Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Si](C)(C)C)[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[C:14]([N+:24]([O-:26])=[O:25])=[C:15]2[S:23][CH2:22][CH2:21][N:16]2[C:17](=[O:20])[C:18]=1[CH3:19].[I:27]Cl.C(OC(=O)C)C>C(Cl)Cl.CCCCCC.F[B-](F)(F)F.[Ag+]>[F:1][C:2]1[CH:7]=[C:6]([I:27])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[C:14]([N+:24]([O-:26])=[O:25])=[C:15]2[S:23][CH2:22][CH2:21][N:16]2[C:17](=[O:20])[C:18]=1[CH3:19]
Reactant: ClI
Reactant: Cc1c(Nc2ccc([Si](C)(C)C)cc2F)c([N+](=O)[O-])c2n(c1=O)CCS2
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1c(Nc2ccc(I)cc2F)c([N+](=O)[O-])c2n(c1=O)CCS2
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
7-(2-Fluoro-4-trimethylsilanyl-phenylamino)-6-methyl-8-nitro-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (0.5 g, 1.27 mmol) in DCM (10 mL) was added to silver tetrafluoroborate (0.74 g, 3.81 mmol) in DCM (10 mL) previously degassed with nitrogen at −60° C. and the resulting mixture was stirred at −60° C. for 30 minutes. This was followed by the addition of iodine monochloride (1.3 mL, 1.399 mmol) and continued stirring for a further 30 minutes at −60° C. to −50° C. The reaction was monitored by TLC (50% ethylacetate in hexane). The reaction mixture was diluted with DCM, quenched with sodium thiosulphate solution, filtered through celite and the filtrate was extracted with DCM. The organic layer was washed with NH3 solution, brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (40% ethylacetate in hexane) afforded 0.45 g of the product (80% yield).
Reaction SMILES: S(=O)(=O)(O)O.N1C(N)=NC(N)=NC=1N.C1(N)NC(N)=NC(=[O:18])N=1.[C:24]1([NH2:32])[NH:31][C:29](=[O:30])[NH:28][C:26](=[O:27])[N:25]=1>>[NH:31]1[C:24](=[O:18])[NH:25][C:26](=[O:27])[NH:28][C:29]1=[O:30].[C:24]1([NH2:32])[NH:31][C:29](=[O:30])[NH:28][C:26](=[O:27])[N:25]=1
Reactant: Nc1nc(=O)nc(N)[nH]1
Agent: Nc1nc(=O)[nH]c(=O)[nH]1
Agent: Nc1nc(N)nc(N)n1
Agent: O=S(=O)(O)O
Product: O=c1[nH]c(=O)[nH]c(=O)[nH]1
Temperature: 160 °C
Yield: 93.9 %

Procedure:
333 kg Of 70% strength sulfuric acid is initially introduced into an enamel kettle and 100 kg of a waste melamine which contains ammeline and ammelide and has a melamine content of about 95% is added, with stirring, the temperature rising to about 90° C. This suspension is heated to the boiling point of 132° C. and is then heated up to 160° C. in the course of one hour, whilst distilling off water. The suspension is kept at the boil under reflux, at 160° C. for 4 hours and 310 l. of water is then added, the temperature falling to 120° C. After cooling to room temperature, the cyanuric acid is centrifuged off, washed and suspended in water, using a weight ratio of 1 part of cyanuric acid to 2 parts of water, the suspension is stirred for one hour at room temperature and the cyanuric acid is centrifuged off and washed. About 96 kg. (93.9%) of a cyanuric acid with an ammelide content of less than 0.3% is obtained. The ammonium bisulfate impurity amounts to about 0.03%. Melamine and ammeline are not detectable.
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:7]([CH2:17][C:18]2([OH:24])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH2:6][CH2:5]1)=[N+]=[N-]>[Pd].CO>[NH2:1][C@H:4]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[C@@H:7]([CH2:17][C:18]2([OH:24])[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])CC[C@@H]1CC1(O)CCOCC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H](N)CC[C@@H]1CC1(O)CCOCC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
The mixture of tert-butyl cis-5-azido-2-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidine-1-carboxylate (253 mg, 0.743 mmol, step 4 of Example 2) and 10 wt. % palladium on carbon (50 mg) in methanol (5 mL) was stirred under hydrogen (4 atom) at room temperature for 7 h. The mixture was filtered through a pad of Celite washing with methanol and the filtrate was concentrated to give 244 mg (quant.) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[C:11](C(O)=O)=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].S(=O)(=O)(O)O.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O>[CH2:1]([C:3]1[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nn2ccccc2c1C(=O)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1cc2ccccn2n1
Temperature: 70 °C
Yield: 80.8 %

