Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[C:27]([Cl:35])[CH:26]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:18]([CH:19]([OH:21])[CH3:20])=[CH:17][CH:16]=[CH:15][N:14]3[CH:22]=2)=[CH:7][CH:6]=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C.[CH3:58][N:59]([CH3:64])[CH2:60][C:61](O)=[O:62]>C(Cl)Cl.O>[Cl:35][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[O:31][CH:32]([CH3:33])[CH3:34])[C:24]([NH:23][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:18]([CH:19]([OH:21])[CH3:20])=[CH:17][CH:16]=[CH:15][N:14]3[CH:22]=2)=[CH:7][CH:6]=1)[CH2:2][NH:1][C:61](=[O:62])[CH2:60][N:59]([CH3:64])[CH3:58])=[O:36]
Reactant: CC(C)Oc1ccc(C(=O)N[C@H](CN)Cc2ccc(-c3cn4cccc(C(C)O)c4n3)cc2)cc1Cl
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)Oc1ccc(C(=O)N[C@H](CNC(=O)CN(C)C)Cc2ccc(-c3cn4cccc(C(C)O)c4n3)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.3 %

Procedure:
A mixture of N-[(1S)-2-amino-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-3-chloro-4-[(1-methylethyl)oxy]benzamide (0.912 g, 1.80 mmol), EDCl (0.69 g, 3.6 mmol), N,N-diisopropylethylamine (0.466 g, 3.6 mmol), and N,N-dimethylglycine (0.372 g, 3.6 mmol) in methylene chloride (17 mL) was stirred overnight at room temperature. The reaction was diluted with water, washed with brine, dried (Na2SO4), and concentrated. The residue was purified by flash chromatography on silica gel (8%-10% MeOH:CH2Cl2) to give the title compound (0.515 g, 48%) as a pale yellow solid. MS(ES+) m/e 592 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=O>C(OC(=O)C)(=O)C>[Br:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cccc(C)n1
Reactant: O=Cc1cccc(Br)c1
Solvent: CC(=O)OC(C)=O
Product: Cc1cccc(C=Cc2cccc(Br)c2)n1
Yield: 7.7 %

Procedure:
A solution of 24 ml (200 mMol) of 2,6-dimethyl pyridine and 25.6 ml (207 mMol) of 3-bromobenzaidehyde in 38 ml of acetic anhydride is heated under reflux for 7.5 hours. The acetic anhydride is then evaporated in vacuo, and the residue is dissolved in 500 ml of 4N hydrochloric acid and twice extracted with 200 ml each of hexane. The water phase is then extracted four times with 300 ml each of tert.-butyl methyl ether. The combined organic phases are washed twice with 300 ml each of a saturated solution of NaHCO3 in water, then once with 300 ml of brine (300 ml), dried over sodium sulfate, filtrated and evaporated in vacuo yielding 4.2 g of the title compound as colorless crystals of melting point 58-590.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:6]=[N:7][C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[CH:14]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.C(=O)(O)[O-].[Na+]>ClCCl>[F:16][C:2]([F:1])([F:15])[CH2:3][O:4][C:5]1[CH:6]=[N+:7]([O-:25])[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[CH:14]=1
Reactant: FC(F)(F)COc1cnc2c(c1)CCCC2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1cc(OCC(F)(F)F)cc2c1CCCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 142.5 %

