Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:23]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([O:17][CH3:23])=[O:16])=[CH:11][O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)CCc1conc1-c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1conc1-c1ccc(Cl)cc1
Yield: 92 %

Procedure:
A mixture of 3-[3-(4-chlorophenyl)-4-isoxazolyl]propionic acid (4.05 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[3-(4-chlorophenyl)-4-isoxazolyl]propionate (3.93 g, yield 92%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 56–57° C.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5][NH:4]1.Cl[C:11]1[N:16]([CH3:17])[C:15](=[O:18])[CH:14]=[C:13]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][N:20]=2)[N:12]=1.C(N(CC)CC)C.O>O1CCCC1>[CH3:2][CH:3]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:11]1[N:16]([CH3:17])[C:15](=[O:18])[CH:14]=[C:13]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][N:20]=2)[N:12]=1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: CC1CCOCCN1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC1CCOCCN1c1nc(-c2ccncn2)cc(=O)n1C
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 22.5 %

Procedure:
To a suspension of 5-methyl-[1,4]oxazepane hydrochloride (0.08 g, 0.50 mmol) and 2-chloro-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (0.09 g, 0.40 mmol) in tetrahydrofuran (2 mL) in a sealed tube was added triethylamine (0.14 mL) at room temperature. The mixture was heated to 150° C. under microwave irradiation and stirred for 30 min. After cooling to room temperature, the reaction mixture was poured into water and extracted with chloroform. The extracts were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (chloroform/methanol=10/1 as an eluant) to yield 2-(5-methyl-[1,4]oxazepane-4-yl)-3-methyl-6-pyrimidin-4-yl-3H-pyrimidin-4-one (0.03 g, 0.09 mmol, 22%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=1.[S:16](N)(N)(=[O:18])=[O:17]>COCCOCCOC.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][S:16]1(=[O:18])=[O:17]
Reactant: Nc1ccccc1Nc1ccccc1F
Reactant: NS(N)(=O)=O
Solvent: COCCOCCOC
Solvent: CCOCC
Product: O=S1(=O)Nc2ccccc2N1c1ccccc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23.3 %

Procedure:
Dry diglyme (10 mL) was added to a flask equipped with a dropping funnel under a nitrogen atmosphere and brought to a vigorous reflux N-(2-fluorophenyl)benzene-1,2-diamine (1.2 g, 6.0 mmol) and sulfamide (0.69 g, 7.2 mmol) were dissolved in 5 mL of diglyme and placed in the dropping funnel. The mixture was added dropwise to the flask over 15 minutes and then refluxing was continued for an additional 15 minutes. The mixture was cooled to ambient temperature and diluted with ether, washed with water, 2N HCl, water, brine, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified via Isco chromatography (Redisep, silica, gradient 5-50% (ethyl acetate containing 2% formic acid) in hexane) to afford 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.37 g).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].Cl[CH2:12][CH2:13][N:14]=[C:15]=[S:16]>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:15]1[S:16][CH2:12][CH2:13][N:14]=1
Reactant: S=C=NCCCl
Reactant: NCc1cccc(Cl)c1Cl
Solvent: C1COCCO1
Product: Cl
Product: Clc1cccc(CNC2=NCCS2)c1Cl
Temperature: 80 °C
Reaction time: 18 h
Yield: 163.2 %

Procedure:
A mixture of 0.5 gram (0.0028 mole) of 2,3-dichlorobenzylamine and 0.27 gram (0.0081 mole) of 2-chloroethylisothiocyanate in 10 mL of 1,4-dioxane was placed in a sealed reaction vial. The reaction mixture was heated to 80° C. where it stirred for about 18 hours. The reaction mixture was allowed to cool and a solid precipitate that had formed was collected by filtration. The solid was rinsed with diethyl ether and was dried under reduced pressure to yield 0.68 gram of the title compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][OH:17])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7].C(N(CC)CC)C>ClCCl.O>[CH3:1][S:2]([O:17][CH2:16][CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([N+:6]([O-:8])=[O:7])[CH:10]=1)(=[O:4])=[O:3]
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cccc([N+](=O)[O-])c1
Reaction time: 5 h
Yield: 84 %

