Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2N=C(C3C=CC([N+]([O-])=O)=CC=3)[NH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].[NH4+:22].[OH-]>>[NH2:10][C:7]1[CH:6]=[C:5]([NH2:22])[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1ccc(-c2nc3cc([N+](=O)[O-])cnc3[nH]2)cc1
Agent: [OH-]
Product: Nc1cc(N)c([N+](=O)[O-])cn1
Temperature: 25 °C
Yield: 77 %

Procedure:
A solution of 4-amino-2-chloro-5-nitropyridine (4) (1.0 g, 5.76 mmol) in 50 ml 28% NH4OH was heated in a sealed tube at 120° C. for overnight. After cooling the reaction mixture to room temperature afforded orange red solid 5 (0.770 g, 77%). 1H NMR (DMSO-d6, 500 MHz): δ 8.66 (1H, s), 7.35 (1H, br s), 6.73 (1H, brs), 5.67 (1H, s); EIMS m/z: 155.2 (M+1), 153.2 (M−1)
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)[Br:17]>ClCCl>[Br:17][CH2:2][C:3]1[CH:4]=[C:5]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)COc1cccc(CO)c1
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)COc1cccc(CBr)c1
Reaction time: 1 h

Procedure:
To a solution of 3-hydroxymethyl-1-ethoxycarbonylmethoxybenzene (1 g) in dichloromethane (10 ml) was added BBr3 (0.45 ml). After 1 hour, the solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with NaHCO3 and brine. The dried solvent was evaporated in vacuo to give 3-bromomethyl-1-ethoxycarbonylmethoxybenzene (0.76 g). NMR (CDCl3, δ): 1.29 (3H, t, J=7 Hz), 4.24 (2H, d, J=7 Hz), 4.61 (2H, s), 5.00 (1H, d, J=3.0 Hz), 5.05 (1H, d, J=3.0 Hz), 6.7-7.1 (3H, m), 7.2-7.3 (1H, m)
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([CH2:17][C:16]3[CH:18]=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(OC(Cl)=O)C>C1(C)C=CC=CC=1>[F:25][C:22]([F:23])([F:24])[C:19]1[CH:20]=[CH:21][C:15]2[O:14][C:11]3([CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH2:17][C:16]=2[CH:18]=1
Reactant: FC(F)(F)c1ccc2c(c1)CC1(CCN(Cc3ccccc3)CC1)O2
Agent: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc2c(c1)CC1(CCNCC1)O2
Temperature: 25 °C
Yield: 75.2 %

Procedure:
To a solution of 1′-benzyl-5-(trifluoromethyl)-3H-spiro[1-benzofuran-2,4′-piperidin] (280 mg, 0.806 mmol) in toluene (3 mL) was added ethylchloroformate (0.093 mL, 0.967 mmol) and the reaction mixture was stirred at reflux temperature overnight, cooled to room temperature, diluted by addition of toluene and washed with aqueous NaHCO3 and water successively. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was dissolved in ethanol ((4 mL), aqueous KOH (1.14 g KOH in 1.2 mL of H2O) was added and the reaction mixture was refluxed overnight, cooled to room temperature, ethanol was removed in vacuo. Aqueous layer was extracted with Et2O, combined ether layer was washed with 3N aqueous HCl. Combined acidic layer was made pH 10 by addition of aqueous NaOH. The basic solution was extracted with ethyl acetate. The combined organic layer was washed with water, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-2% methanol in dichloromethane, 0.2% NH4OH) to give the subtitled compound (156 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N+:9]([O-])=[CH:8][CH:7]=[CH:6]2.CC(OC(C)=O)=[O:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([OH:16])[CH:7]=[CH:6]2
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(ccc[n+]2[O-])c1
Product: COc1ccc2nc(O)ccc2c1
Yield: 67 %

