Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:25][C:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1>O1CCOCC1.O.[Pd]>[F:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:16]=[CH:15][C:5]3[N:6]=[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=3[CH:3]=2)[CH:29]=[CH:28][N:27]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: CCOC(=O)Cc1nc2ccc(Br)cc2s1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)Cc1nc2ccc(-c3ccnc(F)c3)cc2s1
Temperature: 90 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
SiliaCat DPP-Pd (0.26 mmol/g loading, from Silicycle, 100 mg, 0.67 mmol), ethyl 2-(6-bromobenzo[d]thiazol-2-yl)acetate (described in WO2011/074560, 200 mg, 0.67 mmol), potassium phosphate (348 mg, 2.00 mmol) and (2-fluoropyridin-4-yl)boronic acid (141 mg, 1.00 mmol) in dioxane (5 mL)/water (0.2 mL) were purged with argon for 5 minutes and then heated at 90° C. After 4 hours, the reaction mixture was diluted with water (50 mL), extracted with DCM (3×50 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes over 15 minutes) to give Compound B23a (120 mg, 57% yield) as a brown solid. HPLC: RT=0.95 min (LCMS Method M). MS (ES): m/z=316.9 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.68 (d, J=1.7 Hz, 1H), 8.35 (d, J=5.2 Hz, 1H), 8.12 (d, J=8.5 Hz, 1H), 8.02 (dd, J=8.5, 1.9 Hz, 1H), 7.81 (d, J=5.2 Hz, 1H), 7.64 (s, 1H), 4.38 (s, 2H), 4.19 (q, J=7.1 Hz, 2H), 1.24 (t, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.Cl[C:13]1[C:14](=[O:32])[N:15]([CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:16](=[O:24])[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:13]2[C:14](=[O:32])[N:15]([CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:16](=[O:24])[C:17]=2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:6][CH:5]=1
Reactant: O=C1C(Cl)=C(c2ccccc2)C(=O)N1Cc1cccnc1
Reactant: Nc1ccc(OC(F)F)cc1
Solvent: CC#N
Product: O=C1C(Nc2ccc(OC(F)F)cc2)=C(c2ccccc2)C(=O)N1Cc1cccnc1
Temperature: 140 °C
Yield: 74.2 %

Procedure:
4-(Difluoromethoxy)aniline (0.94 mmol, 149 mg) dissolved in dry CH3CN (2.3 mL) was added to crude 3-chloro-4-phenyl-1-(pyridin-3-ylmethyl)-1H-pyrrole-2,5-dione (0.39 mmol, 115 mg) and the reaction mixture was subjected to microwave heating single node 140° C., one h. The reaction mixture was purified using HPLC (57% 0.1M ammonium acetate buffer: 43% CH3CN→100% CH3CN, 20 mL/min) to give 122 mg (75%) of the title compound. 1H NMR (400 MHz, CD3CN) δ 8.63 (d, 1H), 8.51 (dd,1H), 7.92 (bs, 1H), 7.79-7.74 (m, 1H), 7.34 (dd, 1H), 7.20-7.07 (m, 3H), 7.00-6.94 (m, 2H), 6.78 (s, 4H), 6.59 (t, J=74.1 Hz, 1H), 4.76 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[I-].C[N+]1C=CN([C:16](=[O:25])[N:17]([CH3:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)C=1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:16](=[O:25])[N:17]([CH3:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:6][CH:7]=1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: Oc1ccc(Cl)cn1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C(=O)Oc1ccc(Cl)cn1)c1ccccc1
Yield: 99 %

Procedure:
A solution of 5-chloro-2-pyridol (0.39 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 3 days. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (30:70)) yielding the title compound (0.78 g, 99% yield) as a white solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[CH3:19])=[O:13])=CN(C)C)=[C:5]([N+:22]([O-:24])=[O:23])[CH:4]=1.O1CCOCC1>O>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:21]=[CH:20][C:6]([CH2:7][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[CH3:19])=[O:13])=[C:5]([N+:22]([O-:24])=[O:23])[CH:4]=1
Reactant: Cc1ccsc1C(=O)C(=CN(C)C)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccsc1C(=O)Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 34.7 %