Procedure:
2-Ethylpyrazolo[1,5-a]pyridine-3-carboxylic acid (4.1 g, 22 mmol) was stirred in water (100 mL) and sulfuric acid (2.5 mL) was added. The mixture was heated at 70° C. for 2 h and cooled to 20° C. The mixture was poured into ethyl acetate and neutralized with saturated sodium bicarbonate. The extracts were separated and the aqueous layer was extracted with ethyl acetate. The combined extracts were dried (sodium sulfate) and evaporated to give the desired compound (2.6 g, 82%). LCMS for C9H11N2 (M+H)+: m/z=147.1. 1H NMR (300 MHz, DMSO-d6): δ 8.52 (m, 1 H), 7.57 (m, 1 H), 7.11 (m, 1 H), 6.75 (m, 1 H), 6.38 (s, 1 H), 2.73 (m, 2 H), 1.22 (m, 3 H).
Reaction SMILES: [CH2:1]([Li])CCC.[Br-].[PH4+].[C:8]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH2:21][CH2:22][CH2:23][CH3:24])=[N:15][C:14]2=[O:25])(=O)[CH3:9]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:21]([C:16]1[NH:17][C:18]2[C:13]([C:14](=[O:25])[N:15]=1)=[CH:12][C:11]([C:8]([CH3:1])=[CH2:9])=[CH:20][CH:19]=2)[CH2:22][CH2:23][CH3:24]
Reactant: [Li]CCCC
Reactant: CCCCc1nc(=O)c2cc(C(C)=O)ccc2[nH]1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [PH4+]
Solvent: C1CCOC1
Product: C=C(C)c1ccc2[nH]c(CCCC)nc(=O)c2c1
Temperature: -78 °C
Reaction time: 24 h

Procedure:
To a suspension of 3.66 g of methyltriphenylphosphonium bromide in 30 ml of dry tetrahydrofuran, cooled to -78° C., is added dropwise 5.9 ml of a 1.73M solution of n-butyllithium in hexanes. Following complete addition, the reaction mixture is allowed to warm to room temperature and stirred for 15 minutes, until all the phosphonium bromide is dissolved. The reaction mixture is then recooled to -78° C. and a suspension of 6-acetyl-2-butyl-4(1H)-quinazolinone in 15 ml of dry tetrahydrofuran is added. The reaction is allowed to warm to room temperature and stirred for 24 hours followed by quenching with saturated ammonium chloride solution. After diluting with 10 ml of water, the aqueous layer is extracted with chloroform and the combined organics dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel, eluting with 1:2 ethyl acetate-hexanes to give 0.23 g of the desired product as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[N:27]=2)[CH:8]=1)=[O:6]
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Reactant: FC(F)(F)c1cccc(CBr)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(C(F)(F)F)n3)c3ccccc3c2=O)cc1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Compound 4xx was prepared following the procedure described in Step 3 of Example 1 using 55 mg (0.20 mmol) of 3-(3,4-dimethyl-benzoyl)-1H-quinolin-4-one, 10 mg (0.26 mmol) of 60% sodium hydride and 62 mg (0.26 mmol) of 2-bromomethyl-6-trifluoromethyl-pyridine, and 1.7 mL N,N-dimethylformamide and stirring the reaction mixture for 6 h at rt. The crude product was purified by flash chromatography using 20-75% ethyl acetate in hexane yielded to provide 45 mg of the product as white solid: LC-MSD, m/z for C25H19F3N2O2 [M+H]+: 437.3; Reverse phase HPLC gradient, 20-95% acetonitrile with 0.1% TFA in 4 minutes, retention time=2.8 min; 1H NMR (400 MHz, CDCl3): δ 2.25 (s, 3H), 2.3 (s, 3H), 5.6 (s, 2H), 7.1-7.2 (m, 1H), 7.2-7.3 (m, 1H), 7.3-7.4 (m, 2H), 7.5-7.65 (m, 15 4H), 7.8-7.9 (m, 1H), 8.35 (s, 1H), 8.4-8.5 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]([C:22]2[C:23](=[O:35])[N:24]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[N:25]=[CH:26][CH:27]=2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[CH3:36][N:37]1[CH:41]=[CH:40][N:39]=[C:38]1[Sn](CCCC)(CCCC)CCCC>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.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]([C:22]2[C:23](=[O:35])[N:24]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[N:25]=[CH:26][CH:27]=2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:38]3[N:37]([CH3:36])[CH:41]=[CH:40][N:39]=3)[S:17][C:10]=12
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=O)c4ccnn(-c5ccc(F)cc5)c4=O)cc3F)c2s1
Temperature: 100 °C
Yield: 75.2 %

