Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4]Br.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Fc1ccc(F)c(CBr)c1
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: O=C(O)Cc1ccc2ccn(Cc3cc(F)ccc3F)c2c1

Procedure:
The titled compound (18 mg) as a white solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 2,5-difluorobenzyl bromide according to the method of the process (7) of Example 4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:25])[C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[N:19]1[C:23]([CH3:24])=[CH:22][N:21]=[CH:20]1.[CH2:26]=[O:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:25])[C:9]1[CH:14]=[C:13]([C:15]([F:16])([F:18])[F:17])[CH:12]=[CH:11][C:10]=1[N:19]1[C:23]([CH3:24])=[CH:22][N:21]=[C:20]1[CH2:26][OH:27]
Reactant: Cc1cncn1-c1ccc(C(F)(F)F)cc1C(=O)c1ccccc1Cl
Reactant: C=O
Product: Cc1cnc(CO)n1-c1ccc(C(F)(F)F)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 1, 2'-chloro-5-(trifluoromethyl)-2-(5-methylimidazol-1-yl)benzophenone is heated in a bomb with 37% aqueous formaldehyde solution to give 2'-chloro-5-(trifluoromethyl)-2-[2-(hydroxymethyl)-5-methylimidazol-1-yl]benzophenone.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH:7]2[CH:5]([CH2:6]2)[N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].CC#N.C(Cl)(Cl)(Cl)Cl.O.I([O-])(=O)(=O)=[O:26].[Na+]>[Ru](Cl)(Cl)Cl>[C:12]([O:11][C:9]([N:4]1[CH:3]([C:2]([OH:26])=[O:1])[CH2:8][CH:7]2[CH:5]1[CH2:6]2)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1C2CC2C[C@@H]1CO
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1C(C(=O)O)CC2CC21
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.1 %

Procedure:
To a solution of (3R)-tert-butyl 3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (D32) (440 mg, 2.06 mmol) in a mixture MeCN/CCl4/H2O (6/6/9 ml), sodium periodate (1.76 g, 8.25 mmol) was added and the reaction stirred vigorously for 5 min before addition of Ruthenium trichloride (12.8 mg, 0.062 mmol). The resulting solution was stirred 18 hrs at RT then quenched by addition of isopropanol (6 ml). The resulting black mixture was diluted with Et2O (50 ml) and filtered through a celite pad. The filtrate was evaporated and the residue was dissolved in water, the pH was adjusted to pH˜9-10 with K2CO3 and the aqueous was washed with Et2O (3×30 ml). Aqueous was then acidified to pH˜4-5 and re-extracted with EtOAc (3×30 ml). Collected organics after solvent evaporation afforded the title compound (D33) (216 mg).
Reaction SMILES: [O:1]=[S:2]1(=[O:22])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]1[C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.C(Cl)(=O)C([Cl:26])=O.CN(C=O)C>ClCCl>[O:1]=[S:2]1(=[O:22])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]1[C:13]1[CH:21]=[CH:20][C:16]([C:17]([Cl:26])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(N2S(=O)(=O)c3ccccc3S2(=O)=O)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(N2S(=O)(=O)c3ccccc3S2(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-(1,1,3,3-tetraoxidobenzo[d][1,3,2]dithiazol-2-yl)benzoic acid (0.39 g; 1.0 mmol) in dichloromethane (6 mL) was treated with oxalyl chloride (1 mL), a drop of DMF, and allowed to stir at ambient temperature for a period of 2 hours. The solvent was removed under reduced pressure to afford 4-(1,1,3,3-tetraoxidobenzo[d][1,3,2]dithiazol-2-yl)benzoyl chloride, 7, (0.3 g, quant.) which was used without further purification.
Reaction SMILES: Cl.[F:2][C:3]([F:27])([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[C:4]([NH:6][C@H:7]1[CH2:11][CH2:10][C@H:9]([NH:12]C(=O)OC(C)(C)C)[CH2:8]1)=[O:5]>CCOC(C)=O>[NH2:12][C@H:9]1[CH2:10][CH2:11][C@H:7]([NH:6][C:4](=[O:5])[C:3]([F:27])([F:2])[C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[CH2:8]1
Reactant: Cc1ccc(C(F)(F)C(=O)N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)C2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(C(F)(F)C(=O)N[C@H]2CC[C@H](N)C2)cc1
Yield: 101.2 %

