Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[C:15]([Cl:17])[CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:6][C:5]2=O.Cl.O([NH2:22])C.N1C=CC=CC=1.[OH-].[K+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[C:15]([Cl:17])[CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:6][CH:5]2[NH2:22]
Reactant: CON
Reactant: O=C1CC2(CCCCC2)Oc2c(Cl)cc(Cl)cc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Solvent: CO
Product: NC1CC2(CCCCC2)Oc2c(Cl)cc(Cl)cc21
Temperature: 25 °C

Procedure:
A mixture of Example 6A (1.001 g, 3.51 mmol), methoxylamine hydrochloride (293 mg, 3.51 mmol), and pyridine (1.4 mL, 17.3 mmol) in methanol (25 mL) was stirred overnight at room temperature. After this time, the solvent was evaporated in vacuo, and the residue was dissolved in ether and washed with water and brine. The organic layer was dried (Na2SO4), filtered and evaporated in vacuo, and the residue further dried azeotropically (CH3CN). A solution of the residue in tetrahydrofuran (4 mL) was cooled to 0° and was then treated slowly with 1M BH3-tetrahydrofuran (5 mL, 5 mmol). After the addition was complete, the reaction was refluxed for 2.5 h. The mixture was cooled to room temperature and was treated carefully with H2O (3 mL) and 20% aq. KOH (3 mL), then was refluxed for 1 h. The mixture was cooled and extracted with ethyl acetate. The organic extracts were washed with 1N HCl. The aqueous layer was basified with 2M NaOH, followed by extraction with ethyl acetate, afforded the title compound as a yellow oil, 64 mg (6%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.55 (dd; J=14.9, 2.7 Hz; 1H), 7.36 (m, 1H), 3.82 (m, 1H), 2.11 (m, 2H), 1.20-1.82 (m, 10H). MS (DCI+) m/z 286 (M+H).
Reaction SMILES: [C:1]([C:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4][CH2:5][C:6](OCC)=[O:7])#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH2:2][CH2:1][C:3]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:4][CH2:5][CH2:6][OH:7]
Reactant: CCOC(=O)CCC(C#N)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCC(CCCO)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
To a stirred solution of ethyl 4-cyano-4,4-diphenylbutyrate (1.2 g) in tetrahydrofuran (30 ml) was added lithium aluminum hydride (0.44 g) in small portion under ice-cooling. After completion of dropwise addition, the mixture was heated and stirred at 60° C. for 3 hours. The reaction mixture was then cooled with ice again, and water (1 ml), 15% aqueous sodium hydroxide (3 ml) and water (1 ml) were added in succession. The insoluble matter that had separated out was filtered off and the filtrate was extracted with ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic layer was taken, washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness. The group was washed with isopropyl ether to provide the title compound (0.82 g) as colorless powder.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[C:22]([NH:23][C:24]3[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[CH:25]=3)=[N:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>C(#N)C.C(Cl)Cl>[CH3:33][O:32][C:26]1[CH:25]=[C:24]([NH:23][C:22]2[C:13]([NH:12][S:9]([C:6]3[CH:7]=[N:8][C:3]([CH2:2][N:47]4[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]4)=[CH:4][CH:5]=3)(=[O:10])=[O:11])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=1
Reactant: CN1CCNCC1
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(CCl)nc2)cc(OC)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(CN3CCN(C)CC3)nc2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.1 %

Procedure:
6-(chloromethyl)-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}pyridine-3-sulfonamide (100 mg; 0.12 mmol; 1 eq.) and N-ethyl-N-isopropylpropan-2-amine (0.03 ml; 0.25 mmol; 2 eq.) are dissolved in ACN (25 ml) at room temperature then 1-methylpiperazine (0.06 ml; 0.62 mmol; 5 eq.) is added. The reaction mixture is stirred at room temperature for 2 hours. The reaction is quenched by addition of water and neutralized by addition of aqueous Na2CO3. The mixture is concentrated under reduced pressure. The residue obtained is taken up in DCM. The product is extracted with DCM, the organic phase is washed with citric acid 10% then dried over MgSO4. After evaporation of the solvent, the crude residue obtained is purified by flash chromatography to afford 6 mg (9%) of the title compound as a white powder. 1H NMR (DMSO-d6) δ 9.17 (d, J=3 Hz, 1H), 8.30 (m, 1H), 8.24 (dd, J=9 and 3 Hz, 1H), 7.72 (dd. J=9 and 3 Hz, 1H), 7.63 (d, J=9 Hz, 1H), 7.44-7.38 (m, 3H). 7.15 (d, J=3 Hz, 2H), 6.27 (m, 1H), 3.85 (s, 6H), 3.75 (s, 2H), 2.57 (m, 8H), 2.52 (s, 3H). HPLC (max plot) 90%, Rt 3.34 min. LC/MS: MS: (ES+) 550.5, (ES−): 548.5.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][N:13]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:12](=[O:31])[C:6]3=[CH:7][CH2:8][CH2:9][C:10]([CH:11]=1)=[C:5]23.C(Cl)Cl.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CO>[CH:2]([C:3]1[N:4]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][N:13]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:12](=[O:31])[C:6]3=[CH:7][CH2:8][CH2:9][C:10]([CH:11]=1)=[C:5]23)=[O:1]
Reactant: O=C(NN1C=C(c2ccccc2)n2c(CO)cc3c2C(=CCC3)C1=O)c1ccncc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: ClCCl
Product: O=Cc1cc2c3n1C(c1ccccc1)=CN(NC(=O)c1ccncc1)C(=O)C3=CCC2

