Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[NH:5][C:4](=[O:14])[C:3]=1[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23].[CH3:24][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1>[OH:1][C:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[N:5]([CH3:24])[C:4](=[O:14])[C:3]=1[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23]
Reactant: CON1CCC2(CC1)NC(=O)C(c1c(C)cc(C)cc1C)=C2O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CON1CCC2(CC1)C(O)=C(c1c(C)cc(C)cc1C)C(=O)N2C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-hydroxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one [starting material (SM) prepared according to WO09/049851] (500 mg, 1.58 mmol) in tetrahydrofuran (20 ml) at 0° C. was added a 1.0 M lithium bis(trimethylsilyl)amide solution in hexanes (3.32 ml, 3.32 mmol) dropwise over 15 minutes. The mixture was stirred one hour at 0° C., treated with methyl iodide (0.099 ml, 225 mg, 1.59 mmol) dropwise over 10 minutes, and further stirred at 0° C. for 30 minutes and at room temperature for one hour. The reaction mixture was quenched over cold saturated aqueous ammonium chloride and extracted with tert-butyl methyl ether (3×), the combined organic phases washed with brine, dried over sodium sulfate and concentrated. The residue (210 mg) was suspended in hexane, stirred at room temperature for 10 minutes, filtered and dried. Yield: 171 mg of a clean mixture of starting material (SM) and 4-hydroxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (title compound P2.2) as a beige solid. 1H-NMR and LC-MS analysis of the crude material indicated a ˜1:2.5 ratio of this mixture SM/compound P2.2.
Reaction SMILES: [CH2:1]([C:4]1([CH3:36])[C:10](=[O:11])[N:9]([CH2:12][C:13]([N:15]([CH:22]([CH3:24])[CH3:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[C:8]2[CH:25]=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:5]1=[O:35])[CH:2]=C.I([O-])(=O)(=O)=[O:38].[Na+].CCOC(C)=O>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH:22]([N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](=[O:14])[CH2:12][N:9]1[C:10](=[O:11])[C:4]([CH3:36])([CH2:1][CH:2]=[O:38])[C:5](=[O:35])[N:6]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:7]2[CH:28]=[CH:27][CH:26]=[CH:25][C:8]1=2)([CH3:23])[CH3:24]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCC1(C)C(=O)N(CC(=O)N(c2ccccc2)C(C)C)c2ccccc2N(c2ccccc2)C1=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)N(C(=O)CN1C(=O)C(C)(CC=O)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Reaction time: 0.02 h
Yield: 69.4 %

Procedure:
To a stirring solution of 200 mg (0.42 mmol) of 2-(3-Allyl-3-methyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl acetamide, prepared as in Intermediate 6, in 10 mL of 1,4-dioxane and 3 mL of H2O is added 0.5 mL of a 4% solution of osmium tetraoxide in H2O. The resulting solution is stirred 1 min, then 220 mg (1.03 mmol, 2.5 equiv) of sodium periodate is added. The reaction mixture is stirred 3 h at RT then poured into 25 mL of EtOAc and extracted with H2O (1×25 mL), sat. NaHSO3 (1×25 mL), dried (MgSO4), and the solvents removed in vacuo. Purification of the crude material by silica gel flash column chromatography using hexane/EtOAc 1/1 as eluent afforded 141 mg of the title compound as a white foam: 1H NMR (CDCl3, 300 MHz, mixture of conformations) δ9.65 (s, 0.8H), 9.40 (s, 0.2H), 7.50-7.03 (m, 13H), 6.83 (d, 0.8H), 6.75 (d, 0.2H), 5.07 (m, 0.8H), 4.96 (m, 0.2H), 4.41 (d, 1H), 4.02 (d, 1H), 2.96 (dd, 2H), 1.62 (s, 0.6H), 1.17 (s, 2.4H), 1.09 (m, 6H); low resolution MS (FAB) m/e 619 (MH+), 574.
Reaction SMILES: [F:1][C:2]([F:22])([C:6]([F:21])([F:20])[C:7]([F:19])([F:18])[C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[CH2:3][CH2:4]I.[P:23]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])[O:24]CC.[I-]>>[CH2:31]([O:30][P:23]([CH2:4][CH2:3][C:2]([F:1])([F:22])[C:6]([F:20])([F:21])[C:7]([F:18])([F:19])[C:8]([F:16])([F:17])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])(=[O:24])[O:27][CH2:28][CH3:29])[CH3:32]
Reactant: CCOP(OCC)OCC
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI
Agent: [I-]
Product: CCOP(=O)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OCC

