Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH:16]1[CH2:22][CH2:21][CH2:20][C:19]2[CH:23]=[CH:24][C:25](OC(F)(F)F)=[CH:26][C:18]=2[CH2:17]1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6]C=[CH:4][CH:3]=1.[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[C:41](=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH:16]1[CH2:22][CH2:21][CH2:20][C:19]2[CH:23]=[CH:24][C:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:26][C:18]=2[CH2:17]1)[C:2]1[CH:3]=[CH:4][CH:41]=[CH:6][CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CCCc2ccc(OC(F)(F)F)cc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CCCc2ccc(-c3ccccc3)cc2C1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 115.5 %

Procedure:
To a suspension of N-benzyl-N-tert-butoxycarbonyl-(3-trifluoromethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (500 mg) in toluene (6 ml) and water (2 ml) were added phenylboronic acid (122 mg), sodium carbonate (210 mg) and tetrakis(triphenylphosphine)palladium(0) (35 mg), and the mixture was stirred at 80° C. for 3.5 hours. The resulting mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=30:1 to 20:1) to give N-benzyl-N-(3-phenyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (494 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C:12](=[O:24])[CH2:13][NH:14][C@@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][OH:17])=[CH:11][C:5]=2[CH2:4][O:3]1.[BH4-].[Na+]>CO.C(#N)C>[CH3:1][C:2]1([CH3:25])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:24])[CH2:13][NH:14][C@@H:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:16][OH:17])=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2cc(C(=O)CN[C@H](CO)c3ccccc3)ccc2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC1(C)OCc2cc([C@@H](O)CN[C@H](CO)c3ccccc3)ccc2O1
Temperature: 0 °C
Yield: 52.9 %

Procedure:
To a cooled mixture (internal temp. 2° C.) of 1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[(1S)-2-hydroxy-1-phenylethyl]amino}ethanone (44.9 g) in methanol (450 ml) under nitrogen was added CaCl2.2H2O (38.7 g) in one portion resulting in a slight exotherm (max temp ˜12° C.). After the resulting clear solution had cooled to 0° C., sodium borohydride (10.5 g) was added in four portions over a 50 min period. After a further 2 h at this temperature the volatile material was removed in vacuo resulting in a thick white slurry, to which ethyl acetate (500 ml) was added. The mixture was filtered through a short plug of Hyflo Supercel and the filtrate was washed with water (150 ml), brine (150 ml), dried (Na2SO4) and concentrated in vacuo to give a thick orange oil. The oil was dissolved in acetonitrile (150 ml) and cooled to 5° C. for 18 h. The resulting crystals were filtered and washed with acetonitrile (3×30 ml) to give the title compound (23.9 g). The mother liquor from the filtration was concentrated in vacuo and taken up in acetonitrile (50 ml), cooled to 5° C. for 18 h to provide (after filtration and washing) a second crop of the title compound (3.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([NH:26]C(=O)OC(C)(C)C)[C:10](=[O:25])[NH:11][C:12]2[C:13](=[O:24])[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH:17]=2)[CH:5]=[CH:6][CH:7]=1.Cl>C(Cl)Cl>[NH2:26][C@@H:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C:10]([NH:11][C:12]1[C:13](=[O:24])[NH:14][CH:15]=[C:16]([C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[CH:17]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(Cl)c1)C(=O)Nc1cc(-c2ccncc2)c[nH]c1=O
Agent: Cl
Solvent: ClCCl
Product: N[C@@H](Cc1cccc(Cl)c1)C(=O)Nc1cc(-c2ccncc2)c[nH]c1=O
Yield: 47 %

