Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[C:14]([CH3:16])[CH:15]=1.[F-].[Cs+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>[CH3:9][C:10]1[CH:11]=[C:12]([C:2]2[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=2)[NH2:5])[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: Cc1cc(C)cc(B(O)O)c1
Reactant: Nc1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2cccc(N)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 3-bromoaniline, 25, (17.2 g, 0.10 mol), 3,5-dimethylphenylboronic acid (16.5 g, 0.11 mol), CsF (50 g, 0.33 mol), Pd2(dba)3 (0.92 g, 5 mmol) in 50 mL anhydrous THF was added a solution of P(t-Bu)3 (0.49 g, 2.4 mmol) in 3 mL of THF. The exothermal reaction was cooled using a water bath. The solution mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was dissolved in methylene chloride and washed with water. The combined organic layers were dried over MgSO4 and solvents were evaporated. Purification of the orange residue by flash chromatography (100:10:1 hexanes:ethyl acetate:triethylamine) afforded 26 (20.0 g, 99%) as a brown oil. 1H-NMR δ=2.30 (s, 6H), 3.53 (bs, 2H), 6.50 (dd, J=2.5 Hz, 7.1 Hz, 1H), 6.77 (d, J=1.6 Hz, 2.2 Hz, 1H), 6.91 (s, 1H), 6.94 (dd, J=1.2 Hz, 2.5 Hz, 1H), 7.10-7.15 (m, 3H). 13C-NMR δ=22.2, 115.4, 119.3, 125.7, 129.5, 130.2, 138.7, 141.8, 143.3, 145.7. Anal. calcd. for C14H15N: C, 85.28; H, 7.61; N, 7.11. Found: C, 85.61; H, 8.01; N, 7.00.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(C)=O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:8]([O:7][CH2:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:8]=2)=[C:9]([CH:13]=1)[C:10]([O:12][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:11]
Reactant: BrCc1ccccc1
Reactant: COc1ccc(O)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
Potassium carbonate (690 mg, 5.00 mmol) was added to a stirred solution of 2-hydroxy-5-(methyloxy)benzoic acid (336 mg, 2.00 mmol) in acetone (20 ml) followed by the addition of ((bromomethyl)benzene (854 mg, 5.00 mmol). The mixture was refluxed for 12 h and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated to a yellow solid. Flash chromatography over silica gel eluting with 1:10 ethyl acetate:petroleum ether yielded the title compound as a pure, white powder. 500 mg.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[N:11]3[N:12]=[C:13]([CH3:17])[C:14](O)=[N:15][C:10]3=[N:9][N:8]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:14]1[C:13]([CH3:17])=[N:12][N:11]2[C:7]([CH2:6][C:5]3[CH:18]=[CH:19][C:2]([OH:1])=[CH:3][CH:4]=3)=[N:8][N:9]=[C:10]2[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nn2c(Cc3ccc(O)cc3)nnc2nc1O
Product: Cc1nn2c(Cc3ccc(O)cc3)nnc2nc1Cl

Procedure:
A solution of 3-(4-hydroxy-benzyl)-6-methyl-[1,2,4]triazolo[4,3-b][1,2,4]triazin-7-ol (170 mg, 0.62 mmol) in POCl3 (5 mL) was heated at 80° C. for 15 minutes, and then POCl3 was evaporated. The residue was purified on a silica gel column eluting with 5% methanol in dichloromethane to provide 4-(7-chloro-6-methyl-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-ylmethyl)-phenol (80 mg). MS (m/z) 275 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH:12]([CH3:16])[N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:34]=[C:35]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)[CH3:36]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:34]=[C:35](/[C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)\[CH3:36])[C:6]3[CH2:11][CH:12]([CH3:16])[N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC1Cc2[nH]c3ccc(Cl)cc3c2CN1C
Reactant: CC(=CBr)c1ccc(F)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)C(C)C2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
8-Chloro-2,3-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (117 mg, 0.5 mmol) was dissolved in DMF. Copper (I) iodide (9.5 mg, 0.05 mmol), L-proline (11.5 mg, 0.1 mmol) and potassium phosphate (212 mg, 1 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(1-Bromoprop-1-en-2-yl)-4-fluorobenzene (118 mg, 0.55 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 90° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-7% MeOH-DCM. 1H NMR (DMSO-d6, oxalate salt) δ (ppm): 7.72 (m, 2H), 7.61 (s, 1H), 7.30 (m, 3H), 7.20 (d, 1H), 7.11 (s, 1H), 4.40 (m, 2H), 3.20 (m, 1H), 2.80 (m, 5H), 1.84 (s, 3H), 1.40 (d, 3H).
Reaction SMILES: [Li].O=O.O1[CH2:8][CH2:7][CH2:6][CH2:5]1>>[CH3:5][C:6]1[CH:5]=[CH:6][C:7]2[C:8]3[CH:8]=[CH:7][C:6]([CH3:5])=[C:7]4[C:8]=3[C:7]([C:8]3[C:8]=2[C:7]=1[C:6]([CH3:5])=[CH:7][CH:8]=3)=[CH:6][CH:5]=[C:6]4[CH3:5]
Reactant: C1CCOC1
Agent: O=O
Agent: [Li]
Product: Cc1ccc2c3ccc(C)c4c(C)ccc(c5ccc(C)c1c25)c43
Reaction time: 5 h