Procedure:
3,3,4,4,5,5,6,6,7,7,8,8,8-Tridecafluoro-1-iodooctane (5.68 g, 11.98 mmol) and P(OEt)3 (4 ml, excess) were placed in a 50 ml RBF fitted with a reflux condenser. The mixture was subjected to microwave irradiation (300 W) for 2 hours (max. temp ca. 155° C.) after which time the starting iodide was no longer visible by TLC. Volatiles were distilled in vacuo (150° C., 0.01 torr) to give the crude material as a thick yellow oil. Column chromatography (silica gel, EtOAc elution) afforded the desired product as a thick pale yellow oil. Yield 3.71 g, 64%. Analysis found (calculated) %: C, 29.25 (29.77); H, 2.96 (2.91). 1H NMR (CDCl3, 400 MHz, 298 K): δ 4.11 (m, 4H), 2.36 (m, 2H), 1.98 (m, 2H), 1.33 (t, J=7 Hz). 13C{1H} NMR (CDCl3, 100 MHz, 298 K): δ 121-105 (m, C-F coupling unresolved), 62.18 (d, JC-P=6 Hz), 25.15 (t, JC-F=24 Hz), 17.10 (d of t, JC-P=148 Hz, JC-F=4 Hz), 16.34 (d, JC-P=6 Hz). 31P{1H} NMR (CDCl3, 162 MHz, 298 K): δ 28.96. MS (FAB, m/z): 485 ([M+H]+, 100%). Exact mass found (calculated for [M+H]+, m/z): 485.05499 (485.05513).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]([C:10](=O)[CH3:11])[C:7](=O)[CH3:8])[CH3:2].Cl.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1.C([O-])(=O)C.[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[C:10]([CH3:11])=[N:24][N:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[C:7]=1[CH3:8])[CH3:2]
Reactant: CCOC(=O)CC(C(C)=O)C(C)=O
Reactant: COc1ccc(NN)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cc1c(C)nn(-c2ccc(OC)cc2)c1C
Yield: 64 %

Procedure:
9.3 grams 3,3-diacetyl-propionic acid-ethyl ester, 8.7 grams p-methoxy phenyl-hydrazinehydrochloride, 4.9 grams anhydrous sodium acetate and 90 milliliters ethanol were mixed and the mixture heated to boiling temperature under reflux for 2.5 hours. The reaction mixture was thereafter evaporated and ether added to the residue. The ether phase was extracted with water and the ether evaporated. The crystalline residue was recrystallized twice from a mixture of ethanol and water. 9.2 grams 3,5-dimethyl-1-(p-methoxy phenyl)-pyrazol-4-acetic acid-ethyl ester, melting at 71°-72° C. were obtained, representing a yield of 64%.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:15]=1.CB(Br)C.C([O-])(O)=O.[Na+].Cl>ClCCCl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:15]=1
Reactant: CCOC(=O)c1cccc(-c2c(OC)cccc2C(=O)OCC)c1
Agent: CB(C)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCCl
Product: CCOC(=O)c1cccc(-c2c(O)cccc2C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 71.2 %