Procedure:
Methanesulfonyl chloride (0.28 mL) was added dropwise to a stirred solution of 2-(3-nitrophenyl)ethanol (0.5 g; 1 eq) in dichloromethane (3 mL) and triethylamine (0.5 mL; 1.2 eq) at 0° C. under an inert atmosphere. The solution was allowed to reach r.t. and stirred for 5 hours. The reaction mixture was diluted with water (3 mL) and extracted into dichloromethane (3×3 mL). The organic layers were combined, dried over Na2SO4 and concentrated under reduced pressure. The crude was purified by flash chromatography, eluting with a gradient from dichloromethane to dichloromethane/MeOH (98/2) affording the title compound in 84% yield (0.62 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=[CH:11][C:12]=2[OH:13])=[CH:3][N:2]=1.[C:20]([C:22]1[CH:23]=[C:24]([S:29]([N:32](CC2C=CC(OC)=CC=2OC)[C:33]2[S:34][CH:35]=[N:36][N:37]=2)(=[O:31])=[O:30])[CH:25]=[CH:26][C:27]=1F)#[N:21].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:20]([C:22]1[CH:23]=[C:24]([S:29]([NH:32][C:33]2[S:34][CH:35]=[N:36][N:37]=2)(=[O:31])=[O:30])[CH:25]=[CH:26][C:27]=1[O:13][C:12]1[CH:11]=[CH:10][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:7]=1[C:4]1[CH:5]=[CH:6][N:1]=[N:2][CH:3]=1)#[N:21]
Reactant: Oc1ccc(-c2ccccc2)cc1-c1ccnnc1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cc(S(=O)(=O)Nc2nncs2)ccc1Oc1ccc(-c2ccccc2)cc1-c1ccnnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.4 %

Procedure:
3-Pyridazin-4-ylbiphenyl-4-ol (Preparation 4, 50 mg, 0.2 mmol) and 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 15, 87.3 mg, 0.2 mmol) were dissolved in dimethylsulfoxide (2 mL). Potassium carbonate (83 mg, 0.6 mmol) was added and the reaction stirred at room temperature for 16 hours. The crude material was partitioned between ethyl acetate (20 mL) and water (20 mL), the organic layer separated, concentrated in vacuo, dissolved in trifluoroacetic acid (1 mL) and the solution stirred for 16 hours at room temperature. The reaction was concentrated in vacuo then purified by reverse phase column chromatography (ISCO™, 12 g, C18, 20:1 water:acetonitrile to 1:4 water:acetonitrile). The appropriate fractions were combined and concentrated in vacuo to afford the title compound as a white solid (25 mg, 24%).
Reaction SMILES: [CH3:1][Mg]Cl.[C:4]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][C:8]=1[O:17][CH3:18])(=[O:6])[CH3:5]>C1COCC1>[OH:6][C:4]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][C:8]=1[O:17][CH3:18])([CH3:1])[CH3:5]
Reactant: COc1cc(NC(C)=O)ccc1C(C)=O
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: COc1cc(NC(C)=O)ccc1C(C)(C)O
Temperature: 25 °C
Yield: 108 %

Procedure:
Methyl magnesium chloride (49.9 ml, 150 mmol, 3 M solution in THF) in 100 ml THF was cooled to zero degrees C, and N-(4-Acetyl-3-methoxy-phenyl)-acetamide (14.1 g, 68 mmol) in 200 ml THF was added via cannula to over 25 minutes. The reaction mixture was stirred and allowed to warm to room temperature over 2.5 hours. The reaction was quenched by addition of 1 N NH4Cl and extracted with EtOAc. The combined organic layers were washed with 1 N ammonium chloride, brine, dried over MgSO4, and concentrated under reduced pressure to afford N-[4-(1-Hydroxy-1-methyl-ethyl)-3-methoxy-phenyl]-acetamide (16.4 g, 100% ).
Reaction SMILES: [C-:1]#[N:2].[Na+].O.[O:5]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:20][C:21]([Br:31])=[CH:22][CH:23]1[CH:25]([C:26](Cl)=[O:27])[C:24]1([CH3:30])[CH3:29]>O.O1CCCC1.O1CCCC1>[Br:20][C:21]([Br:31])=[CH:22][CH:23]1[CH:25]([C:26]([O:16][CH:15]([C:1]#[N:2])[C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([O:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:13]=2)=[O:27])[C:24]1([CH3:30])[CH3:29]
Reactant: CC1(C)C(C=C(Br)Br)C1C(=O)Cl
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C(C=C(Br)Br)C1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Reaction time: 2 h
Yield: 115 %