Procedure:
A solution of 6-methoxyquinoline 1-oxide (300 mg, 1.71 mmol) in Ac2O (5.0 mL) was refluxed for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL), the organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product which was purified by silica gel column (PE/EtOAc=1/2) to give 6-methoxyquinolin-2-ol (200 mg, yield 67%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[NH:17][N:16]=[N:15][N:14]=3)[CH:10]=[CH:9][C:8]=2[NH:18][C:19]([C:21]2[NH:22][C:23]([C:26]#[N:27])=[CH:24][N:25]=2)=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:36][CH2:37][N:38]([CH3:40])[CH3:39].Cl[CH2:42][CH2:43][N:44]([CH3:46])[CH3:45].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[N:17]([CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])[N:16]=[N:15][N:14]=3)[CH:10]=[CH:9][C:8]=2[NH:18][C:19]([C:21]2[N:22]([CH2:42][CH2:43][N:44]([CH3:46])[CH3:45])[C:23]([C:26]#[N:27])=[CH:24][N:25]=2)=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: N#Cc1cnc(C(=O)Nc2ccc(-c3nnn[nH]3)cc2C2=CCCCC2)[nH]1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(C)CCn1nnnc1-c1ccc(NC(=O)c2ncc(C#N)n2CCN(C)C)c(C2=CCCCC2)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 21.3 %

Procedure:
To a solution of 5-cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(1H-tetrazol-5-yl)-phenyl]-amide (as prepared in Example 57, step (e), 37 mg, 0.10 mmol) in DMF (0.5 mL) was added K2CO3 (42 mg, 0.30 mmol) followed by 2-chloro-ethyl-dimethyl-amine hydrochloride salt (18 mg, 0.12 mmol). The reaction was heated to 70° C. After 3 h, 2-chloro-ethyl-dimethyl-amine (14.6 mg, 0.102 mmol) was again added, followed by K2CO3 (28 mg, 0.20 mmol) and the resulting mixture heated to 100° C. After 1 h, 2-chloro-ethyl-dimethyl-amine (18 mg, 0.12 mmol) and DIEA (35 μL, 0.20) were added and the resulting mixture stirred at 100° C. overnight. The mixture was poured into EtOAc (20 mL) and washed with saturated aqueous NaHCO3 (2×10 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. Purification of the residue by preparative TLC (15% MeOH—CHCl3) afforded 10.7 mg (21%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 9.85 (s, 1H), 8.44 (d, 1H, J=8.5 Hz), 7.98 (dd, 1H, J=8.5, 2.0 Hz), 7.89 (d, 1H, J=1.9 Hz), 7.66 (s, 1H), 5.84 (m, 1H), 4.67 (t, 2H, J=6.7 Hz), 4.60 (t, 2H, J=5.9 Hz), 2.92 (t, 2H, J=6.7 Hz), 2.68 (t, 2H, J=5.9 Hz), 2.25 (s, 6H), 2.22 (s, 6H), 1.81-1.73 (m, 8H). Mass spectrum (ESI, m/z): Calcd. for C26H34N10O, 503.2, found 503.2.
Reaction SMILES: [Br:1]Br.[C:3]([O:6][CH2:7][CH2:8][C:9]1[N:10]=[C:11]([NH:14][C:15](=[O:17])[CH3:16])[S:12][CH:13]=1)(=[O:5])[CH3:4]>CC(O)=O>[C:3]([O:6][CH2:7][CH2:8][C:9]1[N:10]=[C:11]([NH:14][C:15](=[O:17])[CH3:16])[S:12][C:13]=1[Br:1])(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1nc(CCOC(C)=O)cs1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(CCOC(C)=O)c(Br)s1
Yield: 75.1 %

Procedure:
Br2 (0.46 g, 2.9mmol) was dropped into 2-(2-acetamidothiazol-4-yl)ethyl acetate (0.60 g, 2.6 mmol) in 20 mL AcOH. The reaction was instantaneous. Acetic acid was evaporated from the reaction and saturated sodium bicarbonate was slowly added to the residue. The resulting mixture was extracted twice with EtOAc. The organic layer was washed with brine and dried over sodium sulfate. 2-(2-Acetamido-5-bromothiazol-4-yl)ethyl acetate (0.6 g, yield=74.3%) was obtained as a white solid. LCMS (API-ES) m/z (%): 309.0 (100%, M++H).
Reaction SMILES: [CH3:1][S-:2].[Na+].[Br:4][C:5]1[CH:6]=[CH:7][C:8](F)=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.O>CN(C=O)C>[CH3:1][S:2][C:8]1[CH:7]=[CH:6][C:5]([Br:4])=[CH:10][C:9]=1[C:11]([F:14])([F:13])[F:12]
Reactant: Fc1ccc(Br)cc1C(F)(F)F
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(Br)cc1C(F)(F)F
Temperature: 50 °C

