Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C(C(O)C)=CC=CN=1.NN.CC1C2C(=NC=CC=2)NN=1.[NH:23]1[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[C:25]([C:32]([O:34][CH3:35])=[O:33])=[N:24]1.[Br:36]Br>>[Br:36][C:30]1[CH:31]=[C:26]2[C:25]([C:32]([O:34][CH3:35])=[O:33])=[N:24][NH:23][C:27]2=[N:28][CH:29]=1
Reactant: COC(=O)c1n[nH]c2ncccc12
Reactant: BrBr
Agent: CC(O)c1cccnc1Cl
Agent: Cc1n[nH]c2ncccc12
Agent: NN
Product: COC(=O)c1n[nH]c2ncc(Br)cc12

Procedure:
Scheme 1 describes a method for preparation of 1H-pyrazolo[3,4-b]pyridine derivatives (XVI) by reacting the 3-anion of 2-chloropyridine (I) with acetaldehyde to form 1-(2-chloropyridin-3-yl)ethanol (II). The alcohol is then oxidized to (III) before cyclizing in the presence of hydrazine to 3-methyl-1H-pyrazolo[3,4-b]pyridine (IV). The methyl is oxidized and esterified to methyl 1H-pyrazolo[3,4-b]pyridine-3-carboxylate (VI). The ester (VI) is treated with bromine to form methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (VII) before hydrolyzing the ester to acid VIII. Acid VIII was reacted with N,O-dimethylhydroxylamine to form the Weinreb amide (IX). After protection of the 1H-pyrazolo[3,4-b]pyridine NH, the Weinreb amide is reduced to aldehyde XI. 5-substituted 1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde derivatives (XIII) are prepared by Suzuki Coupling of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (XI) with various boronic acid derivatives (XII). Aldehyde XIII is reacted with various substituted and unsubstituted aryl/heteroaryl-3,4-diamines (XIV) to form XV. Final deprotection of the pyrazolone nitrogen yields the desired 1H-pyrazolo[3,4-b]pyridine derivative (XVI).
Reaction SMILES: C1(C)C=CC(C2C=CC=CN=2)=CC=1.[Br:14]Br.[Br:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:20][CH:19]=1>ClC1C=CC=CC=1>[Br:16][CH:17]([Br:14])[C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:22][CH:23]=1
Reactant: BrCc1ccc(-c2ccccn2)cc1
Reactant: BrBr
Agent: Cc1ccc(-c2ccccn2)cc1
Solvent: Clc1ccccc1
Product: BrC(Br)c1ccc(-c2ccccn2)cc1
Temperature: 115 °C
Yield: 60.7 %

Procedure:
In a 100 ml four neck flask were placed 2-(4-tolyl)pyridine (5.0 g, 29.6 mmol) and chlorobenzene (18 ml), and bromine (9.4 g, 59.1 mmol) was added dropwise while heating the mixture at 110-120 ° C. over 12 hours. The reaction mixture was stirred with heating at a temperature in the above-mentioned range for 1 hour and analyzed by HPLC. As a result, 2-(4-bromomethylphenyl)pyridine was confirmed to have been produced in a 60.7% yield. The obtained reaction mixture was cooled and the precipitated 2-(4-bromomethylphenyl)pyridine salt was collected by filtration. The filtrate was neutralized with 5% aqueous sodium hydroxide solution. After washing with water, the mixture was dried over anhydrous magnesium sulfate. Chlorobenzene was evaporated under reduced pressure and the residue was subjected to silica gel column chromatography (eluent: ethyl acetate-hexane) to give 2-(4-dibromomethylphenyl)pyridine in a 1.2 g yield. From the 1H-NMR analysis, the product was found to be 2-(4-dibromomethylphenyl)pyridine. 2-(4-dibromomethylphenyl)pyridine 1H-NMR(CDCl3, ppm) δ: 6.70(s,1H), 7.23-7.29(m,1H), 7.66-7.68(d,2H), 7.68-7.78(m,2H), 7.98-8.01(d,2H), 8.69-8.71(m,1H)
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3][CH:2]=1>C(O)C.CCOC(C)=O.[Rh]>[CH:10]1([CH:1]2[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: [Rh]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)C1CCC(C2CCCCC2)CC1
Yield: 93.5 %

