl3) δ 8.62-8.61 (m, 1H), 8.50 (d, J=9.9 Hz, 1H), 8.12 (dd, J=8.4, 0.6 Hz, 1H), 8.04-8.00 (m, 1H), 7.18 (d, J=9.0 Hz, 2H), 6.78 (d, J=8.0 Hz, 2H), 6.28 (t, J=9.6 Hz, 1H), 4.55 (d, J=9.6 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:64]1[CH2:69][CH2:68][CH:67]([NH:70][C:71](=[O:80])[O:72][CH2:73][C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)[CH2:66][CH2:65]1>O1CCOCC1.CN(C)C=O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:73]([O:72][C:71]([NH:70][CH:67]1[CH2:68][CH2:69][N:64]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:65][CH2:66]1)=[O:80])[C:74]1[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: O=C(NC1CCNCC1)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(N2CCC(NC(=O)OCc3ccccc3)CC2)c1
Temperature: 100 °C
Reaction time: 20 h
Yield: 26.6 %

Procedure:
Methyl 3-bromobenzoate (230 mg, 1.07 mmol), palladium acetate (12 mg, 0.054 mmol), BINAP (133 mg, 0.214 mmol) and cesium carbonate (767 mg, 2.35 mmol) were added to a solution of benzyl piperidin-4-yl-carbamate obtained in Example (192b) (248 mg, 0.817 mmol) in 1,4-dioxane (10 mL) and N,N-dimethylformamide (2.5 mL), and the mixture was stirred at 100° C. for 20 hours. The reaction solution was cooled, diluted with ethyl acetate, and washed with brine. The organic layer was dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=3/1) to obtain 80 mg of the title compound as a colorless oily substance (20%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][C:19]2C=[CH:25][C:24]([F:27])=[CH:23][C:20]=2C#N)=[CH:4][C:5]([NH:8][C:9]2[N:13]([CH:14]([CH3:16])[CH3:15])[N:12]=[C:11]([CH3:17])[CH:10]=2)=[N:6][CH:7]=1.[OH-].[Na+].[C:30]([O:33]CC)(=[O:32])[CH3:31]>O1CCOCC1>[Cl:1][C:2]1[C:3]([NH:18][C:19]2[CH:20]=[CH:23][C:24]([F:27])=[CH:25][C:31]=2[C:30]([OH:33])=[O:32])=[CH:4][C:5]([NH:8][C:9]2[N:13]([CH:14]([CH3:15])[CH3:16])[N:12]=[C:11]([CH3:17])[CH:10]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2cc(Nc3ccc(F)cc3C#N)c(Cl)cn2)n(C(C)C)n1
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(Nc3ccc(F)cc3C(=O)O)c(Cl)cn2)n(C(C)C)n1
Yield: 27.2 %

Procedure:
A solution of 2-[(5-chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]-5-fluorobenzonitrile (1.3 g, 3.38 mmol) in sodium hydroxide −1 M (10 mL, 10.00 mmol) and 1,4-dioxane (10 mL) was refluxed overnight. Ethyl acetate was added and the layers were separated. The organic layer was washed with 1 M NaOH (40 ml). The combined aqueous layers were washed with ethyl acetate, and neutralized with acetic acid. The product was isolated by filtration. 2-[(5-Chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]-5-fluorobenzoic acid (1.1 g, 2.72 mmol, 27.2% yield) was isolated as a yellow solid. 1H NMR (400 MHz, DMSO-d6) ppm 1.27 (d, J=6.57 Hz, 6 H) 2.11 (s, 3 H) 4.39 (quin, J=6.57 Hz, 1 H) 5.95 (s, 1 H) 6.70 (s, 1 H) 7.51 (td, J=8.40, 3.16 Hz, 1 H) 7.61 (dd, J=9.09, 4.80 Hz, 1 H) 7.72 (dd, J=9.22, 3.16 Hz, 1 H) 8.00 (s, 1 H) 8.53 (s, 1 H) 9.66 (br. s., 1 H) 13.88 (br. s., 1 H); HPLC Rt=2.44 min, MS (ESI): 404.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([CH:24]=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.[CH3:28][C@H:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([CH2:24][NH:36][C@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH3:28])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1
Reactant: O=CC1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: C[C@H](N)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@H](NCC1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(F)cc2)CC1)c1ccccc1
Reaction time: 14 h