Procedure:
A mixture of 3-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydroquinoline (495 mg, 2.1 mmol) and 3-chloroperbenzoic acid (ca 75%, 739 mg, 3.2 mmol) in dichloromethane (10 mL) was stirred at room temperature for 1.5 hour. Then, the mixture was poured into saturated sodium bicarbonate aqueous solution (50 mL), and the aqueous phase was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give 740 mg of the crude title compound. This was used for the next step without further purification:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:29])([F:28])[C:13]1[NH:17][CH:16]2[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH:15]2[N:14]=1.C(N(CC)CC)C>ClCCl>[F:29][C:12]([F:11])([F:28])[C:13]1[NH:17][C:16]2[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:20][C:15]=2[N:14]=1
Reactant: CC(C)(C)OC(=O)N1CC2N=C(C(F)(F)F)NC2C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1Cc2nc(C(F)(F)F)[nH]c2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To oxalyl chloride (0.124 mL, 2.0M in dichloromethane) in dichloromethane (2 mL) at −78° C. was added dimethylsulfoxide (0.035 mL) in dichloromethane (0.2 mL). The mixture was stirred for 10 min and the product from Step D (69 mg) was added as a solution in dichloromethane (2 mL). The reaction mixture was stirred for 30 min at −78° C. and triethylamine (17 mL) was added rapidly. After 30 min, the −78° C. bath was removed and the reaction warmed to ambient temperature over 30 min at which point the reaction was quenched with saturated aqueous sodium bicarbonate solution (5 mL) The phases were separated and the aqueous phase extracted with dichloromethane (3×10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, evaporated in vacuo and used without further purification. LC/MS 278.2 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][S:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][CH2:32][C:33]([NH:1][CH:2]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[CH2:6][S:5][C:4]4[CH:13]=[CH:14][CH:15]=[CH:16][C:3]3=4)=[O:34])[CH2:28][CH2:29]2)=[CH:22][CH:23]=1
Reactant: NC1c2ccccc2CSc2ccccc21
Reactant: O=C(O)CCCN1CCN(c2ccc(F)cc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CCCN1CCN(c2ccc(F)cc2)CC1)NC1c2ccccc2CSc2ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 39.5 %

Procedure:
A mixture of 2.3 g of 11-amino-6,11-dihydrodibenzo[b,e]thiepin, 2.9 g of 4-[4-(4-fluorophenyl)-1-piperazinyl]butyric acid, 2.3 g of dicyclohexylcarbodiimide and 50 ml of methylene chloride is stirred at room temperature for 15 hours. After removal of the precipitated crystals by filtration, the filtrate is concentrated under reduced pressure. The residue is recrystallized from chloroform-n-hexane to give 1.9 g of the title compound, m.p. 194°-194.5° C.;
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=[O:11])=[C:7]([CH2:12][O:13][CH3:14])[C:6]=2[CH:15]=1.[CH:16]1([Mg]Br)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[Cl-].[NH4+].C[N+]1([O-])CCOCC1>O1CCCC1.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.C(#N)C>[CH:16]1([C:10]([C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:15][C:6]=3[C:7]=2[CH2:12][O:13][CH3:14])=[O:11])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Br[Mg]C1CCCCC1
Reactant: COCc1c(C=O)oc2ccc(F)cc12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: C1CCOC1
Product: COCc1c(C(=O)C2CCCCC2)oc2ccc(F)cc12
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution (20 mL) of 5-fluoro-3-(methoxymethyl)-1-benzofuran-2-carbaldehyde (1.07 g) synthesized above in tetrahydrofuran was added a 1.0M solution (7.71 mL) of cyclohexylmagnesium bromide in tetrahydrofuran at 0° C., and the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, tetrahydrofuran was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10-50% ethyl acetate/hexane) to give a pale-yellow oil. To a mixture of the obtained oil, 4-methylmorpholine N-oxide (841 mg) and acetonitrile (20 mL) was added tetrapropylammonium perruthenate (126 mg), and the mixture was stirred at room temperature for 1.5 hr and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% ethyl acetate/hexane) to give the title object compound (857 mg, 57%) as a colorless oil.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[CH3:8][NH:9][CH3:10].Cl>C1C=CC=CC=1>[CH3:8][N:9]([CH3:10])[C@@H:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[OH:7]
Reactant: CNC
Reactant: C1CCC2OC2C1
Agent: Cl
Solvent: c1ccccc1
Product: CN(C)[C@@H]1CCCC[C@H]1O

Procedure:
This compound was previously prepared from cyclohexene oxide and dimethylamine in benzene at room temperature for 14 days in 95% yield, b.p. 90° (20 mm): J. Chem. Soc., 4835 (1965); or in autoclave: C. A. 67, 63899 d, Rocz. Chem. 41, 541 (1967) b.p. 88° (14 mm); also Bull. Soc. Chim. France, 850 (1947): hydrochloride and resolution reported.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>CO.O.[Zn]>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]([O:12][CH3:13])=[O:11])=[CH:20][CH:19]=1
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C

