Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]2[S:19][C:20]([S:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:30]([O:32]C)=[O:31])[C:25]=3[F:34])=[CH:21][N:22]=2)=[N:15][CH:16]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]2[S:19][C:20]([S:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:30]([OH:32])=[O:31])[C:25]=3[F:34])=[CH:21][N:22]=2)=[N:15][CH:16]=1)[CH3:9])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1nccc(Sc2cnc(Nc3ccc(CN(C)C(=O)OC(C)(C)C)cn3)s2)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1ccc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)nc1)C(=O)OC(C)(C)C
Temperature: 23 °C
Reaction time: 0.17 h
Yield: 104.1 %

Procedure:
A solution of methyl 4-(2-(5-((tert-butoxycarbonyl(methyl)amino)methyl)pyridine-2-ylamino)thiazol-5-ylthio)-3-fluoropicolinate (2.56 g, 5.06 mmol) in THF (100 mL) was treated with NaOH 5N (6 eq, 30.4 mmol, 6 mL) and stirred at 23° C. for 10 min. Water (10 mL) was added to the mixture which was them stirred at 23° C. for 2 hours. The mixture was then acidified with HCl conc. to pH=4. Water was added and the aqueous phase was extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated to give the crude title material (2.59 g) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 1.41 (9H, s), 2.75 (3H, s), 4.33 (2H, s), 7.04-7.18 (2H, m) 7.66 (1H, d, J=7.33 Hz) 7.84 (1H, s) 8.20 (1H, d, J=1.52 Hz) 8.30 (1H, d, J=4.80 Hz) 11.92 (1H, s). LC/MS (M+H)+: 492. Ret. time: 1.308 min. (Condition B).
Reaction SMILES: [CH:1]1([N:7]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:8](=[O:27])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]2[NH:23][C:24](=[O:26])[CH2:25][N:17]2[CH2:16]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:36][CH2:37][CH2:38][CH3:39]>CN(C)C=O>[CH:1]1([N:7]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:8](=[O:27])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]2[N:23]([CH2:36][CH2:37][CH2:38][CH3:39])[C:24](=[O:26])[CH2:25][N:17]2[CH2:16]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCCCBr
Reactant: COC(=O)CN(C(=O)CCCOc1ccc2c(c1)CN1CC(=O)NC1=N2)C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN1C(=O)CN2Cc3cc(OCCCC(=O)N(CC(=O)OC)C4CCCCC4)ccc3N=C21
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-(N-cyclohexyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramidyl)acetate in dry dimethylformamide was added sodium hydride (1.05 equivalents). The mixture was stirred at 60° C. for 30 minutes to give a homogeneous solution. 1-Bromobutane (1.1 equivalents) was added via a syringe after which the mixture was evaporated. The residue was dissolved in ethyl acetate and washed with saturated brine, dried and filtered. Evaporation of the solvent afforded methyl 2-(N-cyclohexyl-4-(1-butyl-2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramidyl)acetate.
Reaction SMILES: Br[C:2]1[C:3]([Cl:21])=[CH:4][C:5]([Cl:20])=[C:6]([CH:19]=1)[CH2:7][O:8][Si](C(C)C)(C(C)C)C(C)C.[CH2:22]([O:29][C@@H:30]1[C@@H:36]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:35]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C@@H:34]([CH2:53][O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[O:33][CH:31]1O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[Cl:20][C:5]1[CH:4]=[C:3]([Cl:21])[C:2]([CH:31]2[C@H:30]([O:29][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C@@H:36]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C@H:35]([O:45][CH2:46][C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C@@H:34]([CH2:53][O:54][CH2:55][C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)[O:33]2)=[CH:19][C:6]=1[CH2:7][OH:8]
Reactant: CC(C)[Si](OCc1cc(Br)c(Cl)cc1Cl)(C(C)C)C(C)C
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Product: OCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c(Cl)cc1Cl

Procedure:
With similar method described in Step 3 of Example 92, (5-bromo-2,4-dichlorobenzyloxy)triisopropylsilane (compound 82, 41.7 g, 101 mmol) and 2,3,4,6-tetra-O-benzyl-D-glucopyranose (compound 2, 45.4 g, 84.0 mmol) were converted to title compound (47.6 g, 81%, ca. 8:1 mixture of anomers (13:0) as a white solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][CH2:14][O:15][CH2:16][C:17]([CH2:19][CH3:20])=[CH2:18]>C(Cl)Cl>[CH2:19]([C:17]1([CH2:16][O:15][CH2:14][O:13][CH3:12])[CH2:18][O:9]1)[CH3:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(CC)COCOC