Procedure:
A round-bottomed flask was charged with N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (230 mg, 0.382 mmol), 1-methyl-2-(tributylstannyl)-1H-imidazole (850.3 mg, 2.29 mmol), tetrakis(triphenylphosphine)palladium (88.25 mg, 0.0764 mmol) and toluene (25 mL). The reaction mixture was stirred at 100° C. until LC-MS showed that the starting material had been consumed (4 hours). Then the reaction was cooled to room temperature and partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford product (159.8 mg, 75.2%). LRMS (APCI pos): >99% purity, 254 nm, m/e 557 (M+1). 1H NMR (400 MHz, CDCl3) δ 11.82 (s, 1H), 8.50 (m, 1H), 8.41 (m, 1H), 8.22 (m, 1H), 7.98 (m, 1H), 7.46-7.42 (m, 4H), 7.40 (m, 2H), 7.24 (m, 2H), 6.98 (d, 1H), 6.54 (m, 1H), 3.84 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[O-][Si]([O-])=O.[Mg+2]>CO.Cl[Cu]>[C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc([N+](=O)[O-])cc21
Agent: Cl[Cu]
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCc2ccc(N)cc21
Reaction time: 1 h
Yield: 72.9 %

Procedure:
Add KBH4 (1.59 g, 29.4 mmol) slowly to a mixture of (6-nitro-indan-1-yl)carbamic acid tert-butyl ester (1.17 g, 4.2 mmol) and CuCl (1.25 g, 12.6 mmol) in 50 mL of methanol at 0° C. over 15 min. Stir the mixture for 1 h and then pass through a Florisil pad. Evaporate the THF and dissolve the solid in EtOAc. Wash the mixture with water, dry, and concentrate to afford 0.76 g (73%) of (6-aminoindan-1-yl)carbamic acid tert-butyl ester. 1H NMR (CDCl3) d 6.99 (1H, d, J=8.0 Hz), 6.65 (1H, s), 6.56 (1H, dd, J=8.0 and 2.0 Hz), 5.09 (1H, q, J=8.0 Hz), 4.70 (1H, br d, J=7.2 Hz), 3.60 (2H, s), 2.86-2.79 (1H, m), 2.75-2.67 (1H, m), 2.58-2.47 (1H, m), 1.78-1.69 (1H, m), 1.48 (3H, s). 2.86-2.79 (1H, m), 2.75-2.67 (1H, m), 2.58-2.47 (1H, m), 1.78-1.69 (1H, m), 1.48 (3H, s).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[CH:16][CH:15]=1)([O-:13])=[O:12].CCN(CC)CC>C(Cl)Cl>[N+:11]([C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][CH2:22][CH:23]=[O:24])=[CH:18][CH:19]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(CCCCO)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=CCCCc1ccc([N+](=O)[O-])cc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a cooled solution (−70° C.) of oxalyl chloride (2.0 M in CH2Cl2, 14.1 mL, 28.2 mmol), dimethylsulfoxide (DMSO) (4.40 g, 56.32 mmol) in CH2Cl2 (20 mL) was added dropwise. The resulting reaction mixture was then stirred for 30 minutes at −70° C. under a nitrogen atmosphere. A solution