Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[F:28])[NH2:24].C(OCC)(=O)C>CCCCCC>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1[N+](=O)[O-]
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 103.4 %

Procedure:
4-Chloro-7-ethoxy-6-nitro-quinoline-3-carbonitrile (26.8 g 96.5 mmol) and 3-chloro-4-fluoroaniline 14.05 g 96.5 mmol) in 900 ml of iso-propanaol were refluxed under N2 for 3.5 hrs. TLC (ethyl acetate: hexane=1:1) showed no starting material left. After standing at room temperature overnight, the hydrochloride salt was filtered off and washed with isopropanol and ether giving 4-(3-chloro-4-fluoro-phenylamino)-7-ethoxy-6-nitro-quinoline-3-carbonitrile 38.6 g (95%) as a yellow hydrochloride salt.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7](=[O:13])[C:8](OCC)=[O:9])[CH2:3][CH2:2]1.O.[NH2:15][NH2:16]>C(O)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7](=[O:13])[C:8]([NH:15][NH2:16])=[O:9])[CH2:3][CH2:2]1
Reactant: NN
Reactant: CCOC(=O)C(=O)N1CCOCC1
Solvent: O
Solvent: CCO
Product: NNC(=O)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.3 %

Procedure:
Ethyl 2-morpholino-2-oxoacetate (1.0 g, 5.34 mmol) was dissolved in ethanol (7 mL) and hydrazine hydrate (0.267 g, 5.34 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure to give 0.9 g of the crude product, which was used without further purification in the following step. Crude yield 90%. 1H NMR (400 MHz, CDCl3) δ 9.79 (s, 1H), 4.43-4.48 (m, 2H), 3.56-3.61 (m, 4H), 3.40-3.48 (m, 4H). LCMS m/z 174.16 [M+H]+, tR=2.031 min.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([C:20]4[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=4)=[CH:15][C:14]=3[Cl:27])[C:8]2=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].[Na+].ClC1C=C(C2C=CC(C([O-])=O)=CC=2)C=CC=1CC1CCN(C2CCCCC2)C1=O>CN(C=O)C>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:16]2[CH:15]=[C:14]([Cl:27])[C:13]([CH2:12][CH:9]3[CH2:10][CH2:11][N:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[C:8]3=[O:28])=[C:18]([Cl:19])[CH:17]=2)=[CH:21][CH:22]=1)[CH3:35]
Reactant: O=C1C(Cc2c(Cl)cc(-c3ccc(O)cc3)cc2Cl)CCN1C1CCCCC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])c1ccc(-c2ccc(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1
Yield: 87.6 %

Procedure:
Combine 1-cyclohexyl-3-(3,5-dichloro-4′-hydroxy-biphenyl-4-ylmethyl)-pyrrolidin-2-one (Preparation 52) (0.15 g, 0.36 mmol), ethyl bromoacetate (0.12 g, 0.718 mmol) and Cs2CO 3 (0.29 g, 0.89 mmol) in DMF (6 mL) and heat to 60° C. for 16 hours. Cool the reaction, extract with diethyl ether and water, dry the organic layer (Na2SO4) and then purify by normal phase chromatography (30 to 80% gradient of ethyl acetate in hexanes) to afford 159 mg (88%) of the title compound: LC-MS (ES+) m/z=exact mass calcd for C27H31Cl2NO4 503, found 504 and 506 (M+1 and M+3, 100%).
Reaction SMILES: [NH:1]([CH:5]=O)[NH:2][CH:3]=O.Cl[Si](C)(C)C.C(N(CC)CC)C.[NH2:19][C:20]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)=[C:24]([C:33](=[O:35])[CH3:34])[CH:23]=[C:22]([Cl:36])[C:21]=1[CH3:37]>N1C=CC=CC=1.O>[Cl:36][C:22]1[C:21]([CH3:37])=[C:20]([N:19]2[CH:3]=[N:2][N:1]=[CH:5]2)[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)=[C:24]([C:33](=[O:35])[CH3:34])[CH:23]=1
Reactant: O=CNNC=O
Reactant: CC(=O)c1cc(Cl)c(C)c(N)c1-c1cccc(F)c1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)c1cc(Cl)c(C)c(-n2cnnc2)c1-c1cccc(F)c1
Temperature: 100 °C
Yield: 37.1 %