Procedure:
A stirred solution of 6.4 g of 4-trifluoromethyl-β-(dimethylamino)-α-(3-methyl-2-thienoyl)-2-nitrostyrene, 49 ml of 1,4-dioxane, and 10 ml of water was refluxed for 42 hr. The cooled solution was concentrated, and the residue was partitioned between dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue crystallized upon standing at room temperature. The solid was recrystallized from 95% ethanol to afford 1.9 g (35%) of product, mp 120°-122° C.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:4]1[CH2:8][O:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:15]=[C:16]([OH:26])[CH:17]=[C:18]([O:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[CH:19]=3)=[CH:11][CH:10]=2)=[N:5]1)[CH3:3].Cl[C:28]1[CH:33]=[N:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:24][O:23][CH2:22][C@@H:21]([O:20][C:18]1[CH:19]=[C:14]([C:12]2[NH:13][C:9]([C:6]3[O:7][CH2:8][C@@H:4]([C@H:2]([OH:1])[CH3:3])[N:5]=3)=[CH:10][CH:11]=2)[CH:15]=[C:16]([O:26][C:28]2[CH:33]=[N:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][N:29]=2)[CH:17]=1)[CH3:25]
Reactant: CS(=O)(=O)c1cnc(Cl)cn1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=N[C@H]([C@@H](C)O)CO3)[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C3=N[C@H]([C@@H](C)O)CO3)[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.9 %

Procedure:
3-(5-{(4S)-4-[(1R)-1-Hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-yl}-1H-pyrrol-2-yl)-5-{[(2S)-1-methoxypropan-2-yl]oxy}phenol (766 mg, 2.13 mmol) synthesized in Example (114c) was dissolved in acetonitrile (15 mL), and 2-chloro-5-(methylsulfonyl)pyrazine (590 mg, 3.06 mmol) synthesized in Example (97c) and potassium carbonate (870 mg, 6.29 mmol) were added, followed by stirring at room temperature for 4 hours under nitrogen atmosphere. Water (50 mL) was added, and extraction was carried out with methylene chloride (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/ethyl acetate=5%-8%) to afford the desired compound (890 mg, yield 81%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2)[N:5]2[N:22]=[CH:23][N:24]=[C:4]2[CH:3]=1.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1B(O)O.C(=O)([O-])[O-].[Na+].[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.O1CCOCC1>[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2)[N:5]2[N:22]=[CH:23][N:24]=[C:4]2[CH:3]=1
Reactant: Nc1nc(NCCNc2nc(Cl)cc3ncnn23)ccc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(Cl)cc1Cl
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: C1COCCO1
Product: Nc1nc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3ncnn23)ccc1[N+](=O)[O-]
Temperature: 150 °C

Procedure:
60 mg (0.16 mmol) of N6-{2-[(7-chloro[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)amino]ethyl}-3-nitropyridine-2,6-diamine (Example 6A), 30.3 mg (0.16 mmol) of (2,4-dichlorphenyl)boronic acid and 18.4 mg (0.016 mmol) of tetrakis(triphenylphosphine)palladium(0) are introduced into a mixture of 3.4 ml of dioxane and 1.1 ml of saturated aqueous sodium carbonate solution under argon. The mixture is degassed with argon and then heated in a microwave at 150° C. for 30 min Cooling is followed by filtration through an Extrelut® cartridge. Purification by preparative HPLC results in 10.9 mg (13% of theory) of the product as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2=[N:12][N:13]([CH2:21][CH2:22][CH3:23])[C:14]([CH2:15][C:16]([CH3:20])([CH3:19])[C:17]#[N:18])=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C([OH:26])C.[OH-].[NH4+].OO>O>[NH2:1][C:2]1[C:11]2=[N:12][N:13]([CH2:21][CH2:22][CH3:23])[C:14]([CH2:15][C:16]([CH3:19])([CH3:20])[C:17]([NH2:18])=[O:26])=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)C#N
Reactant: CCO
Agent: OO
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)C(N)=O
Temperature: 70 °C