Procedure:
0.100 g (0.24 mmol) of N-(9-hydroxymethyl-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)-isonicotinamide and 20 ml of CH2Cl2 are introduced successively into a 50-ml one-necked flask. The mixture is stirred and 0.200 g (0.93 mmol) of pyridinium chlorochromate are added. The suspension is stirred for 1 h at 20-25° C. The purification is carried out directly on the reaction mixture by rapid chromatography on a silica column, eluting with CH2Cl2 enriched with MeOH. The residue obtained after removal of the solvent is concreted in a few millilitres of ether. 0.022 g (0.054 mmol) of a beige powder is obtained.—TLC (CH2Cl2/MeOH 95/5 v/v): Rf=0.50.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][C:11]2([O:16][CH:15]([C:17](O)=[O:18])[CH2:14][N:13]([CH2:20][CH:21]([F:23])[F:22])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:26][CH2:27][C:28](=[O:31])[CH2:29][CH3:30].C(N(CC)CC)C>CC1CCCO1>[F:22][CH:21]([F:23])[CH2:20][N:13]1[CH2:12][C:11]2([CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:25][CH2:24]2)[O:16][CH:15]([C:17](=[O:18])[NH:26][CH2:27][C:28](=[O:31])[CH2:29][CH3:30])[CH2:14]1
Reactant: CCC(=O)CN
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(CC(F)F)CC(C(=O)O)O2
Solvent: CCN(CC)CC
Solvent: CC1CCCO1
Product: CCC(=O)CNC(=O)C1CN(CC(F)F)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Temperature: 40 °C
Yield: 60.2 %

Procedure:
To 9-(tert-butoxycarbonyl)-4-(2,2-difluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-2-carboxylic acid (418 mg, 1.15 mmol), 1-aminobutan-2-one (156 mg, 1.26 mmol) and propane phosphonic acid anhydride (T3P) (1.095 g, 1.0 mL of 50% w/w, 1.72 mmol) in 2-methyltetrahydrofuran (3.1 mL) was added triethylamine (640 μL, 4.59 mmol) at room temperature. The reaction mixture was then heated at 40° C. for 5 hours. The reaction mixture was cooled quenched with sat. aq. NaHCO3 and extracted with ethyl acetate. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo, then purified by silica gel column chromatography using 0-50% EtOAc in DCM to yield tert-butyl 4-(2,2-difluoroethyl)-2-((2-oxobutyl)carbamoyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (300 mg, 60%). 1H NMR (400 MHz, CDCl3) δ 7.40-7.30 (m, 1H), 6.09-5.64 (m, 1H), 4.31 (dd, J=11.0, 3.0 Hz, 1H), 4.21-4.05 (m, 2H), 3.77 (ddt, J=10.9, 7.5, 6.3 Hz, 2H), 3.39-3.17 (m, 2H), 3.14-2.95 (m, 1H), 2.80-2.63 (m, 3H), 2.50 (q, J=7.3 Hz, 2H), 2.41-2.27 (m, 1H), 2.25-2.11 (m, 2H), 1.67-1.51 (m, 3H), 1.46 (s, 9H), 1.13 (t, J=7.4 Hz, 3H). ESI-MS m/z calc. 433.2. found 434.5 (M+1)+; Retention time: 1.78 minutes (3 min run).
Reaction SMILES: [F:1][C:2]1[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][C:5]([C:17]2[N:21]3[N:22]=[CH:23][C:24]([C:26]([OH:29])([CH3:28])[CH3:27])=[N:25][C:20]3=[N:19][CH:18]=2)=[C:4]([O:30][CH3:31])[CH:3]=1.Br[C:33]1[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:34]=1[C:35]#[N:36]>>[F:41][C:40]1[CH:39]=[CH:38][CH:37]=[C:34]([C:35]#[N:36])[C:33]=1[C:7]1[CH:6]=[C:5]([C:17]2[N:21]3[N:22]=[CH:23][C:24]([C:26]([OH:29])([CH3:27])[CH3:28])=[N:25][C:20]3=[N:19][CH:18]=2)[C:4]([O:30][CH3:31])=[CH:3][C:2]=1[F:1]
Reactant: COc1cc(F)c(B2OC(C)(C)C(C)(C)O2)cc1-c1cnc2nc(C(C)(C)O)cnn12
Reactant: N#Cc1cccc(F)c1Br
Product: COc1cc(F)c(-c2c(F)cccc2C#N)cc1-c1cnc2nc(C(C)(C)O)cnn12
Yield: 40 %

