Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]2[S:10][C:11]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][NH2:25]>CO>[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][NH:25][C:3]([C:5]1[S:9][C:8]2[S:10][C:11]([S:13]([NH2:16])(=[O:14])=[O:15])=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2cc(S(N)(=O)=O)sc2s1
Reactant: COCCOCCCN
Solvent: CO
Product: COCCOCCCNC(=O)c1cc2cc(S(N)(=O)=O)sc2s1
Yield: 64.7 %

Procedure:
5-Methoxycarbonylthieno[2,3-b]thiophene-2-sulfonamide (0.55 g., 2 mmoles) and 3-(methoxyethoxy)propylamine (0.80 g., 6 mmoles) were refluxed in methanol (5 mL) for 96 hours. The solution was cooled and evaporated in vacuo to remove most of the methanol. Ether was added and the resulting product was recrystallized from 1,2-dichloroethane to give 0.49 g of 5-(N-methoxyethoxypropylcarbamoyl)thieno[2,3-b]thiophene-2-sulfonamide, m.p. 154°-155° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:11]=2[C:12]([O:14]C)=O)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:22]([Li])([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[F:1][C:2]1[C:3]([C:10]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:11]=2[C:12](=[O:14])[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: [Li]C(C)(C)C
Reactant: COC(=O)c1cc(CO)ccc1-c1cc(OC)ncc1F
Solvent: C1CCOC1
Product: COc1cc(-c2ccc(CO)cc2C(=O)C(C)(C)C)c(F)cn1
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a stirred solution of methyl 2-(5-fluoro-2-methoxypyridin-4-yl)-5-(hydroxymethyl)benzoate 83.21C (0.307 g, 1 mmol) in THF (11 mL) at −78° C. was added tert-butyl lithium (2 mL, 3 mmol). The reaction mixture was stirred for one hour and then quenched with a saturated solution of ammonium chloride and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-40% EtOAc in hexanes) to yield 83.21D as a colorless solid (0.28 g, 84% yield).
Reaction SMILES: [C:1]([CH2:4][CH2:5][S:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][C:26]([Cl:32])=[CH:27][CH:28]=3)[N:23]=2)[CH:15]=1)[S:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=O)[NH2:2].N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.Cl>C1COCC1>[Cl:32][C:26]1[CH:25]=[C:24]2[C:29]([CH:30]=[CH:31][C:22]([CH2:21][O:20][C:16]3[CH:15]=[C:14]([CH:7]([S:6][CH2:5][CH2:4][C:1]#[N:2])[S:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:19]=[CH:18][CH:17]=3)=[N:23]2)=[CH:28][CH:27]=1
Reactant: NC(=O)CCSC(SCCC(=O)O)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#CCCSC(SCCC(=O)O)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To the amide acid (Example 17) (2.788 g, 3.63 mmoles) in THF (40 mL) at -23° C., pyridine (2.2 mL, 7.5 equiv.) and trifluoroacetic anhydride (1.1 mL, 2.2 equiv.) were added. After one hour of stirring at 0° C., 10% HCl was added, the mixture was extracted with EtOAc, dried over sodium sulfate and evaporated. Flash chromatography on silica with EtOAc:toluene:AcOH 30:70:1 afforded 1.447 g of the title compound.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([CH2:9][NH:10][NH2:11])=[CH:7][CH:6]=1.C(N(CC)CC)C.[C:21](OC)(=[O:26])[CH2:22][C:23]([CH3:25])=O>C1(C)C=CC=CC=1>[CH3:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([CH2:9][N:10]2[C:21]([OH:26])=[CH:22][C:23]([CH3:25])=[N:11]2)=[CH:7][CH:6]=1
Reactant: COc1ccc(CNN)cc1
Reactant: COC(=O)CC(C)=O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2nc(C)cc2O)cc1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
A solution containing 2.75 g of (4-methoxybenzyl)hydrazine dihydrochloride in 50 ml of toluene was treated with 1.7 ml of triethylamine at rt and then stirred for 5 min. The mixture was then treated with 1.32 ml of methyl acetoacetate and heated at 100° C. for 15 min. The solvent was evaporated under reduced pressure and then the residue partitioned between dichloromethane/10% citric acid and extracted three times. Combined extracts were washed with brine, then dried over anhydrous magnesium sulphate, filtered and evaporated to give a yellow solid. The solid was purified by flash chromatography on silica gel using methanol/dichloromethane (1:49) for the elution to give 2.3 g of 2-(4-methoxybenzyl)-5-methyl-2H-pyrazol-3-ol as a white solid. Mass spectrum (ES) m/z 219 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([OH:16])=O)[CH2:11][C@@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(Cl)C.