Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]2[CH:10]([CH2:11]2)[C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][Li].[Cl-].[NH4+]>O1CCCC1.CCOCC>[CH2:1]([N:8]1[C:13]([OH:14])([CH3:16])[CH:12]2[CH:10]([CH2:11]2)[C:9]1=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]C
Reactant: O=C1C2CC2C(=O)N1Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(O)C2CC2C(=O)N1Cc1ccccc1
Temperature: -78 °C

Procedure:
3-benzyl-3-azabicyclo[3.1.0]hexane-2,4-dione (Prepared as per U.S. Pat. No. 4,183,857, 1.9 gm, 9.5 mmol) was dissolved in 100 ml of tetrahydrofuran and cooled to −78° C. Methyllithium (10.5 ml of a 0.98M solution in ether, 10.2 mmol) was added dropwise. Saturated aqueous ammonium chloride was added to the cold reaction mixture. The mixture was then extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo to provide the title compound.
Reaction SMILES: [C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:20])[C@@H:12]2[C@H:15]([O:17][CH:18]=[O:19])[CH3:16])[C:9]=1[C:21]([O:23]CC1C=CC([N+]([O-])=O)=CC=1)=[O:22])(=[O:3])[CH3:2].[H][H].C(=O)(O)[O-].[Na+:40]>O1CCOCC1.[Pd]>[C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:20])[C@@H:12]2[C@H:15]([O:17][CH:18]=[O:19])[CH3:16])[C:9]=1[C:21]([O-:23])=[O:22])(=[O:3])[CH3:2].[Na+:40]
Reactant: [H][H]
Reactant: CC(=O)N/C=C/SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)OC=O)[C@H]2C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)N/C=C/SC1=C(C(=O)[O-])N2C(=O)[C@H]([C@@H](C)OC=O)[C@H]2C1

Procedure:
The formate ester (e4, 10 mg) was dissolved in 30% aqueous 1,4-dioxan (10 ml) and shaken with hydrogen in the presence of 5% palladium on carbon catalyst (15 mg) for 3.5 hours. Sodium bicarbonate (2.3 mg) was then added and the solution filtered through Celite, washing well with water (20 ml). The filtrate was concentrated at reduced pressure to approximately 15 ml and washed with ethylacetate (3×20 ml). The resulting aqueous solution was estimated to contain 2.2 mg of the title compound (e7) based on εm 14,000 at λmax 307 nm in the uv spectrum,λmax (H2O) 307 nm 229 nm.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12](=[O:48])[CH2:13][CH:14]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][C:26]=1[O:35][CH2:36][CH2:37][C:38]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:39]=1[CH:40]=[CH:41][CH:42]=[N:43]2)(=[O:24])=[O:23])[C:15](N(OC)C)=[O:16])([CH3:10])([CH3:9])[CH3:8].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>CCOCC.C1COCC1>[C:7]([O:11][C:12](=[O:48])[CH2:13][CH:14]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][C:26]=1[O:35][CH2:36][CH2:37][C:38]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:39]=1[CH:40]=[CH:41][CH:42]=[N:43]2)(=[O:24])=[O:23])[CH:15]=[O:16])([CH3:8])([CH3:9])[CH3:10]
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1OCCc1cccc2ncccc12
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(S(=O)(=O)NC(C=O)CC(=O)OC(C)(C)C)c(OCCc2cccc3ncccc23)c1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
Lithium aluminum hydride solution (0.9 mL of a 1.0 M solution in ether) was dissolved in 15 mL diethyl ether and cooled to 65° C. 3-[4-Acetylamino-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-N-methoxy-N-methyl-succinamic acid tert-butyl ester (180 mg, 0.3 mmol) was dissolved in 5 mL THF and added to the LiAlH4 solution via canula. The reaction was stirred for 10 minutes at 65° C. and then warmed to −44° C. for 15 minutes. The reaction was cooled to −65° C. and saturated Rochelle's salt was added. The reaction was warmed to room temperature, and then extracted with ethyl acetate. The extract was dried with sodium sulfate, and then concentrated in vacuo. The crude product was chromatographed with 5% methanol in ethyl acetate to yield 3-[4-acetylamino-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid tert-butyl ester 130 mg (80%) of a light brown solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:23](=O)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:11][C:12]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=3)=O)=[CH:9][C:4]=2[O:3][CH2:2]1.C([O-])(=O)C.[NH4+:35]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([C:14]4[CH:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[CH:21][CH:22]=4)[NH:35][C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: [NH4+]
Reactant: NC(=O)c1ccc(C(=O)CC(C(=O)c2ccccn2)c2ccc3c(c2)OCO3)cc1
Agent: CC(=O)[O-]
Solvent: CO
Product: NC(=O)c1ccc(-c2cc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)cc1