of 4-(4-nitrophenyl)butan-1-ol (5.00 g, 25.6 mmol) in CH2Cl2 (3 mL) was added dropwise, and the reaction mixture was stirred for 1 hour at −70° C. Et3N (16 mL, 115 mmol) was added, and the reaction mixture was then allowed to gradually warm to room temperature and stir for 30 minutes. The mixture was then quenched with H2O and extracted with EtOAc. The organic layers were washed with 0.1N HCl solution, H2O, brine, dried (Na2SO4), filtered, and concentrated in vacuo to give a lightly brown oil. Purification by flash chromatography (silica gel, 50% EtOAc/hexane) yielded 3.20 g (16.56 mmol, 65%) of the desired product.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:3].[CH:11]1[C:17]([NH2:18])=[N:16][C:14](=[O:15])[N:13]([C@@H:19]2[O:23][C@H:22]([CH2:24][OH:25])[C@@H:21]([OH:26])[C:20]2([F:28])[F:27])[CH:12]=1.Cl>>[F:28][C:20]1([F:27])[C@H:21]([OH:26])[C@@H:22]([CH2:24][OH:25])[O:23][C@H:19]1[N:13]1[CH:12]=[CH:11][C:17]([NH:18][C:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:3])=[N:16][C:14]1=[O:15]
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Reactant: CCCCCCOC(=O)Cl
Agent: Cl
Product: CCCCCCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Yield: 99 %

Procedure:
Using Method A and hexyl chloroformate, gemcitabine hydrochloride was converted to 36 (white solid, 99% yield): 1H NMR (200 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.23-8.28 (d, 1H), 7.11-7.15 (d, 1H), 6.34-6.37 (d, 1H), 6.16-6.24 (t, 1H), 5.34 (s, 1H), 4.21-4.26 (m, 1H), 4.10-4.18 (t, 2H), 3.65-3.94 (m, 3H), 1.60-1.67 (t, 2H), 1.31-1.33 (t, 6H), 0.87-0.94 (t, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]([OH:28])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH:9]=[CH:10][CH:11]=1.C1C(=O)N([O:36][C:37]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:45]([CH2:47][CH2:48][CH2:49][CH2:50][CH:51]2[S:55][CH2:54][CH:53]3[NH:56][C:57]([NH:59][CH:52]23)=[O:58])=[O:46])=O)C(=O)C1>CN(C=O)C.CO.C(Cl)(Cl)Cl>[OH:28][C:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][C:37](=[O:36])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:45](=[O:46])[CH2:47][CH2:48][CH2:49][CH2:50][CH:51]2[CH:52]3[CH:53]([NH:56][C:57](=[O:58])[NH:59]3)[CH2:54][S:55]2)[CH:7]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1
Reactant: NCCCOc1cccc(C(O)(c2ccccc2)c2ccc(C(=O)O)cc2)c1
Reactant: O=C(CCCCC1SCC2NC(=O)NC21)NCCCCCC(=O)ON1C(=O)CCC1=O
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(CCCCC1SCC2NC(=O)NC21)NCCCCCC(=O)NCCCOc1cccc(C(O)(c2ccccc2)c2ccc(C(=O)O)cc2)c1