Procedure:
Methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-nitrophenyl)propanoate (44.0 g, 136 mmol) in methanol (750 mL) and water (75 mL) was treated with ammonium chloride (10.9 g, 203 mmol) and then zinc (71 g, 1.1 mol). The solution was stirred at reflux for 1 h. The solution was filtered through celite, the residue concentrated under vacuum to remove methanol, the water solution extracted with ethyl acetate (500 mL) and dried over sodium sulfate. The product was a yellow foam (38.2 g, 96%). 1H NMR (400 MHz, CD3OD): δ 6.91 (d, J=8.4 Hz, 2H), 6.65 (d, J=8.3 Hz, 2H), 4.28–4.22 (m, 1H), 3.66 (s, 3H), 2.98–2.90 (m, 1H), 2.86–2.78 (m, 1H), 1.39 (s, 9H). LCMS found for C15H22N2O4Na (M+Na)+: m/z=317.
Reaction SMILES: Br[C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([C:14]([N:16]3[CH2:21][CH2:20][CH:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)=[O:15])[CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:34]1(B(O)O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[NH4+].[OH-]>C1(C)C=CC=CC=1.CO.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.O.C(Cl)Cl>[C:34]1([C:2]2[C:7]3[CH2:8][CH2:9][CH:10]([C:14]([N:16]4[CH2:21][CH2:20][CH:19]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:18][CH2:17]4)=[O:15])[CH2:11][C:12](=[O:13])[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C1CC(C(=O)N2CCC(c3ccccc3)CC2)CCc2c(Br)cccc21
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CC(C(=O)N2CCC(c3ccccc3)CC2)CCc2c1cccc2-c1ccccc1
Yield: 101.2 %

Procedure:
0.6 g (1.54 mmol) of (±)-1-bromo-7-[(4-phenylpiperidin-1-yl)carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one were dissolved in 5 mL of toluene under a nitrogen atmosphere, then 54 mg (0.016 mmol) of Pd(PPh3)4 were added, followed by 1.5 mL of 2M Na2CO3 solution and 225 mg (1.85 mmol) of benzeneboronic acid dissolved in 2 mL of MeOH. The resulting heterogeneous mixture was refluxed for 8 h under vigorous stirring, then after cooling it was taken up with CH2Cl2 and water. 8 mL of 2M Na2CO3 solution and 1 mL of conc. NH4OH were added, the organic layer was collected and dried, the solvent was removed in vacuo, yielding 660 mg of the title product which was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[O:22]1C2CCCC(N)C=2C=C1>>[CH2:1]([C:3]1[C:4]([NH:11][CH:12]2[C:20]3[CH:15]=[CH:14][O:22][C:19]=3[CH2:18][CH2:17][CH2:16]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: NC1CCCc2occc21
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1cnc(CC)c(NC2CCCc3occc32)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 4,5,6,7-tetrahydro-1-benzofuran-4-amine and making non-critical variations provided the title compound as a oil:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[C:6]([F:12])[CH:5]=1.[CH3:13]I>CN(C=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][CH3:13])=[C:6]([F:12])[CH:5]=1
Reactant: OCc1ccc(Br)cc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.2 %

Procedure:
The title compound was prepared according to General Method 8. To a suspension of NaH (50-60% mineral oil, 8 g, 0.33 mol) in Dry DMF (200 mL) at 0° C. was added (4-bromo-2-fluorophenyl)methanol (27 g, 0.1317 mol). The reaction mixture was stirred for 15 min at 0° C. and then warmed to and stirred at RT for 30 min. The reaction mixture was again cooled to 0° C. and MeI (15 mL, 0.1975 mol) was added drop wise. After addition was complete, the reaction mixture was warmed to room temperature and stirred for 1 h. Ice-water was added and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtained 4-bromo-2-fluoro-1-(methoxymethyl)benzene (24 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].Cl[CH2:15][CH2:16][O:17]C1CCCCO1>>[OH:17][CH2:16][CH2:15][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=2)[C:2]([CH3:13])([CH3:1])[C:3]1=[O:12]
Reactant: ClCCOC1CCCCO1
Reactant: Cc1ccc2c(c1)NC(=O)C2(C)C
Product: Cc1ccc2c(c1)N(CCO)C(=O)C2(C)C

