Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[C:11](=O)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([NH:29][NH2:30])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)/[C:11](=[N:30]/[NH:29][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)/[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccccc1
Reactant: COc1ccc2c(c1)N(Cc1ccccc1)C(=O)C2=O
Product: COc1ccc2c(c1)N(Cc1ccccc1)C(=O)/C2=N\NC(=O)c1ccccc1

Procedure:
The title compound was prepared as a yellow solid, using 1- benzyl-6-methoxy-isatin and benzhydrazide according to the synthetic method E. 1H NMR (CDCl3): δ 3.77 (s, 3H), 4.94 (s, 2H), 6.35 9d, 1H), 6.62 (dd, 1H), 7.29-7.36 (m, 4H), 7.51 (t, 2H), 7.59 (t, 1H), 7.80 (d, 1H), 8.01 (d, 2H), 13.95 (br s, 1H).
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[CH:15]=[CH:16][CH:17]=2)[CH:12]=1)=[O:10])C1C=CC=CC=1>C(O)C>[CH3:27][N:24]1[CH2:25][CH2:26][N:21]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[CH:12]=[C:11]([C:9]([OH:10])=[O:8])[CH:20]=[CH:19]3)[CH2:22][CH2:23]1
Reactant: CN1CCN(c2cccc3ccc(C(=O)OCc4ccccc4)cc23)CC1
Solvent: CCO
Product: CN1CCN(c2cccc3ccc(C(=O)O)cc23)CC1
Reaction time: 5 h

Procedure:
A mixture of 8-(4-methylpiperazin-1-yl)naphthalene-2-carboxylic acid benzyl ester (0.20 g, 5.55 mmol) and Pd(OH) on carbon (0.11 g) in 2 mL of ethanol was hydrogenated on a Parr shaker apparatus at 50 psi for 5 hr. After diluting with ethanol and filtering through diatomaceous earth, the solvent was removed in vacuo to yield the title product as a foam, 138 mg.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:16]1[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]1)[NH:10][C:9]2=O.[CH:32]1([NH2:35])[CH2:34][CH2:33]1>>[CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:16]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]1)[N:10]=[C:9]2[NH:35][CH:32]1[CH2:34][CH2:33]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Product: Cc1cccc(C)c1CNc1ccc2nc(-n3cc(C(=O)O)cn3)nc(NC3CC3)c2c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and cyclopropylamine in step E. MS (ESI/CI): predicted mass C24H24N6O2, 428.2.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH3:13][NH:14][CH2:15][CH2:16][CH2:17][CH:18]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[CH:25][C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]1=2.Cl.C(N(CC)CC)C.[C:41]([O:45][C:46]([NH:48][CH2:49][C:50]([OH:52])=O)=[O:47])([CH3:44])([CH3:43])[CH3:42].C(=O)([O-])O.[Na+]>ClCCl>[CH:32]1[C:27]2[CH:26]=[CH:25][C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH:18]([CH2:17][CH2:16][CH2:15][N:14]([CH3:13])[C:50](=[O:52])[CH2:49][NH:48][C:46](=[O:47])[O:45][C:41]([CH3:42])([CH3:43])[CH3:44])[C:28]=2[CH:29]=[CH:30][CH:31]=1
Reactant: CNCCCC1c2ccccc2C=Cc2ccccc21
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCCC1c2ccccc2C=Cc2ccccc21)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
134 mg (0.70 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride, 176 mg (0.59 mmol) of protriptyline hydrochloride and 0.176 ml (1.26 mmol) of triethylamine were added to 129 mg (0.74 mmol) of t-butoxycarbonylglycine in 5 ml of dichloromethane, and they were stirred at room temperature overnight. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture. After extracting with dichloromethane, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane:ethyl acetate=3:1) to obtain the title compound.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([C:33]1[CH2:34][N:35]([CH3:39])[CH2:36][CH2:37][CH:38]=1)[NH2:32]>>[CH3:39][N:35]1[CH2:36][CH2:37][CH:38]=[C:33]([C:31]2[N:32]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)[O:28][N:30]=2)[CH2:34]1
Reactant: CN1CCC=C(C(N)=NO)C1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: CN1CCC=C(c2noc(C3CC(c4ccc(OC(F)(F)F)cc4)CN(C(=O)N4CCOCC4)C3)n2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 34 mg (0.22 mmol, 1.1 eq.) of N′-hydroxy-1-methyl-1,2,5,6-tetrahydropyridine-3-carboximidamide [P. Sauerberg et al. J. Med. Chem. 1991, 34, 687-692] were reacted according to the General Method 1. Yield: 23 mg (22% of theory)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([N:6]([CH2:18][CH2:19][CH2:20]Cl)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[CH2:5].[I-].[Na+].[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][N:32]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20][CH2:19][CH2:18][N:6]1[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[O:22]
Reactant: NCc1ccccc1
Reactant: C=C(C(=O)OC)N(CCCCl)S(=O)(=O)c1ccc(OC)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(Cc2ccccc2)CCCN1S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.910 g (0.2.619 mmol) of the product of Example 44 in 30 mL of DMF was added 0.432 g (0.2.881 mmol) of sodium iodide. The reaction was stirred for 30 min at room temperature and then 0.590 mL (5.499 mmol) of benzylamine and 0.96 mL (5.499 mmol) of diisopropylethylamine was added and the resulting mixture was heated at 80 degrees for 3 h and then cooled to room temperature.
Reaction SMILES: [NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[CH:14][CH:15]=[C:16]([NH:17][C:18]4[CH:39]=[CH:38][C:21]([C:22]([NH:24][C@H:25]([C:33]([O:35]CC)=[O:34])[CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[O:23])=[CH:20][CH:19]=4)[C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.Cl>C(O)C.[OH-].[Na+]>[NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[CH:14][CH:15]=[C:16]([NH:17][C:18]4[CH:19]=[CH:20][C:21]([C:22]([NH:24][C@H:25]([C:33]([OH:35])=[O:34])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:23])=[CH:38][CH:39]=4)[C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(Nc2cccc3c2ccc2nc(N)[nH]c(=O)c23)cc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc2ccc3c(Nc4ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc4)cccc3c2c(=O)[nH]1
Reaction time: 0.25 h
Yield: 101.4 %

