Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]2[C:11](=[CH:12][C:13]([C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]=1[Br:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:33][CH:34]=[C:35]([CH3:37])[CH3:36].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]2[C:11](=[CH:12][C:13]([C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]=1[Br:29])[CH2:33][CH:34]=[C:35]([CH3:37])[CH3:36])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)=CCBr
Reactant: CC(C)(C)OC(=O)Nc1cc(OCc2ccccc2)c2ccc(C#N)cc2c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCN(C(=O)OC(C)(C)C)c1cc(OCc2ccccc2)c2ccc(C#N)cc2c1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
A solution of 16 (1.77 g, 3.90 mmol) in anhydrous DMF (20 mL) under Ar was treated with NaH (206 mg, 5.1 mmol, 1.3 equiv, 60% oil dispersion) and the reaction mixture was stirred for 30 min. The mixture was cooled to 0° C. and 4-bromo-2-methyl-2-butene (1.35 mL, 11.7 mmol, 3 equiv) was added dropwise by cannula. The solution was stirred at 0° C. for 1 h before being allowed to warm to 25° C. and stirred overnight. Water (20 mL) was added and the aqueous phase was extracted with EtoAc (3×15 mL). The combined organic phases were washed with saturated aqueous NaCl (1×30 mL), dried (Na2SO4) and the solvent was removed under vacuum. Chromatography (SiO2, 4×20 cm, 10% EtOAc-hexane) afforded 17 (2.05 g, 2.03 g theoretical, >99%) as an amber oil: 1H NMR (CDCl3, 400 MHz) δ8.66 (d, 1H, J=0.5 Hz), 8.40 (d, 1H, J=8.6 Hz), 7.63 (d, 1H, J=8.6 Hz), 7.51-7.34 (m, 5H), 6.85 (s, 1H), 5.24 (d, 1H, J=9.5 Hz), 5.20 (d, 1H, J=11.7 Hz), 5.17 (d, 1H, J=11.7 Hz), 4.40 (dd, 1H, J=6.1, 14.5 Hz), 4.01 (dd, 1H, J=7.7, 14.9 Hz), 1.61 (s, 3H), 1.57 (s, 3H), 1.37 and 1.30 (two s, 9H); 13C NMR (CDCl3, 100 MHz) δ153.7, 140.9, 136.3, 135.8, 133.5, 128.8, 128.5, 127.3, 126.7, 124.1, 119.8, 119.5, 118.8, 111.7, 110.9, 81.0, 80.5, 70.8, 47.7, 46.3, 28.5, 28.2, 25.7; IR (film) vmax 3467 (br), 2928, 2229, 1701, 1676, 1596, 1503, 1438, 1387, 1335, 1255, 1164, 1090, 863, 738 cm-1.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:22])(C)(C)C.CC1(C)O[C:29](=[O:31])[CH:28]=[C:27]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:39][O:38][C:34]1[CH:33]=[C:32]([C:27]2[CH2:28][C:29](=[O:31])[NH:22][C:9]3[CH:10]=[C:11]([C:14]#[C:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1N
Reactant: COc1cccc(C2=CC(=O)OC(C)(C)O2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(C2=Nc3ccc(C#Cc4ccccc4)cc3NC(=O)C2)c1

Procedure:
Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example G2) and 2,2-dimethyl-6-(3-methoxy-phenyl)-[1,3]dioxin-4-one (Example J11) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (131 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]1([CH:28]([CH3:32])[C:29](O)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.C(OCC)C.CCCCCC.C(OCC)(=O)C>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:29](=[O:30])[CH:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:32])[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: CC(C(=O)O)c1ccccc1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)c1ccccc1
Yield: 31.5 %