Solvent: ClCCl
Product: CCC1(COCOC)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
m-Chloroperbenzoic acid (143.7 g, 833 mmol) was gradually added to a solution of 2-methoxymethoxymethyl-1-butene (98 g, 757 mmol) prepared in Reference Example 206 in methylene chloride (8800 ml) while cooling in an ice-bath, and the mixture was stirred at room temperature overnight. The reaction mixture was washed with water, 10% sodium sulfide aqueous solution and sodium hydrogencarbonate aqueous solution, dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 2-ethyl-2-methoxymethoxymethyloxirane (111 g, quantitative) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([CH3:12])[CH:3]=1.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][N:15]=1>>[Cl:13][C:14]1[N:15]=[CH:16][C:17]([C:18]([NH:6][C:5]2[C:4]([CH3:12])=[CH:3][C:2]([Cl:1])=[CH:8][C:7]=2[N+:9]([O-:11])=[O:10])=[O:19])=[CH:21][CH:22]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Cc1cc(Cl)cc([N+](=O)[O-])c1N
Product: Cc1cc(Cl)cc([N+](=O)[O-])c1NC(=O)c1ccc(Cl)nc1

Procedure:
The title compound was prepared from 4-chloro-2-methyl-6-nitroaniline (204 mg, 1.09 mmol) and 6-chloronicotinoyl chloride (192 mg, 1.09 mmol) and obtained as a light yellow solid as described in Example 62. 1H NMR (CDCl3): 9.13 (s, 1H), 8.96 (dd, J=0.6, 2.4 Hz, 1H), 8.20 (dd, J=2.7, 8.4 Hz, 1H), 7.93 (d, J=2.4 Hz, 1H), 7.59 (d, J=2.4 Hz, 1H), 7.51 (dd, J=0.6, 8.1 Hz, 1H), 2.38 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12]C)=[C:10]([CH3:14])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.B(Br)(Br)Br.CO>C(Cl)Cl>[Br:1][C:2]1[C:11]([OH:12])=[C:10]([CH3:14])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COc1c(C)cc2ncccc2c1Br
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Cc1cc2ncccc2c(Br)c1O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To the solution of 5-bromo-6-methoxy-7-methylquinoline (6.5 g, 25.8 mmol) in DCM (150 mL) was added boron tribromide slowly (77.3 mL, 1.0 M in DCM, 77.3 mmol). The mixture was stirred for 3 hours and cooled to 0° C. Methanol (40 mL) was added slowly and the mixture was stirred for 20 minutes. The solvents were removed under reduced pressure. The solid was dissolved in methanol (100 mL) and was treated with 1.0 N sodium hydroxide solution (50 mL) (pH ˜12). The mixture was stirred for 12 hours and acetic acid was added to adjust pH to between 4-5. The mixture was filtered and washed with water. The gray solid was dried under reduced pressure to give 5-bromo-7-methylquinolin-6-ol. LCMS-ESI+ (m/z): 238.2, 240.1 (M+H)+, 236.1, 238.0 (M−H).
Reaction SMILES: N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[CH3:22].CC1(C)N([Br:29])C(=O)N(Br)C1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClC1C=CC=CC=1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[CH2:22][Br:29]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: COc1ccc(Br)c(C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: Clc1ccccc1
Product: COc1ccc(Br)c(CBr)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Azobisisobutyronitrile (0.60 g) was added to a mixture of 2-bromo-5-methoxytoluene (77.38 g, 384 mmol), 5,5-dimethy-1,3-dibromohydantoin (57.5 g, 200 mmol) and chlorobenzene (1500 mL), followed by stirring at 70° C. for 2 hours. Azobisisobutyronitrile (0.60 g) was added thereto again and stirred for another 1 hour. A 10% aqueous sodium thiosulfate solution (500 mL) was added to the reaction mixture, and the resulting mixture was washed with a saturated aqueous sodium chloride solution. The mixture washed was dried over anhydrous magnesium sulfate and then concentrated to dryness to obtain a crude product of 2-bromo-5-methoxybenzyl bromide. Thereto was added 100 mL of ice-cooled hexane to obtain a homogeneous slurry, which was filtered. The residue was washed with 100 mL of ice-cooled hexane and then dried under reduced pressure to obtain 65.75 g (235 mmol, 61.1%) of 2-bromo-5-methoxybenzyl bromide.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][CH2:4][C@@:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33].[OH-].[Na+:38]>O>[CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][CH2:4][C@@:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O-:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33].[Na+:38]
