Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12](Br)=[CH:11][N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li]CCCC.[Mg+2].[Br-].[Br-].BrCCBr.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([C:42]([C:44]2[C:45]3[CH:55]=[CH:54][C:53]([O:56][CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)=[CH:52][C:46]=3[S:47][C:48]=2N(C)C)=[O:43])[CH:33]=[CH:34][C:35]=1[CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.[NH4+].[Cl-]>C1COCC1>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([C:42]([C:44]2[C:45]3[CH:55]=[CH:54][C:53]([O:56][CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)=[CH:52][C:46]=3[S:47][C:48]=2[C:12]2[CH:11]=[N:10][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:14][CH:13]=2)=[O:43])[CH:33]=[CH:34][C:35]=1[CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: COc1cc(C(=O)c2c(N(C)C)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Reactant: Brc1ccc(OCCN2CCCC2)nc1
Agent: [Br-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)nc3)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A −78° C. solution of 5-bromopyrid-2-yl 2-(1-pyrrolidinyl)ethyl ether (3.25 g, 12.0 mmol) in 40 mL of anhydrous THF was treated with n-BuLi (8.1 mL, 13.0 mmol, 1.6 M in hexanes). After 1 h, a slurry of MgBr2 [freshly prepared from Mg (365 mg, 15.0 mmol) and 1.3 mL of 1,2-dibromoethane] in 20 mL of anhydrous THF was added. The reaction mixture was stirred at −78° C. for an additional 10 min, and then the cold bath was removed. After 45 min, the Grignard reagent was added dropwise via a cannula to a solution of 6-benzyloxy-2-(dimethylamino)benzo[b]thiophen-3-yl 3-methoxy-4-[(1-pyrrolidinyl)methyl]phenyl ketone (5 g, 10.0 mmol) in 50 mL of THF at 0° C. The resulting mixture was stirred for 2 h at 0° C. and then was allowed to warm to ambient temperature. After 5 h, the reaction mixture was poured into 200 mL of saturated aqueous NH4Cl. The layers were separated, and the aqueous phase was extracted with CHCl3 (3×50 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by PrepLC (SiO2; gradient of 85:10:5 hexanes-THF-TEA to 75:20:5 hexanes-THF-TEA) afforded 2.9 g (4.48 mmol; 45%) of the title product as a viscous orange oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42][NH2:43]>CC(N(C)C)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:43][CH2:42][C:41]2[CH:44]=[CH:45][CH:46]=[C:39]([CH3:38])[CH:40]=2)=[O:15])[CH:3]=1
Reactant: Cc1cccc(CN)c1
Reactant: CCOc1nc(C(=O)O)cc(N)c1C#N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Product: CCOc1nc(C(=O)NCc2cccc(C)c2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a 20 mL scintillation vial, 4-amino-5-cyano-6-ethoxy-pyridine-2-carboxylic acid (19 mg, 0.09 mmol) was dissolved in DMA (0.7 mL). Then TBTU (30 mg, 0.09 mmol) dissolved in DMA (0.7 mL) was added, followed by the addition of 3-methylbenzylamine (12 mg, 0.11 mmol, 1.2 eq.) in DMA (0.6 mL). Then TEA (9.37 mg, 0.09 mmol) dissolved in DMA (0.7 mL) was added. The reaction mixture was shaken at room temperature for 24 hours. The crude mixture was purified using reverse phase HPLC (TFA). 1H NMR (500 MHz, DMSO-D6/D2O) δ ppm 1.28-1.35 (m, 3H) 2.23-2.31 (m, 3H) 4.40-4.54 (m, 4H) 7.03-7.12 (m, 3H) 7.17-7.24 (m, 1H) 9.02-9.12 (m, 1H). MS (ESI) positive ion 311 (M+H)+; negative ion 309 (M−H)−.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:24])[CH:2]=[CH2:3].[H-].[Na+]>BrC(CC)CC>[CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH:1]([CH2:4][CH3:5])[CH2:2][CH3:3])[C:5]1=[O:24])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCC(Br)CC
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(CC)CC)C1=O
Temperature: 120 °C
Reaction time: 24 h

