Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]1[N:22]([NH2:23])[C:21]([OH:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:32])[CH:19]=2)[N:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Cl:33][CH2:34][C:35](Cl)=[O:36].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CN(C)C=O>[C:1]([NH:11][CH2:12][C:13]1[N:22]([NH:23][C:35](=[O:36])[CH2:34][Cl:33])[C:21]([OH:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:32])[CH:19]=2)[N:14]=1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(Cl)CCl
Reactant: NN1C(CNC(=O)OCc2ccccc2)=Nc2ccc(Cl)cc2C1(O)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CCl)NN1C(CNC(=O)OCc2ccccc2)=Nc2ccc(Cl)cc2C1(O)c1ccccc1Cl
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a solution of 2-carbobenzoxyaminomethyl-3-amino-4-hydroxy-4-(2-chlorophenyl)-6-chloro-3,4-dihydroquinazoline (18.84 g) in dimethylformamide (100 ml), chloroacetyl chloride (8.48 g) is added, and the resultant mixture is stirred at room temperature for 1 hour and allowed to stand overnight. The reaction mixture is neutralized with aqueous sodium bicarbonate and shaked with ethyl acetate. The ethyl acetate layer is evaporated under reduced pressure to remove the solvent, and the residue is washed with ether to give 2-carbobenzoxyaminomethyl-3-(2-chloroacetamido)-4-hydroxy-4-(2-chlorophenyl)-6-chloro-3,4-dihydroquinazoline (18.9 g). This product is recrystallized from ethyl acetate to give crystals melting at 130° to 134° C.
Reaction SMILES: C(NC(C)C)(C)C.CCCCCC.C([Li])CCC.[C:19]([O:24][CH2:25][CH3:26])(=[O:23])[CH:20]([CH3:22])[CH3:21].[C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34]I)(=[O:29])[CH3:28].Cl>O1CCCC1>[C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][C:20]([CH3:22])([CH3:21])[C:19]([O:24][CH2:25][CH3:26])=[O:23])(=[O:29])[CH3:28]
Reactant: CCOC(=O)C(C)C
Reactant: CC(=O)OCCCCI
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)CCCCOC(C)=O
Temperature: -70 °C
Yield: 50.7 %

Procedure:
Diisopropylamine (8.25 ml) was dissolved in anhydrous tetrahydrofuran (100 ml) under an argon atmosphere, and the solution was cooled at -70° C. 1.6M n-butyllithium hexane solution (37 ml, 60 mmole) was added dropwise to the solution, to which a solution of ethyl isobutyrate (5.6 g, 48 mmole) in anhydrous tetrahydrofuran (5 ml) was then added, while maintaining the reaction temperature at not higher than -60° C. After stirring was continued for 30 minutes under the same reaction conditions, a solution of 4-acetoxybutyl iodide (12 g, 50 mmole) in hexamethylphosphortriamide (5 ml) was added dropwise to the reaction solution, and the reaction was allowed to proceed until the mixture rose to room temperature. After the completion of the reaction, 2N hydrochloric acid (10 ml) was added, and the mixture was concentrated under reduced pressure. The resulting product was dissolved in ethyl acetate (100 ml), and the organic layer was washed with water, dried and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel using isopropyl ether to give ethyl 6-acetoxy-2,2-dimethylhexanoate (5.6 g, 50%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[N:18]=[C:17]2[NH:19][CH:20]=[CH:21][C:16]2=[CH:15][CH:14]=1>C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>[CH3:12][C:13]1[N+:18]([O-:9])=[C:17]2[NH:19][CH:20]=[CH:21][C:16]2=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc2cc[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1ccc2cc[nH]c2[n+]1[O-]
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
65% m-Chloroperbenzoic acid (1374 mg) was added to a solution of 6-methyl-1H-pyrrolo[2,3-b]pyridine (570 mg) in ethyl acetate (20 ml) under ice-cooling and the mixture was stirred at room temperature for 20 minutes. After concentration of the reaction mixture in vacuo, the resulted residue was diluted with 2% aqueous solution of potassium carbonate and extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The resulted residue was purified with a NH-silica gel column chromatography (eluting solvent: chloroform/methanol=30/1 to 9/1) to give 6-methyl-1H-pyrrolo[2,3-b]pyridin-7-oxide (575 mg) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14].[C:16](=O)([O:18]CC)[NH2:17]>CC(C)=O.[Cl-].[Zn+2].[Cl-]>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]1[C:6]2[CH:5]=[CH:4][S:3][C:2]=2[NH:1][C:16](=[O:18])[N:17]=1
Reactant: CCOC(N)=O
Reactant: Nc1sccc1C(=O)c1ccccc1F
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)=O
Product: O=c1nc(-c2ccccc2F)c2ccsc2[nH]1
Temperature: 200 °C

