Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Br[CH:10]([CH3:16])[C:11]([CH:13]1[CH2:15][CH2:14]1)=O.C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH3:16])=[C:11]([CH:13]3[CH2:15][CH2:14]3)[N:8]=2)[N:7]=1
Reactant: CC(Br)C(=O)C1CC1
Reactant: Nc1ccc(Br)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C2CC2)nc2ccc(Br)nn12
Temperature: 80 °C
Reaction time: 16 h
Yield: 75.9 %

Procedure:
To a solution of 6-bromopyridazin-3-amine (1.0 g) in DMA (10 ml) were added 2-bromo-1-cyclopropylpropan-1-one (2.04 g) and NaHCO3 (0.966 g) at room temperature, and the mixture was stirred at 80° C. for 16 h. The mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried over MgSO4, concentrated in vacuo, and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (1.10 g) as yellow crystals.
Reaction SMILES: C(OC([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:11][CH:10]([CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)[C:9]1=[O:38])=O)(C)(C)C.[I-:39].[Na+]>C(#N)C>[C:17]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:19][C:14]([CH2:13][C@H:12]2[NH:8][C:9](=[O:38])[CH:10]([CH2:26][I:39])[CH2:11]2)=[CH:15][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2C[C@@H](Cc3ccc(-c4ccccc4)cc3)N(C(=O)OC(C)(C)C)C2=O)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=C1N[C@H](Cc2ccc(-c3ccccc3)cc2)CC1CI

Procedure:
122 mg (3R/S,5S)-5-Biphenyl-4-ylmethyl-2-oxo-3-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (11-a, R1=Boc, R4=Tosyl) prepared according to Example 49, Method 2 is added to acetonitrile (3 ml). Sodium iodide (105 mg) is then added to the mixture. The resulting mixture is heated at reflux overnight. The mixture is then concentrated under reduced pressure. Purification by column chromatography, eluting with ethyl acetate-heptane (1:1) gives (3R/S,5S)-5-biphenyl-4-ylmethyl-3-iodomethyl-pyrrolidin-2-one (12-a, R1=H, R5=I). 1H NMR (CDCl3): 2.13 (2H), 2.69 (2H), 2.82 (1H), 3.28 (1H), 3.35 (1H), 3.85 (1H), 5.84 (1H), 7.17 (2H), 7.28 (1H), 7.37 (2H), 7.49 (4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][N:15]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16]2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][N:15]4[CH2:19][CH2:18][CH:17]([C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH2:16]4)=[CH:6][CH:7]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CN1CCC(c2ccccc2)C1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN4CCC(c5ccccc5)C4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 5-(4-bromo-phenyl)-3-methyl-4-(3-phenyl-pyrrolidin-1-ylmethyl)-isoxazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]([CH3:54])[C:3](=[O:53])[CH2:4][C@@H:5]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41]([O:43]C(C)(C)C)=[O:42])=[CH:35][C:34]=3[O:48][CH3:49])=[CH:29][CH:28]=2)=[O:26])(=[O:23])=[O:22])=[CH:17][C:16]=1[N+:50]([O-:52])=[O:51])[CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)(C(F)(F)F)=O.ClCCl>[CH3:54][N:2]([CH3:1])[C:3](=[O:53])[CH2:4][C@@H:5]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[CH:35][C:34]=3[O:48][CH3:49])=[CH:29][CH:28]=2)=[O:26])(=[O:22])=[O:23])=[CH:17][C:16]=1[N+:50]([O-:52])=[O:51])[CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1cc(CCC(=O)OC(C)(C)C)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(N[C@@H](CSc3ccccc3)CC(=O)N(C)C)c([N+](=O)[O-])c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(CCC(=O)O)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(N[C@@H](CSc3ccccc3)CC(=O)N(C)C)c([N+](=O)[O-])c2)cc1

Procedure:
A mixture of Example 126B in TFA (20 mL) and dichloromethane (20 mL) at room temperature was stirred for 1 hour and concentrated to provide the desired product. MS (ESI (+)) m/e 721 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[C@@H:7]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)#[N:2]>C(O)(=O)C.C(O)C.[Pt]>[NH2:2][CH2:1][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[C@@H:7]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccccc1CN[C@H]1CCCN(CCCC#N)[C@H]1c1ccccc1
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccccc1CN[C@H]1CCCN(CCCCN)[C@H]1c1ccccc1
Reaction time: 4 h
Yield: 83.3 %