Procedure:
The synthesis is then continued in accordance with the general reaction scheme described above, using the chemical reaction illustrated in FIG. 1. A suspension of lithium powder is prepared in an inert solvent, for example in tetrahydrofurane (THF). The proportion may be the following: 1.5 g, i.e. 220 millimoles, of lithium per 170 ml of THF. Argon can be used as the neutral atmosphere in the refluxing apparatus. 3 millimoles of solid 4,4',5,5'-tetramethyl 1,1'-dinaphthalene are then added. The refluxing is continued at 65° C. during 5 hours, which corresponds to the disappearing of the original 1,1'-dinaphthalene. The reaction mixture turns blue after the first three hours of heating. After cooling and injection of oxygen, the colour of the mixture turns yellow. The excess lithium is removed and the solvent is evaporated. A chromatography is performed on silicagel, using dichloromethane as the eluant. The 3,4,9,10-tetramethyl perylene is obtained by recrystallization with xylene. The yield in this preparation is 40%.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[CH:21]=O.Cl.[NH2:24][OH:25].C([O-])(=O)C.[Na+].O>C(O)C>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[CH:21]=[N:24][OH:25]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C=NO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-formylpyrazole (0.25 g) in ethanol (3 ml) was added hydroxylamine hydrochloride (0.075 g), sodium acetate (0.1 g) and water (0.1 ml). After stirring at room temperature overnight the mixture was evaporated. The residue was taken up in ether and washed with water, then brine, then dried and evaporated. The residue was crystallised from propan-2-ol/water and further purified by column chromatography on silica gel eluted with dichloromethane then dichloromethane:methanol (99:1). After combination and evaporation of suitable fractions the residue was further purified by column chromatography on silica gel eluted with ether. Combination and evaporation of suitable fractions gave the title compound as a white solid, m.p. 175-178° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][OH:29])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:4]([F:30])[CH:3]=1.ClC1C(Cl)=CC(NC2C3C(=CC(F)=C([N+]([O-])=O)C=3)N=CN=2)=C(F)C=1.C([Si](C)(C)[O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71]OCCOCCO)(C)(C)C.[K]>CS(C)=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:71][CH2:70][O:69][CH2:68][CH2:67][O:66][CH2:65][CH2:64][O:63][CH2:62][CH2:61][OH:60])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:4]([F:30])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCOCCOCCOCCOCCOCCO
Reactant: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCO
Agent: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1F
Agent: [K]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCOCCOCCOCCOCCO
Yield: 56 %