Procedure:
Crude 25.1.C was stirred in DCM with HCl (4.0 M, dioxane) until the deprotection was complete. The reaction mixture was concentrated to a solid and partitioned with saturated NaHCO3(aq)/CHCl3:IPA (4:1). The aqueous layer was further extracted (2×) and the organics were combined, dried with sodium sulfate, filtered, and concentrated to give a light tan solid (230 mg, 47%).
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][CH:10]=[N:9][C:8]=2[N:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]1=[O:6])[CH2:2][CH3:3].CC(O[Na])=O.[Br:27]Br>C(O)(=O)C>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([Br:27])=[N:9][C:8]=2[N:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]1=[O:6])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)c2[nH]cnc2n(Cc2ccccc2)c1=O
Reactant: BrBr
Agent: CC(=O)O[Na]
Solvent: CC(=O)O
Product: CCCn1c(=O)c2[nH]c(Br)nc2n(Cc2ccccc2)c1=O
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A mixture of 1-propyl-3-benzyl xanthine (2.82 mmol), CH3CO2Na (2.82 mmol) and acetic acid (15 mL) was heated at 40-50° C. To the solution was added Br2 (2.82 mmol) and the reaction was stirred for further 30 minutes at 45° C. After cooling at room temperature the precipitate was collected by filtration and finally crystallized from EtOH. (White solid. Yield 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:23]=[CH:22][C:14]([O:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:26][C:27]1([CH3:35])[CH2:32][CH:31]([CH3:33])[CH2:30][CH:29](O)[CH2:28]1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]([CH3:20])([CH3:21])[C:17]([O:19][C@H:29]3[CH2:30][C@H:31]([CH3:33])[CH2:32][C:27]([CH3:35])([CH3:26])[CH2:28]3)=[O:18])=[CH:22][CH:23]=2)=[O:7])=[CH:24][CH:25]=1
Reactant: CC(C)(Oc1ccc(CCNC(=O)c2ccc(Cl)cc2)cc1)C(=O)O
Reactant: CC1CC(O)CC(C)(C)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Product: C[C@H]1C[C@H](OC(=O)C(C)(C)Oc2ccc(CCNC(=O)c3ccc(Cl)cc3)cc2)CC(C)(C)C1
Reaction time: 24 h
Yield: 45 %

Procedure:
12.5 g (0.034 mol) of 2-(4-(2-parachlorobenzamidoethyl)phenoxy)-2-methylpropionic acid are dissolved in 100 ml of anhydrous dimethylformamide, and 4.8 g of 3,3,5-trimethylcyclohexanol (transform) (0.034 mol) and 0.5 g of dimethylaminopyridine are added. After solubilization, a solution of 7 g of dicyclohexylcarbodiimide (0.034 mol) in 20 ml of dimethylformamide is added slowly at a temperature of around 0° C. The reaction is allowed to continue for 24 hours at ordinary temperature and the precipitate of dicyclohexylurea is filtered off; after evaporation of the filtrate under reduced pressure, the residue is chromatographed on a silica column in a mixture of petroleum ether and ethyl acetate. After evaporation of the solvent, the title derivative is obtained in the form of white crystals melting at 100° C.; the yield is 45%. This product, chromatographed under the conditions of Example 1, shows a single spot of Rf 0.2. The IR spectrum run in KBr has the following characteristic bands: one broad band at 3250 cm-1, a group of fine bands at 3000-2840 cm-1 an strong bands at 1750 cm-1 and 1640 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:23])[C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7].[N-]=[N+]=[N-].[Na+].[NH3:29].[C:30]([OH:33])(=O)[CH3:31]>OS(O)(=O)=O>[CH3:1][O:2][C:3](=[O:24])[CH2:4][NH:5][C:6]([C:8]1[N:29]=[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:15]2[C:10]([C:9]=1[O:23][C:30](=[O:33])[CH3:31])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:7]
Reactant: COC(=O)CNC(=O)C1=C(c2ccccc2)c2ccccc2C1=O
Reactant: N
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Product: COC(=O)CNC(=O)c1nc(-c2ccccc2)c2ccccc2c1OC(C)=O
Reaction time: 0.5 h

Procedure:
[(1-Oxo-3-phenyl-1H-indene-2-carbonyl)-amino]-acetic acid methyl ester (1.864 g, 5.8 mmol) was dissolved in a mixture of concentrated H2SO4 (16 ml) and glacial acetic acid (16 ml) at 50 to 60° C. Then NaN3 (985 mg, 15 mmol) was added in portions with stirring so that the temperature did not exceed 60° C. Stirring was then continued at 50 to 60° C. for additional 30 min before the mixture was poured onto ice (200 g). The resulting mixture was basified by addition of concentrated aqueous NH3 (55 ml, D=0.89 g/ml) and extracted with CH2Cl2 (2×100 ml). The combined organic phases were dried over MgSO4 and then filtered through silica gel. The filtrate was discarded. The silica gel was washed with EtOAc (ca. 400 ml). The resulting solution was concentrated in vacuo to give a dark oil (250 mg). Further purification by flash column chromatography on silica gel using EtOAc and then EtOAc:hexanes=7:3 as the eluent gave the title compound as a tan solid (19 mg); 1H NMR (CDCl3): δ=7.11 to 7.98 (m), 3.75 (d, 2H), 3.68 (s, 1H), 2.19 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][C:7](=O)[CH2:8][O:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=1[Cl:18])[CH3:2].CSC.B.CO>C1(C)C=CC=CC=1>[ClH:16].[Cl:16][C:15]1[CH:14]=[C:13]([Cl:17])[CH:12]=[C:11]([Cl:18])[C:10]=1[O:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2]
Reactant: CCOCCNC(=O)COc1c(Cl)cc(Cl)cc1Cl
Agent: B
Solvent: Cc1ccccc1
Solvent: CSC
Solvent: CO
Product: CCOCCNCCOc1c(Cl)cc(Cl)cc1Cl
Product: Cl
Temperature: 60 °C
Yield: 206.5 %