Procedure:
Preparation of example 17 from the title compound of Example 7 (15 mg, 0.054 mmol), 2-phenyl-propionic acid (9 mg, 0.062 mmol), triethylamine (0.030 mL, 0.22 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (25 mg, 0.065 mmol) in N,N-dimethylformamide (1.0 mL) was carried out analogously to Example 11. Silica gel chromatography (1:1 ethyl acetate:hexane), also in an analogous manner, followed by diethyl ether trituration afforded the title compound (7 mg, 0.017 mmol) as a yellow powder in 32% yield.
Reaction SMILES: [C:1]([C:5]1[CH:39]=[CH:38][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[S:17][CH:18]=[CH:19][N:20]=3)[C@@H:14]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH2:13][C@@:12]2([CH2:34][CH:35]([CH3:37])[CH3:36])[C:27]([O:29]C(C)(C)C)=[O:28])=[O:10])=[CH:7][C:6]=1[O:40][CH2:41][CH3:42])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([C:5]1[CH:39]=[CH:38][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[S:17][CH:18]=[CH:19][N:20]=3)[C@@H:14]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH2:13][C@@:12]2([CH2:34][CH:35]([CH3:36])[CH3:37])[C:27]([OH:29])=[O:28])=[O:10])=[CH:7][C:6]=1[O:40][CH2:41][CH3:42])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOc1cc(C(=O)N2[C@@H](c3nccs3)[C@@H](c3cnccn3)C[C@@]2(CC(C)C)C(=O)OC(C)(C)C)ccc1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(C(=O)N2[C@@H](c3nccs3)[C@@H](c3cnccn3)C[C@@]2(CC(C)C)C(=O)O)ccc1C(C)(C)C

Procedure:
The tert-butyl ester from stage A was deprotected with TFA in a similar manner to that described in Example 1 to afford the title compound as a solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][C@@H:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[N:5](C(OCC2C=CC=CC=2)=O)[C:4]1=[O:25])[CH3:2]>[Pd].CO>[CH2:1]([N:3]1[CH2:7][C@@H:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[NH:5][C:4]1=[O:25])[CH3:2]
Reactant: CCN1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: CCN1C[C@@H](C(=O)OC(C)(C)C)NC1=O
Yield: 96.8 %

Procedure:
4.2 g of tert.-butyl (4S)-1-ethyl-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate, 0.1 g of palladium-black and 100 ml of methanol are treated in the same manner as described in Example 1-(3). 2.5 g of tert.-butyl (4S)-1-ethyl-2-oxo-imidazolidine-4-carboxylate are thereby obtained as colorless crystals. Yield: 96.9% M.p. 86°-87° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:35])[C:5]2=[C:6]([CH2:8][C@H:9]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[N:28]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH:14]2[CH2:18][CH2:17][O:16][C:15]2=[O:19])[N:7]=1.[NH3:36].CO>>[NH2:1][C:2]1[N:3]=[C:4]([CH3:35])[C:5]2=[C:6]([CH2:8][C@H:9]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[N:28]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH:14]([CH2:18][CH2:17][OH:16])[C:15]([NH2:36])=[O:19])[N:7]=1
Reactant: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OC3CCOC3=O)N2)n1
Reactant: N
Solvent: CO
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OC(CCO)C(N)=O)N2)n1
Reaction time: 8 h
Yield: 89 %

Procedure:
3-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)dihydrofuran-2(3H)one (14.3 mg, 0.03 mmol) was dissolved in 7N NH3-MeOH solution and stirred overnight in a sealed tube. The solvent was removed and residue dried to afford the title compound 2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxybutanamide (13.2 mg, 89%) as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ 1.83-2.16 (m, 2H) 2.58 (d, J=6.06 Hz, 3H) 2.85-3.03 (m, 1H) 3.07-3.25 (m, 1H) 3.70 (q, J=7.24 Hz, 2H) 3.90 (d, J=11.37 Hz, 3H) 4.54 (td, J=7.83, 5.05 Hz, 1H) 4.97-5.17 (m, 1H) 6.69-6.85 (m, 1H) 7.11 (dd, J=7.71, 2.40 Hz, 1H) 7.14-7.26 (m, 2H) 7.57-7.72 (m, 1H) 7.76 (dd, J=15.03, 6.69 Hz, 1H). MS (ES) [M+H] calculated for C24H27FN7O4, 496.50. found 496.40.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10](Cl)(=[O:14])[CH:11]([CH3:13])[CH3:12].Cl.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([N:27]2[CH2:36][C:35]3[CH:34]=[N:33][N:32]([CH3:37])[C:31]=3[NH:30][C:29]3[CH:38]=[C:39]([Cl:42])[CH:40]=[CH:41][C:28]2=3)=[O:26])=[CH:21][C:20]=1[F:43].C1C(N=NC2C(=O)N(C3C=CC(S([O-])(=O)=O)=CC=3)N=C2C([O-])=O)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+]>ClCCl>[Cl:42][C:39]1[CH:40]=[CH:41][C:28]2[N:27]([C:25]([C:22]3[CH:23]=[CH:24][C:19]([CH2:18][NH:17][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[C:20]([F:43])[CH:21]=3)=[O:26])[CH2:36][C:35]3[CH:34]=[N:33][N:32]([CH3:37])[C:31]=3[NH:30][C:29]=2[CH:38]=1
Reactant: CC(C)C(=O)Cl
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CN)c(F)c1)C2
Agent: Cl
Agent: O=C([O-])C1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1N=Nc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)NCc1ccc(C(=O)N2Cc3cnn(C)c3Nc3cc(Cl)ccc32)cc1F
Reaction time: 1 h
Yield: 71 %