Procedure:
A mixture of sodium thiomethoxide (0.317 g) and 5-bromo-2-fluorobenzotrifluoride (1.0 g) in DMF (4 ml) was heated at 50° C. for 1 h then poured into water and extracted with isohexane. The organics were washed with brine, dried and evaporated under reduced pressure. Yield 0.762 g
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:11])[CH2:8][CH2:9][CH3:10].[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[O:22][CH2:23][CH2:24][CH2:25]Cl>CS(C)=O.O>[CH2:7]([NH:11][CH2:25][CH2:24][CH2:23][O:22][C:13]1[CH:14]=[CH:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=1)[CH2:8][CH2:9][CH3:10]
Reactant: ClCCCOc1ccc2ccccc2c1
Reactant: CCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCNCCCOc1ccc2ccccc2c1
Temperature: 135 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and n-butylamine (0.34 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 135° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(n-butyl)-(3-(naphthalen-2-yloxy)propyl)amine, solid, m.p. 112° C., (yield 0.55 gm, 94.5%).
Reaction SMILES: [NH2:1][CH:2]1[N:7]=[C:6]2[N:8]=[CH:9][C:10]([CH2:11][NH2:12])=[C:5]2[C:4](=[O:13])[N:3]1[CH2:14][O:15][CH:16]([CH3:18])[CH3:17].[CH:19](=O)[CH2:20][CH3:21].[BH4-].[Na+].C(O)(=O)C>CO>[NH2:1][CH:2]1[N:7]=[C:6]2[N:8]=[CH:9][C:10]([CH2:11][NH:12][CH2:19][CH2:20][CH3:21])=[C:5]2[C:4](=[O:13])[N:3]1[CH2:14][O:15][CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)OCN1C(=O)C2=C(CN)C=NC2=NC1N
Reactant: CCC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCNCC1=C2C(=O)N(COC(C)C)C(N)N=C2N=C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.9 %

Procedure:
In 5.0 ml of dry methanol were dissolved 251 mg of 2-amino-5-aminomethyl-3-isopropyloxymethylpyrrolo[2,3-d]pyrimidin-4-one and 64 mg of propionaldehyde and the solution was allowed to stand under stirring at room temperature for 30 min. Then, 20 mg of sodium borohydride was added and the mixture was reacted at room temperature for an hour. The excess reagent was decomposed with a small amount of acetic acid, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to give 76 mg of 2-amino-5-propylaminomethyl-3-isopropyloxymethylpyrrolo[2,3-d]pyrimidin-4-one. The whole amount of this product was dissolved in 30 ml of 2 N--HCl and, after nitrogen purging, hydrolyzed under heating at 70° C. for 6.5 hours. The solvent was then evaporated off under reduced pressure to give 73 mg of the desired compound.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:24]1[CH2:28][CH2:27][NH:26][C:25]1=[O:29]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[N:7][C:2]([N:26]4[CH2:27][CH2:28][O:24][C:25]4=[O:29])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: O=C1NCCO1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)nn3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)nn3)CC2)c(C)c1
Yield: 25.1 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (152 mg) described in Preparation Example 230 and oxazolidin-2-one (40 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (44 mg) was obtained.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13]Cl)[CH:8]=1>>[CH3:1][N:2]([CH2:13][C:9]1[CH:8]=[N:7][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][NH:5][CH3:6]
Reactant: ClCc1cccnc1
Reactant: CNCCNC
Product: CNCCN(C)Cc1cccnc1
Reaction time: 1 h
Yield: 47.3 %