Procedure:
A saturated solution of HCl in EtOAc (10 mL) was added to a stirred solution of tert-butyl (1S,3S)-3-{[difluoro(4-methylphenyl)acetyl]amino}cyclopentylcarbamate (1.05 g, 2.85 mmol) in EtOAc (10 mL). After 1 h the solution was concentrated to dryness. The residue was dissolved in 1:1 CH3CN/H2O (18 mL) and loaded onto SCX ion exchange resin (10 g, 60 mL, 6.9 meq), rinsing with CH3CN (15 mL), and then eluting with EtOH/NH3 (25 mL). The eluent was concentrated to give the title compound (774 mg) as a solid: MS=252.4 (M+1-ammonia).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[C:36]([O:38][CH3:39])=[O:37]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:39][O:38][C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[CH:31][C:30]=1[Cl:29]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)cc1Cl

Procedure:
In analogy to Example 5, 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 56, step 4) was reacted with 3-chloro-4-(methoxycarbonyl)phenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a white solid. MS (m/e, ISP neg. ion)=582.2 [M−H+]
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:12][CH:11]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[C:21]([O:20][C:18](=[O:19])[NH:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][OH:8])=[CH:15][CH:14]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(CO)cc1
Yield: 85.1 %

Procedure:
Lithium aluminum hydride (5.21 g) was suspended in THF (243 ml). Then, a solution of the compound (24.3 g) obtained in Example 103-1 in THF (243 ml) was gradually added to the suspension over 50 minutes while stirring under ice-cooling, followed by stirring at room temperature for 1 hour. The reaction solution was added with sodium sulfate decahydrate and a 20% sodium hydroxide aqueous solution and then filtrated through Celite. The filtrate was concentrated under reduced pressure and dried under vacuum, thereby obtaining the subject compound (18.5 g).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[CH2:20][CH:21]([CH3:23])[CH3:22].[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:28]Br>>[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:28][O:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][CH2:13]2)=[O:7])=[CH:4][C:3]=1[CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)Cc1cc(C(=O)N2CCN(CC(C)C)CC2)ccc1O
Reactant: Fc1ccc(CBr)cc1F
Product: CC(C)Cc1cc(C(=O)N2CCN(CC(C)C)CC2)ccc1OCc1ccc(F)c(F)c1
Yield: 96.5 %

Procedure:
As in the case of Example 18, 1-(4-hydroxy-3-isobutylbenzoyl)-4-isobutylpiperazine (1.24 g) was benzylated with 3,4-difluorobenzyl bromide (1.60 g), thereby yielding 1.67 g of the aimed compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH:24][CH2:25][CH2:26][CH2:27][N:28]1[CH:32]=[CH:31][N:30]=[CH:29]1)(=[O:23])=[O:22]>ClCCl.N1C=CC=CC=1.C(OCC)(=O)C>[N:28]1([CH2:27][CH2:26][CH2:25][NH:24][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=2)(=[O:23])=[O:22])[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1ccccc1S(=O)(=O)NCCCn1ccnc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1S(=O)(=O)NCCCn1ccnc1)c1cccc(C(F)(F)F)c1
Yield: 58.9 %