Procedure:
DIEA (0.135 ml, 0.78 mmol) and isobutyryl chloride (0.029 ml, 0.27 mmol) were added to a solution of (4-aminomethyl-3-fluoro-phenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E102.2 (110 mg, 0.26 mmol) in dichloromethane (3 ml) at room temperature. The mixture was stirred for 1 h, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (85 mg, 71%).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[CH:12]=[N:13][N:14]([C:16]2[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][N:17]=2)[CH:15]=1)(C(C)(C)C)(C)C.Cl.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>C1COCC1.O>[OH:8][CH2:9][CH2:10][C:11]1[CH:12]=[N:13][N:14]([C:16]2[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][N:17]=2)[CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cnn(-c2cc(C#N)ccn2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccnc(-n2cc(CCO)cn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution of 2-[4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrazol-1-yl]pyridine-4-carbonitrile (1.2 g, 3.6 mmol) in THF (15 mL) at 0° C. was added 3N HCl (5 mL). The reaction mixture was then stirred for 2 hours at room temperature. Cool to 0° C., added ethyl acetate, water and acidified with NaHCO3 to pH=8. The mixture was then extracted with ethylacetate, concentrated to afford the title compound (700 mg, 91%). [M+H] Calc'd for C11H10N4O, 215; Found, 215.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[C:19]([CH2:20][N:21]([CH3:23])[CH3:22])=[C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:30][CH3:31])[CH:16]=2)[C:11]1=[O:32])(C)(C)C>C(OCC)(=O)C>[NH2:7][CH2:8][CH2:9][N:10]1[C:19]([CH2:20][N:21]([CH3:23])[CH3:22])=[C:18]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:30][CH3:31])[CH:16]=2)[C:11]1=[O:32]
Reactant: COc1ccc2c(=O)n(CCNC(=O)OC(C)(C)C)c(CN(C)C)c(-c3ccccc3)c2c1
Solvent: CCOC(C)=O
Product: COc1ccc2c(=O)n(CCN)c(CN(C)C)c(-c3ccccc3)c2c1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
A solution of 115 (1.71 g, 3.79 mmol) in ethyl acetate (200 mL) was cooled in an ice bath with stirring. Hydrogen chloride gas was bubbled through the solution for 15 min. then the contents of the reaction flask were warmed to room temperature. After 1.25 h the solvent was removed in vacuo and the remaining residue was triturated with ether to give 116 as a white solid (1.37 g, 3.54 mmol, 93.6%).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:15]=[CH:14][C:13]3[C:8](=[CH:9][C:10]([C:17]([OH:19])=O)=[CH:11][C:12]=3[F:16])[N:7]=2)[CH2:3][CH2:2]1.[F:20][C:21]1[CH:22]=[C:23]([C@@H:29]([C:31]2[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=2)[NH2:30])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>>[F:20][C:21]1[CH:22]=[C:23]([C@H:29]([NH:30][C:17]([C:10]2[CH:9]=[C:8]3[C:13]([CH:14]=[N:15][C:6]([NH:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)=[N:7]3)=[C:12]([F:16])[CH:11]=2)=[O:19])[C:31]2[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: O=C(O)c1cc(F)c2cnc(NCC3CC3)nc2c1
Reactant: COc1ccc([C@H](N)c2cnn(C)c2)cc1F
Product: COc1ccc([C@H](NC(=O)c2cc(F)c3cnc(NCC4CC4)nc3c2)c2cnn(C)c2)cc1F