Procedure:
To a suspension of 1.81 g (4.8 mmol) of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (Example 71, Step D) in 3-bromopentane (17.6 mL) added 967 mg (60 wt. % in mineral oil, 24.2 mmol) of sodium hydride. The resulting milky white slurry was heated at 120° C. for 20 h, and then more 3-bromopentane (5.1 mL) was added. After an additional 24 h at 120° C., the reaction was cooled to room temperature and quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate (3×) and the combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (2 to 26% EtOAc/hexanes, gradient elution) provided the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O)=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([O:10][CH2:9][C:7]2[NH:6][C:5]3[CH:21]=[CH:22][C:2]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH:23]=[O:24])=[CH:3][C:4]=3[N:8]=2)=[CH:12][CH:13]=1
Reactant: O=Cc1ccccc1B(O)O
Reactant: FC(F)(F)c1ccc(OCc2nc3cc(Br)ccc3[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=Cc1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Temperature: 90 °C
Yield: 75.8 %

Procedure:
A mixture of 5-bromo-2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazole (0.700 g, 1.89 mmol), 2-formylphenylboronic acid (0.424 g, 2.83 mmol), sodium carbonate (1.200 g, 11.3 mmol), and 1,1′-[bis(di-tert-butylphosphino)ferrocene]-palladium dichloride (0.123 g, 0.189 mmol) in DME (14 mL) and H2O (3.5 mL) was heated at 90° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography (silica, hexanes: EtOAc, 1:1) to afford the product as a yellow oil (0.568 g, 76%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([Cl:22])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:23])[CH:8]=2)[N:3]=1.CO.C[C:27](C)([O-:29])C.[K+].O1CCOCC1>O>[CH3:27][O:29][C:2]1[CH:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([Cl:22])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:23])[CH:8]=2)[N:3]=1
Reactant: COc1ccc(CNc2cc(Cl)nc3ccc(Cl)cc23)cc1Cl
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: COc1cc(NCc2ccc(OC)c(Cl)c2)c2cc(Cl)ccc2n1
Yield: 75.9 %

Procedure:
A mixture comprising 200 mg of 2.6-dichloro-4-(3-chloro-4-methoxybenzyl)aminoquinoline, 0.5 ml of methanol, 200 mg of potassium t-butoxide and 3 ml of 1,4-dioxane was heated under reflux for one hour and cooled, followed by the addition of water. The resulting mixture was extracted with ethyl acetate and the ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 10 to 30% ethyl acetate/hexane and recrystallized from ethyl acetate/hexane to give 150 mg of the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([C:13](=O)[CH2:14][CH2:15][C:16]2[C:24]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[NH:18][CH:17]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>O1CCCC1.[OH-].[Na+]>[N:7]1([CH2:13][CH2:14][CH2:15][C:16]2[C:24]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[NH:18][CH:17]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: O=C(CCc1c[nH]c2c1CCCC2)N1CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1[nH]c2c(c1CCCN1CCOCC1)CCCC2
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 86.1 %

Procedure:
To a suspension of 1.9 g (50 mmol) of lithium aluminum hydride in 30 mL of tetrahydrofuran was added dropwise a solution of 11.3 g (43 mmol) of 1-morpholin-4-yl-3-(4,5,6,7-tetrahydro-1H-indol-3-yl)-propan-1-one in 20 mL of tetrahydrofuran. The reaction mixture was stirred at 80° C. for 2.5 hours and then cooled in an ice bath. Ice cubes were slowly added to the reaction mixture until no more gas was generated. A few drops of 2 N sodium hydroxide were added and the reaction mixture was stirred at room temperature for 30 minutes, extracted with ethyl acetate and the extract dried over anhydrous sodium sulfate and concentrated to give 9.2 g (89% yield) of 3-(3-morpholin-4-yl-propyl)-4,5,6,7-tetrahydro-1H-indole as a red oil which was used without further purification.
Reaction SMILES: [CH:1]1([O:9][CH2:10][CH2:11][OH:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]#[C:2]1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:15]>C1COCC1>[C:14](=[O:15])([O:16][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1)[O:12][CH2:11][CH2:10][O:9][CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]#[C:2]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCCOC1C#CCCCCC1
Solvent: C1CCOC1
Product: O=C(OCCOC1C#CCCCCC1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
Compound 10 (2.64 g, 15.7 mmol) and TEA (2.63 ml, 18.8 mmol 1.2 eq) dissolved in THF (0.2 M, 79 ml) were added dropwise to a stirred solution of 4-nitrophenyl chloroformate (9.49 g, 47.1 mmol, 3.0 eq) and THF (0.7 M, 22 ml) over a period of 1 h at −10° C. The reaction mixture was stirred overnight at RT and diluted with cHex (100 ml). Then cHex (100 ml) was added and the THF was removed under reduced pressure. Filtration of the reaction mixture followed by FC (cHex:EtOAc 4:1) gave compound 11 as a yellow oil (3.42 g, 10.3 mmol, 65%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)([CH3:11])[CH3:10])=[CH:5][CH:4]=1.C[Si](I)(C)C>C(Cl)(Cl)Cl>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)([CH3:11])[CH3:10])=[CH:17][CH:16]=1
Reactant: COc1ccc(C(C)(C)c2ccc(F)cc2)cc1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: CC(C)(c1ccc(O)cc1)c1ccc(F)cc1
Temperature: 40 °C
Reaction time: 18 h
Yield: 76.2 %