Procedure:
A mixture of Trityl amino acid (4, 100 mg, 0.26 mM) and Biotin-X-NHS (113 mg, 0.25 mM) was stirred at room temperature in 3 mL of anhydrous DMF for overnight. After that DMF was removed under high vacuum and the residue obtained was passed through silica gel column using 50% CH3OH/CHCl3 as a solvent. Evaporation of the solvent yielded biotinylated trityl acid 5. (97.8%). Mass: 739 (M Na+), 715 (M-H).
Reaction SMILES: [CH:1]1([N:4]([CH:32]2[CH2:34][CH2:33]2)[C:5]([C:7]2[N:29]([CH2:30][CH3:31])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][C:22]([C:26](O)=[O:27])=[C:23]([CH3:25])[N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:35][NH:36][CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC=CC=1C>CN(C=O)C>[CH:32]1([N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]([C:7]2[N:29]([CH2:30][CH3:31])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][C:22]([C:26]([N:36]([CH3:37])[CH3:35])=[O:27])=[C:23]([CH3:25])[N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:33][CH2:34]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C)c(C(=O)O)s3)nc21
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C)c(C(=O)N(C)C)s3)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.2 %

Procedure:
A mixture of 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-4-methylthiazole-5-carboxylic acid (example 50B, 51 mg, 0.106 mmol), dimethylamine (40% in water, 0.027 mL, 0.213 mmol), HATU (52.6 mg, 0.138 mmol) and 2,6-lutidine (0.025 mL, 0.213 mmol) in DMF (1 mL) was stirred at room temperature for 2 h. Solvent was evaporated and the residue was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 2-8% methanol/dichloromethane). The product was further purified by preparative HPLC. 2-(7-(Dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-N,N,4-trimethylthiazole-5-carboxamide (17 mg, 0.032 mmol, 30.0% yield) was obtained as a off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[NH:24][C:23]3[CH:25]=[CH:26][CH:27]=[C:28]([C:29](O)=[O:30])[C:22]=3[N:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:32]1[CH:36]=[CH:35][N:34]=[C:33]1[NH2:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[S:32]1[CH:36]=[CH:35][N:34]=[C:33]1[NH:37][C:29]([C:28]1[C:22]2[N:21]=[C:20]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][CH:10]3[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]3)[NH:24][C:23]=2[CH:25]=[CH:26][CH:27]=1)=[O:30]
Reactant: Nc1nccs1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2-c2nc3c(C(=O)O)cccc3[nH]2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2-c2nc3c(C(=O)Nc4nccs4)cccc3[nH]2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.7 %

Procedure:
To a solution of 2-(2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yloxy)phenyl)-1H-benzo[d]imidazole-4-carboxylic acid (31; 150 mg, 0.36 mmol), thiazol-2-amine (4; 35.5 mg, 0.36 mmol), and HATU (202 mg, 0.53 mmol) in DMF (5 mL) was added DIEA (137 mg, 1.06 mmol). The mixture was stirred at room temperature for 18 h. It was then diluted with water (20 mL) and stirred for 30 min. The precipitate was collected by filtration, and then purified by column chromatography to give 85 mg of the title compound 32 (yield: 48%). MS (ESI) calcd for C26H27N5O4S: 505.18; found: 506 [M+H].
Reaction SMILES: FC1C=C(F)C=CC=1NC1C=CC(C(C2C=C(N3C=C(CCO)N=N3)C=CC=2C)=O)=C(C)C=1.Br[C:35]1[CH:40]=[CH:39][C:38]([C:41]([C:43]2[CH:48]=[C:47]([N:49]3[CH:53]=[C:52]([CH2:54][CH2:55][OH:56])[N:51]=[N:50]3)[CH:46]=[CH:45][C:44]=2[CH3:57])=[O:42])=[C:37]([Cl:58])[CH:36]=1.[F:59][C:60]1[CH:65]=[CH:64][C:63]([F:66])=[CH:62][C:61]=1[NH2:67]>>[Cl:58][C:37]1[CH:36]=[C:35]([NH:67][C:61]2[CH:62]=[C:63]([F:66])[CH:64]=[CH:65][C:60]=2[F:59])[CH:40]=[CH:39][C:38]=1[C:41]([C:43]1[CH:48]=[C:47]([N:49]2[CH:53]=[C:52]([CH2:54][CH2:55][OH:56])[N:51]=[N:50]2)[CH:46]=[CH:45][C:44]=1[CH3:57])=[O:42]
Reactant: Cc1ccc(-n2cc(CCO)nn2)cc1C(=O)c1ccc(Br)cc1Cl
Reactant: Nc1cc(F)ccc1F
Agent: Cc1cc(Nc2ccc(F)cc2F)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Product: Cc1ccc(-n2cc(CCO)nn2)cc1C(=O)c1ccc(Nc2cc(F)ccc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 148, using compound 471 (0.13 mmol) and 2,5-difluoro-phenylamine (0.13 mmol). The crude product was purified by flash chromatography using MeOH/DCM 1:20 as the eluent to afford the title compound. 13C NMR (CDCl3) δ 194.9, 158.8 (d), 150.2 (d), 146.3 (d), 140.4, 138.4, 135.2, 134.8, 133.5, 132.7, 129.9, 122.5, 121.0, 119.9, 117.9, 116.6 (dd), 114.5, 109.5 (dd), 107.1 (d), 61.6, 28.7, 20.1
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH:9]2[CH2:14][CH:13]3[CH2:15][CH2:16][N:10]2[CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CN(CCN(C)C)C.Br[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CCCCCC.C1CCCCC1>[C:17]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:8][CH:9]2[CH2:14][CH:13]3[CH2:15][CH2:16][N:10]2[CH2:11][CH2:12]3)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCCCCBr
Reactant: c1ccc(C(CC2CC3CCN2CC3)c2ccccc2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCCCC1
Product: CCCCCC(CC1CC2CCN1CC2)(c1ccccc1)c1ccccc1