Procedure:
4-(3-Benzo[1,3]dioxol-5-yl-4-oxo4-pyridin-2-ylbutanoyl)benzamide (1.69 g; 4.2 mmol) and ammonium acetate (2.1 g; 27.3 mmol) were reacted together according to the method described in Bioorg. Med. Chem. Letters, 1998, 8, 2689-2694. The title compound was isolated as a brown powder from methanol (126 mg; 8%). 1H NMR (DMSO) δ: 6.04 (2H, s), 6.82-6.93 (4H, m), 7.18-7.32 (3H, m), 7.63-7.74 (1H, m), 7.86-7.96 (5H, m), 8.61 (1H, d, J=4 Hz), 11.63 (1H, brs); m/z (LCMS): 383.9 (M+H)+.
Reaction SMILES: [N+:1]([CH2:4][C@@:5]1([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][C@H:10]2[C@@H:6]1[CH:7]=[C:8]([CH:12]([CH2:14][CH3:15])[CH3:13])[CH2:9]2)([O-])=O.[Cl-].[NH4+]>C(O)C.[Fe]>[NH2:1][CH2:4][C@@:5]1([CH2:16][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:11][C@H:10]2[C@@H:6]1[CH:7]=[C:8]([CH:12]([CH2:14][CH3:15])[CH3:13])[CH2:9]2
Reactant: CCC(C)C1=C[C@H]2[C@@H](C1)C[C@]2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCC(C)C1=C[C@H]2[C@@H](C1)C[C@@]2(CN)CC(=O)OC(C)(C)C
Reaction time: 4.5 h

Procedure:
Tert-butyl(±)-[(1S,5R,6R)-6-(nitromethyl)-3-sec-butylbicyclo[3.2.0]hept-3-en-6-yl]acetate (3.28 g, 10.2 mmol) was dissolved in ethanol (60 mL). To the solution, iron powder (4.47 g, 80.0 mmol) and then an aqueous ammonium chloride (0.54 g, 10.0 mmol) solution (20 mL) were added, and the mixture was stirred for 4.5 hours under heating to reflux. The mixture was allowed to cool and then filtered through Celite to remove insoluble matter. The solution was concentrated, and the residue was diluted with ethyl acetate. The dilution was washed with a saturated aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the compound of interest as a colorless oil substance (2.26 g, 75%).
Reaction SMILES: P(=O)(O)(O)O.S(=O)(=O)(O)[OH:7].[C:11]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])(=[O:15])[CH2:12][CH:13]=[CH2:14]>O.ClCCCl.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH3:19][CH:18]([CH3:20])[CH2:17][O:16][C:11](=[O:15])[CH2:12][CH:13]1[O:7][CH2:14]1
Reactant: O=S(=O)(O)O
Reactant: C=CCC(=O)OCC(C)C
Agent: O=[W](=O)([O-])[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CC(C)COC(=O)CC1CO1
Temperature: 70 °C

Procedure:
Sodium tungstate dihydrate (0.852 g, 2.5 mmol), 85% phosphoric acid (0.850 ml, 5 mmol) 36.3% hydrogen peroxide (5.6 ml, 60 mmol) were dissolved in 20 ml of water and the pH was adjusted to 1.6 by 10% sulphuric acid. The solution was heated to 70° C., and under vigorous stirring a solution of 2-methylpropyl 3-butenoate (7.1 g, 50 mmol), trimethylcaprylammonium chloride (0.41 g) in 1,2-dichloroethane (15 ml) was added. After 6 hours the mixture was cooled, then the layers were separated. The aqueous phase was washed with 30 ml of dichloroethane. Organic layers were collected, washed with 2×40 ml of saturated solution or sodium sulphite, dried and distilled. The title compound was obtained as a colourless oil, b.p. 104°-108° 30 mmHg.
Reaction SMILES: N([O-])=O.[Na+].[N+]([O-])(O)=O.N[N:10]1[C:14]([N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)=[N:13][N:12]=[C:11]1[SH:20].C([O-])([O-])=O.[Na+].[Na+]>O>[SH:20][C:11]1[N:10]=[C:14]([N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)[NH:13][N:12]=1
Reactant: Nn1c(S)nnc1-n1cccn1
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: O
Product: Sc1n[nH]c(-n2cccn2)n1
Yield: 50.1 %