Procedure:
Diester 6a (0.968 g., 2.95 mmol, 1 equiv.) is dissolved under argon in 9.8 mL of 1,2-dichloroethane. Dimethylboron bromide (1.16 mL, 11.9 mmol, 4.03 equiv. ) is added, the flask is sealed and the mixture allowed to stir for 21 hours at ambient temperature. Another 1.16 mL of dimethylboron bromide is added, and the mixture stirred, sealed under argon, for 3 days. The flask is cooled to 0° C., and 20 mL of saturated NaHCO3 is added with caution. The mixture is poured into 1N HCl, and extracted thrice with EtOAc. The combined extracts are washed with brine, dried (MgSO4), and evaporated. Chromatography using 10% EtOAc/hexane yields 2-hydroxy-3'-carboethoxy-(1,1'-biphenyl)-6-carboxylic acid, ethyl ester (7a) (0.659 g., 2.10 mmol, 71%) as a yellow oil: UVmax (CHCl3) 242 nm (ε=10155), 296 nm (ε=4591 ); 1H NMR (300 MHz, CDCl3) δ 8.09 (dd, J=2, 8 Hz, 1H, ArH), 7.96 (dd, J=2, 2 Hz, 1H, ArH), 7.57-7.45 (m, 3H, ArH), 7.33 (dd, J=8, 8 Hz, 1H, ArH), 7.14 (dd, J=2, 8 Hz, 1H, ArH), 4.98 (br, 1H, OH), 4.35 (q, J=7 Hz, 2H, CO2CH2), 3.99 (q, J=7 Hz, 2H, CO2CH2), 1.36 (t, J=7 Hz, 3H, CH2CH3), 0.95 (t, J=7 Hz, 3H, CH2CH3); 13C NMR (75 MHz, CDCl3) δ 167.18 (C=O), 166.13 (C=O), 153.18, 135.46, 134.13, 131.76, 131.25, 130.67, 129.42, 129.16, 129.03, 127.32, 122.42, 119.19, 61.21, 60.85, 14.30, 13.70; IR (film) 3406, 2982, 1718, 1296, 1236, 758 cm-1 ; MS (DCI) m/e 315 (MH+), 269 (M--C2H5O). HRMS Calcd for C18H18O5Na: 337.1052. Found: 337.1044.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]2[NH:19][CH:18]([C:20]([OH:22])=O)[CH:17]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]2([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[C:28]#[N:29])[CH:12]=[CH:13][CH:14]=1.[NH2:37][CH2:38][CH2:39][CH2:40][OH:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:41][CH2:40][CH2:39][CH2:38][NH:37][C:20]([CH:18]1[CH:17]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:16]([C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)([C:28]#[N:29])[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=2)[NH:19]1)=[O:22]
Reactant: CC(C)(C)CC1C(C(=O)O)NC(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: NCCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1C(C(=O)NCCCO)NC(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 22.3 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5R)-5-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-3-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 32d (0.6 g, 1.1 mmol) was reacted with 3-amino-1-propanol (Aldrich) (0.6 g, 8 mmol), HATU and iPr2NEt in CH2Cl2 at room temperature to give rac-(2R,3R,4R,5R)-5-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-3-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-hydroxy-propyl)-amide as a yellow solid (0.12 g, 22%).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[CH:8][CH:7]=1>O1CCCC1>[CH:14]1([C:12]([C:9]2[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][CH:10]=2)([OH:13])[CH:1]=[CH2:2])[CH2:15][CH2:16]1
Reactant: C=C[Mg]Br
Reactant: O=C(c1ccc(Cl)cc1)C1CC1
Solvent: C1CCOC1
Product: C=CC(O)(c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.4 %

Procedure:
A stirred solution of 73 ml (0.073 mole) of 1 M vinylmagnesium bromide in tetrahydrofuran was cooled in an ice water bath, and a solution of 11.0 grams (0.061 mole) of cyclopropyl 4-chlorophenyl ketone in 20 ml of tetrahydrofuran was added dropwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for about 18 hours. After this time the reaction was quenched by the addition of 100 ml of aqueous 10% hydrochloric acid. The reaction mixture was stirred for 10 minutes and then was extracted with two 50 ml portions of diethyl ether. The combined extracts were washed with 10 ml of water and then were dried with magnesium sulfate. The mixture was filtered through a pad of silica gel, and the filtrate was concentrated under reduced pressure, yielding 11.0 grams of 1-cyclopropyl-1-(4-chlorophenyl)-2-propen-1-ol.
Reaction SMILES: [C:1]([C:6]1([C:13](OCC)=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])(OCC)=[O:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[K+].P([O-])([O-])(O)=O.[K+].[K+].P([O-])(O)(O)=O.[K+]>CCOCC.O>[OH:14][CH2:13][C:6]1([CH2:1][OH:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[OH:12]
Reactant: CCOC(=O)C1(C(=O)OCC)CCCCC1=O
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: [Al+3]
Solvent: O
Solvent: CCOCC
Product: OCC1(CO)CCCCC1O
Reaction time: 6 h
Yield: 60.5 %