Procedure:
A mixture of 500 mg of 2-amino-3-(o-fluorobenzoyl)thiophene, 760 mg of ethyl carbamate and 46 mg of zinc chloride is heated at 200°C for 1 hour. After cooling, the reaction mixture is washed with chloroform and filtered to give crystals, which are disolved in acetone and filtered. The filtrate is condensed under reduced pressure to give 4-(o-fluorophenyl)-1,2-dihydrothieno[2,3-d]pyrimidin-2-one as crystals having a melting point of 254° - 256°C. Recrystallization from acetone gives crystals having a melting point of 278° - 279°C (decomp.)
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O.[NH4+].[Cl-].Cl.[C:15]([O:18][CH2:19][CH3:20])(=[O:17])[CH3:16]>C1COCC1.O>[I:3][C:4]1[CH:5]=[C:6](/[CH:7]=[CH:16]/[C:15]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(C)=O
Reactant: O=Cc1cccc(I)c1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1cccc(I)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (60% dispersion in mineral oil) (120 mg, 3.0 mmol) in THF (20 mL) was added triethyl phosphonoacetate (436 μL, 2.2 mmol) dropwise. 3-iodo-benzaldehyde (465 mg, 2.0 mmol) was added after the bubbling has stopped. The reaction mixture was stirred at room temperature for 15 minutes. Solid NH4Cl was added, followed by 1N HCl to quench the reaction. The mixture was taken up in ethyl acetate and water. The organic phase was washed with aqueous NaHCO3, brine, dried (MgSO4), filtered and concentrated under reduced pressure and purified by flash chromatography on silica gel with hexane/ethyl acetate (4:1) to provide the titled compound (605 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6]2=[N:7][CH:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:10]=[C:5]2[NH:4][CH2:3]1.Cl[C:19]1[C:28]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[C:21]([C:29]2[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=2)[C:20]=1[CH3:36].CC(C)([O-])C.[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:17])[C:6]2=[N:7][CH:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:10]=[C:5]2[N:4]([C:19]2[C:28]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]([C:29]3[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=3)[C:20]=2[CH3:36])[CH2:3]1
Reactant: Cc1ccnc(-c2nc3ncccc3c(Cl)c2C)c1
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccnc(-c2nc3ncccc3c(N3CC(C)(C)c4ncc(N5CCOCC5)cc43)c2C)c1

Procedure:
Prepared according to procedure Y using 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (18 mg, 0.077 mmol), 4-chloro-3-methyl-2-(4-methylpyridin-2-yl)-1,8-naphthyridine (20.81 mg, 0.077 mmol), sodium tert-butoxide (14.86 mg, 0.154 mmol) and XPhos (7.72 mmol, 7.72 mol) in toluene (4 mL) for 2 hours at 110° C. Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-methyl-2-(4-methyl-2-pyridinyl)-1,8-naphthyridine. 1H NMR (400 MHz, chloroform-d) δ ppm 9.12 (1H, dd, J=4.3, 2.0 Hz), 8.57 (1H, d, J=5.1 Hz), 8.17 (1H, dd, J=8.2, 2.0 Hz), 8.00-8.03 (1H, m), 7.61 (1H, d, J=2.3 Hz), 7.44 (1H, dd, J=8.3, 4.2 Hz), 7.22 (1H, ddd, J=5.1, 1.8, 0.8 Hz), 5.81 (1H, d, J=2.3 Hz), 3.86-3.90 (1H, m), 3.77-3.82 (1H, m), 3.72-3.77 (4H, m), 2.93-3.04 (4H, m), 2.50 (3H, s), 2.49 (3H, s), 1.58 (3H, s), 1.53 (3H, s). Mass Spectrum (ESI) m/e=467.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:7][CH:6]([O:8][C:9](=[O:31])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[NH:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)=[O:19])[CH2:5][C:4]([CH3:33])([CH3:32])[NH:3]1.[C:35]([O:39]O)([CH3:38])([CH3:37])C>[Mo](=O)(=O)=O.C1C2C(CCCC2)CCC1>[CH:35]1([O:39][N:24]2[C:23]([CH3:30])([CH3:29])[CH2:22][CH:21]([O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([O:8][CH:6]3[CH2:7][C:2]([CH3:34])([CH3:1])[N:3]([O:39][CH:35]4[CH:38]5[CH:5]([CH2:6][CH2:7][CH2:2][CH2:1]5)[CH2:4][CH2:32][CH2:37]4)[C:4]([CH3:33])([CH3:32])[CH2:5]3)=[O:31])[CH2:26][C:25]2([CH3:28])[CH3:27])[CH:38]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][CH2:9][CH2:37]1
Reactant: CC(C)(C)OO
Reactant: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Agent: O=[Mo](=O)=O
Solvent: C1CCC2CCCCC2C1
Product: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(OC3CCCC4CCCCC43)C(C)(C)C2)CC(C)(C)N1OC1CCCC2CCCCC21
Yield: 141.1 %