Procedure:
To a solution of 4-[1-(4-fluorophenyl)-1-methylethyl]phenyl methyl ether (3.34 g, 13.67 mmol) in chloroform (40 ml) was added trimethylsilyl iodide (4.10 g, 20.51 mmol). The solution was stirred under argon at 40° C. for 18 h, then cooled and poured into ice cold water (50 ml). The aqueous phase was extracted with chloroform (6×20 ml), and the combined organic layers were washed with sodium metabisulfite then brine, and dried over sodium sulfate. After concentration in vacuo the residue was subjected to column chromatography on silica gel eluting with 10-40% diethyl ether in 40-60 petroleum ether to afford the title compound as an oil (2.4 g).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:24][C:23]2[C:25](=[O:26])[C:18](=[CH:19][C:20]([C:22]=2OC)=[O:21])[NH:17][C:15](=[O:16])[C:14]([CH3:29])=[CH:13][CH:12]=[CH:11][C@H:10]([O:30][CH3:31])[C@@H:9]([O:32][C:33]([NH2:35])=[O:34])[C:8]([CH3:36])=[CH:7][C@H:6]([CH3:37])[C@@H:5]([OH:38])[C@@H:4]([O:39][CH3:40])[CH2:3]1.[NH3:41]>C1COCC1>[CH3:1][C@@H:2]1[CH2:24][C:23]2[C:25](=[O:26])[C:18](=[CH:19][C:20]([C:22]=2[NH2:41])=[O:21])[NH:17][C:15](=[O:16])[C:14]([CH3:29])=[CH:13][CH:12]=[CH:11][C@@H:10]([O:30][CH3:31])[C@@H:9]([O:32][C:33]([NH2:35])=[O:34])[C:8]([CH3:36])=[CH:7][C@H:6]([CH3:37])[C@@H:5]([OH:38])[C@H:4]([O:39][CH3:40])[CH2:3]1
Reactant: N
Reactant: COC1=C2C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)C=C(C)[C@H](OC(N)=O)[C@@H](OC)C=CC=C(C)C(=O)NC(=CC1=O)C2=O
Agent: COC1=C2C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)/C=C(\C)[C@H](OC(N)=O)[C@@H](OC)/C=C\C=C(/C)C(=O)NC(=CC1=O)C2=O
Agent: CO[C@@H]1/C=C\C=C(/C)C(=O)NC2=CC(=O)C(N)=C(C[C@@H](C)C[C@@H](OC)[C@H](O)[C@@H](C)/C=C(\C)[C@@H]1OC(N)=O)C2=O
Solvent: C1CCOC1
Product: CO[C@@H]1C=CC=C(C)C(=O)NC2=CC(=O)C(N)=C(C[C@@H](C)C[C@@H](OC)[C@H](O)[C@@H](C)C=C(C)[C@@H]1OC(N)=O)C2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 2.0 g (3.57 mmol) of geldanamycin in 40 ml of dry THF in a flame-dried flask was added 2.55 ml (17.8 mmol, solution in methanol, ca 7N) of ammonia under nitrogen. The reaction mixture was stirred at room temperature for 24 h at which time TLC analysis indicated the reaction was complete. The solvent was removed by rotary evaporation and the crude material was dissolved in 30 mL of EtOH and crystallized by addition of 120 mL of water to give 1.8 g (3.30 mmol) of 17-AG as red crystals (99% pure by HPLC). MP 284-286° C. 1H NMR and HPLC are consistent with the desired product.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH2:10]([SH:14])[CH2:11][CH2:12][SH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:7]=[C:6]([CH:8]2[S:14][CH2:10][CH2:11][CH2:12][S:13]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C=O)n1
Reactant: SCCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(C2SCCCS2)n1
Temperature: 20 °C
Reaction time: 0.67 h
Yield: 51.7 %