Procedure:
3-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-2,2-dimethylpropanenitrile (657 mg, 2.14 mmol), ethanol (10 mL), concentrated ammonium hydroxide (2.1 mL), and 30% w/w hydrogen peroxide (2.8 g) were combined in a sealed glass tube and heated at 70° C. for seven hours. During this time, the reaction was periodically cooled and the pressure released. Additional hydrogen peroxide (1.4 g) was added, and the reaction was heated at 70° C. for five hours, with periodic cooling and venting. The reaction was cooled to 0° C., and water (25 mL) was added. A precipitate formed and was isolated by filtration, washed with water, purified by chromatography on a HORIZON HPFC instrument (40M cartridge), and recrystallized from acetonitrile. The crystals were dried on the vacuum filter funnel for two hours to provide 485 mg of 3-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-2,2-dimethylpropanamide as a white solid, mp 224-225° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:6]=1[Cl:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[N:28]3)[N:18]=1>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:22][C:20]2[N:19]([C:23]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:24]=3[CH:25]=[CH:26][CH:27]=[N:28]4)[N:18]=[C:17]([CH3:16])[CH:21]=2)(=[O:13])=[O:12])=[CH:7][C:6]=1[Cl:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1Cl
Reactant: Cc1cc(N)n(-c2cccc3ncccc23)n1
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc(C(C)(C)C)c(Cl)c2)n(-c2cccc3ncccc23)n1
Temperature: 80 °C
Yield: 168.4 %

Procedure:
A mixture of 4-t-butyl-3-chlorobenzene-1-sulfonyl chloride (0.050 g, 0.19 mmol) and 3-methyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (prepared from Example 4 step b, 0.042 g, 0.095 mmol) in pyridine (0.2 mL) was heated at 80° C. for 1 h with stirring. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the crude residue was purified by flash chromatography (SiO2, 20% ethyl acetate in hexanes) to give the title compound as a white solid (0.066 g, 0.16 mmol, 83%). 1H NMR (400 MHz, DMSO-d6) δ 8.86 (dd, J=2.0, 4.0 Hz, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.76 (t, J=8.4 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.44 (s, 3H), 7.40 (d, J=7.6 Hz, 1H), 7.34 (dd, J=4.0, 8.0 Hz, 1H), 5.48 (s, 1H), 2.02 (s, 3H), 1.44 (s, 9H); MS: (ES) m/z calculated for C23H24ClN4O2S [M+H]+ 455.2. found 455.2.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[NH:11][CH:12]=[CH:13][N:14]=2)=[N:8][CH:9]=1)([OH:3])=[O:2].[CH2:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>S(Cl)(Cl)=O.N1C=CC=CC=1>[NH:14]1[CH:13]=[CH:12][N:11]=[C:10]1[C:7]1[CH:6]=[CH:5][C:4]([C:1]([O:3][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])=[O:2])=[CH:9][N:8]=1
Reactant: CCCCCCCCCCCCCCCCO
Reactant: O=C(O)c1ccc(-c2ncc[nH]2)nc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOC(=O)c1ccc(-c2ncc[nH]2)nc1
Reaction time: 17 h