Procedure:
To a mixture of 31.5 g (0.096 moles) N-(ethoxyethyl)-2.4.6-trichlorophenoxyacetamide in about 200 ml toluene, 18.2 ml (2 equivalents) borane methyl sulfide were added slowly. The resulting mixture was heated to about 60° C. and maintained at that temperature overnight. After cooling, methanol (about 100 ml) was slowly added to the system. After the addition was complete, the mixture was acidified by bubbling in HCl gas. Afterwards, the system was refluxed for about an hour. The solvent was removed by stripping. The residue was re-dissolved in methanol (about 100 ml) and the resulting mixture stripped well. The residue was well dried in vacuum to give 34.6 g of the product, a white solid, melting point 85°-87° C.
Reaction SMILES: C([N:8]1[C:20]2[C:19]([OH:21])=[C:18]3[N:22](C(OC(C)(C)C)=O)[C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][C:28]=4[C:17]3=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([F:37])[CH:13]=2)(OC(C)(C)C)=O.Br[CH2:39][CH2:40][CH2:41][NH:42]C(=O)OC(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[F:37][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:20]1[C:19]([O:21][CH2:39][CH2:40][CH2:41][NH2:42])=[C:18]3[NH:22][C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][C:28]=4[C:17]3=[CH:16][C:15]2=1
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: CC(C)(C)OC(=O)n1c2ccc(F)cc2c2cc3c4cc(F)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: NCCCOc1c2[nH]c3ccc(F)cc3c2cc2c1[nH]c1ccc(F)cc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
A mixture of 5,7-diBOC-2,10-difluoro-6-hydroxyindolo[2,3-b]carbazole (4.03 g, 8.0 mmol), tert-butyl 3-bromopropylcarbamate (2.20 g, 9.2 mmol), and Cs2CO3 (10.0 g, 31 mmol), and anhydrous MeCN (120 mL) was heated at 100° C. under Ar until the starting material disappeared (˜2 h). After cooled to RT, the inorganic salt was removed by filtration, washed with dichloromethane, and the combined filtrate was concentrated. The resulting residue 3-(2,10-difluoro-5,7-diBOC-indolo[2,3-b]carbazol-6-yloxy)propan-1-amine was dissolved in CH2Cl2 (100 mL). TFA (10 mL) was added and the solution was stirred at RT overnight. After evaporation, the residue was subjected to chromatography on silica gel, eluting with ethyl acetate/hexane/MeOH (10% cNH3.H2O) (50/50/10-100/0/10), giving 2.35 g (82%) of 3-(2,10-difluoro-5,7-dihydroindolo[2,3-b]carbazol-6-yloxy)propan-1-amine. 1H NMR (400 MHz, DMSO-d6) δ 11.8 (br s, 2H), 8.56 (s, 1H), 7.89 (dd, J=9.4, 2.6 Hz, 2H), 7.44 (dd, J=8.6, 4.6 Hz, 2H), 7.17 (td, J=9.2, 2.4 Hz, 2H), 4.36 (t, J=6.2 Hz, 2H), 2.97 (t, J=6.2 Hz, 2H), 1.98 (pentalet, J=6.2 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][NH2:8])=[O:6].[CH:13]([C:16]1[CH:35]=[CH:34][C:19]([CH2:20][O:21][C:22]2[C:29]([O:30][CH3:31])=[CH:28][C:25]([CH:26]=O)=[CH:24][C:23]=2[O:32][CH3:33])=[CH:18][CH:17]=1)([CH3:15])[CH3:14]>CC(O)C>[CH:13]([C:16]1[CH:35]=[CH:34][C:19]([CH2:20][O:21][C:22]2[C:29]([O:30][CH3:31])=[CH:28][C:25]([CH:26]=[N:8][NH:7][C:5](=[O:6])[C:4]3[CH:9]=[CH:10][C:11]([OH:12])=[C:2]([NH2:1])[CH:3]=3)=[CH:24][C:23]=2[O:32][CH3:33])=[CH:18][CH:17]=1)([CH3:15])[CH3:14]
Reactant: NNC(=O)c1ccc(O)c(N)c1
Reactant: COc1cc(C=O)cc(OC)c1OCc1ccc(C(C)C)cc1
Solvent: CC(C)O
Product: COc1cc(C=NNC(=O)c2ccc(O)c(N)c2)cc(OC)c1OCc1ccc(C(C)C)cc1
Yield: 103.6 %

