Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][C:34]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.O.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>[Si:24]([O:23][CH2:22][C:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:34]5[CH:35]=[N:36][CH:37]=[CH:38][C:33]=5[O:32][CH3:31])=[CH:3][CH:4]=4)[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: COc1ccncc1B1OC(C)(C)C(C)(C)O1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
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: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: COc1ccncc1-c1ccc(C2(c3nnc4n3CCSC(C)(CO[Si](C)(C)C(C)(C)C)C4)CC2)cc1
Temperature: 25 °C
Yield: 62.8 %

Procedure:
A solution of the compound (508 mg, 1.0 mmol) obtained in Example 16-4), 4-methoxypyridine-3-boronic acid pinacol ester (321 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (337 mg, 63%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[CH:13][CH:12]=[N:11]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[N:10]1([C:2]2[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[N:11]1
Reactant: N#Cc1cccc(Cl)n1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(-n2cccn2)n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
6-Chloro-2-pyridinecarbonitrile (1.0 g, 7.2 mmol) and pyrazole (2.4 g, 35.9 mmol) were dissolved in DMF (10 ml), and potassium carbonate (3.0 g, 21.7 mmol) was added thereto. The mixture was stirred at 100° C. for 18 hrs. The reaction mixture was combined with ethyl acetate and water, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (3:1, v/v) were collected, concentrated and recrystallized from hexane-ethyl acetate to give the titled compound (0.98 g, 80%).
Reaction SMILES: [C:1]([C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([P:30](=[O:37])([O:34]CC)[O:31]CC)[P:22](=[O:29])([O:26]CC)[O:23]CC)[CH:17]=[CH:18][CH:19]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C[Si](Br)(C)C>C(Cl)Cl.O1CCCC1.O>[C:1]([C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([P:30](=[O:31])([OH:34])[OH:37])[P:22](=[O:23])([OH:26])[OH:29])[CH:17]=[CH:18][CH:19]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCC#Cc1cccc(C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC)c1
Agent: C[Si](C)(C)Br
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCCC#Cc1cccc(C=C(P(=O)(O)O)P(=O)(O)O)c1
Reaction time: 6.5 h
Yield: 16 %

Procedure:
Tetraethyl [2-[3-(1-tridecynyl)phenyl]ethenylidene]bisphosphonate (3,247 g, 5.85 mmol) prepared according to Example 1 was dissolved in a mixture of CH2Cl2 --CD2Cl2 (25 ml, 4:1), and stirred under argon while trimethylsilyl bromide (3.5 ml, 26.5 mmol) was added. After the reaction was stirred for 6.5 hours, the solvent was removed under reduced pressure and the residue was briefly placed on the vacuum line. Hydrolysis was effected in tetrahydrofuran-water (9:1, 10 ml), stirring for 39 hours at room temperature. After stripping off the solvent, the residue was recrystallized from heptane-ether to give the product as a white solid, 0.416 g, 0.94 mmol, 16% yield; 1H NMR (CD3OD) ∂0.89 (t, J=6.9 Hz, 3H), 1.21 to 1.65 (several m, 18H), 2.40 (t, J=7.0 Hz, 2H), 7.55 (m, 2H), 7.71 (m, 2H), 8.03 (dd, J=46.1, 29.2 Hz, 1H); HRMS calcd for (M+H)+C21H33O6P2 m/z 443.1752, found 443.1700.
Reaction SMILES: C1(C)C=CC=CC=1.CB1N2CCC[C@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.B.CSC.[F:33][C:34]1[CH:43]=[C:42]([F:44])[CH:41]=[C:40]2[C:35]=1[C:36](=[O:45])[CH2:37][CH2:38][O:39]2>O1CCCC1>[F:33][C:34]1[CH:43]=[C:42]([F:44])[CH:41]=[C:40]2[C:35]=1[CH:36]([OH:45])[CH2:37][CH2:38][O:39]2
Reactant: O=C1CCOc2cc(F)cc(F)c21
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: CSC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OC1CCOc2cc(F)cc(F)c21
Reaction time: 0.33 h

