Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([N:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[CH2:8]2)=[CH:4][CH:3]=1.[Li]C(C)(C)C.CCCCC.[CH3:28][S:29]SC>C(OCC)C>[CH3:28][S:29][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([N:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: CCCN(CCC)C1Cc2ccc(Br)cc2C1
Reactant: CSSC
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: CCCN(CCC)C1Cc2ccc(SC)cc2C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
Distilled (6-bromo-indan-2-yl)-dipropyl-amine (Example 11, 270 mg, 0.91 mmol) was dissolved in dry diethyl ether (20 mL). The solution was kept under argon and cooled to -78° C. A solution of t-BuLi in pentane 1.7M (0.7 mL, 1.20 mmol) was added and the mixture was stired at -78° C. for 1 h. Freshly distilled methyl disulfide (0.14 mL, 1.55 mmol) was added at -78° C. and the mixture was stirred at this temperature for 30 min. The reaction mixture was allowed to reach room temperature and stirred for an additional 1 h. The organic layer was washed with aq. Na2CO3 (5%), the layers separated, dried (Na2CO3) and evaporated to dryness. The crude product was chromatograped (SiO2) using dichloromethane-methanol (45:1) as eluant. The pure fractions were pooled yielding 180 mg (75%) of (6-methylsulfanyl-indan-2-yl)-dipropyl-amine. The free base was converted to the hydrochloride salt and recrystallized from a mixture of 2-propanol and isopropyl ether. m.p. 180-182 (HCl); 1H NMR (300 MHz, CDCl3) δ 0.90 (t, 6H), 1.55 (m, 4H), 2.45-2.60 (m, 7H), 2.80-3.10 (m, 4H), 3.60-3.75. m (1), 7.05-7.20 (m, 3H); 13C NMR (75.4 MHz, CDCl3) δ 12.01, 16.67, 20.21, 36.22, 36.64, 59.43, 63.32, 123.39, 124.81, 125.49, 135.70, 139.38, 142.91; MS m/e 263 (12, M+), 235 (100), 163 (31), 115 (23), 116 (17).
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][C@H:5]([OH:9])[CH2:6][O:7][CH3:8].F[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=1>CC(N(C)C)=O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([O:9][C@H:5]([CH2:6][O:7][CH3:8])[CH2:4][NH2:3])=[N:12][CH:13]=1
Reactant: COC[C@@H](O)CN
Reactant: Fc1ccc(F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COC[C@H](CN)Oc1ccc(F)cn1
Reaction time: 1 h
Yield: 40.7 %

Procedure:
Suspend sodium hydride (60% in mineral oil, 13.56 g, 339.1 mmol) in dimethylacetamide (245.7 mL) and add a solution of (2S)-1-amino-3-methoxy-2-propanol (31.0 g, 147.4 mmol) in dimethylacetamide (59.0 mL) over 30 minutes. Stir for one hour; then add 2,5-difluoropyridine (17.03 mL, 162.17 mmol) over a 30 min interval; and stir at ambient temperature for an additional 1.5 hours. Slowly add water (930 mL) to quench the reaction. Extract the resulting mixture with EtoAc (4×300 mL) and combine the organic extracts. Dry the combined extracts over magnesium sulfate; filter and concentrate the filtrate under reduced pressure. Purify via flash column chromatography using a gradient of 0 to 10% EtOAc in DCM to give the title compound as a brown oil (12.0 g). MS (m/z): 201 (M+1).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]([NH:11][C:12]3[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=[C:16]([Br:18])[CH:17]=3)=[N:9][CH:10]=2)[CH2:2]1.[CH3:21][CH:22]=O.[OH-].[Na+]>CO.C(O)(=O)C>[Br:18][C:16]1[CH:17]=[C:12]([NH:11][C:8]2[CH:7]=[CH:6][C:5]([CH:3]3[CH2:4][N:1]([CH2:21][CH3:22])[CH2:2]3)=[CH:10][N:9]=2)[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=1
Reactant: CC=O
Reactant: Cn1cc(Br)cc(Nc2ccc(C3CNC3)cn2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCN1CC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Yield: 43 %