Procedure:
Sodium nitrite (0.4 g) was added to 25 ml of conc HNO3 and 75 ml H2O (after R. A. Henry and W. G. Finnegan, J. Am. Chem. Soc., 76, 290 (1954) and C. A. Amsworth and R. G. Jones J. Am. Chem. Soc., 75, 4915 (1953). Solid 4-amino-3-mercapto-5-(1-pyrazolyl)-1,2,4-triazole (5 g) was added in small batches with stirring while keeping the temperature below 40° C. After addition, the solution was stirred for 20 minutes and made basic by the addition of 15% aq. Na2CO3. The yellow solution was filtered and acidified with glacial acetic acid (25 ml). The tan precipitate was collected and boiled with ethanol to give 2.3 g of tan powder m.p. 245°-247°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].Cl[C:13]1[C:14]2[CH2:24][CH2:23][CH2:22][C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[C:15]=2[N:16]=[C:17]([NH2:19])[N:18]=1>>[NH2:19][C:17]1[N:18]=[C:13]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])[C:14]2[CH2:24][CH2:23][CH2:22][C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[C:15]=2[N:16]=1
Reactant: Nc1nc(Cl)c2c(n1)-c1ccccc1CCC2
Reactant: CC(C)(C)OC(=O)NCCN
Product: CC(C)(C)OC(=O)NCCNc1nc(N)nc2c1CCCc1ccccc1-2

Procedure:
tert-Butyl 2-aminoethylcarbamate (595 mg, 3.71 mmol) and the product from Example 1C (702 mg, 2.86 mmol) were treated under the conditions described in Example 1D to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.38 (s, 9H) 1.97-2.08 (m, 2H) 2.15 (t, J=6.27 Hz, 2H) 2.43-2.49 (m, 2H) 3.15 (q, J=6.22 Hz, 2H) 3.33-3.42 (m, 2H) 5.84 (s, 2H) 6.68 (s, 1H) 6.89 (t, J=5.43 Hz, 1H) 7.20-7.27 (m, 1H) 7.27-7.37 (m, 2H) 7.49-7.57 (m, 1H); MS (ESI+) m/z 370.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][C:13]3[N:22]=[C:21]([CH3:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[C:6]3=[N:24][CH2:25][CH2:26][N:5]3[C:4]=2[N:3]=1.CCN(C(C)C)C(C)C.Br[CH2:37][C:38]#[C:39][CH3:40]>CN(C=O)C>[Br:1][C:2]1[N:10]([CH2:37][C:38]#[C:39][CH3:40])[C:9]2[C:8](=[O:11])[N:7]([CH2:12][C:13]3[N:22]=[C:21]([CH3:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[C:6]3=[N:24][CH2:25][CH2:26][N:5]3[C:4]=2[N:3]=1
Reactant: Cc1nc(CN2C(=O)c3[nH]c(Br)nc3N3CCN=C23)nc2ccccc12
Reactant: CC#CCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC#CCn1c(Br)nc2c1C(=O)N(Cc1nc(C)c3ccccc3n1)C1=NCCN12