Procedure:
To a mixture of 1 M (S)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole toluene solution (5.43 mL, 5.43 mmol) and tetrahydrofuran (40 mL) was added 2M borane-methyl sulfide complex tetrahydrofuran solution (29.8 mL, 59.7 mmol) at 0° C. and the mixture was stirred for 20 minutes. To the mixture was added a solution of 5,7-difluoro-2,3-dihydro-4H-chromen-4-one (10.0 g, 54.3 mmol, STEP 7) in tetrahydrofuran (70 mL) at 0° C. over a period of 1 hour, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was quenched with methanol (50 mL) and stirred for 30 minutes at room temperature. The mixture was concentrated in vacuum and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1 as an eluent) to afford crude white solids (8.85 g, 86% ee). The solids were recrystallized from hexane (300 mL) to give the title compound as a colorless needle crystal (5.90 g, 58%, >99% ee).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][OH:8])[S:5][CH:6]=1.[Si:9](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CN=C1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][O:8][Si:9]([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:5][CH:6]=1
Reactant: OCc1cc(Br)cs1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCc1cc(Br)cs1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 101.8 %

Procedure:
To a 250-mL round bottom flask fitted with a magnetic stir bar under a N2 atmosphere was added (4-bromothiophen-2-yl)methanol (2.0 g, 10 mmol, 1 equiv) and 30 mL of anhydrous DCM. The reaction mixture was then cooled to 0° C. and the tert-butyl-diphenylsilyl chloride (3.4 g, 3.2 mL, 12.4 mmol, 1.2 equiv) was added followed by imidazole (1.06 g, 15.5 mmol, 1.5 equiv). The reaction was stirred for 16 h and was allowed to equilibrate to rt. The reaction mixture was subsequently taken up in 75 mL DCM and washed with water (100 mL). The organic layer was then dried (Na2SO4), filtered, and evaporated in vacuo. The resulting residue was chromatographed over silica gel (0-10% EtOAc in heptane over 18 min.-retention time (tR) of product: 4-12 min) to give the desired ((4-bromothiophen-2-yl)methoxy)-tert-butyl diphenyl silane (4.3929 g, 98%). 1H-NMR (400 MHz, CD3CN) δ ppm 7.66-7.71 (m, 4H), 7.39-7.51 (m, 6H), 7.29 (d, J=1.46 Hz, 1H), 6.77-6.81 (m, 1H), 4.89 (d, J=0.93 Hz, 2H), 1.06 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:17])[N:8]([CH:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])[CH:9]=[C:10]([Br:11])[C:5]=2[NH:4][N:3]=1>CCCCCC.C(O)C>[NH2:1][C:2]1[C:6]2[C:7](=[O:17])[N:8]([C@@H:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])[CH:9]=[C:10]([Br:11])[C:5]=2[NH:4][N:3]=1
Reactant: CC(C)C(C)n1cc(Br)c2[nH]nc(N)c2c1=O
Solvent: CCCCCC
Solvent: CCO
Product: CC(C)[C@@H](C)n1cc(Br)c2[nH]nc(N)c2c1=O
Yield: 44.1 %

Procedure:
Racemic 3-amino-7-bromo-5-(3-methylbutan-2-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step G of Example 13 (7.89 g) was resolved by HPLC (column: CHIRALPAK AD, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/ethanol=600/400(v/v)) to give the title compound (3.479 g) having a longer retention time.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=3)=[N:9]2)=[CH:5][CH:4]=1.[Cl-].[NH4+]>O1CCOCC1.O.[Zn]>[NH2:26][C:22]1[CH:21]=[C:20]([C:10]2[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)=[CH:12][N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:30][CH:29]=3)[N:9]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(Cn2cc(-c3ccnc(N)n3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Cn2cc(-c3ccnc(N)n3)c(-c3cccc(N)c3)n2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 67.5 %