Procedure:
To a solution of 3-(5-(azetidin-3-yl)pyridin-2-ylamino)-5-bromo-1-methylpyridin-2(1H)-one 155n (crude, 4.6 mmol) in methanol (50 mL) and acetic acid (5 mL) at 0° C., was added CH3CHO (40% wt in H2O) (10 g, 92 mmol) followed by the addition of NaBH(CH3O)3 (20 g, 92 mmol) in small portions over a period of 1 h. After the reaction was finished, the mixture was adjusted to pH>7 with 2N NaOH. Then the mixture was extracted with DCM (80 mL×3), dried over Na2SO4 and concentrated to get a yellow solid, which was purified on flash column eluting with 50:1 DCM/MeOH containing 0.5% Et3N to afford 250a as a yellow solid (43%, two steps). LCMS: (M+H)+ 364. 1H NMR (500 MHz, DMSO) δ 8.72 (s, 1H), 8.66 (d, J=3, 1H), 8.21 (d, J=3, 1H), 7.68 (dd, J=9, 1H), 7.52 (d, J=2.5, 1H), 7.32 (d, J=9, 1H), 3.54 (m, 6H), 2.99 (m, 2H), 2.42 (m, 2H), 0.89 (t, J=7, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH:15]([O:17][CH2:18][CH2:19]Cl)=[CH2:16].CN(C)C=O>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:8][C:6](=[O:7])[N:5]([CH2:19][CH2:18][O:17][CH:15]=[CH2:16])[C:3]1=[O:4]
Reactant: CN1CC(=O)NC1=O
Reactant: C=COCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C=COCCN1C(=O)CN(C)C1=O

Procedure:
A mixture of 82.6 g (0.72 mol) of 1-methylhydantoin, 50.7 g (0.37 mol) of anhydrous potassium carbonate, 89.6 g (0.84 mol) of 2-chloroethyl vinyl ether, 700 ml of dimethylformamide and 100 ml of toluene is reacted for 2 hours and 30 minutes at 130°-138° C., whilst removing the water of reaction. The mixture is then worked up as described in Example 1, and 128.5 g of a clear, reddish brown, viscous crude product (96.9% of theory) are obtained. The crude product is distilled (boiling point 133° C.-134° C./0.2 mm Hg) and 108.5 g (81.8% of theory) of a colourless, viscous distillate are obtained; this crystallises and melts at 54°-56° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][O:8][C:9]([C:11]2[N:16]3[C:17](=[O:39])[C@@H:18](NC(=O)C(C4N=C(NC(OC(C)(C)C)=O)SC=4)=NOC)[C@H:15]3[S:14][CH2:13][C:12]=2[CH2:40]Cl)=[O:10])=[CH:5][CH:4]=1.[I-:44].[Na+]>CC(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][O:8][C:9]([C:11]2[N:16]3[C:17](=[O:39])[CH2:18][C@H:15]3[S:14][CH2:13][C:12]=2[CH2:40][I:44])=[O:10])=[CH:5][CH:4]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(CCl)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)C2=C(CI)CS[C@@H]3CC(=O)N23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 163.9 %

Procedure:
To a solution of 7β-[2-(2-t-butoxycarbonylamino-4-thiazolyl)-2-methoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (652 mg: 1 mMol.) in acetone (7 ml) is added sodium iodide (450 mg: 3 Eq.), and the mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure to give 7β-[2-(2-t-butoxycarbonylamino-4-thiazolyl)-2-methoxyimino) acetamido]-3-iodomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (730 mg). Yield: 98%.
Reaction SMILES: Cl.[C:2]([C:5]12[CH2:12][CH2:11][C:8]([CH2:13][NH2:14])([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)([OH:4])=[O:3].O.[CH3:16][C:17]([O:20][C:21](ON=C(C1C=CC=CC=1)C#N)=[O:22])([CH3:19])[CH3:18]>C1COCC1>[C:21]([CH:6]1[CH2:7][C:8]2([CH2:13][NH2:14])[CH2:11][CH2:12][C:5]1([C:2]([OH:4])=[O:3])[CH2:10][CH2:9]2)([O:20][C:17]([CH3:19])([CH3:18])[CH3:16])=[O:22]
Reactant: NCC12CCC(C(=O)O)(CC1)CC2
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CC2(CN)CCC1(C(=O)O)CC2
Reaction time: 24 h