Procedure:
To 7.50 gm of N,N'-dimethylethylenediamine which has been cooled in an ice-ethanol bath is added portionwise over a 30 minute period 1.40 gm of 3-picolyl chloride. After stirring cold for 1 hour after the addition is completed, the reaction mixture is concentrated in vacuo and the residue partitioned between 50 ml of ether and 10 ml of 5N NaOH solution. The organic layer is separated and the aqueous layer extracted 2 times with 50 ml of ether. The combined organic extracts are dried through sodium sulfate and concentrated in vacuo. Chromatography on 150 gm silica gel using CH2Cl2 /CH3OH/NH4αH (90/10/1) as eluent gives 0.930 g of N,N'-dimethyl-N-(3-pyridylmethyl)ethylenediamine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([CH:14]=[O:15])=[C:4]([CH3:16])[N:3]=1.[CH:17]([C:20]1[CH:28]=[CH:27][C:26]2[NH:25][N:24]=[CH:23][C:22]=2[C:21]=1B(O)O)([CH3:19])[CH3:18].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH:17]([C:20]1[C:21]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[C:5]([CH:14]=[O:15])=[C:4]([CH3:16])[N:3]=2)=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[CH:23]2)([CH3:19])[CH3:18]
Reactant: COc1ccc2c(Cl)nc(C)c(C=O)c2c1
Reactant: CC(C)c1ccc2[nH]ncc2c1B(O)O
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: [Na+]
Solvent: C1COCCO1
Product: COc1ccc2c(-c3c(C(C)C)ccc4[nH]ncc34)nc(C)c(C=O)c2c1
Temperature: 100 °C
Yield: 33.5 %

Procedure:
A mixture of 1-chloro-6-methoxy-3-methyl-isoquinoline-4-carbaldehyde (670 mg, 2.84 mmol), 5-isopropylindazole-4-boronic acid (580 mg, 2.84 mmol), Pd(PPh3)4 (164 mg, 0.14 mmol), and Na2CO3 (4.3 ml of 2M in H2O) in dioxane (15 ml) is heated for 18 h at 100° C. Usual work-up followed by flash chromatography over silica gel gives 342 mg of 1-(5-isopropyl-1H-indazol-4-yl)-6-methoxy-3-methyl-isoquinoline-4-carbaldehyde. 1H NMR (CDCl3) 10.9 (s, 1H), 8.68 (s, 1H), 7.65-7.37 (m, 3H), 7.42 (d, 1H), 7.01 (d, 1H), 4.01 (s, 3H), 3.15 (s, 3H), 2.71-2.63 (m, 1H), 1.22 (d, 3H), 1.10 (d, 3H).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(O)(=O)C>CN(C)C=O.C(OCC)(=O)C>[NH2:8][C:9]1[C:14]([C:15](=[O:16])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([C:3](=[O:5])[CH3:2])[CH2:28][CH2:27]2)[N:10]=1
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: O=C(O)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccccc1C(=O)c1cnc(NC2CCN(C(C)=O)CC2)nc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt, (31 mg, Example 11) in dimethylformamide (2 mL) were added triethylamine (19 mg, 0.193 mmol, Aldrich), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.6 mg, 0.0344 mmol, Aldrich), 1-hydroxybenzotriazole hydrate (5.0 mg, 0.037 mmol, Aldrich), followed by acetic acid (2.3 mg, 0.034 mmol). The reaction mixture was stirred overnight at room temperature, taken up in ethyl acetate (15 mL), washed with brine and evaporated. The crude product was purified on silica gel with 95:5 of dichloromethane/methanol to give 1-[4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-ethanone (11.2 mg). HRMS, observed: 370.1875; Calcd for (M+H)+: 370.1874.
Reaction SMILES: ClN1C(=O)CCC1=O.N1C=CC=CC=1.[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([CH:20]=[N:21][OH:22])=[CH:18][CH:17]=1.[N+](C1C=C[C:31]([C:32]([O:34][CH:35]=CC(OC)=O)=[O:33])=[CH:30]C=1)([O-])=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:16]1([CH3:15])[CH:24]=[CH:23][C:19]([C:20]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][O:22][N:21]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)C=COC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(C=NO)cc1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COC(=O)c1conc1-c1ccc(C)cc1
Yield: 19.6 %

