Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:20])[NH:7][CH:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1)[CH:9](O)[CH3:10])(C)(C)C.[H-].[Na+]>O>[F:19][C:14]1[CH:13]=[C:12]([CH:8]2[CH:9]([CH3:10])[O:20][C:6](=[O:5])[NH:7]2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: CC(O)C(NC(=O)OC(C)(C)C)c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC1OC(=O)NC1c1ccc(F)c(F)c1
Temperature: 35 °C
Reaction time: 3 h

Procedure:
To a well stirred solution of [1-(3,4-difluorophenyl)-2-hydroxy-propyl]-carbamic acid-tert-butyl ester (0.43 g, 1.5 mmol) THF (20 mL) was added 95% NaH (0.09 g, 3.8 mmol) at room temperature. The resulting suspension was stirred for 3 h at about 35° C. (warm water bath) and then quenched carefully with ice. The biphasic mixture was extracted with 100 mL of EtOAc, washed with brine, dried over Na2SO4, filtered and the solvent was removed in vacuo. The two diastereomers were separated by column chromatography over silica gel (First isomer: 0.11 g, Rf=0.6, 3:1 hexane-EtOAc; second isomer: 0.23 g, Rf=0.5, 3:1 hexane-EtOAc). NOE experiment suggested that the first diastereomer had the methyl and the aryl group in trans configuration while the second diastereomer had cis relationship between the two groups.
Reaction SMILES: [CH2:1]([Sn:11](Cl)([CH2:19][C:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:22])[CH3:21])[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[F-:30].[K+].C1C=CC=CC=1>O>[CH2:1]([Sn:11]([F:30])([CH2:19][C:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:22])[CH3:21])[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: [F-]
Reactant: CC(C)(C[Sn](Cl)(CC(C)(C)c1ccccc1)c1ccc(F)cc1)c1ccccc1
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C[Sn](F)(CC(C)(C)c1ccccc1)c1ccc(F)cc1)c1ccccc1
Yield: 79.5 %

Procedure:
A mixture consisting of the crude dineophyl-parafluorophenyltin chloride (50 g) and potassium fluoride (5.8 g, 0.1 mol) was heated for 2 hours in the presence of benzene (120 g) and water (23 g). The aqueous layer of the reaction mixture was removed, and the organic layer was washed with water, filtered and concentrated under reduced pressure. The residue thus obtained was crystallized from petroleum ether to give 38.5 g of dineophyl-parafluorophenyltin fluoride as a white solid.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:68][O:69][C:70]1[CH:75]=[CH:74][C:73]([CH:76]=O)=[CH:72][CH:71]=1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:76]([C:73]3[CH:74]=[CH:75][C:70]([O:69][CH3:68])=[CH:71][CH:72]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(c1ccccn1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3c(N4CCN(C(C)c5ccccn5)CC4)c(Br)cnc3[nH]2)cc1
Reaction time: 16 h
Yield: 49 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(1-(pyridin-2-yl)ethyl)piperazin-1-yl)pyridin-2-amine (50 mg, 0.12 mmol), DMF (0.85 mL), ethanol (0.15 mL), 1M Na2S2O4 (3 eq, 0.42 mmol, 0.42 mL) and 4-methoxybenzene carboxaldehyde (1.1 eq, 0.14 mmol, 18 mg). After 16 h, concentration in vacuo and preparation by preparative tlc (EtOAc—CH2Cl2-MeOH, 50:50:2) gave the product (29 mg, 48%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.38 (d, J=6.8 Hz, 3H, CHCH3), 2.60 (s, br, 2H, piperazine NCH2), 2.70 (br s, 2H, piperazine NCH2), 3.64 (s, br, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OCH3), 7.10 (d, J=8.9 Hz, 2H, methoxyphenyl), 7.25-7.28 (m, 1H, pyridine H-5), 7.50 (d, J=7.9 Hz, 1H, pyridine H-3), 7.79 (td, J=7.7, 1.5 Hz, 1H, pyridine H-4), 8.12 (d, J=8.9 Hz, 2H, methoxyphenyl), 8.18 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.53 (d, J=4.2 Hz, 1H, pyridine H-6), 13.37 (br s, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([OH:20])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18]O)=[CH:9][N:8]([CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:5]2=[N:6][CH:7]=1.B(F)(F)F.CCOCC>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]3[C:12]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:18][O:20]3)=[CH:9][N:8]([CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:25])([CH3:27])[CH3:26])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)C(=O)OCn1cc(C(O)c2ccccc2CO)c2cc(Br)cnc21
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)C(=O)OCn1cc(C2OCc3ccccc32)c2cc(Br)cnc21
Temperature: 25 °C
Yield: 83.9 %