Procedure:
1,2-Hydrazinedicarboxaldehyde (0.095 g, 1.1 mmol) and then, drop by drop, chlorotrimethylsilane (0.69 mL, 5.4 mmol) and triethylamine (0.35 mL, 2.5 mmol) were added to a suspension of 1-(6-amino-4-chloro-3′-fluoro-5-methylbiphenyl-2-yl)ethanone (0.10 g, 0.36 mmol) in pyridine (2 mL). The mixture was heated at 100° C. overnight. Evaporation at reduced pressure of the solvent yielded a solid that was treated with water and extracted with dichloromethane. The extracts were dried over sodium sulfate and concentrated. The reside was purified on silica gel, eluting with 0 to 50% ethyl acetate in hexane, then 0 to 10% methanol in dichloromethane, to give the desired product (44 mg, 37%). LCMS calculated for C17H14ClFN3O (M+H)+: m/z=330.1. found: 330.0.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[Br:9][C:10]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=1[N:19]([C:22]1[N:27]=[C:26]([C:28](OC)=[O:29])[CH:25]=[C:24]([CH3:32])[N:23]=1)[CH2:20][CH3:21].[OH-].[Na+]>C1COCC1.CCOCC>[Br:9][C:10]1[CH:15]=[C:14]([CH:16]([CH3:17])[CH3:18])[CH:13]=[CH:12][C:11]=1[N:19]([CH2:20][CH3:21])[C:22]1[N:23]=[C:24]([CH3:32])[CH:25]=[C:26]([C:28]([N:3]2[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)=[O:29])[N:27]=1
Reactant: C1COCCN1
Reactant: CCN(c1nc(C)cc(C(=O)OC)n1)c1ccc(C(C)C)cc1Br
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCN(c1nc(C)cc(C(=O)N2CCOCC2)n1)c1ccc(C(C)C)cc1Br
Temperature: 25 °C
Reaction time: 26 h
Yield: 39.4 %

Procedure:
To sodium hydride (60% in oil, 0.24 g, 6.0 mmol) suspended in anhydrous THF (10 mL) was added morpholine (0.52 g, 6.0 mmol) with stirring; the reaction mixture was warmed to reflux temperature and stirred for 1 hour. The reaction mixture was then cooled to ambient temperature and 2-(N-(2-bromo-4-(2-propyl)phenyl)-N-ethylamino)-4-carbomethoxy-6-methyl-pyrimidine (2.0 g, 5.1 mmol) was added. Stirring was continued for 26 hours. The reaction mixture was then poured onto a 1N NaOH solution, stirred and extracted three time with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. Column chromatography (Et2O) afforded the title compound as a solid (900 mg, 39% yield): mp 145° C.; NMR (CDCl3, 300 MHz):d 7.5 (d, 1H, J=1), 7.2 (dd, 1H, J=7,1), 7.1 (d, 1H, J=7), 6.8 (br s, 1H), 4.3-4.15 (m, 1H), 3.9-3.3 (m, 11H), 3.1-3.0 ( m, 1H), 2.9 (septet, 1H, J=7), 1.3 (d, 6H, J=7), 1.15 (t, 3H, J=7); Anal. (C21H27BrN4O2) Calcd: C, 56.38; H, 6.08; N, 12.52; Br, 17.86; Found: C, 56.07; H, 6.05; N, 12.29; Br, 18.08.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].C(O)C.O>>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([CH2:11][CH:8]3[CH2:7][CH2:6][CH:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]3)[CH:13]=2)[CH:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: CC(C)(C)C1CCC(Cc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)C1CCC(Cc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1
Yield: 26.6 %

Procedure:
The mixture of (R)-4-(6-((4-tert-butylcyclohexyl)methyl)naphthalen-2-yl)-4-methyloxazolidin-2-one (18.6 mg, 0.0000490 mol) and lithium hydroxide (12.9 mg, 0.000539 mol) in ethanol (1 mL, 0.02 mol) and water (0.50 mL, 0.028 mol) was heated to reflux overnight. The solvent was removed under vacuum and the residue was partitioned between water/CH2Cl2. The aqueous was extensively extracted with CH2Cl2 and the combined organic phase was dried over Na2SO4. The concentrated residue was taken up into methylene chloride and subjected to chromatography with MeOH/CH2Cl2 (10:90 to 80:20) to give (R)-2-amino-2-(6-((4-tert-butylcyclohexyl)methyl)naphthalen-2-yl)propan-1-ol as a white solid (4.6 mg, 26%). LCMS: Rf=1.76 min 337.36 [M-NH2]+. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.88 (s, 1 H), 7.77 (d, J=8.0 Hz, 1 H), 7.74 (d, J=7.0 Hz, 1 H), 7.56 (s, 1 H), 7.52 (dd, J=1.8, 8.7 Hz, 1 H), 7.32 (d, J=8.3 Hz, 1 H), 3.82-3.75 (m, 1 H), 3.72-3.67 (m, 1 H), 2.80 (d, J=8.0 Hz, 2 H), 2.69 (br. s., 1 H), 2.08 (br. s., 1 H), 1.64 (d, J=12.9 Hz, 2 H), 1.56 (br. s., 5 H), 1.46 (tt, J=4.0, 13.0 Hz, 2 H), 1.38-1.24 (m, 2 H), 1.03 (tt, J=3.1, 11.9 Hz, 1 H), 0.91 (s, 9 H).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=2)=[CH:4][N:3]=[CH:2]1.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([O-:15])=[O:14]>N1C=CC=CC=1>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([C:5]3[O:1][CH:2]=[N:3][CH:4]=3)[CH:7]=2)(=[O:24])=[O:23])=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cccc(-c2cnco2)c1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2cccc(-c3cnco3)c2)cc1
Yield: 58.8 %