Procedure:
The above 3-amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and the above 4-(4-isopropylbenzyloxy)-3,5-dimethoxybenzaldehyde(93 mg, 0.3 mmol) were dissolved in 2-propanol (4 ml) and the mixture was heated at reflux temperature for 16 hours. The cooled mixture was filtered and the precipitate was washed with 2-propanol (2×4 ml) and dried by suction to afford 144 mg (100%) of the title compound as a solid. M.p.: 174-175° C.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]([C:6]1[N:10]2[CH2:11][CH2:12][N:13](C(OCC3C=CC=CC=3)=O)[CH2:14][C:9]2=[N:8][N:7]=1)([CH3:5])[CH3:4]>CO.[Pd]>[CH3:25][N:2]([CH3:1])[C:3]([C:6]1[N:10]2[CH2:11][CH2:12][NH:13][CH2:14][C:9]2=[N:8][N:7]=1)([CH3:5])[CH3:4]
Reactant: CN(C)C(C)(C)c1nnc2n1CCN(C(=O)OCc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: CN(C)C(C)(C)c1nnc2n1CCNC2
Reaction time: 8 h

Procedure:
A mixture of P5 (0.12 mmol) and Pd/C (10%, 22 mg) in MeOH (0.2 M) was stirred under H2 atmosphere overnight. The catalyst was filtered off and the solvent removed under reduced pressure to provide a crude oil used as such in the next step. MS (ES) C10H19N5 required: 209. found: 210 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[Br:15]N1C(=O)CCC1=O>C(#N)C>[Br:15][C:9]1[C:10]([OH:11])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccc(O)c(C(C)(C)C)c1
Solvent: CC#N
Product: CC(=O)c1cc(Br)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
1-(3-tert-Butyl-4-hydroxyphenyl)ethanone (690.9 g, 3.75 mol) was dissolved in acetonitrile (6.05 L), and a solution of N-bromosuccinimide (701.28 g, 3.94 mol) in acetonitrile (5 L) was added dropwise while stirring on ice. After heating to room temperature, the solvent was concentrated to approximately 3 L. For extraction, n-heptane (5 L) and water (5 L) were added, and the solution was separated. The aqueous layer was extracted further with n-heptane (2 L), and the solution was separated. The organic layers were combined, washed with 5% aqueous sodium thiosulfate (1 L) and water (2 L), and concentrated under reduced pressure (35° C.) to obtain 977.0 g of the subject compound as a brownish oily substance (yield: 99.1%, HPLC purity: 95.8%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[F:10]F>C(#N)C>[NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][C:5]([F:10])=[CH:6][N:7]=1
Reactant: N#Cc1nccnc1N
Reactant: FF
Solvent: CC#N
Product: N#Cc1nc(F)cnc1N
Temperature: 25 °C

Procedure:
In 15 mL of acetonitrile was dissolved 0.3 g of 3-amino-2-pyrazinecarbonitrile. While cooling the solution with ice, 10% fluorine gas (a fluorine gas diluted with nitrogen gas) was introduced into the solution at a rate of 45 mL per minute for a period of 20 minutes. Then, while elevating the temperature from the ice-cooled temperature to room temperature, nitrogen gas was introduced for one hour. The reaction mixture was concentrated under reduced pressure, and the oily product thus obtained was purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=3:1] to obtain 0.01 g of 3-amino-6-fluoro-2-pyrazinecarbonitrile as a yellow-colored solid product.
Reaction SMILES: Cl.[NH2:2][O:3][CH2:4][C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6].[CH:11]1[C:20]2[N:21]3[C:25]([C:26](=O)[C:18]4[C:19]=2[C:14]([CH:15]=[CH:16][N:17]=4)=[CH:13][CH:12]=1)=[CH:24][CH:23]=[CH:22]3>O.C(O)C.N1C=CC=CC=1>[CH:8]([O:7][C:5]([CH2:4][O:3][N:2]=[C:26]1[C:18]2[C:19]3[C:14]([CH:15]=[CH:16][N:17]=2)=[CH:13][CH:12]=[CH:11][C:20]=3[N:21]2[C:25]1=[CH:24][CH:23]=[CH:22]2)=[O:6])([CH3:10])[CH3:9]
Reactant: CC(C)OC(=O)CON
Reactant: O=c1c2nccc3cccc(c32)n2cccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCO
Product: CC(C)OC(=O)CON=c1c2nccc3cccc(c32)n2cccc12
Yield: 74.3 %