Procedure:
N-Chlorosuccinimide (9.87 g, 73.4 mmol) and pyridine (175 mg, 2.2 mmol) were dissolved in chloroform (100 ml), 4-methylbenzaldehyde oxime (10 g, 73.4 mmol) was added, and the mixture was stirred until it became clear. A solution of 2-methoxycarbonylvinyl 4-nitrobenzoate (9.22 g, 36.7 mmol) and triethylamine (12.9 g, 128 mmol) in chloroform (180 ml) was slowly added dropwise at 0° C. over 2 hours, and the mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=5:95) to give the title compound (1.56 g, 7.19 mmol, 19.6%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:44][CH2:45][CH:46]([OH:58])[CH2:47][N:48]1[CH2:57][CH2:56][C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:49]1>C(Cl)Cl>[CH2:49]1[C:50]2[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:56][CH2:57][N:48]1[CH2:47][CH:46]([OH:58])[CH2:45][NH:44][C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.5 %

Procedure:
To a solution of 4-(pyridin-2-yl)benzoic acid (100 mg, 0.5 mmol) in DCM (5 mL) was added EDCI (144 mg, 0.75 mmol), HOBt (101 mg, 0.75 mmol), Et3N (152 mg, 1.5 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (103 mg, 0.5 mmol). The mixture was stirred at 25° C. for 16 h. The reaction solution was washed with water and extracted with DCM. The organic layer was concentrated, and the residue was purified by prep-HPLC to give the title compound (30 mg, Yield 15.5%). 1H NMR (CD3OD, 400 MHz): δ 8.70-8.60 (m, 1H), 8.01-7.84 (m, 6H), 7.45-7.36 (m, 1H), 7.16-6.99 (m, 4H), 4.20-4.10 (m, 1H), 3.79 (s, 2H), 3.62-3.46 (m, 2H), 2.92 (s, 4H), 2.78-2.65 (m, 2H). LCMS (m/z): 388.2 (M+1).
Reaction SMILES: Br[C:2]1[N:3]=[N+:4]([O-:17])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH:11]([CH2:15][OH:16])[CH2:12]3)=[CH:8][C:6]=2[N:7]=1.[CH2:18]([NH2:20])[CH3:19]>COCCOC>[CH2:18]([NH:20][C:2]1[N:3]=[N+:4]([O-:17])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH:11]([CH2:15][OH:16])[CH2:12]3)=[CH:8][C:6]=2[N:7]=1)[CH3:19]
Reactant: CCN
Reactant: [O-][n+]1nc(Br)nc2cc3c(cc21)CC(CO)C3
Solvent: COCCOC
Product: CCNc1nc2cc3c(cc2[n+]([O-])n1)CC(CO)C3
Temperature: 20 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A mixture of bromide 125 (91 mg, 0.31 mmol), 70% ethylamine (0.5 mL) and DME (3 mL) was stirred at 20° C. for 3 h. The mixture was partitioned between EtOAc and aqueous Na2CO3 solution. The organic layer was separated, dried and the solvent evaporated to give compound 126 (74 mg, 92%) as yellow solid: mp (EtOAc) 150° C.; 1H NMR δ 8.07 (s, 1H, H-9), 7.40 (s, 1H, H-5), 5.07 (br s, 1H, NH), 3.64-3.72 (m, 2H, CH2O), 3.50-3.58 (m, 2H, CH2N), 3.11-3.21 (m, 2H, CH2), 2.71-2.93 (m, 3H, CH2, CH), 1.29 (t, J=7.2 Hz, 3H, CH3), OH not observed; HRMS calcd for C13H16N4O2 (M+) m/z 260.1271, found 260.1273.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([F:34])[CH:26]=4)=[O:23])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[C:36]1C=C(S(Cl)(=O)=O)C=C(Cl)[CH:41]=1>>[CH2:36]([O:30][C:29](=[O:31])[C:28]1[CH:32]=[CH:33][C:25]([NH:24][C:22]([C:19]2[CH:20]=[C:21]3[C:16]([CH2:15][CH2:14][CH2:13][N:12]3[S:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:11])=[O:10])=[CH:17][CH:18]=2)=[O:23])=[CH:26][C:27]=1[F:34])[CH3:41]
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: O=C(Nc1ccc(C(=O)O)c(F)c1)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)cc(Cl)c1)CCC2
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)cc(Cl)c2)CCC3)cc1F