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:33]1([S:36]([NH2:39])(=[O:38])=[O:37])[CH2:35][CH2:34]1.C1CCN2C(=NCCC2)CC1>>[C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([C:33]2([S:36]([NH2:39])(=[O:38])=[O:37])[CH2:35][CH2:34]2)=[O:16])[CH2:11][C@@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C[C@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)O
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(Cl)Cl
Product: C=C[C@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)C1(S(N)(=O)=O)CC1
Temperature: 50 °C
Reaction time: 15 h
Yield: 44.8 %

Procedure:
(1R,2R)-1-(tert-Butoxycarbonylamino)-2-vinyl-cyclopropane-1-carboxylic acid (1.72 g, 7.57 mmol., 1.0 eq.) and dichloroethane (38 mL) were charged into a 100 mL round bottom flask. 1,1′-Carbonyldiimidazole (1.72 g, 10.61 mmol., 1.4 eq.) was added portionwise and the reaction mixture stirred at 50° C. for 15 hours. Cyclopropanesulfonamide (2.47 g, 20.4 mmol., 2.7 eq.) was added portionwise followed by dropwise addition of DBU (3.11 g, 20.4 mmol., 2.7 eq.). Stirring was continued at 50° C. for a further 15 hours by when LCMS analysis of the reaction mixture showed full consumption of the starting material. The solvent was removed under vacuum. The residue was partitioned between dichloromethane (50 mL) and 0.5 M hydrochloric acid (20 mL). The organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered and the solvent removed under vacuum. The residue was purified by flash column chromatography using heptanes:ethyl acetate gradient (60:50 to 50:50) as eluent. After combining the relevant fractions and removing the solvent under vacuum, 1.12 g (45%) of the title compound was isolated as a yellow semi solid. 1H NMR (500 MHz, CDCl3) δ ppm 9.71 (br. s, 1 H), 5.61 (br. s, 1 H), 5.32 (d, J=16.87 Hz, 1 H), 5.20-5.28 (m, 1 H), 5.18 (d, J=10.27 Hz, 1 H), 2.88-3.00 (m, 1 H), 2.16 (q, J=8.44 Hz, 1 H), 1.87-1.96 (m, 1 H), 1.51 (s, 9 H), 1.40-1.47 (m, 1 H), 1.24-1.36 (m, 2 H), 1.07-1.16 (m, 1 H), 0.99-1.07 (m, 1 H). LC-MS: purity 100% (ELS), tR 1.74 min, m/z [M−H]-329.10.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)C(=O)C1.FC(F)(F)[C:27]([O-:29])=O.[C:32]([CH:34]=[C:35]1[CH2:40][CH2:39][NH2+:38][CH2:37][CH2:36]1)#[N:33]>C(#N)C.CS(C)=O.CCOC(C)=O>[C:32]([CH:34]=[C:35]1[CH2:40][CH2:39][N:38]([C:27]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[O:29])[CH2:37][CH2:36]1)#[N:33]
Reactant: O=C([O-])C(F)(F)F
Reactant: OCC(F)(F)F
Reactant: N#CC=C1CC[NH2+]CC1
Agent: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CC#N
Product: N#CC=C1CCN(C(=O)OCC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2,2,2-Trifluoroethanol (1.6 mL, 22 mmol) and TEA (6.2 mL, 45 mmol) were dissolved in acetonitrile (200 mL). N,N-disuccinimidyl carbonate (8.6 g, 34 mmol) was added and the resulting mixture was stirred at ambient temperature for 90 minutes. 4-(Cyanomethylidene)piperidinium trifluoroacetate (5.3 g, 23 mmol) in DMSO (10 mL) was then added, followed by TEA (6.2 mL, 45 mmol). The resulting mixture was stirred at 50° C. for 16 hours. The reaction mixture was cooled to ambient temperature, diluted with EtOAc and washed sequentially with saturated NaHCO3 (aq) and water. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-5% MeOH in DCM) to afford the title compound. LRMS (ESI) calc'd for C10H11F3N2O2 [M+H]+: 249. Found: 249.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C1COCC1>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:8]([C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:9])[CH2:22][CH2:21]1
Reactant: CN1CCNCC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CN1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Yield: 47.3 %

Procedure:
A 1-liter-3-neck flask was loaded with 4-nitrobenzoyl chloride (50.5 g, 267 mmol) and THF (500 ml) and cooled to 0° C. Pyridine (44 ml, 544 mmol), then 1-methyl-piperazine (35 ml, 316 mmol) were added while mechanically stirring at 0° C. After the addition was completed the ice bath was removed and the mixture stirred for 1 hour, while warming to room temperature. A voluminous precipitate forms. The slurry was diluted with dichloromethane and 1 M aq. KOH and the layers separated. The organic layer was washed one more time with 1 M aq. KOH, then with brine and dried over MgSO4, filtered and concentrated in vacuum. 31.5 g yellow solid (4-methylpiperazin-1-yl)(4-nitrophenyl)methanone were isolated. MS (ESI) m/z 250 (M+H). 1H NMR (CDCl3) δ ppm 8.27 (d, 2H, J=7.9), 7.56 (d, 2H, J=7.9), 3.81 (bs, 2H), 3.37 (bs, 2H), 2.50 (bs, 2H), 2.34 (bs, 2H), 2.32 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:10][O:11][C:12]1[C:20]2[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=2[CH:15]=[CH:14][CH:13]=1)[CH3:6])=[O:4].[CH3:28][NH:29][C:30]([C:32]1[CH:42]=[CH:41][C:35]([CH:36]=[CH:37][C:38](O)=[O:39])=[CH:34][CH:33]=1)=[O:31].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[Cl:27][C:8]1[C:7]([N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:38](=[O:39])[CH:37]=[CH:36][C:35]2[CH:41]=[CH:42][C:32]([C:30](=[O:31])[NH:29][CH3:28])=[CH:33][CH:34]=2)=[CH:25][CH:24]=[C:23]([Cl:26])[C:9]=1[CH2:10][O:11][C:12]1[C:20]2[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1C
Reactant: CNC(=O)c1ccc(C=CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(C)n4C)c2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
To a mixture of 4-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-1,2-dimethyl-1H-benzimidazole (100 mg), 4-(methylcarbamoyl)cinnamic acid (55.4 mg) and dimethylformamide (1 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (61.2 mg) and 1-hydroxybenzotriazole (49.7 mg), and the mixture was stirred for 3 hours at ambient temperature. To the mixture was added water, and the mixture was extracted with dichloromethane. The separated organic layer was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (dichloromethane—methanol) to give 4-[2,6-dichloro-3-[N-methyl-N-[4-(methyl-carbamoyl)cinnamoylglycy]amino]benzyloxy]-1,2-dimethyl-1H-benzimidazole (121 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10](I)[CH2:11][CH3:12].C(N(CC)CC)C>O1CCCC1>[CH2:10]([NH:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:11][CH3:12]
Reactant: CCCI
Reactant: NCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCNCCc1ccccc1

Procedure:
1.2 ml (9.5 mmol) of phenylethylamine, 0.93 ml (9.5 mmol) of n-propyl-iodide, 5 ml of triethylamine and 5 ml of THF (tetrahydrofuran) were placed in a flask, and the reaction mixture was heated at reflux temperature of the reaction mixture for 3.5 hours and then cooled. A salt formed was filtered off, the solution was evaporated and a desired compound was purified by column chromatography on silica gel (silica gel 60, mobile phase: CHCl3:CH3OH=10:3). This yields 0.62 g (40%) of N-propyl-(β-phenylethyl)amine in the form of the oil (molecular weight: 163.264, formula: C11H17N).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:9][O:8][B:7]([OH:10])[C:6]=2[CH:11]=1.N1C=CC=CC=1.[C:18]([C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[S:29](Cl)(=[O:31])=[O:30])#[N:19]>CC#N.CN(C=O)C>[C:18]([C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[S:29]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:9][O:8][B:7]([OH:10])[C:6]=2[CH:11]=1)(=[O:31])=[O:30])#[N:19]
Reactant: Nc1ccc2c(c1)B(O)OC2
Reactant: N#Cc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CC#N
Product: N#Cc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (16.4 g, 0.11 mol) and pyridine (10.3 g, 0.13 mol) in MeCN/DMF (400 mL/100 mL) was added 2-cyano-4-nitrobenzene-1-sulfonyl chloride (24.7 g, 0.1 mol) at 0° C., then the solution was stirred at room temperature overnight. The mixture was concentrated in vacuo, and DCM and water was added to the residue. The organic layer was dried over Na2SO4 and concentrated to give the crude product.