Procedure:
A solution of isopropyl aminooxyacetate hydrochloride (23.4 g.) in water (128 cc.) is added to a stirred boiling suspension of 7H-indolizino[5,6,7-ij]isoquinolin-7-one (16.0 g.) in ethanol (320 cc.) and pyridine (11.05 g.). Boiling is maintained for 2 hours 45 minutes. After cooling to a temperature of about 20° C., water (960 cc.) is added with stirring. After stirring for 16 hours, the brown amorphous product which has precipitated is filtered off, then washed with distilled water and dissolved in ethyl acetate (500 cc.). The resulting organic solution is washed with water (3 × 200 cc.) and then dried over calcined magnesium sulphate. After evaporation of the solvent under reduced pressure, crude 7-isopropoxycarbonylmethoxyimino-7H-indolizino[5,6,7-ij]isoquinoline (18.1 g.) is obtained and is recrystallised from a mixture of ethyl acetate (115 cc.) and cyclohexane (460 cc.). 7-Isopropoxycarbonylmethoxyimino-7H-indolizino[5,6,7-ij]isoquinoline, solvated by ethyl acetate, (12.49 g.), melting at 70° C., is thus obtained.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)CCl)=[CH:5][CH:4]=1.[OH:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:32]2[S:33][CH:34]=[CH:35][C:36]=2[CH3:37])[CH2:27][C:28]([O:30]C)=[O:29])=[CH:22][CH:21]=1.[C:38]([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:11][CH:10]=2)=[CH:7][C:8]=1[CH2:38][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:32]2[S:33][CH:34]=[CH:35][C:36]=2[CH3:37])[CH2:27][C:28]([OH:30])=[O:29])=[CH:22][CH:21]=1
Reactant: COC(=O)CC(c1ccc(O)cc1)c1sccc1C
Reactant: O=C([O-])[O-]
Reactant: FC(F)(F)c1ccc(-c2cccc(CCl)c2)cc1
Agent: [Cs+]
Solvent: CC(C)=O
Product: Cc1ccsc1C(CC(=O)O)c1ccc(OCc2cc(-c3ccccc3)ccc2C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
Benzyl chloride 2.3 (113 mg, 0.434 mmol) and phenol 54.1 (100 mg, 0.362 mmol) were dissolved in acetone (1 mL) and treated with Cs2CO3 (371 mg, 1.14 mmol). The reaction was stirred at 50° C. for 16 h, filtered and concentrated. The residue was purified by column chromatography (silica gel, 30% to 60% ethyl acetate in hexanes). Eluant containing desired compound was concentrated and dissolved in a THF/MeOH/2N LiOH(aq) (1:1:1) solution (2 mL). The mixture was stirred at room temperature for 90 min., the solution was poured into 0.65 N HCl (aq.) (2 mL). The aqueous phase was extracted with dichloromethane (3×10 mL) and the combined organic phases were dried over Na2SO4. After filtration and drying, 154 mg (0.311 mmol) of carboxylic acid 54 was obtained. 1H NMR (400 MHz) (CDCl3) δ 7.43-7.70 (m, 8H), 7.21 (d, 2H, J=8.6 Hz), 7.05 (d, 1H, J=5.0 Hz), 6.92 (d, 2H, J=8.6 Hz), 6.76 (d, 1H, 5.0 Hz), 5.09 (s, 2H), 4.74 (t, 1H, J=7.8 Hz), 3.05 (d, 2H, J=7.8 Hz), 2.15 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[C:18]3[C:17](=[O:19])O[C:15](=[O:20])[C:14]=3[CH:13]=[CH:12][CH:11]=2)=[O:8])=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][NH2:35])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1>C(O)(=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:18]=2[C:17](=[O:19])[N:35]([CH2:34][CH2:33][N:30]2[CH2:29][CH2:28][N:27]([C:24]4[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=4)[CH2:32][CH2:31]2)[C:15]3=[O:20])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccc2c1C(=O)OC2=O)c1ccc(Cl)s1
Reactant: NCCN1CCN(c2ccncc2)CC1
Solvent: CC(=O)O
Product: O=C(Nc1cccc2c1C(=O)N(CCN1CCN(c3ccncc3)CC1)C2=O)c1ccc(Cl)s1
Reaction time: 24 h