Procedure:
Compound 29c was prepared as described hereinabove for Compound 29a, using Compound 25 (0.596 gram, 1.6 mmol), 2-[2-(2-{2-[2-(2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy}-ethoxy]-ethanol (Compound 28c, 0.957 gram, 2.4 mmol), and potassium trimethylsilonate (0.621 gram, 4.74 mmol) dissolved in DMSO (37 ml). The crude residue was purified by silica gel column chromatography, using a mixture of 2% methanol in dichloromethane as eluent, to obtain Compound 29c (0.568 gram, 56%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:22])[C:5]2[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][C:14]3[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][CH:15]=3)[NH:8][C:6]=2[N:7]=1.CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.Cl.[CH2:42]([O:44][C:45](=[O:55])[C@H:46]([CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[NH2:47])[CH3:43]>CN(C=O)C>[CH2:42]([O:44][C:45](=[O:55])[C@@H:46]([NH:47][C:19]([C:17]1[S:18][C:14]([CH2:13][CH2:12][CH2:11][C:9]2[NH:8][C:6]3[N:7]=[C:2]([NH2:1])[NH:3][C:4](=[O:22])[C:5]=3[CH:10]=2)=[CH:15][CH:16]=1)=[O:21])[CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH3:43]
Reactant: Nc1nc2[nH]c(CCCc3ccc(C(=O)O)s3)cc2c(=O)[nH]1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCCc2cc3c(=O)[nH]c(N)nc3[nH]2)s1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
To a solution of 9 (254 mg, 0.8 mmol) in anhydrous DMF (10 mL) was added N-methylmorpholine (145 mg, 1.44 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (253 g, 1.44 mmol). The resulting mixture was stirred at room temperature for 2 h. To this mixture were added N-methylmorpholine (145 mg, 1.44 mmol) and L-glutamate diethyl ester hydrochloride (290 mg, 1.2 mmol). The reaction mixture was stirred for an additional 4 h at room temperature and then evaporated to dryness under reduced pressure. The residue was dissolved in the minimum amount of CHCl3/MeOH (4:1) and chromatographed on a silica gel column (2×15 cm) and with 5% CHCl3 in MeOH as the eluent. Fractions that showed the desired spot (TLC) were pooled and the solvent evaporated to dryness to afford 252 mg of 10 as yellow powder in 63% yield. 1H NMR (DMSO-d6): δ 1.14-1.21 (m, 6H), 1.81-2.05 (m, 4H), 2.32-2.39 (t, J=7.6 Hz, 2H), 2.49-2.52 (t, J=7.2 Hz, 2H), 2.78-2.81 (t, J=7.2 Hz, 2H), 4.02-4.07 (m, 4H), 4.30-4.35 (m, 1H), 5.88 (s, 1H), 5.94 (s, 2H), 6.89-6.90 (d, J=3.6 Hz, 1H), 7.68-7.69 (d, J=3.6 Hz, 1H), 8.61-8.63 (d, J=8 Hz, 1H), 10.71 (s, 1H), 11.19 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]([CH2:22][C:23]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=O)[C:13]([C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=3)=O)=[CH:11][C:6]=2[N:5]([CH2:31][CH3:32])[C:4]1=[O:33])[CH3:2].C([O-])(=O)C.[NH4+:38].[NH4+].[OH-]>C(O)(=O)C>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[CH:22]=[C:23]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[NH:38][C:13]=3[C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=3)=[CH:11][C:6]=2[N:5]([CH2:31][CH3:32])[C:4]1=[O:33])[CH3:2]
Reactant: [NH4+]
Reactant: CCn1c(=O)n(CC)c2cc(C(CC(=O)c3cccnc3)C(=O)c3cccc(C)c3)ccc21
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCn1c(=O)n(CC)c2cc(-c3cc(-c4cccnc4)[nH]c3-c3cccc(C)c3)ccc21
Reaction time: 0.08 h
Yield: 6.3 %

Procedure:
A solution of 2-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-4-pyridin-3-yl-1-m-tolyl-butane-1,4-dione (600 mg, 1.13 mmol) and ammonium acetate (871 mg, 11.3 mmol) in acetic acid (3.77 mL) was heated at 110° C. for 4 hours. The reaction was then poured over a mixture of ice and NH4OH and stirred for 5 minutes. The aqueous mixture was extracted with EtOAc (3×10 mL). The organics were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a orange oil. The oil was purified by flash chromatography using a gradient of Et2O to 50% EtOAc/Et2O, affording 30 mg of the title compound. MS (M+1)=423.2.
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1[C:30]2[C:25](=[CH:26]C=C[CH:29]=2)[CH:24]=[CH:23][C:22]=1[S:31]([CH:34]1[S:38][C:37](=[O:39])[NH:36][C:35]1=[O:40])(=[O:33])=[O:32].C(N(CC)CC)C.ClCCl>O>[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:36]2[C:35](=[O:40])[CH:34]([S:31]([C:22]3[CH:23]=[CH:24][C:25]([CH3:26])=[CH:30][CH:29]=3)(=[O:32])=[O:33])[S:38][C:37]2=[O:39])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)C(S(=O)(=O)c2ccc3ccccc3n2)S1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)C2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Reaction time: 1 h
Yield: 44.7 %