Procedure:
1-(1-(4-fluorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carbaldehyde (35 mg, 0.096 mmol) was dissolved in THF (2 mL) and (S)-α-methylbenzylamine (0.013 mL, 0.115 mmol) was added. The solution was stirred at rt for 10 h, at which time the THF was removed in vacuo and the residue dissolved in EtOH (5 mL), and sodium cyanoborohydride (13 mg, 0.192 mmol) and a catalytic drop of glacial acetic acid were added. Stirring was permitted for 14 h, at which time the solvent was removed in vacuo, the residue was taken up in EtOAc. The organic phase was washed with 10% aq. sodium carbonate, dried over magnesium sulfate, and concentrated. Purification was accomplished via silica gel flash chromatography (30 g silica gel, 5:95 7M methanolic ammonia:ethyl acetate.) The title compound was obtained as a yellow oil. (Yield: 21 mg, 0.045 mmol, 47%) 1H NMR (400 MHz, CDCl3) 7.62, 7.39-7.23, 7.14, 7.09-7.02, 6.86, 6.57, 5.45, 4.59, 4.06, 3.76-3.63, 2.74, 2.39-2.15, 1.76-1.52, 1.33, 0.98, 0.63
Reaction SMILES: [C:1]([Si:5]([CH3:36])([CH3:35])[O:6][CH2:7][CH:8]1[O:12][CH:11]([N:13]2[CH:18]=[C:17]3[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:24][CH:23]=4)[O:21][C:16]3=[N:15][C:14]2=[O:33])[CH2:10][CH:9]1[OH:34])([CH3:4])([CH3:3])[CH3:2].[Cl:37][CH2:38][C:39](Cl)=[O:40]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:37][CH2:38][C:39]([O:34][C@H:9]1[CH2:10][C@H:11]([N:13]2[CH:18]=[C:17]3[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:24][CH:23]=4)[O:21][C:16]3=[N:15][C:14]2=[O:33])[O:12][C@@H:8]1[CH2:7][O:6][Si:5]([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:36])[CH3:35])=[O:40]
Reactant: CCCCCc1ccc(-c2cc3cn(C4CC(O)C(CO[Si](C)(C)C(C)(C)C)O4)c(=O)nc3o2)cc1
Reactant: O=C(Cl)CCl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCc1ccc(-c2cc3cn([C@H]4C[C@H](OC(=O)CCl)[C@@H](CO[Si](C)(C)C(C)(C)C)O4)c(=O)nc3o2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 25 mL flask was added 102 mg (0.2 mmol) of 3-(5-((tert-butyldimethyl silyloxy)methyl)-4-hydroxy-tetrahydrofuran-2-yl)-6-(4-pentylphenyl)furo[2,3-d]pyrimidin-2(3H)-one, 48 mg (0.4 mmol) of DMAP, and 5 mL of DCM. 30 μl (0.4 mmol) of chloroacetyl chloride was added dropwise. The mixture was stirred at rt for 1 h.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([F:11])([F:10])[F:9])=[N:4][NH:5][C:6]=1[CH3:7].C(=O)([O-])[O-].[K+].[K+].[C:18]([O:22][C:23](=[O:26])CBr)([CH3:21])([CH3:20])[CH3:19]>C(#N)C>[C:18]([O:22][C:23]([N:5]1[C:6]([CH3:7])=[C:2]([Cl:1])[C:3]([C:8]([F:9])([F:11])[F:10])=[N:4]1)=[O:26])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1[nH]nc(C(F)(F)F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(Cl)c(C(F)(F)F)nn1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 95 %