Procedure:
A solution of 6-methyl-2-pyridinecarboxaldehyde (100 g), 1,3-propanedithiol (285 g) and para-toluenesulphonic acid (11.8 g) in toluene (2.6 liters) is heated to boiling for 12 hours 40 minutes, the water formed being removed by azeotropic distillation. After being cooled to a temperature in the region of 20° C., the reaction mixture is poured into a mixture of distilled water (1 liter) and ice (500 g), and approximately 10N aqueous potassium hydroxide solution is then added dropwise. After decantation, the organic solution is washed with approximately 5N aqueous potassium hydroxide solution, and 3 times with distilled water (1700 cc in total), dried over anhydrous magnesium sulphate and concentrated to dryness under reduced pressure (25 mm Hg; 3.25 kPa) at 50° C. The product obtained (160.2 g) is chromatographed on neutral silica gel (980 g; 0.063-0.200 mm) contained in a column 8 cm in diameter. The product is eluted with a mixture of cyclohexane and ethyl acetate (70:30 by volume), collecting 300-cc fractions. Fractions 9 to 23 are combined and concentrated to dryness under reduced pressure (25 mm Hg; 3.25 kPa) at 50° C. 2-(6-Methyl-2-pyridyl)-1,3-dithiane (90.2 g), m.p. 74° C., is thereby obtained.
Reaction SMILES: Br[C:2]1[C:3]([CH3:19])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[NH:31][C:32]([NH:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][C:36]=1[CH3:50])=[O:33].FC1C=CC(C(F)(F)F)=CC=1NC(NC1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1)=O>>[NH2:11][C:9]1[C:10]2=[C:2]([C:38]3[CH:39]=[CH:40][C:35]([NH:34][C:32]([NH:31][C:22]4[CH:23]=[C:24]([C:27]([F:29])([F:30])[F:28])[CH:25]=[CH:26][C:21]=4[F:20])=[O:33])=[C:36]([CH3:50])[CH:37]=3)[C:3]([CH3:19])=[C:4]([CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:5]2[N:6]=[CH:7][N:8]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)Nc1cc(C(F)(F)F)ccc1F
Reactant: Cc1c(Br)c2c(N)ncnn2c1CN1CCOCC1
Agent: CC1(C)OB(c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)OC1(C)C
Product: Cc1cc(-c2c(C)c(CN3CCOCC3)n3ncnc(N)c23)ccc1NC(=O)Nc1cc(C(F)(F)F)ccc1F
Yield: 16 %

Procedure:
The title compound was prepared in a manner similar to the procedure described for the preparation of Example 117 Step 4, using the product of step 1, Example 119 (5-bromo-6-methyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine) in place of 5-bromo-6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine and Intermediate AAH (1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea) in place of Intermediate AAN (1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-urea) 28 mg (16%) of the desired product was isolated. 1H-NMR (DMSO-d6) δ 9.41-9.40 (m, 1H), 8.67 (dd, J=2.1, 7.2 Hz, 1H), 8.58 (s, 1H), 8.01 (d, J=8.1 Hz, 1H), 7.85 (s, 1H), 7.53-7.46 (m, 1H), 7.39-7.35 (m, 1H), 7.22 (s, 1H), 7.18-7.15 (m, 1H), 3.80 (s, 2H), 3.53-3.50 (m, 4H), 2.41-2.39 (m, 4H), 2.31 (s, 3H), 2.09 (s, 3H); MS [M+H]+=558.1; LCMS RT=2.59.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([N+:18]([O-])=O)[CH:14]=[CH:15][CH:16]=3)[C:11]([CH:21]=[CH2:22])=[N:10]2)=[N:3]1>CCO.C(Cl)Cl.[OH-].[OH-].[Pd+2]>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([CH2:8][N:9]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([NH2:18])[C:12]=3[C:11]([CH2:21][CH3:22])=[N:10]2)=[N:3]1
Reactant: C=Cc1nn(Cc2cc(C)n(C)n2)c2cccc([N+](=O)[O-])c12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CCc1nn(Cc2cc(C)n(C)n2)c2cccc(N)c12
Reaction time: 3 h
Yield: 93.4 %