Procedure:
The title compound of Example 93 (1.9 g) was dissolved in 10 ml of acetic acid in a bottle. To the system was added 1.9 g of 5% platinum/carbon (60% water), and the mixture was shaken under hydrogen (40 p.s.i.) for 4 hours. The mixture was diluted with ethanol, filtered through diatomaceous earth (Celite (trademark)) and the filtrate was concentrated. Saturated aqueous sodium bicarbonate was added to the residue until the pH of the mixture was ca. 8, and the mixture was extracted with chloroform. The chloroform extracts were dried (sodium sulfate) and concentrated to obtain 1.6 g of the title compound as an oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[N:7][OH:8])[CH2:3][CH2:2]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[F:26][C:27]([F:33])([F:32])[CH2:28][C:29]([OH:31])=[O:30]>>[F:26][C:27]([F:33])([F:32])[CH2:28][C:29]([O:31][C:4]1([N:7]=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:30]
Reactant: ON=C1CCOCC1
Reactant: O=C(O)CC(F)(F)F
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: O=NC1(OC(=O)CC(F)(F)F)CCOCC1

Procedure:
4-Nitrosotetrahydro-2H-pyran-4-yl 3,3,3-trifluoropropanoate was prepared from tetrahydro-pyran-4-one oxime, lead tetraacetate and 3,3,3-trifluoropropionic acid using conditions of General Method 3. 1H NMR (360 MHz, chloroform-d) δ 3.94-4.17 (2H, m), 3.54-3.79 (2H, m), 3.37 (2H, q), 2.23-2.43 (2H, m), 1.65-1.96 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]1>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[N:10]=2)=[CH:4][C:5]([NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]2)=[N:6][CH:7]=1
Reactant: Fc1cc(-c2nc(F)ccc2F)c(Cl)cn1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(-c3nc(F)ccc3F)c(Cl)cn2)CC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of 5′-chloro-2′,3,6-trifluoro-2,4′-bipyridine (95 mg, 0.388 mmol) in DMSO (2.5 mL) was added trans-1,4-diaminocyclohexane (177 mg, 1.55 mmol). The mixture was stirred at 90° C. for 2 hr. The cooled reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (Na2SO4), filtered, and concentrated to give 137 mg of crude trans-N1-(5′-chloro-3,6-difluoro-2,4′-bipyridin-2′-yl)cyclohexane-1,4-diamine which was used without further purification. LCMS (m/z): 339.0 (MH+), retention time=0.54 min
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([S:13]([N:16]2[C:20]3=[N:21][CH:22]=[C:23]([OH:25])[CH:24]=[C:19]3[CH:18]=[C:17]2[C:26]([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:43]([O:45][C:46](=[O:51])[C:47](Br)([CH3:49])[CH3:48])[CH3:44]>CN(C)C=O.C(OCC)(=O)C>[CH2:43]([O:45][C:46](=[O:51])[C:47]([O:25][C:23]1[CH:24]=[C:19]2[CH:18]=[C:17]([C:26]([C:33]3[CH:34]=[CH:35][C:36]([S:39]([CH3:42])(=[O:40])=[O:41])=[CH:37][CH:38]=3)=[CH:27][CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[N:16]([S:13]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)(=[O:14])=[O:15])[C:20]2=[N:21][CH:22]=1)([CH3:49])[CH3:48])[CH3:44]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(O)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
Potassium carbonate (828 mg, 5.99 mmol) was added to a solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-ol (prepared as in Example 13, 1.6 g, 3.07 mmol) in N,N-dimethylformamide (4.0 mL) at room temperature. The mixture was stirred for 30 min at room temperature and then 2-bromo-2-methyl-propionic acid ethyl ester (0.48 mL, 3.21 mmol) was added. The mixture was heated at 80° C. for 1 h. The resulting mixture was diluted with ethyl acetate (150 mL), washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 33% ethyl acetate/hexanes) afforded 2-{1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-2-methyl-propionic acid ethyl ester (1.34 g, 68.7%) as a light yellow solid: LC/MS m/e calcd for C33H36N2O7S2 [M+H]+ 637.79, observed 637.5.
Reaction SMILES: [F:1][C:2](F)=[CH:3][CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][CH:13](/[CH:16]=[CH:17]/[CH3:18])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1.C1(C)C=CC=CC=1.[H-].[H-].COCCO[Al+]OCCOC.[Na+].Cl>C1(C)C=CC=CC=1>[F:1]/[CH:2]=[CH:3]/[CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][CH:13](/[CH:16]=[CH:17]/[CH3:18])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1
Reactant: C/C=C/C1CCC(C2CCC(C=C(F)F)CC2)CC1
Agent: COCCO[Al+]OCCOC
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: C/C=C/C1CCC(C2CCC(/C=C/F)CC2)CC1