Reactant: CC(C)(C)CC[C@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)CC[C@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A suspension of the product of Example 48H in water (3 mL) was treated with 0.997N sodium hydroxide solution (0.410 mL) and stirred at 25° C. for 1 hour. The solution was lyophilized to give 209 mg (74%) of a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 0.43 (m, 1H) 0.70 (s, 9H) 0.81 (m, 1H) 1.38 (s, 3H) 1.71 (m, 1H) 2.16 (m, 1H) 2.90 (s, 3H) 7.28 (m, 3H) 7.44 (m, 3H) 8.05 (d, J=7.35 Hz, 1H) 9.87 (s, 1H) 15.44 (s, 1H); MS (ESI−) m/z 530 (M−H)−.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[N:22])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.[NH2:24][OH:25].C(=O)([O-])[O-].[Na+].[Na+]>CCO.O>[OH:25][NH:24][C:21]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([NH:10][C@H:1]1[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]1)[CH:20]=[CH:19]2)=[NH:22]
Reactant: NO
Reactant: N#Cc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Yield: 87.9 %

Procedure:
A stirred suspension of 2-((R)-indan-1-ylamino)-quinoline-6-carbonitrile (143 mg, 0.5 mmol), hydroxylamine hydrochloride (129 mg, 1.86 mmol), sodium carbonate (106 mg, 1.0 mmol) in EtOH (2 ml) and water (2 ml) was heated under reflux conditions for 6 h, water (40 ml) was added, and the mixture was extracted with ethyl acetate (3×75 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated to yield the crude product as solid which was further purified by crystallization (dichloromethane/methanol/heptane) to yield N-hydroxy-2-((R)-indan-1-ylamino)-quinoline-6-carboxamidine as off-white solid (140 mg, 88%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7]CC)=O.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][NH2:16].C(N(CC)C(C)C)(C)C>C1C=CC=CC=1>[N:16]1([CH2:15][C:11]2[S:10][CH:14]=[CH:13][CH:12]=2)[CH2:2][CH2:3][CH2:4][C:5]1=[O:7]
Reactant: NCc1cccs1
Reactant: CCOC(=O)CCCBr
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCCN1Cc1cccs1
Temperature: 25 °C
Yield: 47.6 %

Procedure:
A mixture of ethyl 4-bromobutyrate (5.85 g, 30.0 mmol), 2-thiophenemethylamine (13.6 g, 120 mmol), and N,N-diisopropylethylamine (3.88 g, 30.0 mmol) in benzene (100 mL) was stirred under N2 at reflux for 2 hours. The reaction mixture was cooled to ambient temperature and filtered. The residue was concentrated in vacuo, dissolved in ether, and washed twice with 2N aqueous HCl, and once with brine, then dried over MgSO4, filtered, and concentrated in vacuo to give 2-(pyrrolodin-2-one-1-ylmethyl)thiophene (2.59 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[S:10]([CH2:20][N+:21]#[C-:22])([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[C-]#N.[Na+]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C@H:6]2[O:7][CH:22]=[N:21][C@@H:20]2[S:10]([C:13]2[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: [C-]#N
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)[C@H]2N=CO[C@@H]2c2ccc(F)cc2)cc1

Procedure:
In a manner analogous to Preparation 1, 4-fluorobenzaldehyde (0.18 g, 1.47 mmol), tosylmethylisocyanide (0.27 g, 1.40 mmol) and NaCN (6.9 mg, 0.14 mmol) gave the desired compound as a tan solid. MS(ES+) m/z 320.6 (M+H+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C:8]1[CH:29]=[CH:28][C:11]([CH2:12][O:13][C:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:25]=O)[CH:21]=3)[N:16]([CH3:27])[CH:15]=2)=[CH:10][CH:9]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][O:13][C:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH2:25][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:21]=3)[N:16]([CH3:27])[CH:15]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(COc2cn(C)c3ccc(C=O)cc3c2=O)cc1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc(COc2cn(C)c3ccc(CN4CCCC4)cc3c2=O)cc1
Reaction time: 1.5 h
Yield: 81.2 %

Procedure:
A solution of pyrrolidine (0.295 mL, 3.57 mmol) and 3-((4-methoxybenzyl)oxy)-1-methyl-4-oxo-1,4-dihydroquinoline-6-carbaldehyde (1.05 g, 3.25 mmol) in 1,2-dichloroethane (DCE) (50 mL) and 1 drop of acetic acid was treated with sodium triacetoxyborohydride (1.032 g, 4.87 mmol). The reaction mixture was stirred for 1.5 h, and was then concentrated under vacuum. The residue was taken in water (50 mL), and extracted with dichloromethane (2×50 mL). The organic layers were combined, washed with brine (50 mL), dried over sodium sulfate, and concentrated. The crude product was purified twice by automatic silica gel column chromatography (Combiflash RF), eluting with a mixture of [dichloromethane/methanol/ammonium hydroxide (80:20:2)]/dichlormethane (0-40%) to afford pure 3-((4-methoxybenzyl)oxy)-1-methyl-6-(pyrrolidin-1-ylmethyl)quinolin-4(1H)-one (1 g, 2.64 mmol, 81% yield) as a light yellow solid. LCMS: (M+H)+: 379.5.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6](O)=[O:7].CC[N:18]=C=NCCCN(C)C.Cl.[OH-].[NH4+]>C(Cl)Cl>[F:1][C:2]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([NH2:18])=[O:7]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(Oc1ccc(F)cc1F)C(=O)O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(Oc1ccc(F)cc1F)C(N)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(2,4-difluorophenoxy)-2-methylpropanoic acid (10.0 g, 46.3 mmol, Chembridge) in methylene chloride (200 mL) were added 1-hydroxybenzotriaole hydrate (8.5 g, 55.5 mmol, Aldrich), N-(3-dimethylaminopropyl)-N-ethylcarbodimide hydrochloride (10.6 g, 55.5 mmol, Aldrich) and ammonium hydroxide (54.0 g, 463 mmol). The reaction mixture was stirred at room temperature for 16 hours and then quenched with water (100 mL). The aqueous layer was extracted with methylene chloride (3×100 mL). The combined organic extracts were washed with brine, 5% citric acid, and brine (100 mL each), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the titled compound. MS (ESI+) m/z 233 (M+NH4)+.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([O:20][Si](C)(C)C)([C:18]#[N:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CSC.B>C1COCC1>[NH2:19][CH2:18][C:16]1([OH:20])[CH2:17][N:14]([CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:15]1
Reactant: C[Si](C)(C)OC1(C#N)CN(C(c2ccccc2)c2ccccc2)C1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: NCC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-benzhydryl-3-(trimethylsilyloxy)azetidine-3-carbonitrile (example 33, step b) (3.5 g) in THF (50 mL) was treated with borane methylsulfide complex (2M in THF, 20.8 mL) and the resultant mixture heated at 70° C. for 1 hour under nitrogen. The mixture was cooled to room temperature and quenched carefully with methanol (50 mL) followed by treatment with ethylenediamine (2.81 mL). This mixture was stirred at 20° C. for 1 hour and then at 55° C. for 1 hour. The mixture was cooled to room temperature and treated with tetrabutylammonium fluoride (1M in THF, 15.6 mL), then stirred at room temperature for 40 minutes. Solvents were evaporated under reduced pressure and the residue partitioned between ethyl acetate and brine. The organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 6 to 7% methanol in dichloromethane with 1% triethylamine. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 1.95 g.
Reaction SMILES: C[Al](C)C.[CH:5]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:7])[CH3:6].[CH2:15]([N:22]1[CH2:26][C@@H:25]2[C@@H:27]([NH:30][C:31](=O)[O:32]C(C)(C)C)[CH2:28][CH2:29][C@@H:24]2[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH2:15]([N:22]1[CH2:26][C@@H:25]2[C@@H:27]([NH:30][C:31](=[O:32])[N:8]([CH:5]([CH3:7])[CH3:6])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:28][CH2:29][C@@H:24]2[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reactant: CC(C)Nc1ccccc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)N(C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2 M Trimethylaluminum in toluene (0.198 mL, 0.395 mmol) was added dropwise to N-isopropylaniline (0.068 mL, 0.474 mmol) in toluene (2 mL) at 0° C. The reaction was warmed to room temperature and stirred for 1 hour. The aluminum amide solution was then added dropwise to a solution of tert-butyl(3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-ylcarbamate from Example 214 Step A (50 mg, 0.158 mmol) in 1 mL of toluene at 0° C. The reaction was