Procedure:
Sodium cyanide (0.80 g, 0.016 mole) was charged to a reaction vessel together with 25 ml of a mixture of water and tetrahydrofuran (1/1 by volume). 3-Phenoxybenzaldehyde (2.31 g, 0.012 mole) in 10 ml of water/tetrahydrofuran solution (1/1 by volume) was then added in one portion, and 3-(2,2-dibromoethenyl)-2,2-dimethylcyclopropanecarbonyl chloride (4.4 g, 0.014 mole) was added dropwise over a 15 minute period. The reaction mixture was stirred for 2 hours at 20°, and the desired ester (6.97 g, 86% pure by glpc) was isolated as described in Example 1E. EXAMPLE 3
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:34](=[O:35])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[C:16](=C)[CH2:17][S:18](=O)[C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]([O:39]C(=O)C)(=[O:38])[CH3:37].[C:43](Cl)(=O)C>C1(C)C=CC=CC=1>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:34](=[O:35])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[C:16]([O:39][C:36](=[O:38])[CH3:37])=[C:17]([CH3:43])[S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: C=C1CS(=O)[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)OC1=C(C)S[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 111 °C

Procedure:
To 10 ml. of dry toluene were added 500 mg. (1 millimole) of p-nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4-carboxylate-1-oxide. To the resulting mixture then were added 2 ml. of acetic anhydride and 0.071 ml. (1 equivalent based upon the cepham sulfoxide) of acetyl chloride. The resulting mixture was refluxed at 111° C. for 5 hours to obtain almost complete conversion of the methylenecepham sulfoxide to p-nitrobenzyl 7-phenoxyacetamido-3-acetoxy-methyl-2-cephem-4-carboxylate as well as a minor amount of the corresponding Δ3 isomer.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[S:11][CH2:10][CH2:9][CH2:8][S:7]1)=[O:5])[CH3:2].C([Li])CCC.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH2:17]([C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[S:7][CH2:8][CH2:9][CH2:10][S:11]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)C1SCCCS1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccccc2)SCCCS1
Temperature: -25 °C
Reaction time: 0.33 h
Yield: 88.5 %

Procedure:
A solution of 3.0 g (15.6 mmol) of 2-ethoxycarbonyl-1,3-dithiane in 40 ml of dry tetrahydrofuran was cooled under inert atmosphere to -78° C. and treated with 7.5 ml (15.6 mmol) of n-butyllithium. The resulting solution was warmed to -25° C., stirred for 20 min, recooled to -78° C., treated with 1.8 ml (15.6 mmol) of benzyl chloride, and stirred at ambient temperature for 16 h. After quenching with aqueous ammonium chloride, the mixture was extracted with ether, washed sequentially with water, aqueous sodium thiosulfate, and brine, dried over MgSO4, and concentrated in vacuo. Flash chromatography using 5% ethyl acetate in hexane gave 3.9 g (88%) of the desired compound. 1H NMR (CDCl3) δ 1.33 (t, J=7 Hz, 3H), 1.85 (qt, J=14, 3 Hz, 1H), 2.11 (dm, J=14 Hz, 1H), 2.69 (dt, J=14, 4 Hz, 2H), 3.23 (ddd, J=14, 12, 3 Hz, 2H), 3.38 (s, 2H), 4.27 (q, J=7 Hz, 2H), 7.25-7.35 (m, 5H). Mass spectrum (M+NH4)+ =300.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N+:10]2[O-:29])=[CH:5][CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2cccnc2c1OCc1ccccc1
Solvent: ClCCl
Product: COc1ccc2ccc[n+]([O-])c2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58 %