Procedure:
1.6 g (3.98 mmol) of 4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]-pyrimidin-2-amine were dissolved in a mixture of 100 ml of dioxane and 30 ml of water and 2.12 g (40 mmol) of ammonium chloride and 1.05 g (16 mmol) of metallic zinc were added successively. The reaction mixture was stirred at 100° C. for 6 hours. The suspension was then filtered through a celite pad and the filtrate evaporated. The residue was partitioned between dichloromethane and aqueous sodium hydrogenocarbonate, dried over sodium sulphate and evaporated again, giving 1 g (67%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[CH:3]=1.P(OCC)(OCC)OCC.O=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.[H-].[Na+]>O.COCCOC>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH:8]=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: BrCc1cccc(Br)c1
Agent: CCOP(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Br)c2)CC1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 51.5 %

Procedure:
The mixture of 1-bromo-3-(bromomethyl)benzene (6.2 g, 24.8 mmol) and triethyl phosphite (4.53 g, 27.28 mmol) was heated at 90° C. for 12 hours, cooled to 0° C., added DME (40 ml) and tert-butyl 4-oxopiperidine-1-carboxylate (5.73 g, 28.8 mmol) and sodium hydride (1.19 g, 49.6 mmol) and stirred at RT for 2-3 hours. Diluted with water and extracted with ether to afford 4.5 g (51.5% yield) of the titled product after purification with (60/120 silica gel) column chromatography using 10% ethyl acetate in hexane as eluent. MS: m/z=353.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[NH:32][C:31]4[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].[CH2:44](Cl)[CH:45]=[CH2:46]>>[CH3:43][O:42][C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[N:29]([CH2:46][CH:45]=[CH2:44])[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[N:32]=3)[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Reactant: C=CCCl
Product: C=CCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 35.1 using 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine and allyl chloride to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:12]([CH2:13][CH3:14])=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[C:12]([CH2:13][CH3:14])=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1
Reactant: CCc1c([N+](=O)[O-])ccc2c1NCC2
Agent: [Pd]
Solvent: CCO
Product: CCc1c(N)ccc2cc[nH]c12

Procedure:
38.4 g of 6-nitro 7-ethylindoline were dissolved in 120 ml of absolute ethanol to which were added 19.2 g of palladium on charcoal at 10% (moisture 50%) and then heated to reflux for 2 hours.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH3:33])[N:5]2[C:10]=1[C:9]([O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)=[N:8][C:7]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-])=O)[CH:25]=1)=[N:6]2>[Pd]>[CH3:1][C:2]1[N:3]=[C:4]([CH3:33])[N:5]2[C:10]=1[C:9]([O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)=[N:8][C:7]([C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[NH2:30])=[N:6]2
Reactant: COc1cc(Oc2nc(-c3cccc([N+](=O)[O-])c3)nn3c(C)nc(C)c23)cc(OC)c1OC
Agent: [Pd]
Product: COc1cc(Oc2nc(-c3cccc(N)c3)nn3c(C)nc(C)c23)cc(OC)c1OC

Procedure:
400 mg (0.89 mmol) of 5,7-dimethyl-2-(3-nitrophenyl)-4-(3,4,5-trimethoxyphenoxy)-imidazo[5,1-f][1,2,4]triazine from example 15A are hydrogenated in the presence of 120 mg of palladium on carbon (10% strength) analogously to example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[CH3:30])[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=2)[N:8]([CH2:23][CH2:24][CH3:25])[C:7]1=[O:26].B(Br)(Br)Br>C(Cl)Cl.CCOCC>[CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[CH3:30])[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)[N:8]([CH2:23][CH2:24][CH3:25])[C:7]1=[O:26]
Reactant: CCCn1c(CCCc2ccc(OC)cc2)c(C)n(Cc2ccc(C)c(C)c2)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOCC
Product: CCCn1c(CCCc2ccc(O)cc2)c(C)n(Cc2ccc(C)c(C)c2)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 120.6 %