Procedure:
4-{[1-(3,5-Dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-2-fluoro-benzoic acid, m/z (ES+): 523.18 (M+H+.), was prepared in analogy to example 48, steps 1 to 5. Step 4 was performed using 3,5-dichloro-benzenesulfonyl chloride, yielding 4-{[1-(3,5-dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][OH:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([O:18][CH3:19])[CH:8]=2)[CH3:2]>CC(C)=O.O=[Mn]=O>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=[O:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([O:18][CH3:19])[CH:8]=2)[CH3:2]
Reactant: CCn1c2ccc(CO)cc2c2cc(OC)ccc21
Agent: O=[Mn]=O
Solvent: CC(C)=O
Product: CCn1c2ccc(C=O)cc2c2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 60 h
Yield: 0.1 %

Procedure:
A solution of 9-ethyl-3-hydroxymethyl-6-methoxycarbazole (0.305 g, 1.2 mmol) in acetone (5 mL) was treated with MnO2 (0.52 g, 6 mmol) and the reaction stirred at room temperature for 60 hours. The reaction mixture was filtered and the solvent evaporated under reduced pressure. The crude was purified by column chromatography (heptane/ethyl acetate 5/1) to afford 0.190 mg of the title compound.
Reaction SMILES: [Br:1][CH:2]1[CH2:8][CH:7]([Br:9])[C:6](=[O:10])[O:5][C:3]1=[O:4].[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[Br:9][CH:7]([CH2:8][CH:2]([Br:1])[C:3]([O:5][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4])[C:6]([O:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]
Reactant: OCc1ccccc1
Reactant: O=C1OC(=O)C(Br)CC1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1)C(Br)CC(Br)C(=O)OCc1ccccc1
Yield: 100.2 %

Procedure:
2.18 g (8 mmol) of 2,4-dibromoglutaric anhydride, 2.1 ml (20 mmol) of benzyl alcohol, and 2 ml of benzene are stirred for 1.5 hours at room temperature. 76 mg (0.4 mmol) of p-toluenesulfonic acid monohydrate and 8 ml of benzene are added, and the solution is refluxed under a Dean-Stark trap for 2 hours. Filtration over silica gel and evaporation yields 3.77 g (100%) of dibenzyl 2,4-dibromoglutarate as a colourless oil. 1H NMR (CDl3): δ7.37 (br. s., 10H), 5.21 (narrow AB system, 4H, J=12.5); dl isomer: δ4.55 (dd, 2H, J=6.5, 7.5), 2.69 (dd, 2H, J=6.5, 7.5); meso isomer: δ4.42 (t, 2H, J=7.5), 2.90 (dt, 1H, J=7.5 (t), 14.5 (d)), 2.66 (dt, 1H, J=7.5 (t), 14.5 (d)); dl/meso=6:1. IR (neat): 3034, 1740, 1499, 1456, 1385, 1273, 1154, 750, 696 cm-1.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:5]=[C:6]([C:12]2[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[O:7][C:8]=1[O:9][CH2:10][CH3:11])[CH3:3].CS([C:24]1[N:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[N:25]=1)(=O)=O.C(=O)([O-])[O-]>CN(C=O)C>[CH3:1][CH:2]([C:4]1[N:5]=[C:6]([C:12]2[C:17]([O:18][C:24]3[N:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[N:25]=3)=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[O:7][C:8]=1[O:9][CH2:10][CH3:11])[CH3:3]
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: CCOc1oc(-c2c(O)cccc2Cl)nc1C(C)C
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOc1oc(-c2c(Cl)cccc2Oc2nc(OC)cc(OC)n2)nc1C(C)C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
5 ml DMF solution containing 0.27 g 4-(2-propyl)-5-ethoxy-2-(2-chloro-6-hydroxyphenyl)oxazole, 0.20 g 2-methanesulfonyl-4,6-dimethoxypyrimidine and 0.41 g pottasium carbonate was stirred for 3 hours at 60° C. After completing the reaction, the solution reacted was poured into ice water and then extracted with ethyl acetate. The organic layer obtained was washed with water and saturated saline solution in turn and was then dried by using anhydrous magnesium sulfate, and the solvent used was removed by distillation under reduced pressure. The residue obtained was purified by using silica gel column chromatography, affording the objective oily substance in an amount of 0.3 g.