Procedure:
5-Carboxy-2-(2-imidazolyl)-pyridine (1.89 g, 0.01 mol) is refluxed in 10 ml of thionyl chloride for 2 h. The solution is evaporated to dryness and the residue dissolved in 20 ml of dichloromethane. The latter solution is added dropwise to a mixture of 1-hexadecanol (2.68 g, 0.011 mol) in 1.6 ml of pyridine. After 17 h at room temperature, the precipitate is filtered off and the filtrate evaporated to dryness. The resulting residue is crystallized in toluene to yield the title compound, m.p. 97°-98°.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.C1C[O:15]CC1>>[CH2:1]1[CH:11]([OH:15])[CH2:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1
Reactant: O=C1CCCc2ccccc21
Reactant: C1CCOC1
Product: OC1CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
In situ Preparation of the Compound of Formula (II) wherein R1 is ##STR11## Borane methylsulfide complex (neat, ~10M, 1.4 mL, 14 mmol) was added to a solution of cis, exo-3-amino-2-hydroxybomane [J. Chem. Soc. (C) 49 1970] (169 mg, 1 mmol) in THF (70 mL) at ambient temperature and stirred for 16 hrs. α-Tetralone (2.92 g, 19.7 mmol) as a solution in THF (10 mL) was added to the preceding solution over 1 hr, stirred for 15 min after addition was completed, cooled to 0° C., and quenched with methanol (27 mL). After stirring the quenched reaction for 18 hrs, the solvents were removed under vacuum, the residual oil was dissolved in methylene chloride (50 mL), and washed with pH 4 phosphate buffer (50 mL), water (50 mL), treated with magnesium sulfate, and the solvent was removed under vacuum to give the (R) tetralol 2.89 g (97% yield) 84% ee.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([OH:19])[CH2:17][CH:16]([CH3:18])[CH2:15][CH:14]2[CH:10]1[CH2:11][NH:12][CH2:13]2.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][C:30](O)=[O:31])=[CH:21]1>>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][C:30]([N:12]2[CH2:11][CH:10]3[CH:14]([CH2:15][CH:16]([CH3:18])[CH2:17][C:9]3([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[OH:19])[CH2:13]2)=[O:31])=[CH:21]1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: COc1ccccc1C1(O)CC(C)CC2CNCC21
Product: COc1ccccc1C1(O)CC(C)CC2CN(C(=O)Cc3c[nH]c4ccccc34)CC21
Yield: 80.5 %

Procedure:
In an identical manner to Example 1, 0.78 g of (3aRS,4RS,6SR,7aSR)-4-(2-methoxyphenyl)-6-methyl-4 perhydroisoindolol and 0.52 g of 3-indoleacetic acid are used. After chromatography on a column of silica gel (0.060-0.200 mm, diameter 3.5 cm, height 40 cm), eluting under a pressure of 0.7 bar with a mixture of dichloromethane and methanol [94/6 by volume] and collecting 45 cm3 fractions, fractions 10 to 16 are concentrated to dryness and, after drying at 40° C. at 15 Pa, 1.0 g of (3aRS,4RS,6SR,7aSR)-2-(3-indolylacetyl)-4-(2-methoxyphenyl)-6-methyl-4-perhydroisoindolol is obtained in the form of a white solid.
Reaction SMILES: [NH2:1][C@:2]1([C:14]([O:16][CH3:17])=[O:15])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=2)[CH2:3]1.[C:18]([OH:27])(=[O:26])[C@@H:19]([C@H:21]([C:23]([OH:25])=[O:24])[OH:22])[OH:20].N1CCCCC1.[CH3:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]#C>CO.[Cu]I>[NH2:1][C@:2]1([C:14]([O:16][CH3:17])=[O:15])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([C:41]#[C:40][CH2:39][CH2:38][CH2:37][CH2:36][O:35][CH3:34])=[CH:9][CH:8]=2)[CH2:3]1.[C:18]([OH:27])(=[O:26])[C@@H:19]([C@H:21]([C:23]([OH:25])=[O:24])[OH:22])[OH:20]
Reactant: COC(=O)[C@@]1(N)CC[C@@H](c2ccc(Br)cc2)C1
Reactant: C#CCCCCCOC
Agent: [Cu]I
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CO
Solvent: C1CCNCC1
Product: COCCCCC#Cc1ccc([C@@H]2CC[C@](N)(C(=O)OC)C2)cc1
Temperature: 65 °C
Reaction time: 20 h