Procedure:
Reduce a solution of 4-biphenylcarboxylic acid (10 g) in ethanol (EtOH) (175 mL) and EtOAc (30 mL) over 5% rhodium/alumina (7 g) under H2 (60 psi) for 8 days. Filter the catalyst and concentrate the solution to obtain the title compound (9.92 g).
Reaction SMILES: C1(O[C:8](=[O:16])[NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)C=CC=CC=1.[F:17][C:18]1([F:34])[O:22][C:21]2[CH:23]=[CH:24][C:25]([CH2:27][N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][C:20]=2[O:19]1>>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([NH:9][C:8]([N:31]2[CH2:32][CH2:33][N:28]([CH2:27][C:25]3[CH:24]=[CH:23][C:21]4[O:22][C:18]([F:34])([F:17])[O:19][C:20]=4[CH:26]=3)[CH2:29][CH2:30]2)=[O:16])[CH:11]=1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: FC1(F)Oc2ccc(CN3CCNCC3)cc2O1
Product: O=C(Nc1cccnc1)N1CCN(Cc2ccc3c(c2)OC(F)(F)O3)CC1

Procedure:
The title compound was prepared from pyridin-3-yl-carbamic acid phenyl ester and 1-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperazine in analogy with Example 142. 1H NMR (400 MHz, CDCl3): 8.46 (d, J=2.5 Hz, 1H), 8.23-8.21 (m, 1H), 7.99-7.96 (m, 1H), 7.22-7.19 (m, 2H), 7.11 (s, 1H), 6.99-6.98 (m, 2H), 3.54-3.52 (m, 4H), 3.49 (s, 2H), 2.46-2.44 (m, 4H).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.Cl>CS(C)=O>[CH3:5][C:2]([C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=1)([CH3:1])[CH:3]=[O:4]
Reactant: CC(C)(CO)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.5 %

Procedure:
To a stirring solution of 41.7 grams (0.226 mole) of 2-methyl-2-(4-chlorophenyl)propanol in 100 mL of dimethyl sulfoxide is added 126 mL (0.904 mole) of triethylamine. A solution of 63.0 grams (0.452 mole) of triethylamine-sulfur trioxide complex in 300 mL of dimethyl sulfoxide is then added portionwise during a 15 minute period. Upon completion of addition, the reaction mixture is stirred at ambient temperature for about five hours. The reaction mixture is then poured into about 500 mL of ice, and made acidic with aqueous 2N hydrochloric acid. The mixture is then extracted with two 100 mL portions of diethyl ether. The combined extracts are dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 22.9 grams of 2-methyl-2-(4-chlorophenyl)propanaldehyde. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[OH:16][CH:17]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]([OH:25])=O)[C:18]1=[O:26].[CH3:27][C@H:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([CH3:34])[N:29]1[CH2:35][CH2:36][NH2:37].O>CN(C)C=O>[CH3:27][C@H:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([CH3:34])[N:29]1[CH2:35][CH2:36][NH:37][C:23](=[O:25])[CH2:22][N:19]1[CH2:20][CH2:21][CH:17]([OH:16])[C:18]1=[O:26]
Reactant: O=C(O)CN1CCC(O)C1=O
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)CN1CCC(O)C1=O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
1.30 g of dicyclohexylcarbodiimide dissolved in 6 ml of dimethylformamide are added dropwise at 0° to 1.0 g of (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetic acid and 1.03 g of 94.7% cis-2-(2,6-dimethyl-1-piperidinyl)ethylamine dissolved in 20 ml of dimethylformamide. The mixture is left to stir at room temperature for 4 days, treated with 0.23 g of ion-free water and evaporated in a water-jet vacuum. The residue is treated five times with toluene and in each case again evaporated. The constituents of the residue which are soluble in chloroform are chromatographed on 60 g of aluminum oxide (activity grade III, neutral). The alcohol eluate is again chromatographed on 15 g of aluminum oxide (activity grade III, neutral). The fractions which are eluted with acetonitrile and ethanol contain, according to the gas chromatogram and mass spectrum, (R/S)-cis-N-[2-(2,6-dimethyl-1piperidinyl)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9]([OH:10])=[C:8]([C:11]3[NH:16][C:15]4[CH:17]=[CH:18][C:19](I)=[CH:20][C:14]=4[S:13](=[O:23])(=[O:22])[N:12]=3)[C:7](=[O:24])[N:6]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[N:5]2[CH:30]=1.[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+].N(CC(O)=O)C.[CH3:55][S:56]([NH2:59])(=[O:58])=[O:57]>[Cu].CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9]([OH:10])=[C:8]([C:11]3[NH:16][C:15]4[CH:17]=[CH:18][C:19]([NH:59][S:56]([CH3:55])(=[O:58])=[O:57])=[CH:20][C:14]=4[S:13](=[O:23])(=[O:22])[N:12]=3)[C:7](=[O:24])[N:6]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[N:5]2[CH:30]=1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(I)ccc3N2)c(O)c2cc(F)cn21
Reactant: CS(N)(=O)=O
Agent: [Cu]
Agent: CNCC(=O)O
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)c(O)c2cc(F)cn21
Temperature: 100 °C
Reaction time: 16 h
Yield: 15.5 %