Procedure:
2-{7-[4-Fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]imidazo[1,2-b][1,2,4]triazin-3-yl}propan-2-ol was coupled to 2-bromo-3-fluorobenzonitrile (from Example 2, step a) under the conditions described in Example 1, step e. The residue was purified by flash column chromatography (silica gel, 3% isopropyl alcohol in dichloromethane) to give the title compound in 40% yield: 1H NMR (400 MHz, CDCl3) δ 1.69 (6H, s), 3.53 (1H, s), 3.96 (3H, s), 6.96 (1H, d, J 10.3), 7.43–7.62 (3H, m), 8.11 (1H, d, J 7.9), 8.34 (1H, s), 8.71(1H, s); MS (ES+) m/z 422 [M+H]+
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[C:13]2[N:12]=[C:11]3[N:14]([C:18]4[C:19]([CH3:26])=[N:20][C:21](Cl)=[N:22][C:23]=4[CH3:24])[CH2:15][CH2:16][CH2:17][N:10]3[C:9]=2[C:8]([CH:27]([O:32][CH:33]([F:35])[F:34])[C:28]([F:31])([F:30])[F:29])=[CH:7][CH:6]=1>O1CCCC1.O.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:4][C:5]1[C:13]2[N:12]=[C:11]3[N:14]([C:18]4[C:23]([CH3:24])=[N:22][C:21]([CH3:1])=[N:20][C:19]=4[CH3:26])[CH2:15][CH2:16][CH2:17][N:10]3[C:9]=2[C:8]([CH:27]([O:32][CH:33]([F:34])[F:35])[C:28]([F:30])([F:31])[F:29])=[CH:7][CH:6]=1
Reactant: C[Mg]Br
Reactant: Cc1nc(Cl)nc(C)c1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(C(OC(F)F)C(F)(F)F)c23)c(C)n1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Methylmagnesium bromide (1.0 M solution in tetrahydrofuran, 0.49 mL, 0.490 mmol) was added dropwise to a stirred suspension of 9-chloro-1-(2-chloro-4,6-dimethylpyrimidin-5-yl)-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (163 mg, 0.328 mmol) and [1,3-bis(diphenylphosphino)propane]dichloronickel (17.8 mg, 0.0328 mmol) in tetrahydrofuran (1.3 mL) at 0° C., and the mixture was stirred at room temperature for 7 hr. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 30-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was purified by preparative HPLC to give a mixture contained an intermediate of the title compound as the trifluoroacetic acid salt. The mixture was washed with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (49.8 mg, 0.105 mmol, 32%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[N:10]1([CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:14][CH2:13][CH2:12][CH2:11]1>>[N:10]1([CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:2]3[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=3)[CH2:18][CH2:17]2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCN(CC2CCNCC2)C1
Reactant: O=Cc1ccc(F)cc1
Product: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)cc1

Procedure:
Prepared from 4-fluorobenzaldehyde and the product of Example 4.
Reaction SMILES: [CH3:1][N:2]1[CH2:20][CH2:19][C:5]2[N:6]([CH2:14][CH2:15][C:16](O)=[O:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[NH:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23][CH2:22]1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.FC(F)(F)C([O-])=O>ClCCl>[CH3:1][N:2]1[CH2:20][CH2:19][C:5]2[N:6]([CH2:14][CH2:15][C:16]([N:21]3[CH2:22][CH2:23][CH:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH2:25][CH2:26]3)=[O:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1ccc2c(c1)c1c(n2CCC(=O)O)CCN(C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CCC(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)CCN(C)C1
Yield: 6.1 %