Procedure:
Prepared from 3,3,6-trimethyloxindole (prepared by the method of Endler and Becker; Organic Syntheses Coll. vol. 4 page 657) and 2-(2-chloroethoxy)tetrahydro-2H-pyran as described above.
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([S:8]([C:11]1[CH:12]=[C:13]([C:17]2[CH:25]=[C:24]([CH2:26]O)[CH:23]=[C:22]3[C:18]=2[C:19]2[CH:31]=[C:30]([CH3:32])[CH:29]=[N:28][C:20]=2[NH:21]3)[CH:14]=[CH:15][CH:16]=1)(=[O:10])=[O:9])[CH3:7].[CH:33]([N:36](C(C)C)[CH2:37]C)(C)C.CNC>C1COCC1>[CH2:6]([S:8]([C:11]1[CH:12]=[C:13]([C:17]2[CH:25]=[C:24]([CH2:26][N:36]([CH3:37])[CH3:33])[CH:23]=[C:22]3[C:18]=2[C:19]2[CH:31]=[C:30]([CH3:32])[CH:29]=[N:28][C:20]=2[NH:21]3)[CH:14]=[CH:15][CH:16]=1)(=[O:10])=[O:9])[CH3:7]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCS(=O)(=O)c1cccc(-c2cc(CO)cc3[nH]c4ncc(C)cc4c23)c1
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1cccc(-c2cc(CN(C)C)cc3[nH]c4ncc(C)cc4c23)c1
Reaction time: 3 h
Yield: 65.4 %

Procedure:
Methanesulfonyl chloride (18 μL, 0.24 mmol) was added to a solution of Compound 133 (46 mg, 0.12 mmol) and diisopropylethylamine (43 μL, 0.25 mmol) in THF (1 mL) at 0° C. After stirring for 3 h, dimethylamine (2M, 1 mL, 2 mmol) was added, and the reaction stirred for 16 h. The solution was concentrated in vacuo and purified by prep-HPLC to give 32 mg (65%) of the title compound as a pale yellow oil. 1H NMR (400 MHz, CD3OD) δ 8.36 (br s, 1H), 8.22 (s, 1H), 8.13 (d, 1H, J=7.6 Hz), 8.05 (d, 1H, J=7.6 Hz), 7.88-7.94 (m, 2H), 7.85 (s, 1H), 7.44 (s, 1H), 4.57 (s, 2H), 3.33 (q, 2H, J=7.2Hz), 2.94 (s, 6H), 2.39 (s, 3H), 1.30 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C23H25N3O2S, 408; found 408.
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([CH:12]3[C:24]4[NH:23][C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16]=4[CH2:15][CH2:14][N:13]3[C:25]3[N:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=4)=[CH:27][N:26]=3)=[CH:6][C:5]=2[O:4]1.CN(C=[O:45])C>>[CH3:40][O:39][C:33]1[CH:32]=[C:31]([C:28]2[CH:29]=[N:30][C:25]([N:13]3[CH2:14][C:15]4[C:16](=[O:45])[C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=5[NH:23][C:24]=4[CH:12]3[C:7]3[CH:8]=[CH:9][C:10]4[O:11][CH2:3][O:4][C:5]=4[CH:6]=3)=[N:26][CH:27]=2)[CH:36]=[CH:35][C:34]=1[O:37][CH3:38]
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2cnc(N3CCc4c([nH]c5ccccc45)C3c3ccc4c(c3)OCO4)nc2)cc1OC
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2cnc(N3Cc4c([nH]c5ccccc5c4=O)C3c3ccc4c(c3)OCO4)nc2)cc1OC