Procedure:
A sample of 8.79 g (40.0 mmol) of 4-carboxybicyclo[2.2.2]octanemethylamine hydrochloride salt suspended in 100 ml each of THF and H2O was treated with 20.0 ml (14.6 g=3.3 equiv.) of TEA, followed by 11.8 g (47.9 mmol) of BOC-ON reagent. All went into solution, and after stirring 24 hr the solution was concentrated in vacuo to a volume of about 50 ml and partitioned between 100 ml of ether and 300 ml of H2O. After addition of about 2 ml of TEA the aqueous layer was washed with ether (3×), each ether in turn washed with H2O, and the combined aqueous layer was acidified with 5% KHSO4 to give the title compound as a white solid, isolated by filtration and drying in vacuo.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([NH:13][C:14]1[C:19]([NH2:20])=[CH:18][N:17]=[C:16]([CH:21]2[CH2:23][CH2:22]2)[N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].C1N=CN([C:30](N2C=NC=C2)=[O:31])C=1>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([N:13]1[C:30](=[O:31])[NH:20][C:19]2[C:14]1=[N:15][C:16]([CH:21]1[CH2:22][CH2:23]1)=[N:17][CH:18]=2)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H](Nc1nc(C2CC2)ncc1N)c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)[nH]c2cnc(C3CC3)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
(R)-3-(5-Amino-2-cyclopropyl-pyrimidin-4-ylamino)-3-phenyl-propionic acid ethyl ester (880 mg, 2.7 mmol) was dissolved in THF (10 ml). To the solution CDI was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with Ethyl acetate (100 ml) washed with water, dried over MgSO4, filtered and evaporated to dryness. The black residue obtained was purified by chromatography, eluded with 3% methanol in dichloromethane to give oil (427 mg, 45%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:33][C:34]1[CH:39]=[CH:38][C:37](Br)=[CH:36][N:35]=1>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20]([C:37]2[CH:36]=[N:35][C:34]([CH3:33])=[CH:39][CH:38]=2)=[CH:19][CH:18]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: Cc1ccc(-c2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)cn1
Yield: 45.6 %

Procedure:
Using an analogous procedure to that described in Method 4, N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Method 13, 1.20 g, 2.74 mmol) was reacted with 2-methyl-5-bromopyridine (505 mg, 2.94 mmol). The crude residue was purified by flash chromatography on silica (90 g), eluting with ethyl acetate/isohexane (40-100%) to give the title compound (504 mg, 46%); NMR Spectrum: (DMSO-d6) 1.46 (s, 9H), 2.51 (s, 3H), 7.19 (m, 2H), 7.40 (d, 1H), 7.58 (m, 2H), 7.91 (d, 2H), 8.08, (d, 3H), 8.66 (s, 1H), 8.86 (d, 1H), 9.89 (s, 1H); Mass Spectrum: M+H+ 404.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C@H:13]([NH:24][C:25]3[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=3[CH3:34])[C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH3:15])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl.N1C=CC=CC=1>[Si:17]([O:16][C@H:14]([CH3:15])[C@H:13]([C:11]1[O:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:35](=[O:42])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:7][CH:6]=2)=[N:9][N:10]=1)[NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=1[CH3:34])([C:20]([CH3:22])([CH3:23])[CH3:21])([CH3:19])[CH3:18]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(N)cc3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(NC(=O)c4ccccc4)cc3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Yield: 99.9 %