Procedure:
A solution of 2,2-dicarbethoxycyclohexanone (3.0 g.) in dry ether (15 ml.) was added dropwise to a stirred suspension of lithium aluminium hydride (1.4 g.) in dry ether (50 ml.) at 0°, under nitrogen. The mixture was refluxed, with stirring, for six hours. Potassium hydroxide (6 g.) in water (100 ml) was added to the stirred mixture. Dipotassium hydrogen phosphate (4.2 g.) and potassium dihydrogen phosphate (3.3 g.) in water (50 ml.) was added. Ether was removed by passing a current of nitrogen through the mixture. The resultant slurry was acidified with glacial acetic acid and the solid was filtered off. The filtrate was evaporated in vacuo. The residue was extracted with acetone and the solution was evaporated in vacuo. 2,2Di-(hydroxymethyl)-cyclohexanol (1.2 g.) was obtained as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([C:12](O)=[O:13])[CH:8]=[CH:7]2.B.C1COCC1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([CH2:12][OH:13])[CH:8]=[CH:7]2
Reactant: O=C(O)c1ccc2cccc(Br)c2c1
Agent: B
Solvent: C1CCOC1
Product: OCc1ccc2cccc(Br)c2c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a cooled (0° C.), stirred suspension of 8-bromo-2-naphthoic acid (2.25 g, 8.96 mmol) in THF (12 mL) was added BH3.THF (1M in THF, 12.5 mL, 12.50 mmol) over 20 minutes. The cooling bath was removed and stirring was continued at room temperature overnight. The mixture was recooled to 0° C. and saturated aqueous K2CO3 (8 mL) was added. H2O (10 mL) was added and the mixture was extracted with ether. The combined extracts were washed with saturated aqueous NaCl, dried (MgSO4) and concentrated. The crude product was recrystallized from ether/hexane to give an off-white solid (1.70 g, 80%), m.p. 110°-111° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[C:15](C)=[N:16]C(C)=C[CH:19]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.[Li]CCCC.C(C1CN([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])C1)=O>C1COCC1>[C:49]([O:48][C:46]([N:16]1[CH2:15][CH:14]([CH:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:29][CH:30]=2)=[C:2]3[Cl:1])[OH:13])[CH2:19]1)=[O:47])([CH3:52])([CH3:51])[CH3:50]
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CC(C=O)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -70 °C
Reaction time: 0.03 h
Yield: 76.3 %