Procedure:
A solution of diethyl N-(4-((3-amino-1,2-dihydro-1-oxobenzo[f]-quinazolin-7-yl)amino)benzoyl)-L-glutamate (31 mg, 0.056 mmol) in ethanol (1 ml) and 0.25N NaOH (4 ml) was stirred under nitrogen at room temperature for 3 hours. The solution was then acidified to pH 3 with 1N hydrochloric acid and the resulting suspension allowed to stir for 15 minutes. The solid was filtered, washed with water, and dried under high vacuum to give N-(4-((3-amino-1,2-dihydro-1-oxobenzo[f]-quinazolin-7-yl)amino)benzoyl)-L-glutamic acid (27 mg). 1H NMR (DMSO-d6, 200 MHz) δ: 1.79-2.16 (m, 2H, glu CH2 ), 2.32 (t, J=7 Hz, 2H, glu CH2), 4.27-4.41 (m, 1H, glu CH), 6.55 (br s, 2H, NH2), 6.85 (d, J=9 Hz, 2H, Ar), 7.27 (d, J=9 Hz, 1H, Ar), 7.34 (d, J=7 Hz, 1H, Ar), 7.55 (t, J=8 Hz, 1H, Ar), 7.72 (d, J=9 Hz, 2H, Ar), 8.16 (d, J=9 Hz, 1H, Ar), 8.24 (d, J=8 Hz, 1H, glu NH), 8.62 (s, 1H, C7 --NH), 9.45 (d, J=9 Hz, 1H, Ar), 11.13 (br s, 1H, N2H), 12.31 (br s, 2H, CO2H's). Anal. Calculated for C24H21N5O6.5/4H2O: C, 57.89; H, 4.76; N, 14.06. Found: C, 57.93; H, 4.73; N 13.99.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH3:11])=[CH:6][C:5]=1[Cl:12].[OH-].[Na+]>CO>[Cl:12][C:5]1[CH:6]=[C:7]([CH3:11])[C:8]([F:10])=[CH:9][C:4]=1[C:3]([OH:13])=[O:2]
Reactant: COC(=O)c1cc(F)c(C)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(Cl)c(C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of 2-chloro-5-fluoro-4-methyl-benzoic acid methyl ester (Preparation 1a, 57.77 g) in methanol (400 mL) was treated with sodium hydroxide 2 M solution (285 mL) under nitrogen. The resulting mixture was stirred at 25° C. for 1 h. The reaction mixture was extracted with diethyl ether (discarded) and the aqueous layer diluted with 2 M hydrochloric acid (250 mL). The reaction mixture was extracted with ethyl acetate (500 mL). The combined organics were dried (MgSO4), filtered and evaporated to afford the subtitle compound (51.6 g).
Reaction SMILES: Cl.[CH2:2]([NH2:5])[CH2:3][CH3:4].[NH2:6][C:7]1[S:8][C:9]2[CH2:15][CH2:14][CH2:13][C:12](=O)[C:10]=2[N:11]=1.C(N)CC.C([BH3-])#N.[Na+]>CO.O.Cl>[NH2:6][C:7]1[S:8][C:9]2[CH2:15][CH:14]([NH:5][CH2:2][CH2:3][CH3:4])[CH2:13][CH2:12][C:10]=2[N:11]=1
Reactant: Nc1nc2c(s1)CCCC2=O
Reactant: CCCN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCNC1CCc2nc(N)sc2C1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
3.0 g of propylamine hydrochloride was dissolved in 60 mL of methanol and 2.2 g of 2-amino-oxo-4,5,6,7-tetrahydrobenzothiazole was added. 1.1 mL of propylamine was poured into the mixture to set pH within the range 6.5-7.0. Then 0.7 g of sodium cyanoborohydride was added and the reaction mixture was stirred for 70 hours under nitrogen atmosphere and at ambient temperature. The reaction mixture was diluted with 50 mL of water and 10 mL of conc. hydrochloric acid. Solvents were removed by evaporation, the yellow residue was stirred with ethanol and the solid was removed by filtration. The filtrate was made alkaline with potassium hydroxide solution and the precipitate was again removed by filtration. Filtrate was several times evaporated with ethanol to remove propylamine. The residue was dissolved in hot ethanol and resulting crystals were collected and dried. Reaction product was characterised by NMR spectra.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH2:10][OH:11])[CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)O1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH2:10][OH:11])[CH:3]=2)=[CH:21][CH:22]=1)([O-:28])=[O:27]
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2)OC1(C)C
Reactant: OCc1ccc(Br)cc1CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-c2ccc(CO)c(CO)c2)cc1
Temperature: 80 °C