Procedure:
7-(methyloxy)-8-[(phenylmethyl)oxy]quinoline (0.30 g; 1.13 mmol) and 77% by weight m-chloroperbenzoic acid (0.38 g; 1.69 mmol) are added in succession to dry CH2Cl2 (11 ml) at 4° C. under argon. The mixture is stirred for 48 hours at ambient temperature, then CH2Cl2 (40 ml) is added. The reaction medium is washed with a saturated aqueous solution of NaHCO3 (2×50 ml) and the solvent is evaporated under reduced pressure. The resulting oil is purified by silica gel chromatography, eluted with a CH2Cl2/CH3OH (95/5, v/v) mixture to yield 7-(methyloxy)-8-[(phenylmethyl)oxy]quinoline-N-oxide in the form of a yellow oil (0.18 g; 0.64 mmol, yield=58%). NMR-1H (250 MHz, CDCl3) δ, ppm: 8.43 (dd, 3J (H, H)=6.0 Hz, 4J ((H, H)=1.0 Hz, 1H); 7.68-7.58 (m, 4H); 7.41-7.30 (m, 4H); 7.10 (dd, 3J (H, H)=8.5 Hz, 3J (H, H)=6.0 Hz, 1H); 5.23 (s, 2H); 3.96 (s, 3H). NMR-13C (63 MHz, CDCl3) δ, ppm: 138.4; 128.9; 128.7; 128.2; 127.8; 127.6; 125.7; 124.9; 123.4; 119.5; 118.8; 116.8; 107.7; 75.2; 57.1. MS (CID, NH3): m/z=282 (MH+). Analysis (%) for C17H15NO3: calculated C, 72.58; H, 5.37; N, 4.98. found C, 72.74; H, 4.91; N, 4.87.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([CH2:10][C:11](OC1C(F)=C(F)C(F)=C(F)C=1F)=O)[CH2:3]2.[Br:25][C:26]1[CH:35]=[CH:34][C:29]2[CH:30]=[C:31]([NH2:33])[S:32][C:28]=2[CH:27]=1.C(=O)([O-])[O-:37].Cl>CN(C=O)C.C(#N)C>[ClH:1].[CH:4]12[CH2:5][CH2:8][CH:9]([CH2:11][CH2:10]1)[N:2]([CH2:7][C:6]([NH:33][C:31]1[S:32][C:28]3[CH:27]=[C:26]([Br:25])[CH:35]=[CH:34][C:29]=3[CH:30]=1)=[O:37])[CH2:3]2
Reactant: O=C([O-])[O-]
Reactant: O=C(CC1CN2CCC1CC2)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: Nc1cc2ccc(Br)cc2s1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(CN1CC2CCC1CC2)Nc1cc2ccc(Br)cc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
89.2 mg (0.24 mmol) of pentafluorophenyl (1-azabicyclo[2.2.2]oct-3-yl)acetate hydrochloride are dissolved in 1 ml of DMF, mixed with 71.2 mg (0.31 mmol) of 6-bromo-1-benzothiophene-2-amine and stirred at room temperature overnight. 1 g of MP-carbonate (polymer-bound carbonate, capacity: 2.5-3.5 mmol/g; from Argonaut Technologies, USA) is added. After 3 h, the polystyrene resin is filtered off and washed with THF. The combined filtrates are concentrated in vacuo, and the crude product is purified by preparative HPLC. The hydrochloride is prepared by mixing the product with a mixture of 1 M hydrochloric acid and acetonitrile and again concentrating. Drying under high vacuum results in 14 mg (14% of theory) of the title compound.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([NH:12][C:13](=O)[C:4]2=[N:3][CH:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.C(N(CC)C1C=CC=CC=1)C.C(Cl)[Cl:27].CO>P(Cl)(Cl)(Cl)=O>[Cl:27][C:13]1[C:4]2[N:5]([CH:1]=[CH:2][N:3]=2)[C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: ClCCl
Reactant: O=c1[nH]c2ccccc2n2ccnc12
Solvent: CO
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: Clc1nc2ccccc2n2ccnc12
Yield: 75 %