Procedure:
310 mg (1 mmol) of 5-chloro-N-(1,3-dioxo-1,3-dihydro-2-benzofuran-4-yl)-2-thiophenecarboxamide and 0.64 g (1 mmol) of 2-[4-(4-pyridinyl)piperazino]ethylamine (obtainable by heating 4-chloropyridine with aminoethylpiperazine or according to German Offenlegungschrift 2024350) are boiled in 40 ml of glacial acetic acid overnight. 340 mg of 5-chloro-N-(1,3-dioxo-1,3-dihydro-2-benzofuran-4-yl)-2-thiophenecarboxamide are added and the mixture is then boiled for another 24 h and subsequently concentrated under reduced pressure, water is added, the aqueous phase is extracted four times with ethyl acetate and the combined organic phases are dried with Na2SO4, admixed with silica gel and concentrated under reduced pressure. Chromatography on silica gel using a toluene/ethyl acetate→toluene/ethanol gradient gives 140 mg (28.2% of theory) of the target compound of m.p. 168° C. and Rf (SiO2, toluene/ethanol=1:1)=0.28.
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH2:12][C@@H:13]([CH3:26])[C:14]([O:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1)=[O:15].[P:27](Cl)(Cl)(=[O:39])[O:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.C(Cl)[Cl:43]>>[Cl:43][C:30]1[CH:31]=[CH:32][C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:29]=1[O:28][P:27](=[N:12][C@@H:13]([CH3:26])[C:14]([O:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1)=[O:15])=[O:39]
Reactant: ClCCl
Reactant: O=P(Cl)(Cl)Oc1cccc2ccccc12
Reactant: C[C@H](N)C(=O)OC1Cc2ccccc2C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: C[C@H](N=[P+]([O-])Oc1c(Cl)ccc2ccccc12)C(=O)OC1Cc2ccccc2C1
Yield: 65 %

Procedure:
Using the general procedure for synthesizing naphthyl (aminoacid ester) phosphorochloridates the tosylate salt of (S)-2,3-dihydro-1H-inden-2-yl 2-aminopropanoate (2.00 g, 5.30 mmol), naphthalen-1-yl phosphorodichloridate (1.38 g, 5.30 mmol) and TEA (1.48 mL, 10.60 mmol) in 30 mL of dry DCM, were combined to give (2S)-2,3-dihydro-1H-inden-2-yl 2-(chloro(naphthalen-1-yloxy)phosphorylamino)propanoate in 65% yield (1.48 g), as a yellow, thick oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:16]O)([CH2:13][O:14][CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:37]1(=[O:47])[NH:41][C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:16][N:41]2[C:37](=[O:47])[C:38]3[C:39](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:40]2=[O:42])([CH2:13][O:14][CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCC1(CO)CCN(Cc2ccccc2)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCC1(CN2C(=O)c3ccccc3C2=O)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.9 %

Procedure:
A solution of (1-benzyl-3-methoxymethylpyrrolidin-3-yl)methanol (Example A19, 1.71 g, 7.27 mmol), triphenylphosphine (2.16 g, 8.22 mmol), phthalimide (1.14 g, 7.73 mmol), and anhydrous tetrahydrofuran is cooled to 0° C. and treated with diethyl azodicarboxylate (1.62 g, 9.31 mmol). The resulting mixture is stirred at room temperature for 18 hours and concentrated under vacuum. The residue is purified by flash column chromatography (1:5 ethyl acetate/hexanes) to afford the title compound, (0.58 g) as a solid. 1H NMR (200 MHz, CDCl3): δ 7.91–7.80 (m, 2H), 7.78–7.66 (m, 2H), 7.39–7.11 (m, 5H), 3.95–3.72 (m, 2H), 3.65–3.40 (m, 2H), 3.31 (s, 2H), 3.27 (s, 3H), 2.72–2.34 (m, 4H), 2.02–1.82 (m, 1H), 1.76–1.56 (m, 1H). MS ES: m/z 365 (MH+).