Procedure:
Compound (1-B) (5.0 g) obtained in the above operation was dissolved in toluene (50 ml), and a 65% sodium bis(2-methoxyethoxy)aluminum dihydride toluene solution (8.0 ml) was added dropwise. After completion of the reaction, 1N hydrochloric acid was added, and extraction was carried out with toluene. An organic layer was washed with a saturated aqueous solution of sodium chloride, a saturated aqueous solution of sodium hydrogencarbonate and water, and then the resultant solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and thus a colorless oily matter was obtained. The resultant material was subjected to silica gel column chromatography (heptane) and recrystallization at a low temperature by using Solmix A-11 (registered trademark) (Japan Alcohol Trading Co., Ltd.), and thus compound (1-1) was obtained as a colorless oily matter (1.2 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[NH2:23]>>[CH3:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: COCC1COc2cc3ncnc(Cl)c3cc2O1
Reactant: Cc1cc(C)cc(N)c1
Product: COCC1COc2cc3ncnc(Nc4cc(C)cc(C)c4)c3cc2O1
Yield: 28.5 %

Procedure:
The titled compound (10 mg, 29%, m.p. 268-270° C.) was prepared in a similar manner as in Example 8, except for employing 4-chloro-7-methoxymethyl-[1,4]dioxano[2,3-g]quinazoline (26 mg, 0.1 mmol) and 3,5-dimethylaniline (24 mg, 0.2 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].CCN(CC)CC.[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH3:16][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:31]([NH:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:32]
Reactant: O=C=Nc1ccccc1
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To a stirred solution of tert-butyl 4-amino-3-methylphenylacetate (1.20 g, 5.42 mmol) and Et3N (830 ml, 5.95 mmol) in THF (10 ml) was added phenyl isocyanate (650 ml, 5.98 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to a small volume and diluted with n-hexane. Resulting precipitate was collected under a reduced pressure and the filtrate was washed with n-hexane to give tert-butyl 3-methyl4-(N′-phenylureido)phenylacetate (1.12 g, 61%) as a white crystalline powder. mp 143–145° C.; 1H-NMR (CDCl3) δ 1.47 (s, 9 H), 2.09 (s, 3 H), 3.47 (s, 2 H), 6.44 (s, 1 H), 7.01–7.07 (m, 4 H), 7.16–7.27 (m, 2 H), 7.30–7.33 (m, 2 H), 7.45–7.47 (m, 1 H).
Reaction SMILES: Br[C:2]1[C:3]([C@@H:8]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:26][C:27]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[C:32]2[C:28]=1[C:29]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])=[N:30][N:31]2[CH3:45]>O1CCOCC1.C([O-])(O)=O.[Na+].C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl>[Cl:26][C:27]1[CH:35]=[CH:34][C:33]([C:2]2[C:3]([C@@H:8]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:9][C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=3)=[N:4][CH:5]=[CH:6][CH:7]=2)=[C:32]2[C:28]=1[C:29]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])=[N:30][N:31]2[CH3:45]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1ncccc1Br
Reactant: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(B3OC(C)(C)C(C)(C)O3)c21
Agent: Cl[Pd]Cl
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3cccnc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)OC(C)(C)C)c21
Temperature: 150 °C