Procedure:
Compound 11 (1.4 g, 6.4 mmol) is solubilized in phosphorus oxychloride (24 ml), and N,N-diethylaniline (3.6 ml). The reaction mixture obtained is carried to reflux for approximately 2 h. The product is insoluble in POCl3 even after heating. The reaction is monitored by TLC, eluent: CH2Cl2/MeOH (95/5). TLC shows the presence of the end product, but also the appearance of breakdown products. The reaction mixture is dark brown in colour. The POCl3 is evaporated under vacuum. The residue is cooled in an ice bath before adding a little water and, dropwise, a saturated sodium bicarbonate solution to neutralize POCl3. A light yellow foam and a brown precipitate appear. The solid is isolated by filtration and is recrystallized in methanol. A beige solid (0.97 g, 75%) is obtained; 1H NMR (300 MHz, DMSO-d6) δ: 8.5 (s, 1H, N—CH—C), 8.06 (d, 1H, ArH), 7.56 (s, 1H, C—CH—N), 7.35 (m, 1H, ArH), 7.25 (m, 2H, ArH). Analysis calculated for C10H6N3C1: C, 58.98; H, 2.97; N, 20.64. Experimental: C, 59.12; H, 2.76; N, 20.45.
Reaction SMILES: [CH2:1]([N:8]([CH2:13][C:14]([OH:16])=O)[CH2:9][C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:19](CC)CC)C.FC(F)(F)C(N)=O.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][C:14](=[O:16])[NH:19][C:10](=[O:11])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)CN(CC(=O)O)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC(=O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CN(Cc2ccccc2)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.1 %

Procedure:
To a suspensiopn of 15 g (67 mmoles) of benzyliminodiacetic acid in 300 ml of CH2Cl2, 28 ml (201 mmoles) of triethylamine, 21.77 g (161 mmoles) of 1H-hydroxybenztriazole and 10.6 g (94 mmoles) of trifluoroacetamide are successively added and then 28.34 g (147.8 mmoles) of 1-[3(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride is added at 0° C. The reaction mixture is allowed to warm to ambient temperature and stirred for 18 hours. The reaction mixture is quenched with cold H2O and extracted with CH2Cl2. The combined extracts are washed with H2O brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: n-Hexane:AcOEt=2:1) to give 10 g of desired 4-benzyl-piperazine-2,6-dione in 73% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[CH:23]([CH3:25])[CH3:24].[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:38](=[O:39])[C:37]([C:40](O)=[O:41])=[CH:36][N:35]([CH:43]([CH3:45])[CH3:44])[C:34]2=[O:46])=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:40]([C:37]2[C:38](=[O:39])[N:33]([C:30]3[CH:29]=[CH:28][C:27]([F:26])=[CH:32][CH:31]=3)[C:34](=[O:46])[N:35]([CH:43]([CH3:45])[CH3:44])[CH:36]=2)=[O:41])=[CH:18][C:17]=1[CH:23]([CH3:25])[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3C(C)C)c2cc1OC
Reactant: CC(C)n1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4cn(C(C)C)c(=O)n(-c5ccc(F)cc5)c4=O)cc3C(C)C)c2cc1OC