Procedure:
A mixture of 25.0 g (0.052 mol) of bis(2,2,6,6-tetramethylpiperidin-4-yl)sebacate, 55.0 g (0.427 mol) of 70% aqueous t-butyl hydroperoxide, 1.5 g (0.010 mol) of molybdenum trioxide, and 180 ml of decahydronaphthalene is heated at reflux for 4.5 hours until the red color disappears. Water is collected in a Dean-Stark trap. The molybdenum trioxide is removed by filtration and the filtrate stirred with a solution of 26 g of sodium sulfite in 500 ml of water to decompose unreacted t-butyl hydroperoxide. The two-phase mixture is diluted with ethyl acetate (200 ml) and the organic layer washed with saturated sodium chloride, dried over magnesium sulfate, and concentrated at reduced pressure to obtain an oil. Purification by flash chromatography (silica gel, 19:1 heptane: ethyl acetate) affords 28.8 g (71% yield) of the title compound, a pale yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([NH2:9])[CH:6]([CH3:8])[CH3:7].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.C(N(CC)CC)C.[BH4-].[Na+]>C(Cl)Cl.[O-]S([O-])(=O)=O.[Mg+2].CO>[CH3:2][O:3][C:4](=[O:10])[C@H:5]([NH:9][CH2:16][C:15]1[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=1)[CH:6]([CH3:8])[CH3:7]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COC(=O)[C@H](N)C(C)C
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](NCc1ccc(Cl)cc1)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
3 g (18 mmoles) of (R)-2-amino-3-methyl-butyric acid methyl ester hydrochloride, 2.1 g (15 mmoles) of 4-chloro-benzaldehyde and 2.94 ml (21 mmoles) of triethyl amine are dissolved in 100 ml of CH2Cl2 and excess of MgSO4 is added at ambient temperature under N2 atmosphere. After being stirred for 18 hours at ambient temperature, the reaction mixture is filtered off and washed with CH2Cl2. The filtrate is concentrated under reduced pressure. To the crude imine in 250 ml of MeOH, 2.04 g (54 mmoles) of NaBH4 is added portionwise at 0° C. The reaction mixture is stirred at 0° C. for 2 hours and concentrated to ¼ of whole volume under reduced pressure. The mixture is extracted with AcOEt and the combined extracts are washed with sat. NaHCO3 and brine, dried over Na2SO4 and concentrated under reduced pressure to give 3.72 g of desired (R)-2-(4-chloro-benzylamino)-3-methyl-butyric acid methyl ester in 97% yield.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH2:23][CH3:24])[CH:17]=3)[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][C:26]1[CH:31]=[C:30]([CH3:32])[N:29]2[N:33]=[C:34]([CH:36]=O)[N:35]=[C:28]2[N:27]=1>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH2:23][CH3:24])[CH:17]=3)[O:11][C:10](=[O:12])[C:9]([CH2:36][C:34]3[N:35]=[C:28]4[N:27]=[C:26]([CH3:25])[CH:31]=[C:30]([CH3:32])[N:29]4[N:33]=3)=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1O
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)ccc1O

Procedure:
The title compound was prepared by coupling 6-Cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione (from Example A(22)) to 5,7-Dimethyl-[1,2,4]triazolo[1,5-α]pyrimidine-2-carbaldehyde using the Me2NHBH3 method described in the synthesis of Example B(31).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.OS(O)(=O)=O.[N+:14]([O-])([OH:16])=[O:15].N>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: Nc1ccc(F)cc1
Agent: N
Agent: O=S(=O)(O)O
Product: Nc1ccc(F)c([N+](=O)[O-])c1
Temperature: 5 °C