Procedure:
To a solution of 4-((1R,2R)-1-(5-(4-aminophenyl)-1,3,4-oxadiazol-2-yl)-2-(tert-butyldimethylsilyloxy)propylamino)-2-chloro-3-methylbenzonitrile (306 mg, 0.61 mmol) in CH2Cl2 (10 mL) and pyridine (1.5 mL) was added benzoylchloride (0.10 mL, 0.86 mmol) at room temperature. The resultant solution stirred for 24 hours and quenched with 2N aq. HCl (15 mL). The mixture was further partitioned between H2O (40 mL) and CH2Cl2 (40 mL). The aqueous layer was extracted with CH2Cl2 (30 mL). The combined organic extracts were washed with sat. aq. NaHCO3 (2×40 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a colourless oil (367 mg, 100%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.84 (s 1H), 8.10-7.98 (m, 6H), 7.67-7.48 (m, 4H), 6.96 (d, J=8.6 Hz, 1H), 5.76 (d, J=9.0 Hz, 1H), 5.05 (dd, J=6.5, 9.0 Hz, 1H), 4.67 (pentet, J=6.3 Hz, 1H), 2.36 (s, 3H), 1.45 (d, J=6.3 Hz, 3H), 0.83 (s, 9H), 0.11 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[NH:15][C:16]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[N:18]=2)[CH2:9]1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:16]2[NH:15][C:14]([CH:10]3[CH2:11][CH2:12][CH2:13][N:8]([CH3:6])[CH2:9]3)=[N:18][C:17]=2[C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2nc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCCC(c2nc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)C1

Procedure:
To a stirring solution of 3-[5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (200 mg) in THF (2.0 mL) was added lithium aluminum hydride (1.14 mmol, 1.14 mL of a 1M solution in THF) and the mixture heated to reflux for 6 h. The reaction was quenched with water (2.0 mL), diluted with ethyl acetate (25 mL) and filtered. The filtrates were washed with saturated sodium bicarbonate (50 mL) and the aqueous layer extracted with CH2Cl2 (2×30 mL). The organic layers were combined, dried over anhydrous sodium sulfate and evaporated under reduced pressure and the residue crystallized from diethyl ether to give 60 mg. of the title compound as an off white powder. mp=195°-197° C.
Reaction SMILES: [N:1]([C:4]1[CH:17]=[C:16]2[C:7]([O:8][C:9]3[C:10]([F:26])=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=3[C@@:15]32[CH2:22][CH2:21][S:20][C:19]([NH2:23])=[N:18]3)=[CH:6][CH:5]=1)=[N+]=[N-].C(O)C>[Pd].CCOC(C)=O>[F:26][C:10]1[C:9]2[O:8][C:7]3[C:16](=[CH:17][C:4]([NH2:1])=[CH:5][CH:6]=3)[C@@:15]3([CH2:22][CH2:21][S:20][C:19]([NH2:23])=[N:18]3)[C:14]=2[CH:13]=[C:12]([O:24][CH3:25])[CH:11]=1
Reactant: COc1cc(F)c2c(c1)[C@]1(CCSC(N)=N1)c1cc(N=[N+]=[N-])ccc1O2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(F)c2c(c1)[C@]1(CCSC(N)=N1)c1cc(N)ccc1O2
Reaction time: 0.08 h
Yield: 75.8 %

Procedure:
To a disposable vial was charged with (S)-7′-azido-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-2-amine (170 mg, 0.458 mmol), Ethanol (1.7 ml) and EtOAc (0.8 ml). The heterogeneous mixture stirred for 5 min and palladium on carbon (48.7 mg, 0.046 mmol) was added to the vial. The mixture was hydrogenated (balloon) at room temperature overnight. The mixture was filtered through celite and concentrated. The dark residue was diluted with DCM and concentrated again. After drying in vacuo, (S)-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthene]-2,7′-diamine (120 mg, 0.347 mmol, 76% yield) was obtained as tan foam. It was used for next step without further purification.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:11]1([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH:15]=[CH:14][N:13]=[CH:12]1.C(=O)(O)[O-].[Na+]>ClCCl>[N:11]1([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: NCCCCn1ccnc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(NCCCCn1ccnc1)c1ccccc1