Procedure:
(S)-tert-butyl (1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (1.0 g, 2.42 mmol), N-(4-chloro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)methanesulfonamide (1.12 g, 2.90 mmol), and PdCl2[P(cy)3]2 (89.0 mg, 0.121 mmol) were suspended in 1,4-dioxane (108 mL) and 1.0 M aqueous NaHCO3 (36 mL). The reaction mixture was degassed by bubbling argon for 5 minutes then sealed and heated 150° C. for 15 minutes in a microwave reactor. Upon cooling, the reaction mixture was diluted with water and extracted with three portions of EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated in vacuo, and purified by silica gel column chromatography, eluting with 0-100% EtOAc in hexanes to give the title compound. MS (m/z) 591.72 [M+H]+.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9](=[N:30]O)[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([N:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:29])[CH2:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]2)[CH:11]=1>>[CH3:26][C:25]([CH3:28])([CH3:27])[CH2:24][CH2:23][C:22]([N:19]1[CH2:20][CH2:21][N:16]([C:12]2[CH:11]=[C:10]([C:9]3[N:30]=[C:5]([CH3:6])[O:7][N:8]=3)[CH:15]=[CH:14][N:13]=2)[CH2:17][CH2:18]1)=[O:29]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)CCC(=O)N1CCN(c2cc(C(N)=NO)ccn2)CC1
Product: Cc1nc(-c2ccnc(N3CCN(C(=O)CCC(C)(C)C)CC3)c2)no1

Procedure:
Acetic anhydride (2 mL) was added to 1-{4-[amino(hydroxyimino)methyl]pyridin-2-yl}-4-(4,4-dimethylpentanoyl)piperazine (104 mg) obtained in Example 56-1), heated under reflux for 2 hours, then the excess acetic anhydride was evaporated away, the residue was diluted with ethyl acetate, washed with aqueous saturated sodium hydrogencarbonate solution and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (hexane/ethyl acetate=1/1) to obtain 14.5 mg of the entitled compound as a yellow solid.
Reaction SMILES: C(OC([CH:6]1[CH2:33][CH2:32][CH2:31][N:9]2[C:10]3[C:15]([C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[C:8]2[C:7]1=[O:34])=[CH:14][C:13]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:12][CH:11]=3)=O)C.[Cl-].[Na+]>CS(C)=O.O.C(OCC)(=O)C>[CH2:24]([O:23][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]1[CH2:31][CH2:32][CH2:33][CH2:6][C:7](=[O:34])[C:8]1=[C:16]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)C1CCCn2c(c(-c3ccccc3)c3cc(OCc4ccccc4)ccc32)C1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: O=C1CCCCn2c1c(-c1ccccc1)c1cc(OCc3ccccc3)ccc12

Procedure:
An amount of 2.8 g (6.17 m mole) of 2-benzyloxy-7,8,9,10-tetrahydro-10-oxo-11-phenyl-6H-9-azepino[1,2-a]indole carboxylic acid ethylester and 0.36 g (6.1 m mole) of sodium chloride were refluxed for four hours in 3.5 ml of dimethylsulfoxide and 0.35 ml of water. After cooling, the mixture was taken up in ethyl acetate, dried over sodium sulfate, suction filtered, and evaporated. The residue was triturated with petroleum ether and suction filtered.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[Al](C)C.CCCCCC.[Br:19][CH2:20][CH2:21][C:22](OC)=[O:23].Cl>C1COCC1>[Br:19][CH2:20][CH2:21][C:22]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)=[O:23]
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)CCBr
Agent: C[Al](C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(CCBr)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
5.75 ml of 4-fluoroaniline (6.65 g, 59.88 mmol, 1 equivalent) were initially charged in 65 ml of THF, 33 ml of 2 M trimethylaluminium solution in hexane (65.87 mmol, 1.1 equivalents) were added at −78° C. and the mixture was stirred for 20 min, slowly warming to RT. At −20° C., this solution was added dropwise to a solution of 6.54 ml (10 g, 59.8 mmol, 1 equivalent) of methyl 3-bromopropanoate in 65 ml of THF and then stirred at RT for 3 h. At 0° C., the reaction solution was acidified carefully with 1 N aqueous hydrochloric acid solution and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated. This gave 12.6 g (67% of theory; purity 78%) of the title compound which was reacted further without purification.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:15](C(OC(C)(C)C)=O)[C:9]2=[N:10][CH:11]=[C:12]([OH:14])[CH:13]=[C:8]2[CH:7]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][Cl:33].[Cl-].[NH4+]>CC(=O)CC>[CH2:2]([O:3][C:4]([C:6]1[NH:15][C:9]2=[N:10][CH:11]=[C:12]([O:14][CH2:30][CH2:31][CH2:32][Cl:33])[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(O)cnc2n1C(=O)OC(C)(C)C
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1cc2cc(OCCCCl)cnc2[nH]1
Yield: 32.4 %