Procedure:
Triphenylmethyl chloride (2.67 g, 9.58 mmol) was added to a stirred, room temperature solution of 5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione [(V), from Example 12, 1.30 g, 4.79 mmol], triethylamine (0.67 mL, 4.79 mmol) and dichloromethane (6.5 mL). After 1 h, water (300 mL) was added and the organic material was extracted with ethyl acetate (2×200 mL). The combined extracts were dried (brine, MgSO4), concentrated and purified by flash chromatography (4:1 petroleum ether:ethyl acetate) to provide the title compound as a white solid (1.1 g, 45%): mp 105°-110° C.; NMR (CDCl3): δ7.85 (d, J=8.3 Hz, 2H, ArH), 7.48 (d, J=8.1 Hz, 6H, CPh3H), 7.38 (d, J=8.3 Hz, 2H, ArH),7.23 (m, 9H, CPh3H), 5.13 (s, 1H, CH), 2.46 (s, 3H, CH3).
Reaction SMILES: [I:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[N:10]=2)=[CH:4][C:3]=1[CH3:16].CI.[C:19]([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[I:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]([C:9]2[CH:14]=[CH:13][N:12]([CH3:19])[C:11](=[O:15])[N:10]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(-c2cc[nH]c(=O)n2)cc(C)c1I
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc(-c2ccn(C)c(=O)n2)cc(C)c1I
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 4-(4-iodo-3,5-dimethylphenyl)pyrimidin-2(1H)-one (500 mg), methyliodide (165 μL) and K2CO3 (254 mg) in N,N-dimethylformamide (10 mL) is stirred for 12 hours at room temperature. Then the mixture is partitioned between water and dichloromethane. The aqueous phase is extracted twice with dichloromethane and the combined organic phases are washed with brine. After drying (MgSO4) the solvents are evaporated. The residue is triturated with diethylether. The solid is filtered off and dried to give the title compound. Yield: 380 mg; LC (method 11): tR=0.96 min; Mass spectrum (ESI+): m/z=341 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)#[N:2].[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([C:1]#[N:2])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:24][CH:23]=1
Reactant: COCCOc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3)c2cc1C#N
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COCCOc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Temperature: 80 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
6-Cyano-7-(2-methoxyethoxy)-4-(4-nitrophenoxy)quinoline (1.8 g), iron (1.8 g) and ammonium chloride (3.6 g) were suspended in an ethanol (30 ml)—water (7 ml) mixed solvent and the suspension was heated and stirred at 80° C. for 2 hours. After completion of the reaction, the reaction mixture was filtered with celite and washed in ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated. The obtained solid was washed with ether and dried to obtain 1.2 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]([CH2:16][CH3:17])[N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:35]=[C:36]([C:38]1[CH:43]=[CH:42][C:41]([F:44])=[C:40]([F:45])[CH:39]=1)[CH3:37]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:35]=[C:36]([C:38]1[CH:43]=[CH:42][C:41]([F:44])=[C:40]([F:45])[CH:39]=1)[CH3:37])[C:6]1[CH:11]([CH2:16][CH3:17])[N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1
Reactant: CCC1c2[nH]c3ccc(Cl)cc3c2CCN1C
Reactant: CC(=CBr)c1ccc(F)c(F)c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CCC1c2c(c3cc(Cl)ccc3n2C=C(C)c2ccc(F)c(F)c2)CCN1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13.2 %

Procedure:
6-chloro-1-ethyl-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (89 mg, 0.36 mmol) was dissolved in DMF (6 mL). To this solution was added CuI (8 mg, 0.035 mmol), L-proline (9 mg, 0.086 mmol), K3PO4 (183 mg, 0.862 mmol). The reaction mixture was stirred for 10 min at room temperature followed by addition of 4-(1-bromoprop-1-en-2-yl)-1,2-difluorobenzene (100 mg, 0.431 mmol). The reaction mixture was heated at 80° C. overnight. Solvent was evaporated under reduced pressure; the residue was diluted with brine and extracted with ethyl acetate. Organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to obtain 19 mg of 6-chloro-9-(2-(3,4-difluorophenyl)prop-1-enyl)-1-ethyl-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. 1H NMR (CD3OD) OXALATE SALT 7.60 (t, 2H), 7.42 (m, 1H), 7.38 (m, 1H), 7.22 (m, 2H), 7.10 (s, 1H), 4.60 (m, 1H), 3.80 (m, 2H), 3.60 (m, 1H), 3.20 (m, 1H), 3.05 (s, 3H), 2.10 (m, 2H), 1.90 (s, 3H), 1.10 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[O:4].[C:17](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[N:10]([CH3:17])[C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1sccc1NC(=O)C(F)(F)F
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1sccc1N(C)C(=O)C(F)(F)F
Reaction time: 48 h
Yield: 97.3 %