Procedure:
To a flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (1.0 g, 2.32 mmol, Intermediate 47: step d) was added THF (30 mL) resulting in a colorless homogeneous mixture. The solution was cooled to −70° C. and then n-BuLi (2.5M in hexanes, 1.08 mL, 2.69 mmol)) was added drop wise. The color of the solution became a dark opaque reddish-brown color. After 2 min, tert-butyl 3-formylazetidine-1-carboxylate (545 mg, 2.94 mmol, in 3 mL THF) was introduced. After 5 min, the reaction mixture was placed in an ice-water bath and allowed to stir for 30 min at which time the mixture was quenched with NH4Cl solution. The contents were diluted further with water and extracted with EtOAc (5×40 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to provide a yellow foam. The crude material was chromatographed on silica gel (20% EtOAc-Hexanes increasing to 50% EtoAc) to give the title compound (950 mg) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.06 (d, J=1.7 Hz, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.63 (dd, J=8.6, 1.9 Hz, 1H), 7.50 (d, J=8.2 Hz, 2H), 7.38 (d, J=8.1 Hz, 2H), 4.99 (dd, J=8.0, 3.3 Hz, 1H), 4.35 (s, 2H), 4.05 (bs, 2H), 3.82 (t, J=8.7 Hz, 1H), 3.74-3.67 (m, 1H), 2.99-2.90 (m, 1H), 2.20-2.15 (m, 1H), 1.41 (s, 9H). MS (ESI): mass calcd. for C27H28ClF3N2O4: 536.98, m/z found 537.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][C@@H:18]3[CH3:30])=[CH:13][CH:12]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([O:34][CH2:35][C:36]1[C:37]([N:51]2[CH2:62][CH2:61][N:60]3[C:53](=[CH:54][C:55]4[CH2:56][C:57]([CH3:64])([CH3:63])[CH2:58][C:59]=43)[C:52]2=[O:65])=[N:38][CH:39]=[CH:40][C:41]=1B1OC(C)(C)C(C)(C)O1)(=O)C.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C([O-])([O-])=O.[Cs+].[Cs+].O.[OH-].[Li+]>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].O.O1CCOCC1>[CH3:63][C:57]1([CH3:64])[CH2:56][C:55]2[CH:54]=[C:53]3[N:60]([CH2:61][CH2:62][N:51]([C:37]4[C:36]([CH2:35][OH:34])=[C:41]([C:2]5[CH:3]=[C:4]([NH:10][C:11]6[N:16]=[CH:15][C:14]([N:17]7[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][C@@H:18]7[CH3:30])=[CH:13][CH:12]=6)[C:5]([O:8][CH3:9])=[N:6][CH:7]=5)[CH:40]=[CH:39][N:38]=4)[C:52]3=[O:65])[C:59]=2[CH2:58]1
Reactant: COc1ncc(Cl)cc1Nc1ccc(N2CCN(C(=O)OC(C)(C)C)C[C@@H]2C)cn1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ncc(-c2ccnc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2CO)cc1Nc1ccc(N2CCN(C(=O)OC(C)(C)C)C[C@@H]2C)cn1
Temperature: 110 °C
Reaction time: 4 h
Yield: 27.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 271a (650 mg, 1.50 mmol), {3-[(acetyloxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (1.79 g, 4.5 mmol), Pd2(dba)3 (137.2 mg, 0.15 mmol), P(cy)3(167.4 mg, 0.60 mmol), Cs2CO3 (978 mg, 3.0 mmol), dioxane (20 mL), and water (0.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 110° C. for 16 h. After this time the reaction was cooled to room temperature. Lithium hydroxide monohydrate (1.89 g, 45 mmol) and water (2.0 mL) were added. The resulting mixture was stirred at 45° C. for 4 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 3:1 ethyl acetate/petroleum ether to afford 271b (290 mg, 27%) as a yellow solid. MS-ESI: [M+H]+ 709.3
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:23])([CH3:22])[CH2:13][C:14](=[O:21])[CH2:15][C:16](OCC)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[OH:21][CH:14]([CH2:15][CH2:16][OH:17])[CH2:13][C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:22])[CH3:23]
Reactant: CCOC(=O)CC(=O)CC(C)(C)NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(CC(O)CCO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.8 %

Procedure:
Ethyl 5-(benzyloxycarbonylamino)-5-methyl-3-oxohexanoate (3.49, 10.9 mmol) was dissolved in ethanol (100 ml). Sodium borohydride (1.64 g, 43.4 mmol) was added to the mixture, and the reaction mixture was stirred for 3 hours at room temperature. The reaction was quenched with 1 N HCl, and the mixture was stirred for 1 hour. The mixture was extracted with ethylacetate, and the combined organic layers were dried over sodium sulfate, filtered, and purified by column chromatography (0 to 4% methanol on dichloromethane) to give 2.14 g (70%) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1)[CH3:2].[Br:12]Br>C(O)C.O>[Br:12][C:11]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH2:1][CH3:2]
Reactant: BrBr
Reactant: CCc1cn2ccccc2n1
Solvent: O
Solvent: CCO
Product: CCc1nc2ccccn2c1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.8 %