Procedure:
To 1-((1,5-dimethyl-1H-pyrazol-3-yl)methyl)-4-nitro-3-vinyl-1H-indazole (5.15 g, 17.3 mmol) in EtOH/DCM (100 mL/10 mL) was cautiously added palladium hydroxide on carbon (2.2 g, 20% wt). The reaction mixture was purged with nitrogen and hydrogen three times each. The reaction was agitated under H2 (45 psi) for 3 hours. The system was evacuated and purged with nitrogen. The mixture was filtered through Celite and the filter pad was washed with MeOH/DCM (10:1, 300 mL). The solution was concentrated under reduced pressure and the residue was purified by silica gel chromatography (EtOAc/Hexane 2:1) to provide the product (4.35 g).
Reaction SMILES: [CH2:1]([N:8]([CH:29]1[CH2:37][C:36]2[C:31](=[CH:32][C:33]([CH2:40][CH3:41])=[C:34]([CH2:38][CH3:39])[CH:35]=2)[CH2:30]1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:14]([N+:26]([O-])=O)[CH:13]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=C([C@@H](O)CN(CC2C=CC=CC=2)C2CC3C(=CC(CC)=C(CC)C=3)C2)C=CC=1OCC1C=CC=CC=1>>[NH2:26][C:14]1[CH:13]=[C:12]([C:10](=[O:11])[CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:29]2[CH2:30][C:31]3[C:36](=[CH:35][C:34]([CH2:38][CH3:39])=[C:33]([CH2:40][CH3:41])[CH:32]=3)[CH2:37]2)[CH:17]=[CH:16][C:15]=1[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCc1cc2c(cc1CC)CC(N(CC(=O)c1ccc(OCc3ccccc3)c([N+](=O)[O-])c1)Cc1ccccc1)C2
Agent: CCc1cc2c(cc1CC)CC(N(Cc1ccccc1)C[C@H](O)c1ccc(OCc3ccccc3)c(N)c1)C2
Product: CCc1cc2c(cc1CC)CC(N(CC(=O)c1ccc(OCc3ccccc3)c(N)c1)Cc1ccccc1)C2
Reaction time: 48 h

Procedure:
1-(3-Amino-4-benzyloxy-phenyl)-2-[benzyl-(5,6-diethyl-indan-2-yl)-amino]-ethanone is prepared from 2-[benzyl-(5,6-diethyl-indan-2-yl)-amino]-1-(4-benzyloxy-3-nitro-phenyl)-ethanone (1.50 g) by an analogous procedure to that used to prepare (R)-1-(3-Amino-4-benzyloxy-phenyl)-2-[benzyl-(5,6-diethyl-indan-2-yl)-amino]-ethanol in Example 19. The reaction is shown to be complete by TLC after 48 hours. The catalyst is filtered off and the solvent is removed in vacuo. The product is purified by flash column chromatography (silica, n-hexane/ethyl acetate 4:1). TLC (Silica, n-hexane/ethyl acetate 2:1 Rf=0.70).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([CH:15]1[CH2:20][CH:19]2[CH2:21][CH2:22][CH:16]1[CH2:17][CH2:18]2)#[N:14].Br[CH2:24][CH:25]1[O:29][CH2:28][CH2:27][O:26]1>O1CCCC1>[C:13]([C:15]1([CH2:24][CH:25]2[O:29][CH2:28][CH2:27][O:26]2)[CH2:20][CH:19]2[CH2:21][CH2:22][CH:16]1[CH2:17][CH2:18]2)#[N:14]
Reactant: BrCC1OCCO1
Reactant: N#CC1CC2CCC1CC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#CC1(CC2OCCO2)CC2CCC1CC2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
84 ml of diisopropylamine are dissolved in 300 ml of absolute tetrahydrofuran. 39.9 ml of n-butyllithium (1.5 molar in hexane) are added at -20° C. under dry argon. After 30 minutes at room temperature, the mixture is cooled down to -78° C. and 8.1 g of 2-cyanobicyclo[2.2.2]octane in 30 ml of absolute tetrahydrofuran are stirred in, and, after 30 minutes at 0° C., the mixture is again cooled down to -78° C. and 10 g of 2-bromomethyl-1,3-dioxolane in 30 ml of tetrahydrofuran are added dropwise. The mixture is stirred for a further 45 minutes at -78° C., warmed up to room temperature and evaporated, and the residue is taken up in 2N acetic acid and ether, washed three times with water and dried over sodium sulfate and the solvent is removed. The crude product is chromatographed on silica gel with ethyl acetate/cyclohexane (1:6) as the mobile phase. 7.9 g of the title compound are obtained as a colorless oil.
Reaction SMILES: B(C1CCCCC1)[CH:2]1[CH2:7]CCC[CH2:3]1.C#CCCCC.[Zn](CC)CC.C(=O)CC.CC(O[C:33]([C@H:35](O)[C@@H:36]([OH:43])[C:37]([O:39][CH:40]([CH3:42])C)=O)=O)C>CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH2:42]([CH:40]1[O:39][CH:37]1[CH:36]([OH:43])[CH2:35][CH3:33])[CH2:3][CH2:2][CH3:7]
Reactant: CC(C)OC(=O)[C@H](O)[C@@H](O)C(=O)OC(C)C
Reactant: B(C1CCCCC1)C1CCCCC1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: C#CCCCC
Agent: CC[Zn]CC
Solvent: CCC=O
Product: CCCCC1OC1C(O)CC
Yield: 68 %