Procedure:
To 2-bromo-5-((4-methylquinazolin-2-yl)methyl)-7,8-dihydro-3H-imidazo[2,1-b]purin-4(5H)-one 15 (470 mg, 1.14 mmol) in DMF (5 ml) was added Hunig's base (0.3 ml, 1.71 mmol) and 1-bromo-2-butyne (0.145 ml, 1.6 mmol) at room temperature. The mixture was stirred over night. Another 0.103 ml (1.14 mmol) of 1-bromo-2-butyne was added and stirred over night. The reaction was extracted by DCM twice, washed with NaHCO3 and brine, dried (MgSO4) and concentrated. The crude product was purified by flash chromatography (MeOH/DCM) to afford 2-bromo-3-(but-2-ynyl)-5-((4-methylquinazolin-2-yl)methyl)-7,8-dihydro-3H-imidazo[2,1-b]purin-4(5H)-one 16. 1H NMR S 8.02 (d, J=7.81, 1H), 7.90 (d, J=7.81, 1H), 7.78 (t, J=8.59, 1H), 7.54 (t, J=8.59, 1H), 5.50 (s, 2H), 5.30 (s, 2H), 5.08 (q, J=2.34, 21-1), 4.12 (t, J=9.38, 2H), 3.92 (t, 0.1=9.38, 2H), 2.89 (s, 3H), 1.79 (t, J=2.34, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[Cl:18].[OH-].[Na+].[Cl:26][C:27]1[CH:28]=[C:29]([N:34]=[C:35]=[S:36])[CH:30]=[CH:31][C:32]=1[Cl:33].C(O)(=O)C>CC(C)=O.CCCCCC.O>[Cl:1][C:2]1[CH:3]=[C:4]([S:20]([NH:23][C:35]([NH:34][C:29]2[CH:30]=[CH:31][C:32]([Cl:33])=[C:27]([Cl:26])[CH:28]=2)=[S:36])(=[O:21])=[O:22])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[Cl:18]
Reactant: NS(=O)(=O)c1cc(Cl)c(Oc2ccc([N+](=O)[O-])cc2Cl)c(Cl)c1
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2c(Cl)cc(S(=O)(=O)NC(=S)Nc3ccc(Cl)c(Cl)c3)cc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
40 mg of 3,5-dichloro-4-(2-chloro-4-nitro phenoxy) benzenesulfonamide (0.1 m.mol) was dissolved in 2.5 ml of acetone. 0.5 ml of 1N NaOH was added to this and the mixture shaken for 30 mins at room temperature. 0.1 m.mole of 3,4-Dichlorophenyl isothiocyanate was added and the reaction stirred at 45° C. for 4 hours. The reaction mixture was neutralized by addition of 1N acetic acid. This was followed by addition of 3 ml of water. The white precipitate formed was extracted with ethyl acetate. The ethyl acetate was evaporated and the residue obtained was purified by radial silica-gel chromatography using 1:4 ethyl acetate:hexane as eluant to give 50.5 mg of desired product as a white solid (84% yield).
Reaction SMILES: [N:1]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][CH:2]1[C:10]([O:12]CC)=[O:11].CO.[Li+:24].[OH-]>C1COCC1>[C:18]([O:17][C:15]([N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][CH:2]1[C:10]([O-:12])=[O:11])=[O:16])([CH3:21])([CH3:19])[CH3:20].[Li+:24]
Reactant: CCOC(=O)C1Cc2cccnc2N1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1c2ncccc2CC1C(=O)[O-]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1-tert-butyl 2-ethyl 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1,2-dicarboxylate (prepared using methods of M Boehringer, et al. U.S. Pat. No. 7,417,144) (200 mg, 684 μmol, Eq: 1.00) in THF (1.2 mL) and MeOH (0.8 mL) was added LiOH (16.4 mg, 684 μmol, Eq: 1.00) in one portion. The reaction mixture was stirred at rt for 72 h. The reaction mixture was concentrated in vacuo and the residue treated with DCM (10 mL) to give lithium 1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate as an off-white solid (200 mg) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[NH:21][C:5]2=[CH:6][C:7]3[C:8]([CH3:20])([CH3:19])[C:9](=[O:18])[N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:11]=3[CH:12]=[C:4]2[N:3]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[CH3:19][C:8]1([CH3:20])[C:7]2[CH:6]=[C:5]3[NH:21][C:2]([NH:1][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:3][C:4]3=[CH:12][C:11]=2[N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:9]1=[O:18]
Reactant: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(N)nc3cc21
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(NC(=O)c4ccccc4)nc3cc21
Reaction time: 2 h

Procedure:
A solution of D5 (100 mg) and benzoyl chloride (298 mg; 2.12 mmol) in pyridine (12 ml) is stirred at RT for 20 h and then at 80° C. for 2 h. After an aqueous work-up the desired compound is obtained by flash chromatography on silica gel eluted with EtOAc/MeOH (99.5:0.5).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[OH:20][CH:21]1[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24][CH2:23][CH:22]1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.N12CCN(CC1)CC2>CS(C)=O>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:33]4[CH2:34][CH2:35][N:30]([CH:22]5[CH:21]([OH:20])[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24][CH2:23]5)[CH2:31][CH2:32]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: CC1(C)OCC(O)C(N2CCNCC2)CO1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Agent: C1CN2CCN1CC2
Solvent: CS(C)=O
Product: CC1(C)OCC(O)C(N2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4C3CC3)CC2)CO1
Yield: 10.5 %