Procedure:
Sodium hydride (60% in mineral oil, 40 mg, 1.0 mmol) and 1-(3,4-methylenedioxyphenyl)-2-[5-(3,4-dimethoxyphenyl)-pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-β-carboline (218 mg, 0.43 mmol) (prepared as in Example 13) in DMF (10 mL, anhydrous) were stirred at room temperature for 30 min. Dry air was then bubbled through the solution for 16 h. Ethyl acetate (100 mL) and saturated NaHCO3 were added, the organic phase was washed with water, brine, and dried with MgSO4. Solvent was evaporated and the residue purified by chromatography (silica gel, ethyl acetate) to yield the product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:26])[C:7]([C:22]([O:24]C)=[O:23])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([N+:19]([O-])=O)[CH:13]=2)=[CH:4][C:3]=1[F:27].C(O)(=O)C.ClC(Cl)C>CO.[Pd]>[NH2:19][C:14]1[CH:13]=[C:12]([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:27])=[C:2]([Cl:1])[N:11]=3)[C:6](=[O:26])[C:7]([C:22]([OH:24])=[O:23])=[CH:8]2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: COC(=O)c1cn(-c2ccc(F)c([N+](=O)[O-])c2)c2nc(Cl)c(F)cc2c1=O
Agent: [Pd]
Solvent: CO
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(Cl)nc32)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
Methyl 7-chloro-6-fluoro-1-(4-fluoro-3-nitrophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (600 mg) was dissolved in 30 ml of methanol, 10 ml of acetic acid and 30 ml of dichloroethane, and 100 mg of 10% palladium on carbon was added thereto. Under a hydrogen atmosphere, the solution was stirred at room temperature overnight. The catalyst was removed by a membrane filter and the filtrate was concentrated in vacua. To the residue were added 4 ml of acetic acid and 1 ml of hydrochloric acid. The solution was heated and stirred at 100° C. overnight. The reaction solution was concentrated in vacua. Diethyl ether was added to the residue whereupon the solid was collected by filtration and washed with diethyl ether to give 160 mg of the title compound.
Reaction SMILES: [CH2:1]([C@@:8]([C@@:31]([CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)([C@:33]([CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)([C@@:35]([CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([CH:37](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[OH:38])[OH:36])[OH:34])[OH:32])([OH:30])[CH:9](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH2:58]([C@@:35]([C@@:33]([CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)([C@:31]([CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)([C@@:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:9][OH:10])[OH:30])[OH:32])[OH:34])([OH:36])[CH2:37][OH:38])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1
Reactant: OC(C(c1ccccc1)(c1ccccc1)c1ccccc1)[C@](O)(Cc1ccccc1)[C@@](O)(Cc1ccccc1)[C@](O)(Cc1ccccc1)[C@@](O)(Cc1ccccc1)C(O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: OC[C@](O)(Cc1ccccc1)[C@@](O)(Cc1ccccc1)[C@](O)(Cc1ccccc1)[C@](O)(CO)Cc1ccccc1
Yield: 50 %