Procedure:
This compound was synthesized using 4-(6,7-dimethoxy-quinolin-4-yloxy)-3-isopropyl-phenylamine and 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid using the procedure for example 1. mp=165-167° C.; LCMS m/z=613 (M+1); 1H NMR (CDCl3) δ: 10.86 (s, 1H), 8.72 (s, 1H), 8.46 (d, 1H, J=5.5 Hz), 7.66 (dd, 1H, J=2.5, 8 Hz), 7.63 (d, 1H, J=2 Hz), 7.60 (s, 1H), 7.44 (s, 1H), 7.27-7.25 (m, 3H), 7.05 (d, 1H, J=9 Hz), 6.37 (d, 1H, J=5.5 Hz), 4.98 (p, 1H, J=8 Hz), 4.06 (s, 6H), 3.09 (p, 1H, J=8 Hz), 1.5 (d, 6H, J=7 Hz), 1.18 (d, 6H, J=7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:6]3[CH2:21][CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH2:25][C:5]=3[C:4]=2[C:3]=1[Cl:33].C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][O:13][C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[C:6]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:5]=3[C:4]=2[C:3]=1[Cl:33]
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCOc3ccc(F)cc3)c3ccc(Cl)c(Cl)c23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cl
Product: Fc1ccc(OCCn2c3c(c4c(Cl)c(Cl)ccc42)CCNCC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To a solution of tert-butyl 9,10-dichloro-6-[2-(4-fluorophenoxy)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.20 g, 0.41 mmol) in CH2Cl2 (6.0 mL), TFA (0.63 mL, 8.1 mmol) was added while stirring at rt. After 30 min, the reaction was made basic with 10% aqueous NaOH, then extracted with CH2Cl2 (3×15 mL). The combined organic layers were washed with brine, dried over Na2SO4, decanted, and concentrated to 0.17 g of a crude solid. After the hydrochloride salt was prepared, it was further purified by a recrystallization from MeOH/EtOAc to give 69 mg (40%) of a white solid: mp 214.0-216.0; 1H NMR (300 MHz, DMSO) δ 7.58 (d, J =8.7 Hz, 1H), 7.31 (d, J=9.0 Hz, 1H), 7.09 (m, 2H), 6.84 (m, 2H), 4.63 (m, 2H), 4.15 (t, J=4.9 Hz, 2H), 3.53 (m, 2H); 13C NMR (400 MHz, DMSO) δ 157.0, 154.7, 153.5, 153.5, 139.5, 134.4, 123.2, 122.0, 121.2, 120.7, 115.2, 115.0, 114.8, 114.7, 110.0, 109.9, 66.6, 44.5, 42.9, 41.6, 21.6, 20.5; IR (diffuse reflectance) 2965, 2838, 2823, 2794, 2770, 2745, 2714, 2697, 2651, 1506, 1442, 1249, 1222, 1206, 831 cm−1; MS (ES+) m/z 393 (M+H+), 364, 238, 221, 175, 79, 74, 66, 64, 62, 61. Anal. Calcd for C20H19Cl2FN2O.HCl: C, 55.90; H, 4.69; N, 6.52, found: C, 55.65; H, 4.72; N, 6.49.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[CH:5]=[C:4]([C:9]2([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.C(N(C(C)C)C(C)C)C.P(Cl)(Cl)([Cl:32])=O>C(#N)C>[Cl:32][C:6]1[CH:5]=[C:4]([C:9]2([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc(O)cc(C2(c3ccc(Cl)cc3)CCCC2)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(Cl)cc(C2(c3ccc(Cl)cc3)CCCC2)n1

Procedure:
360 mg of 2-amino-6-[1-(4-chlorophenyl)cyclopentyl]pyrimidin-4-ol are dissolved in 10 ml of acetonitrile, and 0.8 ml of N-ethyldiisopropylamine is added under nitrogen. 0.5 ml of phosphoryl chloride are subsequently added slowly. The batch is boiled under reflux for 8 h in order to complete the reaction. All volatile constituents are subsequently removed in vacuo, and the batch is added to ice-water and dichloromethane. The organic phase is dried over sodium sulfate, filtered and evaporated. The residue obtained is employed in the subsequent reaction without further purification. (Rt: 2.694 min.; M+H+: 308.2+310.2).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]1[CH2:19][CH2:18][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([N:9]1[CH2:19][CH2:18][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
30 g of benzyl bromide are added dropwise to a mixture of 25 g of ethyl isonipecotate and 25 g of K2CO3 in 125 ml of DMF, while maintaining the temperature of the reaction mixture between 25 and 30° C., and the resulting mixture is then stirred at RT for 1 hour. The reaction mixture is poured onto 1 litre of ice-cold water and extracted twice with ether, the organic phase is washed with water and dried over MgSO4, and the solvent is evaporated off under vacuum. The resulting oil obtained is distilled off under reduced pressure. 29.2 g of the expected product are obtained; b.p.=120-122° C. at 2.7 Pa.