Procedure:
Following the general procedure of Example 8 and reacting the appropriate benzenesulfonyl chloride with 1H-imdazol-1-propanamine or 1H-imidazol-1-butanamine in the presence of saturated sodium bicarbonate in dichloromethane for 16-48 hours, then crystallizing the respective products with ether and, if necessary, recrystallization from ethyl acetate or ethanol/dichloromethane gave the compounds of Examples 9-12 found in Table III below and gives the compounds of Examples 13-15 in Table III.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:46])[C:11](=[O:45])[CH2:12][N:13]([C:30]1[CH:35]=[CH:34][C:33](B2OCC(C)(C)CO2)=[CH:32][C:31]=1[CH3:44])[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH3:22])=[O:16].Br[C:48]1[S:49][CH:50]=[C:51]([C:53]([O:55][CH2:56][CH3:57])=[O:54])[N:52]=1>>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][N:2]1[N:10]([CH3:46])[C:11](=[O:45])[CH2:12][N:13]([C:30]1[CH:35]=[CH:34][C:33]([C:48]2[S:49][CH:50]=[C:51]([C:53]([O:55][CH2:56][CH3:57])=[O:54])[N:52]=2)=[CH:32][C:31]=1[CH3:44])[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:21][CH3:22])=[O:16]
Reactant: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1ccc(B2OCC(C)(C)CO2)cc1C)C(=O)OC(C)(C)C
Reactant: CCOC(=O)c1csc(Br)n1
Product: CCOC(=O)c1csc(-c2ccc(N(CC(=O)NCCN(CC)C(=O)OC(C)(C)C)CC(=O)N(C)N3Cc4ccccc4C3)c(C)c2)n1
Yield: 51.8 %

Procedure:
Using the compound (510 mg, 0.802 mmol) of Example 295, step A and ethyl 2-bromothiazole-4-carboxylate (227 mg, 0.962 mmol), and according to the method of Example 295, step B, the title compound (282 mg, yield 52%) was obtained as a brown oil.
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][N:13]3[C:21]4[C:20](=[O:22])[N:19]([CH3:23])[C:18](=[O:24])[N:17]([CH3:25])[C:16]=4[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][N:3]=1.[N:30]1([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>N1C=CC=CC=1.O>[CH3:23][N:19]1[C:20](=[O:22])[C:21]2[N:13]([CH2:12][C:11]3[CH:26]=[CH:27][C:8]([C:6](=[O:7])[C:5]4[CH:28]=[CH:29][C:2]([N:39]5[CH2:40][CH2:41][CH:36]([N:30]6[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]6)[CH2:37][CH2:38]5)=[N:3][CH:4]=4)=[CH:9][CH:10]=3)[CH:14]=[N:15][C:16]=2[N:17]([CH3:25])[C:18]1=[O:24]
Reactant: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)nc3)cc2)n(C)c1=O
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: O
Solvent: c1ccncc1
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(N4CCC(N5CCCCC5)CC4)nc3)cc2)n(C)c1=O
Yield: 41.7 %

Procedure:
A solution of 7-[4-(6-chloronicotinoyl)benzyl]-1,3-dimethylxanthine (196 mg) and 4-piperidinopiperidine (102 mg) in pyridine (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: acetone: triethylamine 1:1:0.1) to provide the title compound (108 mg).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13](=[O:41])[NH:14][CH2:15][CH2:16][CH2:17][NH:18][CH:19]([C:23]1[N:28]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27](=[O:36])[C:26]2=[C:37]([Cl:40])[CH:38]=[CH:39][N:25]2[N:24]=1)[CH:20]1[CH2:22][CH2:21]1)([CH3:11])([CH3:10])[CH3:9].[CH3:42][C:43]1[CH:51]=[CH:50][C:46]([C:47](Cl)=[O:48])=[CH:45][CH:44]=1>C(Cl)Cl>[C:8]([O:12][C:13](=[O:41])[NH:14][CH2:15][CH2:16][CH2:17][N:18]([CH:19]([C:23]1[N:28]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27](=[O:36])[C:26]2=[C:37]([Cl:40])[CH:38]=[CH:39][N:25]2[N:24]=1)[CH:20]1[CH2:21][CH2:22]1)[C:47](=[O:48])[C:46]1[CH:50]=[CH:51][C:43]([CH3:42])=[CH:44][CH:45]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCCCNC(c1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1)C1CC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(c2nn3ccc(Cl)c3c(=O)n2Cc2ccccc2)C2CC2)cc1
Reaction time: 1.5 h
Yield: 98 %