Procedure:
To a solution of 139 g. of p-fluoroaniline in 834 g. of H2SO4, 100%, a mixture of 81.3 g. of HNO3, 100% in 489 g. H2SO4, 100%, is slowly added at 8°-10°C. One hour after this addition, the mixture is poured on 800 g. of ice and the resulting solution made alkaline with 2300 ml. of conc. aqua ammonia. On cooling to approxiamtely 5°C., the orange crude product is filtered off, sharply sucked off, and stirred with 600 ml. of water and 120 ml. of conc. HCl at room temperature. The insoluble, dark-brown solid is filtered off, the filtrate made alkaline with 82 g. of solid sodium carbonate, and the solid filtered off and dried in vacuo at 60°-70°C or in the air.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[C:10]1[CH:35]=[C:34]([CH3:36])[C:13]2[N:14]=[C:15]([NH:18][C:19]3[CH:20]=[C:21]([S:25]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=3)[N:16]=[N:17][C:12]=2[CH:11]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:10]1[CH:35]=[C:34]([CH3:36])[C:13]2[N:14]=[C:15]([NH:18][C:19]3[CH:20]=[C:21]([S:25]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])(=[O:26])=[O:27])[CH:22]=[CH:23][CH:24]=3)[N:16]=[N:17][C:12]=2[CH:11]=1
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(Nc4cccc(S(=O)(=O)NCCN(C)C)c4)nnc3c2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(-c2cc(O)ccc2Cl)cc2nnc(Nc3cccc(S(=O)(=O)NCCN(C)C)c3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-[7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamino]-N-(2-dimethylamino-ethyl)-benzenesulfonamide (0.32 mmol, 1.0 equiv) was dissolved in 10 mL of anhydrous DCM and placed under an argon atmosphere. 4 mL of BBr3 (0.1 M) added via syringe and the reaction stirred at room temperature for 2 h. BBr3 was quenched with saturated NaHCO3 until pH=7. The mixture was filtered and washed with water and Et2O to give 3-[7-(2-chloro-5-hydroxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamino]-N-(2-dimethylamino-ethyl)-benzenesulfonamide, as an orange solid (132.2 mg, 81% yield). 1H NMR (DMSO-d6): δ 2.71 (s, 2H), 3.01 (bs, 2H), 6.87 (dd, J=8.8 Hz, J=2.9 Hz, 1H), 6.94 (d, J=3.0 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.64 (t, J=8.1 Hz, 2H), 7.90 (s, 1H), 8.06 (d, J=6.7 Hz, 1H), 8.20 (s, 1H), 8.89 (s, 1H), 9.93 (s, 1H), 11.34 (s, 1H). MS (ES+) m/z=513. LC retention time 2.24 min.
Reaction SMILES: Cl[C:2]([C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)=[O:3].BrC1C=CC(C(O)=[O:23])=CC=1.C(OCC)(=O)C=C.C(N(CC)CC)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[C:2]([C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)([OH:23])=[O:3]
Reactant: CCOC(=O)C=Cc1ccc(C(=O)Cl)cc1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: C=CC(=O)OCC
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1ccc(C(=O)O)cc1
Yield: 92 %

Procedure:
The ethyl 4-chloroformylcinnamate can be prepared as follows: 10.05 g (50 mmols) of 4-bromobenzoic acid, 6.25 g (62.5 mmols) of ethyl acrylate, 12.6 g (125 mmols) of triethylamine, 0.1122 g (0.5 mmol) of palladium acetate and 0.608 g (2 mmols) of tri-o-tolylphosphine in 20 ml of toluene are boiled under reflux for 1.5 hours. The reaction mixture is extracted by shaking with 200 ml of 2N hydrochloric acid, and the crude product is filtered off and recrystallised from toluene. 10.1 g (92% of theory) of ethyl 4-carboxycinnamate are obtained in the form of white crystals; melting point 196°-197° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@@H:5]([CH2:7][CH2:8][OH:9])[CH2:4][O:3]1.N1C=CC=CC=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>ClCCl>[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([O:9][CH2:8][CH2:7][C@H:5]2[CH2:4][O:3][C:2]([CH3:10])([CH3:1])[O:6]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)OC[C@H](CCO)O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC[C@H]2COC(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67699.5 %

Procedure:
To a stirred mixture of 2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanol (50.89 g, 0.348 mol) and pyridine (113 ml, 1.39 mol) in dichloromethane (500 ml) was added gradually p-toluenesulfonyl chloride (79.65 g, 0.418 mmol) at ice-bath temperature. After removal of ice-bath, the reaction mixture was stirred at ambient temperature overnight. The mixture was poured into ice-cooled 1N-HCl (400 ml) and the mixture was extracted with dichloromethane. The organic layer was washed with saturated NaHCO3 solution and brine, dried with MgSO4, and concentrated in vacuo. The residue was purified by silica gel (800 g) column chromatography eluting with toluene/ethyl acetate (50:1 to 10:1) to give 2-((4S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl p-toluenesulfonate (85.0 g, 81.3%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1.[CH3:20]C1C(C(N)=N)=NC=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1
Reactant: Clc1cc(-c2cccnc2)nc(-c2ccccn2)n1
Reactant: Cc1cccnc1C(=N)N
Product: Cc1cccnc1-c1nc(Cl)cc(-c2cccnc2)n1