Procedure:
A solution of 4.24 g (0.0203 mol) of m-trifluoromethylbenzoyl chloride in 10 ml of dichloromethane was added dropwise to a solution of 4.35 g (0.0153 mol) of 2-amino-N-[(3-imidazol-1-yl)propyl]benzenesulfonamide, prepared as in Examples 1A and 1B, in 70 ml of pyridine, under nitrogen. When the reaction was complete, as determined by thin layer chromatography, the resulting reaction mixture was reduced to dryness under reduced pressure. The resultant oil was dissolved in an ethyl acetate/aqueous sodium bicarbonate mixture. The resulting layers were separated, the organic layer was washed with water and again reduced to dryness under reduced pressure to provide an oil. This oil was then purified using column chromatography (8000 ml of a gradient eluent of 0-15% methanol in chloroform). The fractions containing the desired product were combined, reduced to dryness under reduced pressure and then recrystallized from an ethanol/hexane/diethyl ether solution to provide 4.08 g of the desired titled compound (m.p. 145°-147° C.).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([F:29])=[C:12]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:20][CH:21]=2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[CH:30]1([C:36](O)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.ClCCCl>[CH:30]1([C:36]([N:26]2[CH2:27][CH2:28][CH:23]([O:22][C:19]3[N:18]=[CH:17][C:16]([C:12]4[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][OH:8])[C:11]=4[F:29])=[CH:21][N:20]=3)[CH2:24][CH2:25]2)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=C(O)C1CCCCC1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(-c2cnc(OC3CCNCC3)nc2)c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: O=C(C1CCCCC1)N1CCC(Oc2ncc(-c3cccc(CO)c3F)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
5-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-(piperidin-4-yloxy)py rimidine (150 mg) and cyclohexane carboxylic acid (82 mg) were mixed with DCE (3.6 ml), and WSC hydrochloride (125 mg) and HOBt (85 mg) were added thereto, followed by stirring at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution and CHCl3 were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was mixed with THF (3.6 ml), and a 1M TBAF/THF solution (0.85 ml) was added thereto, followed by stirring at room temperature for 1 hour. EtOAc and an aqueous ammonium chloride solution were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain cyclohexyl [4-({5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}oxy)piperidin-1-yl]methanone (148 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)=O)=[CH:5][CH:4]=1)#[CH:2].Cl.[NH2:28][OH:29].C(=O)([O-])O.[Na+]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)=[N:28][OH:29])=[CH:5][CH:4]=1)#[CH:2]
Reactant: C#Cc1ccc([C@@H](CC(=O)c2ccnc(C)c2)c2ccccc2C)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: C#Cc1ccc([C@@H](CC(=NO)c2ccnc(C)c2)c2ccccc2C)cc1