Procedure:
The compound of example 669 (7 g, 32.25 mmol), 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane (9.63 g, 38.70 mmol) and [1,1-Bis(diphenylphosphino)-ferrocine]dichloropalladium(II), complex with dichloromethane (789 mg, 0.967 mmol) were taken in dry DMF under Argon atmosphere. Degassed 2M solution of sodium carbonate (8.54 g, 80.62 mmol) was added and the reaction mixture was heated to 80° C. for 3 h. The reaction mixture was cooled and the solvent was removed by distillation. The residue was taken in water and the aqueous mixture was extracted with ethyl acetate. The crude material obtained was purified using column chromatography (silicagel, 30% dichloromethane in petroleum ether) to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:44]1[CH:56]=[CH:55][C:47]2[NH:48][C:49]([NH:51][C:52](=[O:54])[CH3:53])=[N:50][C:46]=2[CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.O1CCOCC1>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([C:56]2[CH:44]=[CH:45][C:46]3[NH:50][C:49]([NH:51][C:52](=[O:54])[CH3:53])=[N:48][C:47]=3[CH:55]=2)=[CH:3][C:4]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: O=S(=O)(Nc1cc(Br)cnc1Cl)c1ccc(F)cc1
Reactant: CC(=O)Nc1nc2cc(Br)ccc2[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(=O)Nc1nc2cc(-c3cnc(Cl)c(NS(=O)(=O)c4ccc(F)cc4)c3)ccc2[nH]1
Temperature: 90 °C
Reaction time: 6 h
Yield: 15.2 %