Procedure:
2.8 g (10 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated at 140° in 30 ml of dimethyl sulphoxide with 2.5 g (11 mmol) of 1-(6-hydroxy-2,2-dimethyl-1,3-dioxepan-5-yl)-piperazine and 2.25 g (20 mmol) of 1,4-diazabicyclo[2.2.2]octane for 4 hours, the reaction mixture is concentrated, the resulting oil is diluted with 20 ml of methanol and the pH is brought to 5 with 2N hydrochloric acid. The precipitate which has separated out is recrystallized from glycol monomethyl ether/methanol. 0.5 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-7-[4-(6-hydroxy-2,2-dimethyl-1,3-dioxepan-5-yl)-1-piperazinyl]-4-oxo-3-quinolinecarboxylic acid of melting point 255°-262° (with decomposition) is obtained, and is dissolved in 10 ml of 2N hydrochloric acid, with warming, to split off the protective group. After the solution has been left to stand at room temperature for 1 hour, 0.3 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-7-[4-(1,3,4-trihydroxy-2-butyl)-1-piperazinyl]-4-oxo-3-quinolinecarboxylic acid of melting point 262°-268° (with decomposition) has precipitated.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[O:12]1[C:16]2([CH2:21][CH2:20][CH:19](O)[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[O:12]1[C:16]2([CH2:21][CH2:20][CH:19]([N:4]3[C:5]4=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]4[C:2]([I:1])=[N:3]3)[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(I)nn2C1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54.8 %

Procedure:
3-Iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (Intermediate LA) (11 g, 0.042 mol) was suspended in tetrahydrofuran (500 mL) at room temperature under a nitrogen atmosphere. A solution of 1,4-dioxaspiro[4.5]decan-8-ol (Intermediate M) (19.98 g, 0.126 mol) in tetrahydrofuran (50 mL) and subsequently triphenylphosphine (22.1 g, 0.084 mol ) was added to the suspension. The suspension was cooled to 0° C. and then diethyl azodicarboxylate (14.67 g, 0.084 mol) was added slowly. After stirring the reaction mixture at 0° C. for 15 min, it was allowed to warm to room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300-400 mL) and allowed to stand overnight. A precipitate formed which was collected by filtration, washed with ethyl acetate, and dried on the lyophilizer to give 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine as a pale yellow solid (54%, 9.12 g, 0.023 mol): 1H NMR (DMSO-d6, 400 MHz) 8.19 (s, 1H), 4.70 (m, 1H), 3.90 (m, 4H), 2.13 (m, 2H), 1.74 (m, 6H). TLC (dichloromethane/methanol=9:1) Rf 0.61.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O.[CH3:49][O:50][C:51]1[CH:83]=[CH:82][C:54]([CH2:55][N:56]2[C:60]3=[N:61][CH:62]=[CH:63][C:64]([O:65][C:66]4[CH:71]=[CH:70][C:69]([NH2:72])=[CH:68][C:67]=4[F:73])=[C:59]3[C:58]([N:74]3[CH2:78][CH2:77][C@H:76]([N:79]([CH3:81])[CH3:80])[CH2:75]3)=[N:57]2)=[CH:53][CH:52]=1>ClCCl>[CH3:80][N:79]([CH3:81])[C@H:76]1[CH2:77][CH2:78][N:74]([C:58]2[C:59]3[C:60](=[N:61][CH:62]=[CH:63][C:64]=3[O:65][C:66]3[CH:71]=[CH:70][C:69]([NH:72][C:15]([C:12]4[C:13](=[O:14])[N:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[N:9]=[CH:10][CH:11]=4)=[O:17])=[CH:68][C:67]=3[F:73])[N:56]([CH2:55][C:54]3[CH:82]=[CH:83][C:51]([O:50][CH3:49])=[CH:52][CH:53]=3)[N:57]=2)[CH2:75]1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(Cn2nc(N3CC[C@H](N(C)C)C3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(Cn2nc(N3CC[C@H](N(C)C)C3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Reaction time: 0.17 h
Yield: 101.1 %