Procedure:
2,2-Dimethyl-propionic acid 5-bromo-3-[hydroxy-(2-hydroxymethyl-phenyl)-methyl]-pyrrolo[2,3-b]pyridin-1-ylmethyl ester (1.60 g, 3.58 mmol) was dissolved in anhydrous dichloromethane (80 ml), and the mixture was stirred at room temperature. Boron trifluoride etherate (374 ul, 2.97 mmol) was added and the mixture stirred for 20 minutes. The reaction was quenched with saturated sodium bicarbonate solution. The organic layer was separated, and the aqueous layer was washed with dichloromethane. The organic layers were combined, dried over magnesium sulfate, and the mixture was concentrated in vacuo. The crude material was purified by flash chromatography (0-100% ethyl acetate in hexanes) to give 1.29 g (84%) of 2,2-dimethyl-propionic acid 5-bromo-3-(1,3-dihydro-isobenzofuran-1-yl)-pyrrolo[2,3-b]pyridin-1-ylmethyl ester. MS: m/z 429.2+431.2 (M+H+).
Reaction SMILES: [C:1]([C@@:11]([C:28](O)=[O:29])([CH2:13][CH2:14][CH2:15][CH:16]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[NH2:17])[NH2:12])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:46]([O:53][C:54](=[O:64])[C@H:55]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[NH2:56])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH2:46]([O:53][C:54](=[O:64])[C@H:55]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[NH:56][C:28](=[O:29])[C@:11]([C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])([CH2:13][CH2:14][CH2:15][CH:16]([C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[NH2:17])[NH2:12])[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: NC(CCC[C@](N)(C(=O)O)C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: NC(CCC[C@](N)(C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of α,ε-dicarbobenzoxy-L-lysine (4) (96 mmol, 39.69 g), toluene (310 ml) and triethylamine (96 mmol, 9.70 g) at 0° C., was added, over a period of 15 minutes, iso-butyl chloroformate (109 mmol, 14.88 g), maintaining the temperature between -5° and 0° C. The resulting jelly-like reaction mixture was stirred for 30 minutes at 0° C. and then a slurry of L-phenylalanine benzyl ester, p-toluene sulphonate (1) (96 mmol, 40.99 g) in chloroform (470 ml) and triethylamine (96 mmol, 9.70 g) was added quickly in one portion and the clear solution was allowed to stir at ambient temperature overnight.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.Cl[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=1.ClC1C=C(Cl)C=CC=1C1[C:39]([C:40]2[NH:41][CH:42]=[CH:43][N:44]=2)=[CH:38][N:37]=[C:36]([NH:45][CH2:46][CH2:47][NH:48]C2C=CC([N+]([O-])=O)=CN=2)[N:35]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[C:39]([C:40]3[NH:41][CH:42]=[CH:43][N:44]=3)=[CH:38][N:37]=[C:36]([NH:45][CH2:46][CH2:47][NH:48][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=3)[N:35]=2)=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Product: Fc1ccc(-c2nc(NCCNc3ccc(C(F)(F)F)cn3)ncc2-c2ncc[nH]2)c(C(F)(F)F)c1

Procedure:
{4-[4-fluoro-2-(trifluoromethyl)phenyl]-5-imidazol-2-ylpyrimidin-2-yl}(2-{[5-(trifluoromethyl)(2-pyridyl)]amino}ethyl)amine was prepared from 4-fluoro-2-(trifluoromethyl)benzoyl chloride and 2-chloro-5-(trifluoromethyl)pyridine using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[CH:5](O)=O>CO>[CH:1]([O:4][CH3:5])=[O:3].[C:1]([O:4][CH3:5])(=[O:3])[CH3:2]
Reactant: O=CO
Reactant: CC(=O)O
Solvent: CO
Product: COC(C)=O
Product: COC=O