Procedure:
A mixture of 2 g of 3-(2,2,2-trifluoro-acetylamino)-thiophene-2-carboxylic acid methyl ester (7.9 mmol), 1.31 g of potassium carbonate (9.48 mmol) and 596 μl of methyl iodide (9.48 mmol) in DMF (7.5 ml) was stirred for 2 d. The reaction mixture was then poured into water and extracted with DCM. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo to give 2.055 g (97%) of 3-[methyl-(2,2,2-trifluoro-acetyl)-amino]-thiophene-2-carboxylic acid methyl ester as a white solid. MS (ISP) 268.1 (M+H)+.
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[O-]CC.[Na+].Br[CH2:14][C:15]([OH:17])=[O:16]>C(O)C>[C:15]([CH2:14][P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4])([OH:17])=[O:16]
Reactant: CCOP([O-])OCC
Reactant: O=C(O)CBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOP(=O)(CC(=O)O)OCC
Yield: 154.6 %

Procedure:
A mixture of 4.0 ml (0.031 mole) of diethyl phosphite, 6.68 g (0.093 mole) of 94% sodium ethoxide, and 4.32 g (0.031 mole) of bromoacetic acid in 50 ml of absolute ethanol was heated under reflux for 1 h. Solvent was removed at reduced pressure, and the residual solid was triturated with ethyl acetate and 15 ml of conc hydrochloric acid with shaking and portionwise addition of water until all the solid was dissolved. The ethyl acetate layer was separated, dried (over MgSO4), and evaporated to give 9.4 g of residual liquid diethyl carboxymethylphosphonate; 1H NMR spectrum confirmed the structure of this compound which is disclosed by Martin and Griffin, J. Org. Chem., 30, 4034-4038 (1965).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH3:34])=[CH:27][CH:26]=4)[CH2:23][CH2:22][C:21]([C:35]([O:37]C)=[O:36])=[CH:20][C:19]=3[CH:39]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][CH3:34])=[CH:29][CH:30]=4)[CH2:23][CH2:22][C:21]([C:35]([OH:37])=[O:36])=[CH:20][C:19]=3[CH:39]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3c2ccc(OCCC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3c2ccc(OCCC)cc2)cc1
Temperature: 50 °C
Yield: 86.3 %

Procedure:
In methanol (50 ml) and THF (50 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.25 g). To the solution was added 1N sodium hydroxide solution (5 ml), and the mixture was heated at 50° C. overnight, concentrated, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.21 g) as yellow crystals.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=[O:3].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C1COCC1>[N:14]1([C:2]([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[C:9](=[O:10])[O:8][CH2:7]3)=[O:3])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=C(Cl)c1ccc2c(c1)COC2=O
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1OCc2cc(C(=O)N3CCOCC3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution-of 5-chlorocarbonylphthalid (39 g, 0.2 mole) in THF (400 ml) is added to a solution of morpholine (22 g, 0.25 mole) and triethylamine (26 g, 0.25 mole) in THF (200 ml) at 0° C. The mixture is stirred for 1 hour and is allowed to warm to room temperature. The reaction mixture is then poured into ice water (500 ml). THF is evaporated off in vacuo and the pH of the solution is adjusted to pH=2. The solution is cooled to 5° C. and the precipitated crystals are filtred off and washed with water (100 ml).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Rh]>[NH2:8][C@@H:7]([CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:17]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: [Rh]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H](N)CC1CCC(O)CC1

Procedure:
L-Tyrosine tert-butyl ester (0.6 g) was hydrogenated in MeOH, with 10% Rh/Al2O3 under 50 psi of hydrogen at room temperature for 2 days. The reaction mixture was filtered through Celite and the solvent evaporated under reduced pressure to afford the title intermediate as a foam.