Procedure:
The suspension consistent of 0.5 g (2.4 mmol) 5-hydroxy-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (as prepared in WO 05/000849), 0.4 g (2.6 mmol) potassium carbonate and 0.29 ml (0.46 g, 2.9 mmol) 1-bromo-3-chloropropane in 10 ml 2-butanone was heated under reflux for 23 hours. The reaction mixture was poured on 10% aqueous ammonium chloride solution and was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was flash-chromatographed on silica gel with n-heptane:ethyl acetate (1:1 v/v) as eluant to give 0.22 g (32%) of the desired compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[CH3:19][NH2:20]>C1COCC1.O>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH2:11][NH:20][CH3:19])[S:8][C:6]=2[N:7]=1
Reactant: CN
Reactant: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Solvent: C1CCOC1
Solvent: O
Product: CNCc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Also, to a solution of 5-chloro-7-morpholinothiazolo[5,4-d]pyrimidine-2-carbaldehyde 44 in 50 mL THF was added 20 mL of 40% methylamine in water. The reaction mixture was stirred at room temperature under N2 for 24 hours. The solvents were removed in vacuo and the residue was dissolved in 50 mL MeOH and 50 mL THF and the NaBH4 added portion-wise. This reaction mixture was stirred at room temperature under N2 for 24 hours and complete reaction was confirmed by LCMS. The solvents were removed in vacuo and the crude product purified by flash chromatography (EtOAc/EtOH) to give of 1-(5-chloro-7-morpholinothiazolo[5,4-d]pyrimidin-2-yl)-N-methylmethanamine 61.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:19])=[C:4]([C:10]([CH3:18])=[C:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:39]([O:46][C:47]1[C:52]([CH2:53][N:54]([CH2:62][CH2:63]O)[C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[C:51]([CH3:65])[CH:50]=[C:49]([CH3:66])[N:48]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[CH2:39]([O:46][C:47]1[C:52]([CH2:53][N:54]([C:55]([O:56][C:57]([CH3:59])([CH3:58])[CH3:60])=[O:61])[CH2:62][CH2:63][O:19][C:3]2[C:2]([Br:1])=[CH:12][C:11]([O:13][S:14]([CH3:17])(=[O:15])=[O:16])=[C:10]([CH3:18])[C:4]=2[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:51]([CH3:65])[CH:50]=[C:49]([CH3:66])[N:48]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: Cc1cc(C)c(CN(CCO)C(=O)OC(C)(C)C)c(OCc2ccccc2)n1
Reactant: CCOC(=O)c1c(C)c(OS(C)(=O)=O)cc(Br)c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)c(OS(C)(=O)=O)cc(Br)c1OCCN(Cc1c(C)cc(C)nc1OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
A solution of ethyl 3-bromo-2-hydroxy-6-methyl-5-((methylsulfonyl)oxy)benzoate (116d, 593 mg, 1.5 mmol), triphenylphosphine (0.50 g, 1.9 mmol), and tert-butyl ((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)(2-hydroxyethyl)carbamate (Cpd LL, 0.54 g, 1.5 mmol) in tetrahydrofuran (12 mL) was cooled to 0° C. then diisopropyl azodicarboxylate (0.40 mL, 1.9 mmol) was added drop wise. The reaction was slowly warmed to room temperature and stirred overnight. The reaction was diluted with water (15 mL) and extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with brine (15 mL), dried over magnesium sulfate, concentrated under vacuum, and purified by column chromatography (20% EtOAc/Heptane) to give ethyl 2-(2-(((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)(tert-butoxycarbonyl)amino)ethoxy)-3-bromo-6-methyl-5-((methylsulfonyl)oxy)benzoate (116e, 0.58 g, 52% yield) as a white solid.