Procedure:
Following the procedure which is described in Example 4, 2.91 parts of 2-(2,2-diphenylethyl)-1-azabicyclo[2.2.2]octane in 40 parts by volume of cyclohexane, 5.1 parts by volume of a 2.17 M solution of butyl lithium in hexane are reacted with 1.5 parts by volume of TMEDA and 1.65 parts of 1-bromopentane to provide 2-(2,2-diphenylheptyl)-1-azabicyclo[2.2.2]octane. This compound is then treated with 0.570 parts of maleic acid to give 2-(2,2-diphenylheptyl)-1-azabicyclo[2.2.2]octane maleate, melting at about 177°-178.5° C. This compound is represented by the following structural formula ##STR11##
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]2[NH:16][C:15](=[O:17])[CH2:14][N:9]2[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>C(O)C.CN(C)C=O>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:4]([C:6]2[N:7]=[C:8]3[NH:16][C:15](=[O:17])[CH2:14][N:9]3[C:10](=[O:13])[C:11]=2[OH:12])=[O:5])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC(=O)N2
Reactant: NCc1ccc(F)cc1
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C1Cn2c(nc(C(=O)NCc3ccc(F)cc3)c(O)c2=O)N1
Yield: 34.4 %

Procedure:
A mixture of intermediate 5, 6-hydroxy-2,5-dioxo-1,2,3,5-tetrahydro-imidazo[1,2-a]pyrimidine-7-carboxylic acid ethyl ester, (0.035 g, 0.146 mmol) and 4-fluorobenzylamine (0.11 g, 0.88 mmol) in anhydrous ethyl alcohol (5 ml) and N,N-dimethylformamide (2 ml) was heated under reflux for 18 h. The solvent was then evaporated in vacuo and the residue was partitioned between ethyl acetate and 0.1 N hydrochloric acid. The organic phase was washed with water and brine then dried over anhydrous sodium sulfate. Evaporation of the solvent and recrystallization of the resulting solid from ethanol gave 0.016 g (34% yield) of the title amide as white crystals. 1HNMR 400 MHz (DMSO-d6) δ (ppm): 4.46 (4H, broad s, 2×CH2), 7.17 (2H, m, aromatics), 7.36 (2H, m, aromatics), 9.07 (1H, broad t, NH), 11.8–12.4 (2H, broad, OH and NH). MS (ESI+) m/z 319 [M+H+].