Procedure:
The product was prepared by General procedure T using 50 mg (0.28 mmol) Cy2BH, 32 μL (0.28 mmol) 1-hexyne, 0.39 mL (0.78 mmol, 2.0 M in hexanes) Et2Zn, 2.4 mg (0.01 mmol) (−)-MIB, 18 μL (0.25 mmol) propanal, 50 μL (0.05 mmol, 1.0 M in hexanes) Ti(OiPr)4, and 21 μL (0.10 mmol) (+)-DIPT. The crude product was purified by column chromatography (5% ethyl acetate in hexanes) to afford the title compound in 68% yield (27 mg, 0.17 mmol). threo-diastereomer: Colorless oil. [α]D20=−12.5 (c=0.12, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 0.88 (t, 3H, J=7.0 Hz), 0.99 (t, 3H, J=7.5 Hz), 1.31-1.41 (m, 4H), 1.48-1.62 (m, 4H), 1.76 (br s, 1H), 2.73 (br t, 1H, J=2.7 Hz), 2.96 (dt, 1H, J=5.7, 2.0 Hz), and 3.70 (m, 1H) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 9.6, 13.9, 22.5, 26.5, 28.1, 31.3, 54.9, 60.7, and 69.7 ppm; IR (neat): 3356, 2960, 2922, 2852, 2355, 2332, 1729, 1463, 1414, 1378, and 1261 cm−1; HRMS-CI m/z 141.1273 [(M−OH)+; calcd for C9H17O: 141.1279]. erythro-diastereomer: Colorless oil. [α]D20=9.2 (c=0.41, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 0.88 (t, 3H, J=7.0 Hz), 0.97 (t, 3H, J=7.5 Hz), 1.22-1.27 (m, 2H), 1.30-1.43 (m, 4H), 1.48-1.56 (m, 2H), 1.82 (br s, 1H), 2.70 (dd, 1H, J=4.9, 2.1 Hz), 2.87 (dt, 1H, J=5.6, 2.0 Hz), and 3.35 (m, 1H) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 9.7, 13.9, 22.5, 27.5, 28.0, 31.3, 56.9, 61.5, and 72.6 ppm; IR (neat): 3424, 2959, 2922, 2851, 2362, 2332, 1731, 1463, 1408, and 1373 cm−1; HRMS-CI m/z 141.1273 [(M−OH)+; calcd for C9H17O: 141.1279].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.Cl.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:24]3[CH2:23][CH2:22][N:21]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[F:14])[CH2:26][CH2:25]3)[N:10]=2)[CH:7]=1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Agent: Cl
Product: Fc1ccccc1N1CCN(Cc2cn3cc(Cl)ccc3n2)CC1
Yield: 53.2 %

Procedure:
Following the general procedure of Example 11 and making non-critical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-α]pyridine (Example 4, Step 1; 0.294 g) and 1-(2-fluorophenyl)piperazine hydrochloride (Aldrich; 0.366 g) are converted to 0.268 g of the title compound after chromatography on silica gel using methanol/dichloromethane (6/94) and crystallization from ethyl acetate/hexane; mp 107-108° C.; MS m/z 344, 346; IR (mineral oil) 1501, 1221, 752, 1335, 927 cm-1 ; 1H NMR (CDCl3) δ2.76, 3.13, 3.78, 6.95, 7.03, 7.12, 7.52, 8.14.