Procedure:
A 0° C. solution of 1-(3,4-dimethyl-benzyl)-4-[3-(4-methoxy-phenyl)-propyl]-5-methyl-3-propyl-1,3-dihydro-imidazol-2-one (0.145 g, 0.357 mmol) in CH2Cl2 (6 mL) was treated dropwise with BBr3 (0.10 mL, 1.06 mmol) and then stirred at 0° C. under N2 for 30 minutes. The reaction was diluted with Et2O and then quenched with ice and then water. The organic layer was dried (MgSO4), and the solvent removed in vacuo to afford 0.169 g (100%) 1-(3,4-dimethyl-benzyl)-4-[3-(4-hydroxy-phenyl)-propyl]-5-methyl-3-propyl-1,3-dihydro-imidazol-2-one that was utilized without purification.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].C(N(CC)CC)C.[Cl:14][C:15]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:16]=1[O:17][C:18]1[CH:19]=[C:20]([C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=1)[C:21](Cl)=[O:22]>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:33]=[C:32]([C:34]([F:35])([F:37])[F:36])[CH:31]=[CH:30][C:16]=1[O:17][C:18]1[CH:19]=[C:20]([C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=1)[C:21]([N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6])=[O:22]
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: O=C1CCCN1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1CCCN1C(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyrrolidin-2-one (7.60 grams; 0.02 mol), triethylamine (2.0 grams; 0.02 mol) and toluene (50 mol) were placed in a three-necked, glass reaction flask equipped with stirrer, thermometer, addition funnel and drying tube. 3-(2-Chloro-4-trifluoromethylphenoxy)-6-nitrobenzoylchloride (7.60 grams; 0.02 mol) in toluene (10 ml) was added to the mixture in the flask. The mixture, after being stirred overnight at room temperature, was washed with water, dried over sodium sulfate and evaporated to give a dark oil. The oil was chromatographed using silica gel into two fractions, the first using toluene as eluant and the second fraction using an equal mixture of toluene and ethyl acetate gave the desired product as a brown oil which solidified upon standing. Trituration with isopropyl ether resulted in white crystals, melting point 88° C. This product analyzed as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([CH:20]2[C@H:25]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@@H:24]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@H:23]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C@@H:22]([CH2:50][O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[O:21]2)=[CH:16][C:3]=1[CH2:4][O:5][Si](C(C)C)(C(C)C)C(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([CH:20]2[C@H:25]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C@@H:24]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@H:23]([O:42][CH2:43][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C@@H:22]([CH2:50][O:51][CH2:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[O:21]2)=[CH:16][C:3]=1[CH2:4][OH:5]
Reactant: CC(C)[Si](OCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
To a solution of (2-chloro-5-((3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxy-methyl)tetrahydro-2H-pyran-2-yl)benzyloxy)triisopropylsilane (198 mmol) from Step 5 in tetrahydrofuran (500 mL) was added tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 594 mL, 594 mmol) and the reaction mixture stirred at ambient temperature for 2 h. After removal of organic volatiles under reduced pressure, the residue was partitioned between ethyl acetate and saturated ammonium chloride solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified on Biotage® purification apparatus (silica gel, 10 to 60% ethyl acetate in hexanes) to yield the title compound (130 g, 195 mmol, 98%, mixture of α,β-anomer in about 1:2 ratio) as a white solid.
Reaction SMILES: [ClH:1].Cl.N[C@H]1CCN(C(C2C3C(=CC=CC=3)C=CC=2)CC2(O)CCCCC2)C1.[OH:28][C:29]1([CH:35]([C:51]2[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH:54]=[CH:53][CH:52]=2)[C:36]([N:38]2[CH2:42][CH2:41][C@H:40]([NH:43]C(=O)OC(C)(C)C)[CH2:39]2)=O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[ClH:1].[ClH:1].[NH2:43][C@H:40]1[CH2:41][CH2:42][N:38]([CH2:36][CH:35]([C:29]2([OH:28])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:51]2[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH:54]=[CH:53][CH:52]=2)[CH2:39]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)C(c2cccc3ccccc23)C2(O)CCCCC2)C1
Agent: Cl
Agent: N[C@H]1CCN(C(CC2(O)CCCCC2)c2cccc3ccccc23)C1
Product: N[C@H]1CCN(CC(c2cccc3ccccc23)C2(O)CCCCC2)C1