Procedure:
A round bottomed flask was charged with copper (1) iodide (0.102 g, 0.536 mmol), bis(tripheynlphosphine)palladium(II)dichloride (1.128 g, 1.608 mmol), and (1R,3R)-methyl 1-amino-3-(4-bromophenyl)cyclopentanecarboxylate, 0.5 L-tartaric acid 2 (20 g, 53.6 mmol) (that had been free based by partitioning between EtOAc and saturated NaHCO3. The organic layer was separated, dried (NaSO4), filtered and concentrated) THF (150 mL) was added and the reaction mixture was purged with nitrogen. After 5 min piperidine (23.88 mL, 241 mmol) and 7-methoxyhept-1-yne (6.0 g, 54 mmol) was added. The reaction mixture was heated to about 65° C. After about 8 hours additional 7-methoxyhept-1-yne (3.1 g, 27 mmol) was added. After about 20 hours total the reaction mixture was cooled to about room temperature and partitioned between EtOAc/NaHCO3. The organic layer was separated dried (Na2SO4) filtered and concentrated. The crude mixture was purified by chromatography on silica gel (eluting with EtOAc/MeOH). The fractions containing the desired product were concentrated in vacuo. The dark brown oil was dissolved in MeOH (50 mL) and a solution of (2R,3R)-2,3-dihydroxysuccinic acid (9.65 g, 64.3 mmol) in MeOH (15 mL) was added. The solution was concentrated in vacuo and the resulting solid was slurried in isopropyl alcohol (approx 100 mL), filtered and dried in vacuo to provide (1R,3R)-methyl 1-amino-3-(4-(6-methoxyhex-1-ynyl)phenyl)cyclopentanecarboxylate, L-tartaric acid (25 g, 52.1 mmol, 97% yield) as a colorless solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH3:14].ClC1C2C(=CC=CC=2)N=CC=1NC=O.Cl.[N+:31]([C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[CH2:36][O:37][NH2:38])([O-:33])=[O:32].Cl.C(ON)C>C(O)(C)C>[CH3:14][C:13]1[N:38]([O:37][CH2:36][C:35]2[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=2[N+:31]([O-:33])=[O:32])[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=1
Reactant: CC(=O)Nc1cnc2ccccc2c1Cl
Reactant: NOCc1ccccc1[N+](=O)[O-]
Agent: CCON
Agent: Cl
Agent: O=CNc1cnc2ccccc2c1Cl
Solvent: CC(C)O
Product: Cc1nc2cnc3ccccc3c2n1OCc1ccccc1[N+](=O)[O-]
Yield: 47.4 %