heated at 90° C. overnight, and then the reaction was quenched with 1 mL of 5% aqueous sodium hydroxide. The separated toluene layer was applied directly to a silica gel cartridge (Analogix®, Burlington, Wis., RS-4) eluting with 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 7.40 (ddd, J=1.8, 3.2, 5.7, 3H), 7.29 (d, J=4.4, 4H), 7.24-7.18 (m, 1H), 7.14 (t, J=2.0, 1H), 7.13-7.10 (m, 1H), 4.87 (dt, J=6.8, 13.6, 1H), 3.94-3.84 (m, 1H), 3.74 (d, J=7.1, 1H), 3.60 (d, J=13.0, 1H), 3.44 (d, J=13.0, 1H), 2.53 (t, J=5.5, 2H), 2.48-2.40 (m, 1H), 2.40-2.33 (m, 1H), 2.22 (dd, J=3.7, 8.8, 1H), 2.07 (ddd, J=5.1, 9.2, 11.7, 1H), 1.95 (td, J=6.0, 12.0, 1H), 1.63-1.52 (m, 1H), 1.40-1.30 (m, 1H), 1.29-1.17 (m, 1H), 1.05 (d, J=3.2, 3H), 1.02 (d, J=3.2, 3H); MS (ESI+) m/z 378 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3[NH:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:18][CH:17]=3)[NH:8][C:7](=[O:31])[C:6]=2[CH:32]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[CH3:67][N:68]1[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:67][N:68]1[CH2:73][CH2:72][N:71]([C:2]2[CH:3]=[CH:4][C:5]3[C:14]4[C:9](=[N:10][CH:11]=[CH:12][C:13]=4[NH:15][C:16]4[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:18][CH:17]=4)[NH:8][C:7](=[O:31])[C:6]=3[CH:32]=2)[CH2:70][CH2:69]1
Reactant: O=C(Nc1ccc(Nc2ccnc3[nH]c(=O)c4cc(Cl)ccc4c23)cc1)c1ccccc1
Reactant: CN1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: CN1CCN(c2ccc3c(c2)c(=O)[nH]c2nccc(Nc4ccc(NC(=O)c5ccccc5)cc4)c23)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
275 (44 mg, 0.10 mmol), Pd(OAc)2 (6 mg 0.02 mmol), X-Phos (19 mg, 0.04 mmol), and 1-methylpiperazine (0.02 mL, 0.20 mmol) were suspended in dioxane (3 mL), and stirred overnight at 100° C. for overnight. The crude reaction mixture purified via HP-LC to provide 276. LC-MS (M+H=505, obsd.=505).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.F[B-](F)(F)F.[O:15]=[N+:16]=[O:17]>C(#N)C.O>[F:1][C:2]1[C:7]([N+:16]([O-:17])=[O:15])=[C:6]([OH:8])[C:5]([CH3:9])=[CH:4][CH:3]=1
Reactant: O=[N+]=O
Reactant: Cc1ccc(F)cc1O
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O
Product: Cc1ccc(F)c([N+](=O)[O-])c1O
Reaction time: 0.75 h
Yield: 67.8 %

Procedure:
A stirred solution of 5-fluoro-2-methylphenol (640 mg, 5 mmol) in 20 mL of anhydrous acetonitrile was cooled to −30° C. to −40° C. and treated with nitronium tetrafluoroborate (740 mg, 5.5 mmol). After 45 minutes, the reaction mixture was diluted with 100 mL of cold water and extracted with three 50 mL portions of dichloromethane. The combined organic layers were washed with three 25 mL portions of water, dried over sodium sulfate, and concentrated in vacuo to give a reddish crystalline solid. Chromatography over SiO2 (5% ethyl acetate in hexanes) gave 0.58 g of the title product as bright yellow solid (68% yield).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:31])[C:5]([O:29][CH3:30])=[C:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[C:16]([O:27][CH3:28])[CH:15]=1)[O:7]2.[C:32](Cl)(=[O:36])[CH:33]([CH3:35])[CH3:34]>N1C=CC=CC=1>[C:32]([O:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:31])[C:5]([O:29][CH3:30])=[C:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:23])[CH3:24])=[C:16]([O:27][CH3:28])[CH:15]=1)[O:7]2)(=[O:36])[CH:33]([CH3:35])[CH3:34]
Reactant: CC(C)C(=O)Cl
Reactant: COc1cc(O)c2c(=O)c(OC)c(-c3ccc(OC(=O)C(C)(C)C)c(OC)c3)oc2c1
Solvent: c1ccncc1
Product: COc1cc(OC(=O)C(C)C)c2c(=O)c(OC)c(-c3ccc(OC(=O)C(C)(C)C)c(OC)c3)oc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution containing 0.2 g of 5-hydroxy-3,3',7-trimethoxy-4'-(pivaloyloxy)-flavone in 3 ml of pyridine was added 0.05 ml of isobutyryl chloride and the mixture was stirred at room temperature for 3 hours. After removal of the solvent by evaporation under reduced pressure, the resulting oily residue was dissolved in 5 ml of a mixed solvent of ethanol and hexane (1:1, v/v). The solution was allowed to stand in a refrigerator overnight, during which time crystallisation occurred. The crystals were collected by filtration, washed with hexane and dried. There were obtained 200 mg of 5-(isobutyryloxy)-3,3',7-trimethoxy-4'-(pivaloyloxy)-flavone as colourless needles: m.p. 151°-152° C.