Procedure:
6-Fluoro-4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6 benzo[1,2,4]thiadiazin-3-yl)-1-(3-methyl-butyl)-pyrrolo[1,2-b]pyridazin-2-one (Example 14j, 0.047 g, 0.086 mmol), potassium triphosphate (0.055 g, 0.258 mmol), sarcosine (0.0046 g, 0.0516 mmol), and copper (J) iodide (0.0066 g, 0.0344 mmol) were combined. Anhydrous N,N-dimethylformamide (3 mL) was added followed by methanesulfonamide (0.0245 g, 0.258 mmol). The flask was purged with nitrogen and the mixture was stirred at 100° C. for 16 h. Upon cooling, the mixture was filtered over Celite, washed with ethyl acetate and the solvent was removed in vacuo. Purification by preparative HPLC (Column Luna 5μ C18 (2) 100 Å size 150×21.2 mm, 5 micron, 40%-95% in 11 min 25 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water) afforded the desired product, N-{3-[6-fluoro-4-hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.0068 g, 0.0133 mmol, 15.4% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.96 (3H, s), 0.97 (3H, s), 1.53-1.59 (2H, m), 1.66-1.76 (1H, m), 3.07 (3H, s), 4.32 (2H, t, J=7.5 Hz), 6.83 (1H, bs), 7.51-7.63 (3H, m), 8.06 (1H, bs), 10.17 (1H, bs). LC-MS (ESI) calcd for C20H22FN5O6S2 511.10. found 512.3 [M+H+].
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][C@@H:6]([NH2:8])[CH3:7].C(N(CC)CC)C.[C:16](N1C=CN=C1)(N1C=CN=C1)=[S:17].Cl>C1COCC1.C(OCC)(=O)C>[N:8]([C@@H:6]([CH3:7])[CH2:5][CH2:4][O:3][CH3:2])=[C:16]=[S:17]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COCC[C@H](C)N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCC[C@H](C)N=C=S
Reaction time: 8 h
Yield: 95.8 %

Procedure:
(S)-4-Methoxybutan-2-amine hydrochloride (25.4 g, 181.92 mmol) is suspended in THF (609 mL) and triethylamine (TEA, 32.17 mL, 230.78 mmol) is added. 1,1′-Thiocarbonyldiimidazole (46.74 g, 251.76 mmol) is added to the white suspension (slightly exothermic reaction) and the resulting yellow suspension is stirred under a nitrogen atmosphere overnight. Ethyl acetate (500 mL) is added to the yellow suspension, followed by 1 N HCl (500 mL). The organic phase is separated and washed with 1 N HCl (3×200 mL), water (200 mL), and brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (25.3 g, 83%) as a yellow oil. 1H NMR (400 MHz, CDCl3); δ 1.37 (3H, d, J=6.6 Hz), 1.83 (2H, q, J=6.6 Hz), 3.35 (3H, s), 3.6-3.4 (2H, m), 3.99 (1H, six, J=6.6 Hz).
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([OH:14])=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.S(Cl)([Cl:17])=O>>[OH:1][C:2]1[C:11]([C:12]([Cl:17])=[O:14])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: O=C(O)c1cc2ccccc2cc1O
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc2ccccc2cc1O