Procedure:
Substitution of acetic acid or formic acid for the R1COOH does not provide the advantageous results described, and instead, with the aforedescribed single reaction system provides methyl formate or methyl acetate distilling off rather than methanol. These (methyl formate or methyl acetate), contrary to R1COOCH3, have lower boiling points than methanol and consequently are distilled off instead of methanol requiring new displacing acid and displacing acid ester disposal or hydrolysis of the displacing acid ester in a second process facility (reactor plus distillation means).
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:44])[CH2:15][C@H:16]([C:39]1[CH:43]=[CH:42][O:41][N:40]=1)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH2:26][CH3:27])=[CH:19][CH:18]=1)C1C=CC=CC=1.[OH:45]O.[OH-].[Li+].Cl>C1COCC1.O>[O:41]1[CH:42]=[CH:43][C:39]([C@H:16]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=3)[CH2:26][CH3:27])=[CH:21][CH:22]=2)[CH2:15][C:14]([OH:44])=[O:45])=[N:40]1
Reactant: CCC(COc1ccc([C@H](CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)c2ccon2)cc1)Oc1ccc(C(F)(F)F)cc1
Reactant: OO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(COc1ccc([C@H](CC(=O)O)c2ccon2)cc1)Oc1ccc(C(F)(F)F)cc1
Reaction time: 1 h
Yield: 32.2 %

Procedure:
To a solution of the oxazolidinone (49.2) (23.0 mg, 0.038 mmol) dissolved in THF (2 mL), was added a 30% hydrogen peroxide solution (43 μL, 0.38 mmol) followed by a 2 M lithium hydroxide solution (94 μL, 0.19 mmol). The resulting slurry was stirred for one hour. The reaction mixture was then diluted with water and acidified with hydrochloric acid to pH ˜3. The mixture was then extracted with EtOAc (1×20 mL), and the organic layer was washed with an acidic sodium sulfite solution (2×15 mL) and brine (1×15 mL), and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase HPLC to give 49 (5.5 mg). MS ESI (pos.) m/e: 450.1 (M+H). 1H NMR (400 MHz, CD3CN) δ ppm 8.33 (1H, d, J=1.6 Hz), 7.51 (2H, d, J=8.6 Hz), 7.12 (2H, d), 6.95 (2H, d, J=8.6 Hz), 6.78 (2H, d, J=8.6 Hz), 6.16 (1H, d, J=1.6 Hz), 4.44 (1H, t, J=7.8 Hz), 4.02 (2H, t, J=6.1 Hz), 3.94 (2H, t, J=6.1 Hz), 3.09 (1H, dd, J=16.6, 8.4 Hz), 2.84 (1H, dd, J=16.4, 7.4 Hz), 1.81-1.84 (4H, m).
Reaction SMILES: [CH2:1]([S:8]NC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([CH2:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([N:28]([CH2:31][CH3:32])CC)C>C(Cl)(Cl)Cl.CCCCCC>[CH2:1]([S:8][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:22][C:23]([NH:28][C:31]1[CH:32]=[CH:4][CH:3]=[CH:2][CH:1]=1)=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CSNc2ccccc2)cc1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCN(CC)CC
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: O=C(Cc1ccccc1SCc1ccccc1)Nc1ccccc1

Procedure:
(Benzylthio)aniline (21.5 g, 0.1 mol) (the preparation of which has been described in Example 1 of U.S. Pat. No. 3,378,586) was reacted with 13.4 ml (0.1 mol) of phenylacetyl chloride in 135 ml of chloroform in the presence of 14.0 ml (0.1 mol) of triethylamine in the manner described under Example 1, part B, to give a solid residue. The latter was redissolved in 35 ml of warm chloroform and diluted with 150 ml of hexane. On seeding and rubbing, a crystalline solid gradually separated. After cooling overnight, the colorless solid was filtered, washed with hexane, and air-dried (22.3 g), m.p. 81°-83°. Following recrystallization from 350 ml of hexane, the title A material weighed 20.8 g, m.p. 82°-84°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:17]=[C:16]([NH:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1>O1CCCC1>[ClH:7].[O:4]1[CH2:5][CH2:6][N:1]([C:8]2[N:17]=[C:16]([NH:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: CCN(CC)CCNc1nc(Cl)nc2ccccc12
Solvent: C1CCOC1
Product: CCN(CC)CCNc1nc(N2CCOCC2)nc2ccccc12
Product: Cl
Yield: 41.5 %