Reaction SMILES: Cl[Si:2]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4].[OH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:15]([CH2:26][OH:27])[CH2:14]1.C(N(CC)CC)C.O>CN(C)C1C=CN=CC=1.ClCCl>[OH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@H:15]([CH2:26][O:27][Si:2]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C[C@H]1CO
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[Si](OC[C@@H]1CC(O)CCN1C(=O)OC(C)(C)C)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Chlorotriisopropylsilane (2.284 g, 11.85 mmol) was added dropwise to a 0° C. solution of Example 260A (2.65 g, 10.77 mmol), triethylamine (1.253 g, 12.39 mmol) and 4-(dimethylamino)pyridine (0.263 g, 2.154 mmol) in dichloromethane (25 mL). The mixture was stirred at 0° C. for 20 minutes and at room temperature for 16 hours. Water (50 mL) was added and the layers were separated. The aqueous layer was extracted with dichloromethane (twice), and the combined extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (gradient of 0-30% ethyl acetate/heptanes) to give the title compound as a mixture of diastereomers. MS (ESI+) m/z 388.0 (M+H)+.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][C:7](N(C)C)=[O:8].[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13]1=O>C(Cl)(Cl)Cl>[C:7]([C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:12][C:13]=1[Cl:3])(=[O:8])[CH3:6]
Reactant: CC(=O)N(C)C
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1Cc2ccccc2N1
Solvent: ClC(Cl)Cl
Product: CC(=O)c1c(Cl)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
13.7 ml POCl3 was slowly added to a mixture of dimethylacetamide (5.6 ml) in 25 ml of chloroform, at 5° C. A solution of 6.66 g of oxindole in 25 ml chloroform was slowly added, and the reaction refluxed for 7 hours, and left overnight at room temperature with stirring. The reaction mixture was added to 250 ml of ice/water, the phases separated, and the organic phase extracted with water (4×50 ml). The aqueous phases were pooled and neutralized with sodium acetate, and stirred for 4 hours at room temperature. Filtration and drying gave (75). Yield 4.8 g.