Procedure:
To 2.70 mmol of 4-chloro-5-methyl-3-trifluoromethylpyrazole and 3.9 mmol of potassium carbonate in 0.5M solution of acetonitrile add 3.25 mmol of t-butylbromoacetate. The reaction was allowed to stir at room temperature for an hour and then heated at 70° C. for 12 hours. The reaction was filtered, the filtrate concentrated to a crude oil. Fresh ether was added and the mixture was allowed to cool. The white crystals obtained were filtered and vaccum dried to give the desired intermediate 4-chloro-5-methyl -3-trifluoromethyl pyrazole-1-carboxylic acid tertbutyl ester in 95% yield. LC-MS in FP m/z=300 (M++1)
Reaction SMILES: [CH3:1][C@H:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH2:3]/[CH:4]=[CH:5]/[C:6](=[O:8])[CH3:7]>[Ni].C(OCC)(=O)C>[CH3:1][C@@H:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:13])[CH3:14])[CH2:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7]
Reactant: CC(=O)/C=C/C[C@H](C)CCC=C(C)C
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CC(=O)CCC[C@@H](C)CCC=C(C)C
Reaction time: 2 h

Procedure:
A 3 l, three-necked, round bottomed flask fitted with a mechanical stirrer was charged with 6 g of Raney-Nickel, 500 ml of ethyl acetate and 127 g of (3E,6R)-6,10-dimethyl-3,9-undecadiene-2-one. The flask was purged with hydrogen and stirring was initiated at room temperature. Hydrogenation was carried out under a pressure of 2 bar. After 2 hours the reaction was stopped. The total hydrogen uptake was about 14.2 l. The reaction mixture was filtered and concentrated to give a pale yellow oil of (R)-6,10-dimethyl-9-undecene-2-one which was distilled under vacuum using a 40 cm Vigreux distillation column, and the following fractions were collected:
Reaction SMILES: Br[C:2]1(Br)[C:10]2[CH:9]=[N:8][C:7]([Cl:11])=[N:6][C:5]=2[N:4]([CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:3]1=[O:17]>C(O)(=O)C.C1COCC1.[Zn]>[Cl:11][C:7]1[N:8]=[CH:9][C:10]2[CH2:2][C:3](=[O:17])[N:4]([CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:5]=2[N:6]=1
Reactant: CCC(CC)N1C(=O)C(Br)(Br)c2cnc(Cl)nc21
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCC(CC)N1C(=O)Cc2cnc(Cl)nc21
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
To a solution of 5,5-Dibromo-2-chloro-7-(1-ethyl-propyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (crude, ˜5.3 mmol) in acetic acid (6 mL) and THF (4 mL) is added Zn dust (1.37 g, 21 mmol) at 0° C. The mixture is stirred at 0° C. for 2 mins then heated to room temperature, stirring for 30 mins. The mixture is filtered through celite, rinsed with ethyl acetate. The filtrate is concentrated in vacuo and the residue is purified by flash chromatography (ethyl acetate:hexane=5:95 to 40:60) to give 2-Chloro-7-(1-ethyl-propyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][CH2:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1.[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[C:35]([F:41])[CH:34]=1>>[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][N:11]([CH2:12][C:13]2[CH:31]=[CH:30][C:16]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=3)=[CH:15][CH:14]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[CH3:1])=[C:35]([F:41])[CH:34]=1
Reactant: Fc1cc(Cl)ccc1CBr
Reactant: COC(=O)CCc1ccc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)cc1
Product: COC(=O)CCc1ccc(Oc2ccc(CN(Cc3ccc(Cl)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)cc1

Procedure:
The product from Example 76C and 4-chloro-2-fluorobenzyl bromide were processed as described in Example 6B to provide the title compound.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](O)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[CH3:21]>FC(F)(F)C(O)=O>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[CH3:21]
Reactant: Oc1ccccc1
Reactant: CCC(O)(CC)c1ccc(Br)c(C)c1
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(c1ccc(O)cc1)c1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.2 %

Procedure:
Phenol (732 mg, 7.78 mmol) was added to a solution of 3-(4-bromo-3-methyl-phenyl)-pentan-3-ol (Example 38-(1); 2.0 g, 7.78 mmol) in trifluoroacetic acid (20 mL), and the mixture was stirred at room temperature for five hours. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 30:70, 40 minutes) to give the target compound as a colorless oil (1.95 g, 75%).