Procedure:
The condensation of 2-(cyclopropylmethylamino)-5-fluoroquinazoline-7-carboxylic acid and (S)-(3-fluoro-4-methoxyphenyl)(1-methyl-1H-pyrazol-4-yl)methanamine (401) to afford I-60 was carried out in accord with the procedure in Example 5.
Reaction SMILES: CON(C)[C:4](=[O:21])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]=1.[CH3:23][Li]>O1CCCC1.Cl.CO>[CH:16]1([O:15][C:9]2[CH:8]=[C:7](/[CH:6]=[CH:5]/[C:4](=[O:21])[CH3:23])[CH:12]=[CH:11][C:10]=2[O:13][CH3:14])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: [Li]C
Reactant: COc1ccc(C=CC(=O)N(C)OC)cc1OC1CCCC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(/C=C/C(C)=O)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a stirred solution of N-methoxy-N-methyl-3-(3-cyclopentyloxy-4-methoxyphenyl)prop-2-enamide (1.986 g, 6.50 mmol) in dry tetrahydrofuran (15 ml) at -78° C. was added methyl lithium (1.4M solution in hexanes, 10.20 ml, 14.3 mmol) dropwise over 3 minutes. The resulting solution was stirred for 1 hour at 0° C., after which time the reaction mixture was diluted with 5% HCl in methanol (20 ml) at 0° C., and partitioned between brine (35 ml) and an equal volume of methylene chloride and diethyl ether (100 ml). The organics were dried (Na2SO4) and concentrated in vacuo to give a light yellow oil. The oil was purified by flash chromatography (SiO2 ; ethyl acetate/hexane (35:65)) to afford the title compound as a colorless oil (1.642 g).
Reaction SMILES: [CH3:1][CH:2]([CH:4]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)[CH:5]=O)[CH3:3].C(=O)(O)[O-].[Na+].Cl.[NH2:23][OH:24].C1(C)C=CC=CC=1>CO.O>[CH3:1][CH:2]([CH:4]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)[CH:5]=[N:23][OH:24])[CH3:3]
Reactant: NO
Reactant: COc1ccc(C(C=O)C(C)C)cc1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc(C(C=NO)C(C)C)cc1OC
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
44.44 Grams (0.02 moles) of α-(1-methylethyl)-3,4-dimethoxybenzeneacetaldehyde prepared in example 2 are dissolved in 180 ml of methanol, then 17.64 g (0.21 moles) of sodium bicarbonate are added and, finally, 14.60 g (0.21 moles) of hydroxylamine hydrochloride are added portionwise in 30 minutes. After stirring for an additional 30 minutes, 150 ml of toluene and 150 ml of water are added and the layers are separated. The aqueous phase is discarded. The toluene phases are collected together, washed with 50 ml of water, dried over anhydrous sodium sulphate, filtered and evaporated to dryness under vacuum. The oily residue is purified by treatment with heptane obtaining 43.40 g of oxime with a yield of 91.4%. An oxime sample crystallized three times from tetrachloroethylene, shows m.p.=89° C.÷91° C. and a 1H-NMR spectrum showing characteristic resonance peaks at the following δ (expressed as p.p.m.): 0.8 (d, 3H); 1.01 (d, 3H); 2.07 (m, 1H); 3.04 (t, 1H); 3.87 (2s, 6H); 6.76 (m, 3H); 7.54 (d, 1H).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([O:25]C(C)C)[CH:23]=3)[N:18]=[C:17]([CH2:31][N:32]3[CH:36]=[N:35][CH:34]=[N:33]3)[C:16]=2[C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:8]=[CH:9][C:10]=1[O:11]C(C)C)(C)C.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:4][C:5]1[CH:6]=[C:7]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([OH:25])[CH:23]=3)[N:18]=[C:17]([CH2:31][N:32]3[CH:36]=[N:35][CH:34]=[N:33]3)[C:16]=2[C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:8]=[CH:9][C:10]=1[OH:11]
Reactant: CCOC(=O)c1c(Cn2cncn2)nc2cc(OC)c(OC(C)C)cc2c1-c1ccc(OC(C)C)c(OC(C)C)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c(Cn2cncn2)nc2cc(OC)c(O)cc2c1-c1ccc(O)c(O)c1
Reaction time: 10 h
Yield: 25.5 %