Procedure:
The title compound, tert-butyl 1-(3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoyl)piperidin-4-ylcarbamate, was obtained as follows. 3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoic acid (500 mg, 1.8 mmol) (See Example 54B) was stirred with tert-butyl piperidin-4-ylcarbamate (0.366 ml, 1.8 mmol), EDCI-HCl (0.35 g, 1.8 mmol) and triethyl amine (0.253 ml, 1.8 mmol) in dichloromethane (20 ml) to obtain 50 mg of tert-butyl 1-(3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoyl)piperidin-4-ylcarbamate as a trifluoroacetate salt after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient followed by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:10])[C:7]([OH:9])=[O:8].Cl.[CH2:12](O)[CH3:13]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:10])[C:7]([O:9][CH2:12][CH3:13])=[O:8]
Reactant: CCO
Reactant: O=C(O)C(=O)c1cccs1
Agent: Cl
Product: CCOC(=O)C(=O)c1cccs1
Temperature: 25 °C

Procedure:
Thiophene-2-glyoxylic acid (2 g, 12.8 mmol) was added to anhydrous ethanol (100 ml) which was saturated with HCl by bubbling HCl gas for 2 min. The resulting mixture was stirred at room temperature. overnight. TLC showed the reaction was complete. Solvent was removed and the residue was purified by chromatography over silica gel eluting with ethyl acetate/hexane 10:90 to give ethyl thiophene-2-glyoxylate (1.5 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C@@H:8]1[C:11](=[O:12])[N:10](CC2C=CC(OC)=CC=2OC)[C@@H:9]1[CH2:24][CH2:25][C:26](=[O:36])[CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])([CH3:4])([CH3:3])[CH3:2].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[C:1]([O:5][C:6](=[O:37])[NH:7][C@@H:8]1[C:11](=[O:12])[NH:10][C@@H:9]1[CH2:24][CH2:25][C:26](=[O:36])[CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]2CCC(=O)CO[Si](C)(C)C(C)(C)C)c(OC)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N[C@@H]1CCC(=O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 830 g (1.50 Mol) (2R, 3S)-[2-[4-(tert-butyl-dimethyl-silanyloxy)-3-oxo-butyl]-1-(2,4-dimethoxy-benzyl)-4-oxo-azetidin-3-yl]-carbamic acid tert-butyl ester (4) in 8.3 l acetonitrile and 4.15 l water were added in intervals of 25 min three portions of 415 g (1.53 Mol) potassium persulfate at 72-75° C. The pH was kept at 4.9-5.3 by addition of a 10% solution of sodium carbonate (3.75 l). The mixture was stirred at the indicated temperature for 2 h and then cooled to room temperature. The solids were removed by filtration and washed with 5.6 l ethyl acetate. The filtrates were thoroughly mixed. The phases were separated and to the organic layer was added 2.54 l sodium bisulfite 40% in water. The phases were thoroughly mixed, cooled to 5-0° C., stirred for 1 h. The solids were removed by filtration and washed with 0.62 l ethyl acetate. The combined filtrates were stirred and the phases were allowed to separate. The organic phase was consecutively washed with aqueous solutions of 1.86 l sodium chloride (10%), 1.86 l sodium carbonate (5%) and twice with 1.86 l sodium chloride (10%), dried over 1.15 kg sodium sulfate and filtered. The solids were washed with 1.25 l ethyl acetate. To the combined filtrates was added 1.25 kg silica gel 60 (230-400 mesh) and the mixture was concentrated under aspirator vacuum. The remaining solid was charged onto a column containing 3.5 kg silica gel 60 (230-400 mesh). The product was eluted with a gradient of n-hexane:ethyl acetate=2:1 to 1:2. The pure product containing fractions were combined and concentrated under aspirator vacuum and dried 0,1 torr at 45° C. to yield 464 g (2R, 3S)-[2-[4-(tert-butyl dimethyl-silanyloxy)-3-oxo-butyl]-4-oxo-azetidin-3-yl]-carbamic acid tert-butyl ester (5) as a yellow amorphous solid (80% Th.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19](O)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.[CH3:40][S:41]([NH2:44])(=[O:43])=[O:42]>CN(C)C1C=CN=CC=1.ClCCl.OS([O-])(=O)=O.[K+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([NH:44][S:41]([CH3:40])(=[O:43])=[O:42])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[CH:3]=1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCOC3)c12
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1c(C(=O)NS(C)(=O)=O)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCOC3)c12
Reaction time: 8 h