Procedure:
The azo pigments of Formula II listed in FIG. 6 may be prepared, for example, by reacting 2-hydroxy-3-naphthoic acid with thionyl chloride to obtain 2-hydroxy-3-naphthoic acid chloride. Subsequently, the formed acid chloride is added to a solution of N,N-diethylaniline, and an appropriately substituted aniline to yield a coupler compound. A 5 millimole amount of 2,7-diaminodibenzothiophene sulfone is then tetrazotized by an excess amount of a metal nitrite such as sodium nitrite in hydrochloric acid at from about 0° C. to about 30° C., and the product is reacted with HBF4. An 11 millimole amount of the coupler compound previously prepared is then added to the resulting tetrazonium salt in a solution of dimethylformamide at from about 0° C. to about 30° C., followed by the addition of a base, such as sodium acetate in water, to the reaction mixture. The resulting precipitated product is a disazo pigment of Formula II, the specific compound obtained depending on the substituents present in the coupler compound. For example, 3,5-difluoroaniline is selected to obtain the coupler compound 2-hydroxy-3-naphtho-3',5'-difluoroanilide, which is then used to prepare 2,7-bis(1'-azo-2'-hydroxy-3'-naphtho-3",5"-difluoroanilide)dibenzothiophene sulfone. The azo pigments are isolated by filtration and purified by repetitive solvent washings, and may be characterized by elemental analysis, melting point, and IR spectroscopy.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:57][N:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1>O1CCOCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:8][C:6]1[CH:7]=[C:2]([N:61]2[CH2:62][CH2:63][N:58]([CH3:57])[CH2:59][CH2:60]2)[CH:3]=[N:4][CH:5]=1
Reactant: CN1CCNCC1
Reactant: Brc1cncc(Br)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN1CCN(c2cncc(Br)c2)CC1
Temperature: 150 °C
Yield: 33.8 %

Procedure:
To a suspension of 3,5-dibromopyridine (0.30 g, 4.6 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (57 mg, 0.098 mmol), tris(dibenzylideneacetone)dipalladium(0) (32 mg, 0.035 mmol) and cesium carbonate (830 mg, 2.5 mmol) in 1,4-dioxane (4.0 mL) in a sealed r×n vessel was added 1-methylpiperazine (0.170 mL, 1.5 mmol) under argon. The reaction mixture was heated for 30 min in a microwave reactor, at 150° C. The reaction mixture was diluted with EtOAc (50 mL), washed with brine and water, dried over Na2SO4, then filtered and concentrated. The crude reaction product was purified by column chromatography to give 1-(5-bromopyridin-3-yl)-4-methylpiperazine (0.13 g, 39%) as a brown oil. LCMS (FA): Rt=1.03 min, m/z=258.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:8][C:6]1[CH:7]=[C:2]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)[CH:3]=[N:4][CH:5]=1
Reactant: CN1CCNCC1
Reactant: Brc1cncc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CN1CCN(c2cncc(Br)c2)CC1

Procedure:
To a solution of 3,5-dibromopyridine (Sigma-Aldrich, St. Louis, USA) (1 eq, 8.4 mmol, 2.0 g) and 1-methylpiperazine (Sigma-Aldrich, St. Louis, USA) (1 eq, 8.4 mmol, 0.94 ml) in toluene (20 ml), Pd2(dba)3 (0.02 eq, 0.167 mmol, 153 mg), Xantphos (0.06 eq, 0.50 mmol, 290 mg), and NaOtBu (1.5 eq, 12.5 mmol, 1.2 g) are added. The resulting mixture is heated using microwave radiation at 120° C. for 15 min. The solvents are evaporated and aqueous HCl solution (1 M) is added. The aqueous layer is washed with DCM, adjusted to pH 10, and extracted with DCM. The organic layer is dried, filtered, and concentrated to give the title compound, [M+H]+=257.
Reaction SMILES: BrC1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:10][C:11](OCC)=O.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[H+].[B-](F)(F)(F)F.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:8][C:5]1[CH:6]=[CH:7][C:11]([CH2:10][C:9]([O:17][CH2:18][CH3:19])=[O:16])=[CH:3][CH:4]=1
Reactant: Cc1ccc(Br)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Pd+2]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Product: CCOC(=O)Cc1ccc(C)cc1
Temperature: 160 °C
Reaction time: 10 h
Yield: 75 %