Procedure:
Compound 78 was dissolved in 20 ml of dioxane, followed by an addition of 2 ml of 1N HCl. The resultant mixture was stirred at 90° C. for 3 hours. After neutralizing the reaction mixture with an aqueous solution of sodium bicarbonate, it was extracted with ether. The extract was washed with water, dried and subjected to flash column chromatography (solvent: 1:2 mixture of ethyl acetate and hexane) to obtain 504 mg of Compound 79 (yield: 50% based on Compound 66).
Reaction SMILES: C(O)(=O)C.Cl.[NH2:6][C@H:7]1[C:15]2[C:10](=[CH:11][C:12]([C:17]([O:19][CH3:20])=[O:18])=[C:13]([F:16])[CH:14]=2)[CH2:9][CH2:8]1.[CH3:21][C:22]([CH3:24])=O.[BH4-].[Na+]>CO>[F:16][C:13]1[CH:14]=[C:15]2[C:10]([CH2:9][CH2:8][C@H:7]2[NH:6][CH:22]([CH3:24])[CH3:21])=[CH:11][C:12]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: CC(C)=O
Reactant: COC(=O)c1cc2c(cc1F)[C@H](N)CC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc2c(cc1F)[C@H](NC(C)C)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
Glacial acetic acid (0.33 ml) was added to a mixture of (R)-methyl 1-amino-6-fluoro-2,3-dihydro-1H-indene-5-carboxylate hydrochloride (A-05) [see above] (4.1 g, 19.6 mmol, 1 eq) and acetone (28.8 ml, 392.3 mmol, 20 eq) in methanol (100 ml), and the reaction mixture was stirred for 3 h at room temperature. It was then cooled to 0° C. and NaBH4 (2.23 g, 58.8 mmol, 3 eq) was added in portions. Stirring was carried out for a further 2 h at room temperature. After monitoring by TLC, concentration was carried out under reduced pressure and the residue was diluted with water (100 ml). Extraction with dichloromethane (150 ml) was carried out and the organic phase was washed with sat. sodium hydrogen carbonate solution (100 ml) and dried over sodium sulfate. The solvent was distilled off under reduced pressure and then the crude product was purified by column chromatography (Alox, 10% ethyl acetate/hexane) to yield the desired product in the form of a light-brown liquid. Yield: 76% (3.75 g, 19.61 mmol)
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[CH2:16][C:11]3[C:12]4=[C:13]2[C:4](=[CH:5][CH:6]=[C:7]4[CH:8]=[CH:9][CH:10]=3)[CH:3]=1.C(Br)CCCCCCC.[OH-].[Na+]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:1][C:2]1[CH:15]=[C:14]2[CH2:16][C:11]3[C:12]4[C:13]2=[C:4]([CH2:5][CH2:6][C:7]=4[CH:8]=[CH:9][CH:10]=3)[CH:3]=1
Reactant: Brc1cc2c3c(ccc4cccc(c43)C2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCCCCCCCBr
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cc2c3c(c1)Cc1cccc(c1-3)CC2
Yield: 136.9 %

Procedure:
2-bromo-4H-cyclopenta[def]phenanthrene (2.6 g, 9.7 mmol) and octyl bromide (3.6 g, 18.5 mmol) in a 50 ml round bottom flask were dissolved with toluene (10 ml), and TBAB (tetrabutylammoniumbromide) (0.125 g, 0.385 mmol) was added thereto. A solution of NaOH (3.1 g, 77 mmol) in water (50 ml) was added to the reaction mixture, and the resultant solution was refluxed for two days. After the reaction was terminated, the reaction solution was extracted with chloroform. The organic phase was dried over MgSO4, concentrated, and purified by silica gel column chromatography (eluent: n-hexane). The eluate was distilled under a reduced pressure to remove unreacted octyl bromide, thereby giving a compound 2 (3.6 g, 75%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[O:4]1.C(N(CC)CC)C.[CH:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(Cl)Cl>[CH3:14][O:13][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[O:4][CH:3]([CH2:2][NH:1][C:28]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:29])[CH2:12][CH2:11]2
Reactant: O=C(Cl)C1CCCCC1
Reactant: COc1cccc2c1OC(CN)CC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2c1OC(CNC(=O)C1CCCCC1)CC2
Reaction time: 8 h

Procedure:
A mixture of 9.5 g (49 mmol) of 2-aminomethyl-8-methoxychroman and 4.9 ml (49 mmol) of triethylamine in 50 ml of anhydrous methylene chloride is added dropwise to a solution of 7.2 g (49 mmol) of cyclohexanecarbonyl chloride in 75 ml of anhydrous methylene chloride, while stirring and cooling with ice. After the mixture has been left to stand overnight, it is poured onto ice. Separation of the phases, extraction of the aqueous phase with methylene chloride, washing with saturated sodium chloride solution and drying of the combined organic phases over anhydrous sodium sulphate gives, after evaporation under a water pump vacuum, 14.5 g of crude amide, which is recrystallised from 160 ml of ethyl acetate. IR (KBr): 3307, 2931, 1642, 1485 and 1256 cm