Reaction SMILES: [C:1]1([CH2:7][C@@H:8]([NH2:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[O-]S([O-])(=O)=O.[Mg+2]>C1C=CC=CC=1>[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[N:10][C@@H:8]([CH3:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: C[C@H](N)Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccccc1
Product: C[C@@H](Cc1ccccc1)N=Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-1-phenylpropan-2-amine (323 mg, 2389 μmol) in benzene (5 mL) was added 4-bromobenzaldehyde (442 mg, 2389 μmol and MgSO4 (500 mg, 4154 μmol) and the suspension was stirred at RT 4 h. The suspension was filtered and the solid washed with benzene (2×2 mL). The combined filtrates were concentrated to give (S)—N-(4-bromobenzylidene)-1-phenylpropan-2-amine which was used without purification in the next step.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[CH2:6][N:5]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([F:21])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:22])[CH2:4]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C(=O)([O-])[O-].[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)[Cl:57]>CO>[ClH:57].[F:21][C:18]1[CH:19]=[C:20]2[C:15]([CH:14]=[CH:13][C:12](=[O:22])[N:11]2[CH2:10][CH2:9][N:5]2[CH2:6][C@@H:7]([OH:8])[C@@H:3]([CH2:2][NH:1][CH2:34][C:32]3[CH:31]=[CH:30][C:27]4[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=4[N:33]=3)[CH2:4]2)=[N:16][CH:17]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: NC[C@H]1CN(CCn2c(=O)ccc3ncc(F)cc32)C[C@H]1O
Reactant: ClCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Cl
Product: O=C1COc2ccc(CNC[C@H]3CN(CCn4c(=O)ccc5ncc(F)cc54)C[C@H]3O)nc2N1
Reaction time: 18 h
Yield: 48 %

Procedure:
1-{2-[(3S,4S)-3-(Aminomethyl)-4-hydroxy-1-pyrrolidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one (108 mg; 0.353 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (for a synthesis see WO2003087098, Example 31(e)) (69 mg; 0.388 mmol) were combined in anhydrous DCM (5 ml) and anhydrous MeOH (1 ml) with a spatula of solid sodium carbonate. The reaction mixture was stirred under nitrogen for 18 h then sodium triacetoxyborohydride (235 mg; 1.06 mmol) was added and stirred for 1 h. The reaction mixture was concentraed and purified to obtain the free base of the title compound as a pale yellow oil (80 mg; 48%) after column chromatography (90:10:1: DCM:MeOH:NH4OH).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C@@H:10]([C@@H:12]([C@@H](CO)O)[OH:13])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19](OC1C=CC([N+]([O-])=O)=CC=1)=[O:20].I(O)(=O)(=O)=[O:32]>>[CH2:1]([N:8]1[CH2:9][C@@H:10]([CH:12]([OH:13])[OH:32])[O:11][C:19]1=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OC[C@@H](O)[C@@H](O)[C@@H](O)CNCc1ccccc1
Product: O=C1O[C@H](C(O)O)CN1Cc1ccccc1

Procedure:
The title compound is prepared from 1-benzylamino-1-deoxy-D-ribitol (cf. Kagan et al., Journal of the American Chemical Society, 79, 3541 [1957]) and 4-nitrophenyl chloroformate, followed by oxidation with periodic acid, according to the procedure of Example 4.
Reaction SMILES: [O:1]=[C:2]1[C:14]2[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5]([C:18]([OH:20])=[O:19])=[CH:6][CH:7]=2.[OH:21]O>S(=O)(=O)(O)O>[O:21]=[C:2]1[O:1][C:14]2[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=[CH:10][C:9]=2[C:8]2[CH:7]=[CH:6][C:5]([C:18]([OH:20])=[O:19])=[CH:4][C:3]1=2
Reactant: OO
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1cc(C(=O)O)ccc1-2
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc2c(c1)oc(=O)c1cc(C(=O)O)ccc12
Temperature: 0 °C

Procedure:
A suspension of 12.0 g (0.045 mole) of 9-oxo-fluorene-2,7-dicarboxylic acid in 100 ml of concentrated sulfuric acid is slowly reacted with 12.0 ml of a 30% hydrogen peroxide solution. The reaction is strongly exothermic and is controlled by cooling the stirred reaction mixture in a water bath. The cooled reaction mixture is poured onto 500 ml of an ice water mixture, filtered and washed with water. The residue is resuspended in water, stirred, filtered and washed with a total of about 350 ml of deionized water, to yield 11.2 g of 6-oxo-6H-dibenzo[b,d] pyran-3,8-dicarboxylic acid having a m.p. greater than 300° C. EXAMPLE IV
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:23][CH:22]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([O:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:27][CH2:26]3)[O:21][C:20]2=[O:40])=[CH:15][CH:14]=1)=O)C1C=CC=CC=1.C(OC(NCC1C=CC(N2CC(CCl)OC2=O)=CC=1)=O)C1C=CC=CC=1.N1CCC(OCC(OC(C)(C)C)=O)CC1.O>CO.[Pd].[C].C(O)(=O)C>[NH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:23][CH:22]([CH2:24][N:25]3[CH2:26][CH2:27][CH:28]([O:31][CH2:32][C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:29][CH2:30]3)[O:21][C:20]2=[O:40])=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)COC1CCN(CC2CN(c3ccc(CNC(=O)OCc4ccccc4)cc3)C(=O)O2)CC1
Agent: [Pd]
Agent: CC(C)(C)OC(=O)COC1CCNCC1
Agent: O=C(NCc1ccc(N2CC(CCl)OC2=O)cc1)OCc1ccccc1
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)COC1CCN(CC2CN(c3ccc(CN)cc3)C(=O)O2)CC1

Procedure:
A solution of 1 g of tert-butyl 1-(3-(4-benzyloxycarbonylaminomethylphenyl)-2-oxo-5-oxazolidinylmethyl)piperidine-4-oxyacetate (obtainable from 3-(4-benzyloxycarbonylaminomethylphenyl)-5-chloromethyl-2-oxazolidinone and tert-butyl piperidine-4-oxyacetate in accordance with the method described in Example 3) in a mixture of 38 ml of methanol, 6 ml of water and 6 ml of acetic acid is hydrogenated on 0.6 g of 5% Pd-carbon at 20° and 1 bar until H2 uptake has ceased. The mixture is filtered and the filtrate is concentrated by evaporation, and tert-butyl 1-(3-(4-aminomethylphenyl)-2-oxo-5-oxazolidinylmethyl)piperidine-4-oxyacetate is obtained, m.p. 95°-96°, FAB 420.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][CH2:19][O:20][CH2:21][C:22]([OH:24])=O)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH:57]1([N:60]2[CH2:65][CH2:64][N:63]([C:66]3([CH2:72][NH:73][C:74](=[O:81])[C:75]4[CH:80]=[CH:79][N:78]=[CH:77][CH:76]=4)[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]3)[CH2:62][CH2:61]2)[CH2:59][CH2:58]1>ClCCl.CN(C=O)C>[CH:1]1([N:4]([CH2:18][CH2:19][O:20][CH2:21][C:22]([N:69]2[CH2:68][CH2:67][C:66]([CH2:72][NH:73][C:74](=[O:81])[C:75]3[CH:80]=[CH:79][N:78]=[CH:77][CH:76]=3)([N:63]3[CH2:62][CH2:61][N:60]([CH:57]4[CH2:58][CH2:59]4)[CH2:65][CH2:64]3)[CH2:71][CH2:70]2)=[O:24])[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(NCC1(N2CCN(C3CC3)CC2)CCNCC1)c1ccncc1
Reactant: COc1cc(C)c(S(=O)(=O)N(CCOCC(=O)O)C2CC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(CCOCC(=O)N2CCC(CNC(=O)c3ccncc3)(N3CCN(C4CC4)CC3)CC2)C2CC2)c(C)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
To a solution of 2-(2-(N-cyclopropyl-4-methoxy-2,6-dimethylphenyl-sulfonamido)ethoxy)acetic acid AC7 (0.225 mmol) in dichloromethane (10 ml/mmol) was added diisopropyl ethylamine (4 equiv.) at 0° C. followed by the addition of HOBT (1.0 equiv.) and EDCI (1.5 equiv.). The resultant solution was stirred at 25° C. for 15 min. It was again cooled to 0° C. and a solution of N-((4-(4-cyclopropylpiperazin-1-yl)piperidin-4-yl)methyl)isonicotinamide dihydrochloride AM12 (1.2 equiv.) in DMF (2 ml) was added. The reaction mixture was stirred for 16 h at 25° C. The mixture was diluted with dichloromethane, washed with saturated ammonium chloride solution, brine, saturated sodium bicarbonate and finally again with brine. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to yield the crude product which was purified by column chromatography. Yield: 60%. MS, Rt=2.8 min, m/z 683.5 [MH]+.