Procedure:
In analogy to example 132, step 6, from (R)-3-(4-ethynyl-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=355.4 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[NH:16][CH:10]([CH2:11][O:12][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1[C:29]2[CH:28]([CH2:30][O:31][C:32](C3CC(=O)N(O)C3=O)=[O:33])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH:17]1[C:29]2[CH:28]([CH2:30][O:31][C:32]([N:16]3[CH:14]4[CH2:15][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH:10]3[CH2:11][O:12][CH2:13]4)=[O:33])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CC2COCC(C1)N2
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)C1CC(=O)N(O)C1=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2COCC(C1)N2C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carboxylic acid tert-butyl ester (716 mg, 3.14 mmol, WuXy AppTech) and 9-fluorenylmethoxycarbonyl-N-hydroxysuccinimide (1058 mg, 3.14 mmol) was prepared in anhydrous THF (11 mL) and stirred at RT for 2.5 hours. The reaction mixture was concentrated under vacuum to give a yellow oil. After purification by flash chromatography (silica, heptane/EtOAc), the title compound was obtained as a white foam (1.36 g, 93%). 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J=7.5 Hz, 2H), 7.55 (d, J=7.3 Hz, 2H), 7.45-7.37 (m, 2H), 7.36-7.28 (m, 2H), 4.65-4.57 (m, 2H), 4.35-3.49 (m, 9H), 3.17-2.78 (m, 2H), 1.46 (s, 9H). HPLC (max plot) 96.5%; Rt 5.07 min. UPLC/MS: (MS+) 451.4 ([M+H]+).
Reaction SMILES: CN(C)C=O.[C:6](=[O:26])([O:22][CH:23](Cl)[CH3:24])[O:7][CH2:8][CH2:9][CH2:10][C@@H:11]([O:18][N+:19]([O-:21])=[O:20])[C@H:12]([O:14][N+:15]([O-:17])=[O:16])[CH3:13].[CH2:27]([O:29][C:30]1[N:34]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[C:48]3[N:52]([C:53]([C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)[C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[N:51]=[N:50][N:49]=3)=[CH:38][CH:37]=2)[C:33]2[C:72]([C:76]([OH:78])=[O:77])=[CH:73][CH:74]=[CH:75][C:32]=2[N:31]=1)[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH2:27]([O:29][C:30]1[N:34]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[C:48]3[N:52]([C:53]([C:60]4[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=4)([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)[C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)[N:51]=[N:50][N:49]=3)=[CH:40][CH:41]=2)[C:33]2[C:72]([C:76]([O:78][CH:23]([O:22][C:6]([O:7][CH2:8][CH2:9][CH2:10][C@@H:11]([O:18][N+:19]([O-:21])=[O:20])[C@H:12]([O:14][N+:15]([O-:17])=[O:16])[CH3:13])=[O:26])[CH3:24])=[O:77])=[CH:73][CH:74]=[CH:75][C:32]=2[N:31]=1)[CH3:28]
Reactant: CC(Cl)OC(=O)OCCC[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-]
Reactant: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OCCC[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-])c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A N,N-dimethylformamide (20 mL) solution of (4R,5R)-4,5-bis(nitrooxy)hexyl 1-chloroethyl carbonate (2.94 g, 8.89 mmol) was added to a stirred N,N-dimethylformamide (20 mL) suspension of 2-ethoxy-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid (7.46 g, 10.9 mmol) and cesium carbonate (3.95 g, 12.1 mmol). The solution was stirred at 70° C. for 2 hours. Water (100 mL) was added, and the solution was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 20-60% ethyl acetate/hexanes to give the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.84 (dd, J=1.6, 7.3 Hz, 1H), 7.76 (dd, J=1.0, 7.9 Hz, 1H), 7.58 (dd, J=1.0, 7.9 Hz, 1H), 7.45 (dt, J=1.7, 7.4 Hz, 1H), 7.42 (dt, J=1.7, 7.4 Hz, 1H), 7.32 (t, J=7.4 Hz, 3H), 7.29 (dd, J=1.5, 7.4 Hz, 1H), 7.24 (t, J=7.8 Hz, 6H), 7.17 (t, J=7.9 Hz, 1H), 6.98 (d, J=8.2 Hz, 2H), 6.92 (d, J=8.2 Hz, 6H), 6.85 (q, J=5.4 Hz, 1H), 6.78 (d, J=8.2 Hz, 2H), 5.56 (s, 2H), 5.12-5.22 (m, 2H), 4.58-4.68 (m, 2H), 4.06-4.20 (m, 2H), 1.64-1.94 (m, 4H), 1.41-1.46 (m, 6H), 1.33 (d, J=6.4 Hz, 3H); LC-MS: m/z 999.5 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[N:3]=1.[NH2:12][C@H:13]([C:15]1[N:20]=[C:19]2[CH:21]=[CH:22][N:23]([CH3:24])[C:18]2=[CH:17][C:16]=1[N:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:27]([CH3:38])[CH2:26]1)[CH3:14].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:12][C@H:13]([C:15]2[N:20]=[C:19]3[CH:21]=[CH:22][N:23]([CH3:24])[C:18]3=[CH:17][C:16]=2[N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[C@H:27]([CH3:38])[CH2:26]2)[CH3:14])[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[N:3]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CCN(C(=O)OC(C)(C)C)[C@H](C)C1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCN(C(=O)OC(C)(C)C)[C@H](C)C2)c1C#N