Procedure:
To a stirred suspension of 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (prepared in Example 19, step C) (7 mg, 0.03 mmol) in 300 μL dichloromethane at room temperature under nitrogen was added DIEA (10 μL, 0.06 mmol) followed by EDCI (5.7 mg, 0.03 mmol) and HOBT-H2O (4.6 mg, 0.03 mmol). After stirring for 10 minutes, a solution of (S)-1-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N,N-dimethylpyrrolidin-3-amine (9.5 mg, 0.02 mmol) in 300 μL dichloromethane was added. After stirring overnight, the reaction was diluted to 30 mL with CH2Cl2 and washed with 10% sodium carbonate solution. The organic layers were dried (MgSO4), filtered and concentrated. The crude product was loaded onto a Biotage 12S column with dichloromethane and eluted with a step gradient of dichloromethane (150 mL), 2.5/97.5 MeOH/dichloromethane (150 mL) and 5/95 MeOH/dichloromethane (200 mL) to afford the desired product as a tan oil (14 mg, 100%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C@H:10]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)[CH3:11])(C)(C)C.[CH3:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][C:36]=1[CH:41]=O>C(Cl)CCl>[NH2:7][CH2:8][CH2:9][C@H:10]([N:12]1[CH2:13][CH2:14][CH:15]([N:18]([C:19]2[CH:20]=[CH:21][C:22]([O:25][Si:26]([C:29]([CH3:30])([CH3:32])[CH3:31])([CH3:27])[CH3:28])=[CH:23][CH:24]=2)[CH2:41][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][C:35]=2[CH3:34])[CH2:16][CH2:17]1)[CH3:11]
Reactant: C[C@H](CCNC(=O)OC(C)(C)C)N1CCC(Nc2ccc(O[Si](C)(C)C(C)(C)C)cc2)CC1
Reactant: Cc1ccncc1C=O
Solvent: ClCCCl
Product: Cc1ccncc1CN(c1ccc(O[Si](C)(C)C(C)(C)C)cc1)C1CCN([C@H](C)CCN)CC1
Yield: 12.8 %

Procedure:
Using general procedure A with ((R)-3-{4-[4-(tert-butyl-dimethyl-silanyloxy)-phenylamino]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester (see EXAMPLE 233) (796 mg, 2.10 mmol) and 4-methyl-3-pyridinecarboxaldehyde (see EXAMPLE 356) (367 mg, 3.00 mmol) in ClCH2CH2Cl (6 mL) followed by general procedure C afforded [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-(4-methyl-pyridin-3-ylmethyl)-amine (130 mg, 17% over 2 steps) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[C:8](Cl)=[N:9][CH:10]=[N:11][C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=O.[OH:26]S(O)(=O)=O.O>C(O)(C)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]2[C:4]([C:3]3[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=3[Cl:1])=[N:6][C:7]3[C:12]2=[N:11][CH:10]=[N:9][C:8]=3[OH:26])=[CH:15][CH:16]=1
Reactant: O=C(Nc1c(Cl)ncnc1Nc1ccc(Cl)cc1)c1ccccc1Cl
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: Oc1ncnc2c1nc(-c1ccccc1Cl)n2-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a suspension of 2-chloro-N-[4-chloro-6-(4-chlorophenylamino)-pyrimidin-5-yl]-benzamide I-(4A-7)a (1.00 g, 2.54 mmol) in isopropanol (20 ml) was added neat H2SO4 (410 μl, 7.4 mmol) at room temperature. The reaction was refluxed for 8 hours followed by cooling to room temperature and stirring for 16 hr. To the heterogeneous solution was added 20 ml of water to promote further product precipitation. After stirring for 1 an additional hour at room temperature, the solid was collected on a sintered glass funnel, rinsing with water followed by hexanes. The product was further dried under reduced pressure to give I-(4A-7)b as a colorless solid (0.72 g, 80%): 1H NMR: (400 MHz, DMSO-d6): δ 12.57 (s, 1H), 8.08 (d, J=4.1 Hz, 1 H), 7.66 (dd, J=7.4, 1.2 Hz, 1H), 7.51–7.41 (m, 5H), 7.33–7.29 (m, 2H).