Procedure:
The method of Part B of Example 20 was followed using N-(4-chloroquinolin-3-yl)acetamide (10.6 g, 48.0 mmol) in lieu of 4-chloroquinolin-3-ylformamide and O-(2-nitrobenzyl)hydroxylamine hydrochloride (10.8 g, 52.8 mmol) in lieu of O-ethylhydroxylamine hydrochloride in isopropanol (120 mL). Chromatographic purification was carried out eluting with 5% methanol in dichloromethane containing 2 mL of aqueous ammonium hydroxide per liter of eluent to provide 7.6 g of 2-methyl-1-[(2-nitrobenzyl)oxy]-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br.Cl[C:13]1[N:18]2[C:19]([CH3:23])=[C:20]([CH3:22])[N:21]=[C:17]2[CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[C:4]1([CH2:3][O:10][C:13]2[N:18]3[C:19]([CH3:23])=[C:20]([CH3:22])[N:21]=[C:17]3[CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: Cc1nc2cccc(Cl)n2c1C
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2cccc(OCc3ccccc3)n2c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (50% in oil, 4.8 g) is added to a solution of benzyl alcohol(6.48 g) in dimethylformamide (200 ml). 5-chloro-2,3-dimethylimidazo[1,2-a]pyridine hydrobromide (10.5 g) is addedand the mixture is stirred at room temperature for two hours.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][O:11]2.C[Si]([N:21]=[C:22]=[S:23])(C)C.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.C1([I+2])C=CC=CC=1>FC(F)(F)C(O)C(F)(F)F>[CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([S:23][C:22]#[N:21])=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][O:11]2
Reactant: C[Si](C)(C)N=C=S
Reactant: COC(=O)COc1cccc2c1CCCO2
Agent: O=C([O-])C(F)(F)F
Agent: [I+2]c1ccccc1
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: COC(=O)COc1ccc(SC#N)c2c1CCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
A stirred solution of (chroman-5-yloxy)-acetic acid methyl ester (2.1 g, 9.4 mmol) and trimethylsilyl isothiocyanate (2 mL, 14.1 mmol) in 30 mL 1,1,1,3,3,3-hexafluoro-propan-2-ol under a N2 atmosphere was treated with phenyliodine(III) bis(trifluoroacetate). The reaction mixture stirred at room temperature for 1 h and concentrated in vacuo. Purification by flash column chromatography (gradient elution: 10% EtOAc/hexanes to 40% EtOAc/hexanes) gave the title compound (1.3 g, 50%) as a pale yellow solid. 400 MHz 1H NMR (DMSO-d6) δ 7.31 (d, 1H, J=8.8 Hz), 6.54 (d, 1H, J=8.8 Hz), 4.83 (s, 2H), 4.21 (t, 2H, J=4.9 Hz), 3.64 (s, 3H), 2.60 (t, 2H, J=6.4 Hz), 1.89 (m, 2H).
Reaction SMILES: C(C1C=C(C=CC=1)OCC1C=CC=CC=1C1SC(NC(=O)[C@@H](NC(=O)[C@@H](O)C(C)(C)C)CCC)=NC=1)#N.[C:38]([C:40]1C=C[CH:72]=[CH:71][C:41]=1[O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:50]1[S:54][C:53]([NH:55][C:56](=[O:70])[C@@H:57]([NH:61][C:62](=[O:69])[C@@H:63]([OH:68])[C:64]([CH3:67])([CH3:66])[CH3:65])[CH2:58][CH2:59][CH3:60])=[N:52][CH:51]=1)#[N:39].C(C1C=C(O)C=CC=1)#N.C(C1C=CC=CC=1O)#N>>[OH:68][C@@H:63]([C:64]([CH3:67])([CH3:65])[CH3:66])[C:62]([NH:61][C@@H:57]([CH2:58][CH2:59][CH3:60])[C:56]([NH:55][C:53]1[S:54][C:50]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[CH2:43][O:42][C:41]2[CH:40]=[CH:38][N:39]=[CH:72][CH:71]=2)=[CH:51][N:52]=1)=[O:70])=[O:69]
Reactant: CCC[C@H](NC(=O)[C@@H](O)C(C)(C)C)C(=O)Nc1ncc(-c2ccccc2COc2ccccc2C#N)s1
Agent: CCC[C@H](NC(=O)[C@@H](O)C(C)(C)C)C(=O)Nc1ncc(-c2ccccc2COc2cccc(C#N)c2)s1
Agent: N#Cc1cccc(O)c1
Agent: N#Cc1ccccc1O
Product: CCC[C@H](NC(=O)[C@@H](O)C(C)(C)C)C(=O)Nc1ncc(-c2ccccc2COc2ccncc2)s1

Procedure:
Compounds No. 61 ((2S)—N-(5-{2-[(3-cyano-phenoxy)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethylbutanoyl]amino}pentanamide) and No. 69 ((2S)—N-(5-{2-[(2-cyanophenoxy)methyl]phenyl}-1,3-thiazol-2-yl)-2-{[(2S)-2-hydroxy-3,3-dimethyl-butanoyl]amino}pentanamide) may be prepared according to the method described in Example 7, replacing 4-hydroxypyridine with 3-cyanophenol or 2-cyanophenol, respectively.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[CH:6][CH:7]=1>[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C#Cc1cccc(F)c1
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CCc1cccc(F)c1
Reaction time: 18 h
Yield: 43.1 %

Procedure:
A solution of tert-butyl (S)-2-(3-fluorophenylethynyl)pyrrolidine-1-carboxylate (Intermediate 235, 1.26 g) in IMS (70 mL) was carefully added to 20% palladium on carbon (0.6 g) under a carbon dioxide atmosphere. The mixture was degassed under vacuum and placed under an atmosphere of hydrogen. This was repeated three times then the mixture was stirred under an atmosphere of hydrogen for 18 hours. The mixture was filtered through Celite and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of DCM and pentane with a gradient of 0-100% to give tert-butyl (R)-2-[2-(3-fluoro-phenyl)ethyl]pyrrolidine-1-carboxylate (0.55 g) as an oil.