Procedure:
This compound is prepared analogously to Intermediate A by replacing pyridine-2-carboxamide (step 1) with 3-methyl-pyridine-2-carboxamidine (Intermediate C)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH2:25]([CH:27]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:36])[C:30]=2[CH2:29][CH2:28]1)[CH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:36][C:31]3[CH:32]=[CH:33][CH:34]=[C:35]4[C:30]=3[CH2:29][CH2:28][CH:27]4[CH2:25][CH3:26])[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CCC1CCc2c(O)cccc21
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CCC1CCc2c(Oc3nc(C(=O)NC(C)c4cc(F)c(NS(C)(=O)=O)c(F)c4)co3)cccc21
Yield: 60.9 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 1-ethyl-indan-4-ol (43 mg, 0.26 mmol) to give the title compound (40 mg, 60%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH2:15][N:16](S(C(F)(F)F)(=O)=O)[CH:17]2[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCCC1C=NCCC2.P([O-])([O-])([O-])=O>C(Cl)Cl>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH2:15][N:16]=[C:17]2[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C1SCN(S(=O)(=O)C(F)(F)F)C2C(=O)OCc1ccccc1
Agent: C1=NCCCN2CCCCC12
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccccc3)=NCSC12
Reaction time: 0.75 h
Yield: 49.3 %

Procedure:
To a solution of benzyl 7-phenoxyacetamido-8-oxo-3-trifluoromethanesulfonyl-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylate (88 mg.) in methylene chloride (2 ml.) was added a solution of 1,5-diazabicyclo[5,4,0]undec-5-ene (24 mg.) in methylene chloride (0.5 ml.) at -20° C. After stirring at the same temperature for 45 minutes, the reaction mixture was poured into a chilled phosphate buffer solution (pH 7) and then extracted with ethyl acetate. The extract was washed with water and an aqueous solution of sodium chloride. Drying over magnesium sulfate and removal of the solvent left an oil (69 mg.), which was chromatographed on silica gel (2 g.) with a mixed solvent of benzene and ethyl acetate (5:1 by volume) to give an oil (33 mg.) of benzyl 7-phenoxyacetamido-8-oxo-5-thia-1,3-diazabicyclo[4,2,0]oct-2-ene-2-carboxylate.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:6]=[N:5][N:4]=1.[NH:18]1[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]1.C(N(CC)CC)C>C(#N)C>[F:15][C:14]([F:17])([F:16])[C:10]1[CH:9]=[C:8]([N:7]2[C:3]([CH2:2][N:18]3[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]3)=[N:4][N:5]=[N:6]2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=S1(=O)CCNCC1
Reactant: FC(F)(F)c1cccc(-n2nnnc2CCl)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=S1(=O)CCN(Cc2nnnn2-c2cccc(C(F)(F)F)c2)CC1
Temperature: 120 °C

Procedure:
To a solution of 5-(chloromethyl)-1-[3-(trifluoromethyl)phenyl]-1H-tetrazole (300 mg, 1.14 mmol, commercially available from Otava, Kiev, Ukraine) in acetonitrile (4 mL) was added thiomorpholine 1,1-dioxide (309 mg, 2.29 mmol, Apollo Scientific, Stockport, UK) and triethylamine (0.175 mL, 1.26 mmol). The reaction mixture was heated at 120° C. for 20 minutes in a microwave reactor. The reaction mixture was cooled and then the solvent removed under vacuum. The residue was purified by MDAP. Fractions containing the desired product were combined and the solvent removed to yield a colourless gum. The product was partitioned between DCM (6 mL) and saturated aqueous NaHCO3 (3 mL) and the organic layer collected via a hydrophobic frit. The solvent was removed under a stream of argon to yield the title compound as a white solid (0.246 g)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:20][C:21]([OH:23])=[O:22])=[C:7]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][CH:15]=[C:14](Cl)[CH:13]=3)[NH:8]2)=[CH:4][CH:3]=1.BrC1C=CC([F:31])=CC=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:20][C:21]([OH:23])=[O:22])=[C:7]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][C:15]([F:31])=[CH:14][CH:13]=3)[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12
Reactant: Fc1ccc(Br)cc1
Product: O=C(O)Cc1c(C(=O)c2ccc(F)cc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 7 from 6-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (Example 7, step 1) and 4-bromofluorobenzene.