Procedure:
A solution of 5 g of morpholine in 50 ml of tetrahydrofuran was added to 6.8 g of 2-chloro-4-(2-diethylaminoethylamino)quinazoline in 50 ml of tetrahydrofuran. The reaction mixture was heated at reflux overnight and then evaporated to dryness. The residue was suspended in dilute sodium hydroxide solution and the crude product was extracted into ether. The ether extract was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated to dryness. Attempts to crystallize the residue were unsuccessful. The residue then was distilled under reduced pressure. The distillate was dissolved in ether and treated with hydrogen chloride. The product was collected by filtraton and dried, giving 3.7 g of 2-morpholino-4-(2-diethylaminoethylamino)quinazoline hydrochloride; m.p. 216°-220°. The following elemental analysis was obtained:
Reaction SMILES: [C:1]1([C@@H:7]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]([O:10][C@@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([N:36]([CH2:39][CH3:40])[CH2:37][CH3:38])=[CH:32][CH:31]=1)=[O:29]>CCOC(C)=O>[Br-:26].[CH2:39]([N:36]([CH2:37][CH3:38])[C:33]1[CH:34]=[CH:35][C:30]([C:28](=[O:29])[CH2:27][N+:13]23[CH2:14][CH2:15][CH:16]([CH2:17][CH2:18]2)[C@@H:11]([O:10][C:8](=[O:9])[C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12]3)=[CH:31][CH:32]=1)[CH3:40]
Reactant: O=C(O[C@H]1CN2CCC1CC2)[C@H](Nc1ccccc1)c1ccccc1
Reactant: CCN(CC)c1ccc(C(=O)CBr)cc1
Solvent: CCOC(C)=O
Product: CCN(CC)c1ccc(C(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)[C@H](Nc2ccccc2)c2ccccc2)C3)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.2 %