Procedure:
To a 25 mL round-bottomed flask was added N-(5-bromo-2-chloropyridin-3-yl)-4-fluorobenzenesulfonamide (0.150 g, 0.410 mmol) (Step 1, Example 48), bis(pinacolato)diboron (0.156 g, 0.615 mmol, Aldrich, St, Louis, Mo.), potassium acetate (0.161 g, 1.64 mmol) and 1,4-dioxane (4.0 mL). The mixture was carefully evacuated and backfilled with N2. To the solution was added dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (0.030 g, 0.041 mmol, Strem Chemical, Inc., Newburyport, Mass.). The mixture was carefully evacuated and backfilled with N2 again. The mixture was stirred at 90° C. for 6 h. The reaction mixture was cooled to rt and to it was added DMF (4.0 mL), N-(5-bromo-1H-benzo[d]imidazol-2-yl)acetamide (0.080 g, 0.31 mmol) and aq sodium carbonate (0.79 mL, 1.6 mmol, 2 M). The mixture was carefully evacuated and backfilled with N2. To the mixture was added trans-dichlorobis(triphenylphosphine)palladium(II) (0.022 g, 0.031 mmol, Strem Chemical, Inc., Newburyport, Mass.). Once again the mixture was carefully evacuated and backfilled with N2. The mixture was stirred at 90° C. for 16 h and then, after cooling to rt, was poured into aq. NaCl (100 mL) and extracted with 25% iPrOH/CHCl3 (3×75 mL). The combined extracts were dried (Na2SO4) and concentrated. The material was then taken up in MeOH/CH2Cl2 and concentrated onto silica. Purification by silica gel chromatography (0.5 to 5.0% MeOH (2 M in NH3)/CH2Cl2) afforded the title compound as a white solid (0.0217 g, 15%). MS (ESI, positive ion) m/z: 460 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.18 (s, 3H), 7.37 (br s, 1H), 7.44 (t, J=8.8 Hz, 2H), 7.56 (br s, 1H), 7.70 (br s, 1H), 7.83 (dd, J=8.8, 5.3 Hz, 2H), 7.91 (s, 1H), 8.56 (br s, 1H), 10.44 (br s, 1H), 11.62 (br s, 1H), 12.16 (br s, 1H).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13](=[O:24])[N:14]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:15]4=[N:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)(Cl)Cl.CO.[OH-].[OH-].[Pd+2]>[CH2:8]([C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:24])[N:14]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:15]3=[N:16]2)=[CH:11][CH:10]=1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1c2ccc(C#Cc3ccccc3)cc2nc2n1CCCCC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=c1c2ccc(CCc3ccccc3)cc2nc2n1CCCCC2
Yield: 39.3 %

Procedure:
A solution of 3-(phenylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]-quinazolin-12(6H)-one (50 mg, 0.16 mmol) and Pd(OH)2/C in CHCl3 (10 mL) and MeOH (10 mL) was stirred under H2 (1 atm) at room temperature for 8 h. The reaction mixture was filtered and the filter cake was washed with water. The combined filtrate was extracted with ethyl acetate (3×20 mL) and dried over Na2SO4. After filtration and concentration, the residue was purified by preparative HPLC to give 20 mg of the desired product. MS (ESI): 319 (MH+); 1H NMR (300 MHz, CDCl3) δ 7.99-7.97 (d, J=8.10 Hz, 1H), 7.40 (s, 1H), 7.38-7.33 (d, J=8.22 Hz, 1H), 7.29-7.17 (m, 5H), 4.32-4.29 (t, J=4.98 Hz, 2H), 3.06-2.91 (m, 6H), 1.75 (broad, 4H), 1.68 (broad, 2H). mGluR5 PAM EC50: ++.
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([OH:18])=O)=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.CN(C([O:26][N:27]1N=N[C:29]2[CH:30]=[CH:31][CH:32]=[N:33][C:28]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N=P1N(C)CCCN1C)(C)(C)C.C(C1ON=C(N)C=1)C>C1COCC1.CN(C=O)C>[CH2:31]([C:30]1[O:26][N:27]=[C:28]([NH:33][C:16]([C:13]2[CH:12]=[CH:11][C:10]3[CH:9]=[C:8]4[C:2](=[O:1])[NH:3][CH2:4][CH2:5][CH2:6][N:7]4[C:15]=3[CH:14]=2)=[O:18])[CH:29]=1)[CH3:32]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc2cc3n(c2c1)CCCNC3=O
Agent: CCc1cc(N)no1
Agent: CN1CCCN(C)[PH]1=NC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCc1cc(NC(=O)c2ccc3cc4n(c3c2)CCCNC4=O)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.8 %

Procedure:
To a solution of 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylic acid (Intermediate J, 75 mg, 0.31 mmol) in THF (2 mL) and DMF (0.5 mL) is added HATU (128 mg, 0.34 mmol). The mixture is stirred at room temperature for 1 h, after which polystyrene bound 2-tert-butylimino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (419 mg, 0.92 mmol) is added. The mixture is stirred at room temperature for 10 min and 5-ethyl-3-aminoisoxazole (103 mg, 0.92 mmol) is added. The reaction is stirred at 60° C. for 16 h and is then cooled to room temperature. The mixture is filtered, washing with methanol and the filtrate is concentrated under reduced pressure. The residue is purified via preparative HPLC using a gradient elution from 10-90% acetonitrile/water with 0.1% TFA to obtain the title compound (5 mg, 5%). LCMS: 339.20 (M+H+). (System V1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[CH3:30][NH:31][CH3:32].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:30][N:31]([CH2:26][C:25]1[CH:28]=[CH:29][C:22]([CH:9]2[NH:10][C:11]3[C:12]4[C:13](=[N:14][NH:15][C:16](=[O:21])[C:17]=4[CH:18]=[CH:19][CH:20]=3)[CH:8]2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:23][CH:24]=1)[CH3:32]
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(C)Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.1 %