Procedure:
Titanium tetrachloride (TiCl4)(316 mg) was added at 0° C. to a solution of ethyl 4-(3,4-diisopropoxyphenyl)-6-isopropoxy-7-methoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylate (96.0 mg) in dichloromethane (1.0 ml), and the mixture was stirred at the same temperature for 10 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution and water, and dried over magnesium sulfate. The solvent was evaporated. The residual oil was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate/methanol (10/1, v/v) gave ethyl 4-(3,4-dihydroxyphenyl)-6-hydroxy-7-methoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylate (19.0 mg, 26%). mp. 264°-266° C.
Reaction SMILES: Cl.Cl.Cl.Cl.[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:19][CH2:18]3)=[O:14])=[CH:8][C:7]=1[NH:30][C:31]1[N:36]=[C:35]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH:34]=[CH:33][N:32]=1.[CH2:43](N(CC)CC)[CH3:44].C(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[CH2:43]([N:27]1[CH2:26][CH2:25][N:24]([CH:20]2[C:21]3[C:17](=[CH:16][C:15]([C:13]([NH:12][C:9]4[CH:10]=[CH:11][C:6]([CH3:5])=[C:7]([NH:30][C:31]5[N:36]=[C:35]([C:37]6[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=6)[CH:34]=[CH:33][N:32]=5)[CH:8]=4)=[O:14])=[CH:23][CH:22]=3)[CH2:18][CH2:19]2)[CH2:29][CH2:28]1)[CH3:44]
Reactant: CCN(CC)CC
Reactant: Cc1ccc(NC(=O)c2ccc3c(c2)CCC3N2CCNCC2)cc1Nc1nccc(-c2cccnc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: Cl
Solvent: CN(C)C=O
Product: CCN1CCN(C2CCc3cc(C(=O)Nc4ccc(C)c(Nc5nccc(-c6cccnc6)n5)c4)ccc32)CC1
Reaction time: 0.33 h
Yield: 62.5 %

Procedure:
N-(4-Methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl)-1-piperazin-1-yl-2,3-dihydro-1H-indene-5-carboxamide tetrahydrochloride (100 mg, 0.15 mmol) was dissolved in DMF (2 mL) and triethylamine (101 mg, 1 mmol) was added followed by acetaldehyde (26 mg, 0.6 mmol). After the solution was stirred for 20 minutes, sodium triacetoxyborohydride (128 mg, 0.6 mmol) was added. The solution obtained was stirred overnight at room temperature and then purified by high performance liquid chromatography at pH=10 to obtain 50 mg (63% yield) of the title compound. MS (M+1)=523.29. 1HNMR (DMSO-d6, ppm): δ 10.14 (s, 1H); 9.25 (s, 1H); 8.98 (s, 1H); 8.67 (d, J=4.8 Hz, 1H); 8.49 (d, J=5.2 Hz, 1H); 8.46 (d, J=8.6 Hz, 1H); 8.05 (s, 1H); 7.77 (s, 1H); 7.75 (d, J=8.8 Hz, 1H); 7.50 (dd, J=8.0 Hz, 4.8 Hz, 1H); 7.46 (d, J=8.2 Hz, 1H); 7.41 (d, J=5.2 Hz, 1H); 7.35 (d, J=7.6 Hz, 1H); 7.17 (d, J=8.8 Hz, 1H); 4.31 (t, J=6.8 Hz, 1H); 2.2-3.0 (m, 12H); 2.20 (s, 3H); 2.03 (m, 2H); 0.95 (t, J=7.0 Hz, 3H).
Reaction SMILES: C([N:8]1[CH2:14][CH:13]2[N:15]([CH3:16])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:16][N:15]1[CH:10]2[CH2:11][CH2:12][CH:13]1[CH2:14][NH:8][CH2:9]2
Reactant: CN1C2CCC1CN(Cc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1C2CCC1CNC2