Procedure:
To a solution of 2-ethyl-imidazo[1,2-a]pyridine (2.17 g, 14.9 mmol) in ethanol (25 mL) was added bromine (2.0 g, 12.5 mmol) in water (5 mL) dropwise at rt. After stirring at rt for 4 h, ethanol was evaporated under reduced pressure. The residue was basified with aqueous sodium bicarbonate and extracted with methylene chloride (3×). The organic phase was washed with brine and dried over anhydrous magnesium sulfate. Concentration followed by flash chromatography eluting with 20% ethyl acetate in hexanes, followed by 50% ethyl acetate in hexanes afforded the title compound (1.88 g) as a viscous oil.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:36]=[CH:35][C:12]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][C:18]4[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=4)[O:21][C:22]([CH3:31])([CH3:30])[C:23]([O:25]C(C)(C)C)=[O:24])=[CH:11][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.Cl[C:38]1[O:39][C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=1.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O>C1COCC1>[O:39]1[C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=[C:38]1[N:14]([CH2:13][C:12]1[CH:35]=[CH:36][C:9]([C:6]2[N:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[O:8][N:7]=2)=[CH:10][CH:11]=1)[CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=1)[O:21][C:22]([CH3:31])([CH3:30])[C:23]([OH:25])=[O:24]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CCCNCc2ccc(-c3noc(C4CC4)n3)cc2)c1
Reactant: Clc1nc2ccccc2o1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(Oc1cccc(CCCN(Cc2ccc(-c3noc(C4CC4)n3)cc2)c2nc3ccccc3o2)c1)C(=O)O

Procedure:
Condensation of tert-butyl 2-[3-(3-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}propyl)phenoxy]-2-methylpropanoate with 1.5 eq of 2-chlorobenzoxazole, as per general procedure E (conditions: 3 eq DIEA, THF, 100C, 8 hr), followed by standard TFA hydrolysis (general procedure 1) provided the title compound.
Reaction SMILES: [N:1]1([C:7]2[N:12]3[N:13]=[C:14]([C:16]4[CH:21]=[N:20][CH:19]=[CH:18][N:17]=4)[CH:15]=[C:11]3[N:10]=[C:9]([NH:22][NH2:23])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=O.C(O)(=O)C>C(O)C>[NH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]([CH:24]=[N:23][NH:22][C:9]2[CH:8]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:12]3[N:13]=[C:14]([C:16]4[CH:21]=[N:20][CH:19]=[CH:18][N:17]=4)[CH:15]=[C:11]3[N:10]=2)=[CH:27]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3cnccn3)cc2n1
Solvent: CC(=O)O
Solvent: CCO
Product: C(=NNc1cc(N2CCOCC2)n2nc(-c3cnccn3)cc2n1)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.3 %

Procedure:
To a solution of (7-Morpholin-4-yl-2-pyrazin-2-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (20 mg, 0.064 mM) in ethanol (2.0 mL), there were added 3-formyl-indole (19 mg, 0.13 mM) and acetic acid (5 μL) and the mixture was stirred at room temperature for 3 hours. The precipitated solid was recovered through filtration and then washed with ethanol to thus give the title compound (15 mg, yield: 54%).
Reaction SMILES: [BH4-].[K+].[N+:3]([C:6]1[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][C:14]#[CH:15])[CH:7]=1)([O-:5])=[O:4].O1CCCC1.[Cl-].[Na+]>O>[N+:3]([C:6]1[C:10]([CH2:11][OH:12])=[CH:9][N:8]([CH2:13][C:14]#[CH:15])[CH:7]=1)([O-:5])=[O:4]
Reactant: C#CCn1cc(C=O)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCn1cc(CO)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 101.4 %

Procedure:
At 20° C., 242 mg of potassium borohydride were introduced into a solution of 400 mg of the product of Step A, 30 ml of tetrahydrofuran and 4 ml of water and the mixture was stirred for 15 minutes at ambient temperature. 10 ml of a saturated aqueous solution of sodium chloride were added with stirring for 5 minutes at 20° C. and after extracting with ethyl acetate, drying and concentrating, 410 mg of 3-nitro-1-(2-propynyl)-1H-pyrrole-4-methanol were obtained melting at 60° C.