Procedure:
4-{4-Fluoro-2-[(R)-(tetrahydro-furan-3-yl)oxy]-phenylamino}-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (150 mg), 4-dimethylaminopyridine (61 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (96 mg) was dissolved in dichloromethane. To this mixture methanesulfonamide (48 mg) was added and the reaction was stirred overnight. The reaction mixture was diluted with KHSO4 The organic layer was separated, dried and concentrated. The residue was purified by silica chromatography (Dichloromethane/MeOH/NH3 10:1:0,1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].[C:12]1(=[O:18])[O:17][C:15](=[O:16])[CH2:14][CH2:13]1>C(OCC)(=O)C.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH:8][C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:6]
Reactant: NNC(=O)c1cccc(Cl)c1
Reactant: O=C1CCC(=O)O1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(O)CCC(=O)NNC(=O)c1cccc(Cl)c1
Yield: 94.2 %

Procedure:
3-Chloro-benzoic acid hydrazide (3.4 g, 20 mmol) and succinic anhydride (2. g, 20 mmol) was mixed in ethyl acetate (50 ml) at room temperature for 15 min. The reaction mixture was diluted with ether and the precipitate was filtered to give 5.1 g of 4-[N′-(3-chloro-benzoyl)-hydrazino]-4-oxo-butyric acid. 1H-NMR(CDCl3+DMSO-d6) d(ppm): 10.01 (s, 1H), 9.53 (s, 1H), 7.68 (s, 1H), 7.55 (d, 1H), 7.21 (d, 1H), 7.12 (t, 1H) and 2.35 (m, 4H). This solid was mixed with conc. H2SO4 and stirred at room temperature for 45 min and the reaction mixture was carefully added to crashed ice (400 g). The precipitate was filtered to give 4.07 g (80.6%) of 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid as white solid. 1H-NMR(DMSO-d6) d(ppm): 12.4 (w, 1H), 7.96 (s, 1H), 7.91 (d, 1H), 7.71 (d, 1H), 7.63 (t, 1H), 3.15 (t, 2H) and 2.82 (t, 2H). Step 2: 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid hydrazide: 3-[5-(3-Chloro-phenyl)-[1,3,4)oxadiazol-2-yl]-propionic acid (2.52 g, 10 mmol) was mixed with iodomethane (5.68 g, 40 mmol) and K2CO3 (5.52 g, 40 mmol) in DMF (25 ml) at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water 3 times, dried with MgSO4 and concentrated to give 2.57 g of 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid methyl ester. The methyl ester (2.54 g, 9.52 mmol) was mixed with 98% hydrazine hydrate (4.76 g, 95.2 mmol) in methanol (10 ml) for an h. The reaction mixture was concentrated, diluted with water, filtered to give 2.17 g (81.4%) of 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid hydrazide as white solid. 1H-NMR(CDCl3+DMSO-d6) d(ppm): 8.75 (w, 1H), 7.91 (s, 1H), 7.82 (d, 1H), 7.42 (m, 2H), 3.45 (w, 2H), 3.19 (t, 2H) and 2.68 (t, 2H).
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[C:14]([N:15]3[CH2:25][CH2:24][C:18]4[N:19]=[C:20]([NH2:23])[N:21]=[CH:22][C:17]=4[CH2:16]3)=[CH:13][CH:12]=[CH:11][N:10]=2)=CC=1.FC(F)(F)C(O)=O>ClCCl>[NH2:23][C:20]1[N:21]=[CH:22][C:17]2[CH2:16][N:15]([C:14]3[C:9](=[O:8])[NH:10][CH:11]=[CH:12][CH:13]=3)[CH2:25][CH2:24][C:18]=2[N:19]=1
Reactant: COc1ccc(COc2ncccc2N2CCc3nc(N)ncc3C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc2c(n1)CCN(c1ccc[nH]c1=O)C2
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
A solution of 6-{2-[(4-methoxybenzyl)oxy]pyridin-3-yl}-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (1.77 g, 4.87 mmol) in dichloromethane (70 ml) was treated with trifluoroacetic acid (2.68 ml, 36.04 mmol) at room temperature. After stirring for 30 minutes, the solvent and excess acid was removed in vacuo and the residue was treated with ethyl acetate. Washing with sat'd NaHCO3(aq.) gave a yellow, amorphous precipitate. The solid was collected, washed with water, EtOAc, MeOH and dried (774 mg, 65%). The product was suspended in a 2:1 (v/v) mixture of water: MeOH (125 ml) and heated to boiling with vigorous stirring for 1.5 hours. The undissolved solid remaining was collected by filtration while the mixture was still hot and washed with water, MeOH, and dried to give the title compound (478 mg, 40%).