Procedure:
To a solution of (R)—((R)-quinuclidin-3-yl) 2-phenyl-2-(phenylamino)acetate (diastereomer 1 of I2) (75 mg, 0.22 mmol) in EtOAc (5 ml), was added 2-bromo-1-(4-(diethylamino)phenyl)ethanone (66.3 mg, 0.24 mmol), and the reaction was stirred at room temperature for 15 hours. The solvent was evaporated and the crude was triturated with i-Pr2O to obtain (R)-1-(2-(4-(diethylamino)phenyl)-2-oxoethyl)-3-((R)-2-phenyl-2(phenylamino)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (129.7 mg, 96% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])([F:14])[F:13])[N:8]=[C:7]([C:23]([OH:25])=O)[CH:6]=[CH:5]2.CCN=C=NCCCN(C)C.Cl.[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:18]([O:17][P:15]([C:12]([C:11]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([C:23]([NH:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:25])=[N:8]2)=[CH:3][C:2]=1[Br:1])([F:13])[F:14])(=[O:16])[O:20][CH2:21][CH3:22])[CH3:19]
Reactant: CCOP(=O)(OCC)C(F)(F)c1cc2nc(C(=O)O)ccc2cc1Br
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(OCC)C(F)(F)c1cc2nc(C(=O)Nc3ccccc3)ccc2cc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the product of step 5 (109 mg) in 5 mL CH2Cl2 was added EDCl (96 mg), aniline (0.1 mL) and Hunig's base (0.1 mL). The solution was stirred at ambient temperature for 3 hours and after concentration and flash chromatography on silica with a gradient of 10-25% EtOAc/toluene the amide was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.C1N=CN([C:29]([N:31]2[CH:35]=N[CH:33]=[CH:32]2)=[O:30])C=1.Cl.N1CC([OH:41])C1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:29]([N:31]3[CH2:32][CH:33]([OH:41])[CH2:35]3)=[O:30])=[C:16]2[N:15]=1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reactant: OC1CNC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12)N1CC(O)C1
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a DCM (1.0 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 50 mg, 0.16 mmol), was added CDI (39 mg, 0.24 mmol) at ambient temperature in one portion. After stirring two hours, azetidin-3-ol hydrochloride (35 mg, 0.32 mmol) [purchased from Oakwood] was added in one portion, followed by addition of DIEA (0.083 mL, 0.48 mmol). After stirring for 5 minutes, the reaction was concentrated and directly purified by reverse-phase column chromatography, eluting with 5 to 48% acetonitrile/water to yield the final product as a yellowish foamy powder (66 mg, 100% yield). MS (apci) m/z=415.2 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([N+:15]([O-:17])=[O:16])=[C:8]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:5]=1[CH:6]=O)[CH3:2].[C:33]([O:39][CH2:40][CH3:41])(=[O:38])[CH2:34][C:35]([CH3:37])=O.C(O)(=O)C.N1CCCCC1.[CH3:52][CH2:53][O:54][C:55](/[CH:57]=[C:58](\[NH2:60])/[CH3:59])=[O:56]>C(O)CCC>[CH2:1]([O:3][C:4]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([N+:15]([O-:17])=[O:16])=[C:8]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:5]=1[CH:6]1[C:34]([C:33]([O:39][CH2:40][CH3:41])=[O:38])=[C:35]([CH3:37])[NH:60][C:58]([CH3:59])=[C:57]1[C:55]([O:54][CH2:53][CH3:52])=[O:56])[CH3:2]
Reactant: CCCCCCCCCCCCCCCc1c([N+](=O)[O-])cc([N+](=O)[O-])c(OCC)c1C=O
Reactant: CCOC(=O)CC(C)=O
Reactant: CCOC(=O)/C=C(/C)N
Solvent: C1CCNCC1
Solvent: CCCCO
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCc1c([N+](=O)[O-])cc([N+](=O)[O-])c(OCC)c1C1C(C(=O)OCC)=C(C)NC(C)=C1C(=O)OCC
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
2-Ethoxy-3,5-dinitro-6-pentadecyl benzaldehyde (3.73 g, 8.3 mmol) and ethyl acetoacetate (1.08 g, 8.3 mmol) were dissolved in n-butanol (20 mL). Acetic acid (0.5 g, 8.3 mmol) and piperidine (0.7 g, 8.3 mmol) were added and stirred at room temperature for 3-4 hrs. Ethyl-3-amino crotonate (1.08 g, 8.3 mmol) was then added and refluxed for 10 hrs. n-Butanol was evaporated and reaction mixture was washed with distilled water and extracted with dichloromethane (10 mL). Organic layer was dried over sodium sulfate, evaporated and compound was purified by column chromatography using silicagel (100-200 mesh) with hexane:EtOAc (94:6) solvent system to give diethyl 1,4-dihydro-4-(2′-ethoxy-3′,5′-dinitro-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[C:15]4[N:16]([N:25]=[CH:26][N:27]=4)[C:17]([C:20]4[CH:21]=[N:22][NH:23][CH:24]=4)=[CH:18][N:19]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5]OCC1.BrC1N2N=CN=C2C(NC2C=CC(N3CC[NH:48][CH2:47][C:46]3=[O:51])=CC=2)=NC=1.CC([O-])(C)C.[Na+]>CN(C=O)C.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>[NH:22]1[CH:21]=[C:20]([C:17]2[N:16]3[N:25]=[CH:26][N:27]=[C:15]3[C:14]([NH:13][C:10]3[CH:11]=[CH:12][C:7]([N:1]4[CH2:6][CH2:5][NH:48][CH2:47][C:46]4=[O:51])=[CH:8][CH:9]=3)=[N:19][CH:18]=2)[CH:24]=[N:23]1
Reactant: c1nc2c(Nc3ccc(N4CCOCC4)cc3)ncc(-c3cn[nH]c3)n2n1
Reactant: O=C1CNCCN1c1ccc(Nc2ncc(Br)n3ncnc23)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CNCCN1c1ccc(Nc2ncc(-c3cn[nH]c3)n3ncnc23)cc1

Procedure:
This compound may be prepared using methods as described for Compound 1, step 5 using 1-[4-(5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino)-phenyl]-piperazin-2-one (70 mg, 0.18 mmol) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (64 mg, 0.33 mmol), Pd(PPh3)4 (21 mg, 18 μmol) and NaOtBu (70 mg, 0.72 mmol) in 2 mL of 3:1 DMF/water. The reaction mixture is concentrated under vacuum and the residue is purified by silica gel column chromatography eluting with a gradient 99:1 to 90:10 DCM:NH3 (7M in MeOH). The title compound is isolated as a pale green solid (13 mg, 19%). 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 3.05 (2H, m), 3.42 (2H, s), 3.62 (2H, m), 7.32 (2H, d), 8.07 (2H, d), 8.26 (1H, s), 8.39 (1H, br s), 8.67 (1H, br s), 8.81 (1H, s), 10.05 (1H, s), 13.32 (1H, br s). LCMS: Rt 6.98 min (92.4%), m/z (APCI) 376 (M+H)+.