Procedure:
A dry Schlenk vessel was initially charged with 171 mg [1 mmol] of 4-bromotoluene, 1056 mg [6.6 mmol] of diethyl malonate, 1.12 mg [0.005 mmol] of Pd(OAc)2, 3.19 mg [0.011 mmol] of P(tert-Bu)3×HBF4, 594 mg [2.8 mmol] of dried K3PO4 and 132 mg [0.5 mmol] of 18-crown-6. The reaction vessel was three times evacuated and filled with nitrogen. This was followed by stirring at 160° C. until completion of conversion (8 to 12 hours). After cooling to room temperature, the reaction mixture was diluted with ethyl acetate. The resulting solution was washed successively with 20 ml each of water, saturated aq. NaHCO3 solution and saturated aq. NaCl solution, dried over MgSO4, filtered and concentrated under reduced pressure. Chromatographic purification using silica gel (hexane/ethyl acetate) gave ethyl 4-methylphenylacetate in a yield of 75% of theory.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]([NH:11][C:12]3[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=[C:16]([Br:18])[CH:17]=3)=[N:9][CH:10]=2)[CH2:2]1.C=O.[BH3-][C:24]#N.[Na+].C(OCCOCC)C>CO.[Cl-].[Zn+2].[Cl-].O>[Br:18][C:16]1[CH:17]=[C:12]([NH:11][C:8]2[CH:7]=[CH:6][C:5]([CH:3]3[CH2:4][N:1]([CH3:24])[CH2:2]3)=[CH:10][N:9]=2)[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=1
Reactant: [BH3-]C#N
Reactant: Cn1cc(Br)cc(Nc2ccc(C3CNC3)cn2)c1=O
Agent: C=O
Agent: CCOCCOCC
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CN1CC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
A mixture of 3-(5-(azetidin-3-yl)pyridin-2-ylamino)-5-bromo-1-methylpyridin-2(1H)-one 155n (469 mg, 1.4 mmol), 37% aqueous formaldehyde solution (4 g, 50 mmol), NaBH3CN (261 mg, 4.2 mmol), and 1 M zinc chloride in 1,2-diethoxyethane (4 mL, 4.2 mmol) and methanol (40 mL) was stirred for 2 hours at room temperature. The mixture was added to water (20 mL) and extracted with methylene chloride (50 mL×3). The organic layers were concentrated under reduced pressure. The residue was purified by column chromatography eluting with 10:1 methylene chloride/methanol to give 172a as a yellow solid (0.3 g, 83%). MS: [M+H]+ 348.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][OH:13])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[C:1]1([C:7]2[CH:11]=[C:10]([CH:12]=[O:13])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1cc(-c2ccccc2)no1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
To (3-phenylisoxazol-5-yl)methanol (0.9 g, 5.1 mmol) in DCM (10 mL) was added pyridinium chlorochromate (PCC) (2.1 g, 10.2 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with water, extracted with EtOAc and dried over anhydrous sodium sulfate. The solution was then concentrated under vacuum to give 3-phenylisoxazole-5-carbaldehyde as a light yellow solid (600 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[C@H:24]1[C@H:29]([CH2:30][CH:31]=[CH2:32])[CH2:28][CH2:27][C:26](=[O:33])[CH2:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34](O)[CH2:35][OH:36].C1(C)C=CC(S(=O)=O)=CC=1.[OH-].[Na+]>CCCCC.CCOCC.C1C=CC=CC=1>[CH2:35]1[O:36][C:26]2([CH2:27][CH2:28][C@@H:29]([CH2:30][CH:31]=[CH2:32])[C@H:24]([C:10]3[CH:11]=[CH:12][C:13]([C:15]([CH3:22])([CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:25]2)[O:33][CH2:34]1
Reactant: OCCO
Reactant: C=CC[C@@H]1CCC(=O)C[C@H]1c1ccc(C(C)(C)CCCCCC)cc1OCc1ccccc1
Agent: Cc1ccc([SH](=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCC
Solvent: CCOCC
Solvent: c1ccccc1
Product: C=CC[C@@H]1CCC2(C[C@H]1c1ccc(C(C)(C)CCCCCC)cc1OCc1ccccc1)OCCO2