Procedure:
In an analogous manner to Example 1, step 2, 1-[2-[(3S)-3-aminopyrrolidin-1-yl]-(1-naphthyl)ethyl]cyclohexanol dihydrochloride was prepared from tert-butyl {(3S)-1-[(1-hydroxycyclohexyl)(1-naphthyl)acetyl]pyrrolidin-3-yl}carbamate MS (ESI) m/z 339; HRMS: calcd for C22H30N2O+H, 339.24364; found (ESI, [M+H]+), 339.2421.
Reaction SMILES: Br[C:2]1[C:3](=[O:32])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[N:59]1[C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:62]=[C:61](B(O)O)[CH:60]=1>>[F:18][C:13]1[CH:12]=[C:11]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][CH:22]4[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:24][CH2:23]4)=[CH:7][CH:8]=3)[C:3](=[O:32])[C:2]=2[C:61]2[CH:60]=[N:59][C:68]3[C:63]([CH:62]=2)=[CH:64][CH:65]=[CH:66][CH:67]=3)[CH:16]=[C:15]([F:17])[CH:14]=1
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: CS(=O)(=O)N1CCC(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: CS(=O)(=O)N1CCC(CCOc2ccc3c(c2)C(=O)C(c2cnc4ccccc4c2)=C3c2cc(F)cc(F)c2)CC1
Yield: 79 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-{2-[1-(methylsulfonyl)piperidin-4-yl]ethoxy}-1H-inden-1-one obtained in Step 3 of Example 100 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 3-quinolinylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (EtOAc/hexanes=1:1) to obtain the title compound (79%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]([CH3:14])([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])[CH3:3].C(N(C(C)C)C(C)C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:46]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[O:54][C:55]1[N:60]=[CH:59][C:58]([NH2:61])=[CH:57][CH:56]=1)[CH3:47]>CN(C)C=O>[CH2:46]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[O:54][C:55]1[N:60]=[CH:59][C:58]([NH:61][C:11](=[O:13])[C:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:10])[CH3:14])=[CH:57][CH:56]=1)[CH3:47]
Reactant: CCc1ccccc1Oc1ccc(N)cn1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccccc1Oc1ccc(NC(=O)C(C)(C)NC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21.7 %

Procedure:
In a 8 mL vial N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-methylalanine (208 mg, 1.022 mmol) was dissolved in N,N-dimethylformamide (4 mL) to give a colourless solution. N-ethyl-N-(1-methylethyl)-2-propanamine (0.223 mL, 1.277 mmol) and N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylidene]-N-methylmethanaminium tetrafluoroborate (328 mg, 1.022 mmol) were added. The reaction mixture was stirred at room temperature for 15 min. 6-[(2-ethylphenyl)oxy]-3-pyridinamine (Intermediate 46, 228 mg) was added and the reaction mixture was warmed to 60° C. After 24 hours, additional 150 mg of N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylidene]-N-methylmethanaminium tetrafluoroborate were added. After additional 8 hours, the solvent was evaporated under vacuum using the Genevac affording a dark brown oil which was purified by silica gel chromatography (Biotage system, 25 g SNAP column) with as eluent a gradient Cyclohexane/EtOAc from 3:1 to 1:1 in 10 CV, then 1:1 for 5 CV. The collected fractions afforded the title compound as a pale orange solid (88.6 mg).