Procedure:
Triethylamine (0.425 mL, 3.05 mmol) was added to a 0° C. solution of (3-{[(3-benzyl-5-chloro-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-cyclopropyl-methyl]-amino}-propyl)-carbamic acid tert-butyl ester (0.74 g, 1.52 mmol) and 4-methylbenzoyl chloride (0.403 mL, 3.05 mmol) in CH2Cl2 (10 mL) and was stirred at 0° for 1.5 h. The reaction mixture was quenched with 1 N HCl (30 mL) and extracted with CHCl3 (3×50 mL). The combined organic extracts were washed with saturated NaHCO3 (1×100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 3/1 hexane/EtOAc to afford the title compound (0.90 g, 98%) as a solid: MS (ESI+) 604 (M++H); HRMS (ESI+) calculated: 604.2691 (M++H). found: 604.2702 (M++H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].[CH2:11]([O:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17])[CH3:12]>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[O:13][CH2:11][CH3:12])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNC1
Reactant: CCOc1ccccc1C(=O)Cl
Product: CCOC(=O)C1CCN(C(=O)c2ccccc2OCC)C1
Yield: 83 %

Procedure:
The title compound was prepared according to the method described for Preparation 2 using pyrrolidine-3-carboxylic acid ethyl ester (see Preparation 1) and 2-ethoxy-benzoyl chloride to afford the title compound as a pale yellow oil (5.13 g, 83%).
Reaction SMILES: COC(OC)[N:4]([CH3:6])[CH3:5].[CH3:9][C:10]1[CH:11]=[CH:12][N:13]=C2[C:24](=[O:25])[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:16](=O)[C:15]=12>CN(C)C=O>[CH:20]1[CH:21]=[CH:22][C:23]2[C:24](=[O:25])[C:5]3[C:15]4[C:10]([CH:9]=[CH:6][N:4]=3)=[CH:11][CH:12]=[N:13][C:16]=4[C:18]=2[CH:19]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1ccnc2c1C(=O)c1ccccc1C2=O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2-c2nccc3ccnc1c23

Procedure:
Dimethylformamide dimethyl acetal (1.50 mL, 11.34 mmol, Aldrich) was added to a solution of cleistopholine, (1.95 g, 8.73 mmol) in dimethylformamide (5 mL). The mixture was then heated for 30 min by submerging
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([CH:16]3[CH:20]([C:21]([O:23]CC)=O)[CH2:19][NH:18][CH2:17]3)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[CH2:8]([N:18]1[CH2:19][CH:20]([CH2:21][OH:23])[CH:16]([CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[CH2:17]1)[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: CCOC(=O)C1CNCC1C(=O)N1CCC(c2ccc(F)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCC1CN(Cc2ccccc2)CC1CN1CCC(c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6.4 g (14.6 mmol) of 1-benzyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylcarbonyl)-4-(RS)-(ethoxycarbonyl)pyrrolidine in 60 mL of THF at 0° C. was added 17.5 mL (17.5 mmol) of a 1M solution of lithium aluminum hydride (LAH) in ether and the reaction was stirred at 0° C. for 30 min. The reaction mixture was quenched with 5N NaOH. The reaction mixture was extracted with ether and the combined organic fractions were washed with 5N NaOH solution. The organic fractions were dried over Na2SO4, filtered and the filtrate was purified by chromatography [silica, hexanes: ethyl acetate: (2N NH3 in MeOH), 10: 10: 1] to give 4.7 g of the title compound. Spectrum (ESI) m/e=383 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([NH2:15])=[C:7]([Cl:14])[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4].[Br:16]Br>C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:6]([NH2:15])=[C:7]([Cl:14])[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[C:10]2[Br:16])=[O:4]
Reactant: BrBr
Reactant: COC(=O)c1c(N)c(Cl)cc2cn[nH]c12
Solvent: CC(=O)O
Product: COC(=O)c1c(N)c(Cl)cc2c(Br)n[nH]c12
Temperature: 80 °C
Yield: 11 %

Procedure:
To a solution of 9 g (29.92 mmol) of 6-amino-5-chloro-1H-indazole-7-carboxylic acid methyl ester in 68 mL of acetic acid at 80° C., is added dropwise 2 mL (38.89 mmol) of bromine. The mixture is stirred over the night at 80° C. The solvents are evaporated and water is added to the residue. The product is precipitated at pH 5 by addition of 1N aqueous NaOH, filtrated, washed with a minimum of water and dried under high vacuum. 1 g (3.28 mmol, 11%) of pure product is obtained; LC/MS:305/306 (M+H)+.