Procedure:
A mixture of 17.0 g. (38.1 mmoles) of trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(2-propenyl)cyclohexanone, 47.2 g. (0.762 mole) ethylene glycol and 250 mg. of p-toluenesulfonic acid monohydride in 200 ml. of benzene was heated at reflux for 3 hours with a Dean-Stark trap. The reaction was cooled and added to 200 ml. 1 N sodium hydroxide, 100 ml. ether and 100 ml. pentane. The organic extract was washed twice with 200 ml. portions of water, twice with 200 ml. portions of saturated sodium chloride, dried over magnesium sulfate and evaporated (aspirator) giving a quantitative yield of the title compound.
Reaction SMILES: [C-:1]#[N:2].[K+].[I:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1>>[I:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][C:1]#[N:2])=[CH:7][CH:6]=1
Reactant: BrCc1ccc(I)cc1
Reactant: [C-]#N
Agent: [K+]
Product: N#CCc1ccc(I)cc1
Temperature: 25 °C

Procedure:
A mixture of potassium cyanide (33.23 g, Sigma-Aldrich) and 4-iodobenzyl bromide (101 g, Apollo Scientific) in 3:1 IMS/water (1 L) was heated to reflux for 2 hours then cooled to room temperature. The organics were removed in vacuo and the aqueous was extracted with EtOAc (2×750 mL). The combined organics were washed with brine (300 mL), dried (magnesium sulphate) and concentrated in vacuo to give the product as oil that solidified on standing. Yield: 78.4 g. 1H NMR (400 MHz, CDCl3): δ 7.71 (2H, d, ArH), 7.08 (2H, d, ArH) 3.66 (2H, s, ArCH2CN).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=O)(C)(C)C.[ClH:27]>C(OCC)(=O)C>[ClH:27].[NH2:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl (S)-2-(t-butoxycarbonylamino)-3-(4-biphenylyl)-propionate (1.25 mmol) in ethyl acetate (2 mL), is added a saturated solution of anhydrous hydrogen chloride in ethyl acetate (4.5 mL). The solution is stirred at room temperature for 3 hours. The reaction mixture is concentrated to obtain methyl (S)-2-amino-3-(4-biphenylyl)-propionate hydrochloride, m.p. 205°-207°; [α]D20 +11.8° (c=1, CH3OH), also named (S)-(4-biphenyl)-alanine methyl ester hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].ON1C2N=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>C1COCC1.C(Cl)Cl>[N:42]1([C:7]([C:6]2[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:9])[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(c1cc([N+](=O)[O-])cc(C(F)(F)F)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Dissolve 3-nitro-5-trifluoromethyl-benzoic acid (2.9 g, 12.6 mmol) and 1-hydroxy-7-azabenzotriazole (25 mL of 0.5 M solution in DMF) in THF. Add 1,3-dicyclohexylcarbodiimide (2.6 g, 12.6 mmol) and morpholine (1 g, 11 mmol). Stir the mixture for 48-72 hours at room temperature. Dilute the resulting suspension with DCM and quench with saturated aqueous ammonium chloride. Wash the organic layer further by aqueous saturated sodium chloride and water, dry (MgSO4) and concentrate to a yellow-white residue. Purify by silica gel column chromatography, with a gradient from 100% hexane to 50% hexane in ethyl acetate, yielding the title compound as 2.5 g white solid (75% yield). LCMS (ES), m/z 305 (M+1).