Procedure:
To a degassed by argon solution of 3-benzyl-8-methyl-3,8-diazabicyclo[3.2.1]octane (17.6 g, 0.08 mol) in methanol (50 ml), 10% Pd/C (1.0 g) was added and hydrogen passed into reaction mixture for 24 h. The catalyst was filtered off, the filtrate evaporated and the residue distilled on Büchi oven for distillation at 100° C. and 0.1 mbar. Yield 8.5 g (85%).
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54]C(OC(C)(C)C)=O)[S:52][CH:53]=4)=[N:28]\[O:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:64][S:65][C:66]2[N:70]=[CH:69][N:68](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:67]=2)=[S:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.Cl.O>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:27](=[N:28]/[OH:29])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:63])[N:22]3[C:17]([C:15]([OH:14])=[S:16])=[C:18]([CH2:64][S:65][C:66]4[N:70]=[CH:69][NH:68][N:67]=4)[CH2:19][S:20][C@H:21]23)=[O:62])[N:50]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=S)OC(c4ccccc4)c4ccccc4)=C(CSc4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)CS[C@H]23)cs1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: C[N+](=O)[O-]
Solvent: O
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(O)=S)=C(CSc4nc[nH]n4)CS[C@H]23)cs1
Reaction time: 1 h
Yield: 55.9 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(1-trityl-1,2,4-triazol-3-yl)thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (1.89 g: 1.50 mMol.) in a mixture of anisole (7 ml) and nitromethane (28 ml) is added dropwise a solution of aluminum chloride (1.99 g: 15 mMol.) in anisole (7 ml) at -30°--40° C., and the mixture is stirred at the same temperature for 1 hour. The reaction mixture is diluted with 1N-hydrochloric acid (15 ml) and water and washed with ethyl acetate. The aqueous layer is concentrated under reduced pressure to remove organic solvents and passed through a column of styrene-divinylbenzene copolymer adsorbent. The product is eluted with methanol-water (2:3) to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(1,2,4-triazol-3-yl)thiomethylthio-3-cephem-4-carboxylic acid as pale yellow powder (418 mg). Over-all yield: 34%.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]1[CH2:12][CH:7]2[CH:6](O)[CH:5]1O.O.I([O-])(=O)(=O)=O.[Na+].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClC(Cl)C.ClCCCl>[CH2:22]([N:29]1[CH2:5][CH:4]2[CH2:12][CH:7]([C:8]3[CH:9]=[CH:10][CH:11]=[C:2]([I:1])[C:3]=32)[CH2:6]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: OC1C2CC(c3c(I)cccc32)C1O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: Ic1cccc2c1C1CC2CN(Cc2ccccc2)C1
Reaction time: 1.5 h
Yield: 60.8 %

Procedure:
5-Iodo-1,2,3,4-tetrahydro-1,4-methano-naphthalene-2,3-diol (8.33 g, 27.6 mmol) and Et3NBnCl (10 mg) were vigorously stirred in dichloroethane (25 mL) and H2O (75 mL) then treated with sodium periodate (6.17 g, 29.0 mmol). After 1.5 hours, the layers were separated and the aqueous layer extracted with DCE (2×40 mL). The combined organic layer was washed with H2O-(4×30 mL) until no reaction to starch iodide paper was observed, then with saturated aqueous NaCl solution (30 mL). The organic layer was dried through a cotton plug and treated with benzyl amine (3.16 mL, 29.0 mmol) and stirred for 2 minutes then transferred to an addition funnel. This solution was added over ˜10 minutes to a vigorously stirred cooled (0° C.) mixture of NaHB(OAc)3 (18.72 g, 88.0 mmol) in DCE (150 mL). After addition was complete, the mixture was stirred without cooling for 2 hours. The mixture was quenched with saturated aqueous Na2CO3 solution (100 mL) and stirred for 1 hour, then the layers were separated and the aqueous layer was extracted with CH2Cl2 (3×50 mL). The combined organic layer was washed with saturated aqueous NaCl solution (50 mL), dried through a cotton plug and concentrated. Chromatography on Silica gel provided an oil (6.3 g, 61%). (TLC 5% ethyl acetate/hexanes Rf 0.10). 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J=8.0 Hz, 1H), 7.28–7.22 (m, 3H), 7.13 (d, J=8.0 Hz,1H), 6.98–6.94 (m, 3H), 3.58 (AB dd, J=14.2 Hz, 2H), 3.26 (br s, 1H), 3.21 (br s, 1H), 3.04 (br d, J=10.2 Hz, 1H), 2.83 (br d, J=10.2 Hz, 1H), 2.47 (d, J=10.0 Hz, 1H), 2.39 (d, J=10.0 Hz, 1H), 2.34 (m, 1H), 1.72 (d, J=10.5 Hz, 1H). APCI MS m/e 376.0 [(M+1)+].