Temperature: 80 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a 50 mL pear flask were added 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (30.5 mg, 0.181 mmol) and tert-butyl (R)-4-(5-((S)-1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-2-methylpiperazine-1-carboxylate (45 mg, 0.120 mmol) in DMSO (0.60 mL). Triethylamine (84 μL, 0.60 mmol) was added, and the mixture was stirred at 80° C. for 2 hours. Additional triethylamine (84 μL, 0.602 mmol) and 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (10 mg, 0.060 mmol) were added and the mixture was heated for another 3 hours at 80° C. The cooled mixture was partitioned between saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and concentrated. The residue was purified by liquid chromatography (SiO2, 25-100% EtOAc/heptanes gradient) to give the title compound as a white solid (51 mg, 84%). 1H NMR (400 MHz, CDCl3) δ ppm 1.48-1.52 (m, 12H), 1.54 (d, J=6.82 Hz, 3H), 2.39 (s, 3H), 2.79-2.86 (m, 1H), 2.89-3.09 (m, 3H), 3.35 (br s, 1H), 3.78 (s, 3H), 4.05 (d, J=9.85 Hz, 1H), 4.34 (br s, 1H), 5.27 (br s, 1H), 5.94 (quin, J=6.76 Hz, 1H), 6.66 (d, J=3.28 Hz, 1H), 7.24 (d, J=3.28 Hz, 1H), 7.31 (d, J=7.83 Hz, 1H), 7.40 (s, 1H); ESI-MS m/z [M+H]+ calc'd for C26H35N9O2, 506. found 506.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]=[C:10]=S)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.Cl.[NH2:14][CH2:15][C@@:16]1([OH:23])[C@H:21]2[CH2:22][N:18]([CH2:19][CH2:20]2)[CH2:17]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(N=C=NC(C)C)(C)C>CN(C)C=O.O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:9][C:10]2[O:23][C@@:16]3([C@H:21]4[CH2:22][N:18]([CH2:19][CH2:20]4)[CH2:17]3)[CH2:15][N:14]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: S=C=Nc1ncc(Cl)cc1Cl
Reactant: NC[C@]1(O)CN2CC[C@@H]1C2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Clc1cnc(NC2=NC[C@@]3(CN4CC[C@@H]3C4)O2)c(Cl)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
To a solution of 3,5-dichloro-2-isothiocyanatopyridine (57 mg, 0.279 mmol) in N,N-dimethylformamide (2 mL) was added (3S*,4R*)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol dihydrochloride (60 mg, 0.279 mmol). The reaction was treated with cesium carbonate (227 mg, 0.697 mmol) and heated to 80° C. After 2 hours, the reaction was further treated with 1,3-diisopropylcarbodiimide (0.152 mL, 0.976 mmol). The reaction was heated at 80° C. for a further 18 hours and then cooled to room temperature. The reaction was poured into chloroform (20 ml) and water (20 ml). The organic was collected and purified by silica gel chromatography eluting with 5-40% (10% NH4OH/Methanol)/chloroform. The product fractions were collected and concentrated in vacuo followed by trituration in diethyl ether to yield (3R*,4R*)—N-(3,5-dichloropyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine (42 mg, 0.134 mmol, 48%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.91 (s, 1H) 8.16 (d, J=2.26 Hz, 1H) 7.97 (d, J=2.51 Hz, 1H) 3.79 (d, J=10.04 Hz, 1H) 3.58 (d, J=9.79 Hz, 1H) 2.71-2.98 (m, 2H) 2.56-2.71 (m, 4H) 2.37 (dd, J=10.04, 3.76 Hz, 1H) 1.83-2.00 (m, 1H) 1.48 (s, 1H). MS (LC/MS) R.T=1.423; (M+H=312.99).
Reaction SMILES: [CH2:1]([N:8]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31](Br)=[CH:30][CH:29]=1)[CH2:9][C@H:10]([O:18][Si](C(C)(C)C)(C)C)[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si]([O:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)(C(C)(C)C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([N:8]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:46]2[CH:45]=[CH:44][C:43]([OH:42])=[CH:48][CH:47]=2)=[CH:30][CH:29]=1)[CH2:9][C@@H:10]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[OH:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN(CCc1ccc(Br)cc1)Cc1ccccc1)c1cccc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1ccc(-c2ccc(CCN(Cc3ccccc3)C[C@H](O)c3cccc(Cl)c3)cc2)cc1
Temperature: 75 °C
Reaction time: 10 h
Yield: 77.5 %

Procedure:
To a solution of (2R)-N-benzyl-N-[2-(4-bromophenyl)-ethyl]-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-chlorophenyl)ethanamine (850 mg) in 1,2-dimethoxyethane (9 ml) was added 4-[[tert-butyl(dimethyl)silyl]oxy]-phenylboronic acid (498 mg), tetrakis(triphenylphosphine)-palladium (88 mg) and aqueous solution of sodium carbonate (2M, 1.6 ml), and the mixture was stirred at 75° C. for 10 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. To a solution of the residue in tetrahydrofuran (10 ml) was added 1M tetrabutylammonium fluoride in tetrahydrofuran (3.6 ml), and the mixture was stirred at room temperature for 8 hours under nitrogen. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give 4′-[2-[N-benzyl-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-ol (540 mg).