Procedure:
A mixture of 4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (80 mg, 0.21 mmol), dimethlyamine (47 mg, 1.04 mmol) and acetic acid (62 mg, 1.04 mmol) in methanol (50 mL) was stirred at room temperature for 60 min. Then the mixture was cooled to 0° C. Sodium cyanoborohydride (20 mg, 0.3 mmol) was added. After the addition, the mixture was stirred at room temperature for overnight. Methanol was removed under reduced pressure. The crude product was purified by pre-HPLC to give 8-(4-((dimethylamino)methyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (21 mg, yield 24%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.82 (s, 6H), 4.26 (s, 2H), 4.32 (d, J=8.0 Hz, 1H), 4.77 (d, J=8.0 Hz, 1H), 6.93-6.95 (m, 2H), 7.10-7.11 (m, 2H), 7.23 (m, 1H), 7.40-7.41 (m, 4H), 7.59 (d, J=8.0 Hz, 1H), 7.65 (t, J=8.0 Hz, 1H). 19F-NMR (400 MHz, CD3OD) δ (ppm): −77.09, −118.00; LC-MS (ESI) m/z: 415 (M+1)+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:8][CH:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[C:5]=1[CH2:13][CH3:14].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Br:3][C:4]1[N:8]([S:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])[CH:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[C:5]=1[CH2:13][CH3:14]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCc1c(C(=O)OC)c[nH]c1Br
Agent: [H-]
Agent: [Na+]
Product: CCc1c(C(=O)OC)cn(S(=O)(=O)c2ccccc2)c1Br
Yield: 91 %

Procedure:
Using sodium hydride (60% in oil, 393 mg), methyl 5-bromo-4-ethyl-1H-pyrrole-3-carboxylate (2.00 g) and benzenesulfonyl chloride (1.25 mL), a procedure as in Reference Example 41 was performed to give the title compound as white crystals (yield 2.93 g, 91%).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:24]=[CH:23][C:11]2[CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][N:17]([CH2:19][CH:20](O)[CH3:21])[C:18]=3[C:10]=2[CH:9]=1.C(N(CC)CC)C.[N-:32]=[N+:33]=[N-:34].[Na+]>ClCCl.C(OCC)C.CN(C)C=O.O>[N:32]([C@H:20]([CH3:21])[CH2:19][N:17]1[C:18]2[C:10]3[CH:9]=[C:8]([O:7][CH3:6])[CH:24]=[CH:23][C:11]=3[CH2:12][CH2:13][C:14]=2[CH:15]=[CH:16]1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)-c1c(ccn1CC(C)O)CC2
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2c(c1)-c1c(ccn1C[C@@H](C)N=[N+]=[N-])CC2
Yield: 58 %

Procedure:
1.8 ml of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 3 g of (S)-1-(4,5-dihydro-8-methoxy-1H-benz[g]indol-1-yl-propan-2-ol and 6.55 ml of triethyl-amine in 80 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 300 ml of diethyl ether, washed twice with 100 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 100 ml of diethyl ether. The combined organic phases were washed with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The oil obtained was dissolved in 70 ml of anhydrous dimethylformamide, treated with 1.52 g of sodium azide and the reaction mixture was heated to 60° for 15 hours while stirring. After cooling, the solution was poured into 140 ml of water and extracted twice with 140 ml of diethyl ether each time. The combined organic phases were washed once with 100 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 1.9 g (58%) of (R)-1-(2-azido-propyl)-4,5-dihydro-8-methoxy-1H-benz[g]indole were obtained as a light yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:16])([CH3:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[CH:17]1[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH2:18]1.[C:24](OC(=O)C)(=[O:26])[CH3:25].Cl>N1C=CC=CC=1>[C:24]([O:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:16])([CH3:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[CH:17]1[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH2:18]1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCC(C)(C)c1ccc(C2CCCC(=O)C2)c(O)c1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCC(C)(C)c1ccc(C2CCCC(=O)C2)c(OC(C)=O)c1
Reaction time: 18 h

Procedure:
A solution of 2.0 g of 3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]cyclohexanone in 15 ml of pyridine is treated at 10° C. with 10 ml acetic anhydride and the mixture stirred for 18 hours under nitrogen. It is then poured onto ice/water and acidified with dilute hydrochloric acid. The acidified mixture is extracted with ethyl acetate (2×100 ml), the extracts combined, washed with brine and dried (MgSO4). Evaporation under reduced pressure give the title product as an oil.