Procedure:
A solution of 3-oxazol-5-yl-phenylamine (0.5 g, 3.1 mmol) and 4-nitro-benzenesulfonyl chloride (0.91 g, 4.1 mmol) in pyridine (20 ml) was stirred over weekend at room temperature. The residue was partitioned between EtOAc and H2O. The organic layer was separated, washed twice with H2O and once with saturated aqueous sodium chloride solution, dried and concentrated by evaporation. The residue was purified by column chromatography on silica-gel (5%-15% EtOAc-hexane) to afford 0.63 g of product.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[Cl:16][C:17]1[C:23]([Cl:24])=[CH:22][C:20]([NH2:21])=[C:19]([N+:25]([O-:27])=[O:26])[CH:18]=1>CCOCC>[C:1]([CH2:3][C:4]([NH:21][C:20]1[CH:22]=[C:23]([Cl:24])[C:17]([Cl:16])=[CH:18][C:19]=1[N+:25]([O-:27])=[O:26])=[O:6])#[N:2]
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: N#CCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: N#CCC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a suspension of cyanoacetic acid (1.70 g, 20 mmol) in CH2Cl2 (50 mL) oxalyl chloride (2.2 mL, 25 mmol) was added. The mixture was stirred for 2 h, more oxalyl chloride (2.2 mL, 25 mmol) was added and the mixture was refluxed while stirring for 3 h. The mixture was cooled to room temperature and evaporated twice with ethanol-free CHCl3 (20 mL) to remove excess of (COCl)2. To the residue was added 4,5-dichloro-2-nitroaniline (1.035 g, 5 mmol) and CH2Cl2 (10 mL) and the resulting mixture was stirred for 3 h, then diluted with ether (50 mL). The precipitate was filtered, washed with ether (5×10 mL) to give 0.891 g (65%) of the title compound as an orange solid: mp 156°-158° C. (from EtOH); IR (KBr) 3369, 3118, 2928, 2261, 1694, 1609, 1576, 1498, 1346 and 1280 cm-1 ; 1H NMR (DMSO-d6) δ4.00 (s, 2H), 7.94 (s, 1H), 8.31 (s, 1H), 10.70 (s, 1H, N--H). HRMS Calcd for C9H5N3O3Cl2 : 272.9708. Found: 272.9712.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([N+:22]([O-])=O)[CH:14]=1)[CH3:11].[H][H]>C(O)C.[Pt]=O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[CH:14]=[C:15]([NH2:22])[C:16]([NH2:19])=[CH:17][CH:18]=1)[CH3:11]
Reactant: CC(Oc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1c(Cl)ccc(F)c1Cl
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CC(Oc1ccc(N)c(N)c1)c1c(Cl)ccc(F)c1Cl
Yield: 62.7 %

Procedure:
In an autoclave, cover 36 mg of platinum oxide with 5 cm3 of ethanol; add a solution of 600 mg of 4-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1,2-dinitrobenzene in 67 cm3 of ethanol. This mixture is hydrogenated under 200 kPa of hydrogen and at a temperature close to 20° C. After reaction for about twenty hours, the mixture is filtered and concentrated under vacuum under reduced pressure (0.2 kPa). After filtration on silica [eluent: dichloromethane/methanol (98/2 by volume)], we obtain 316 mg of 4-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]benzene-1,2-diamine in the form of a brown resin, which has the following characteristics:
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][N:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:10]=1)=[O:5])C.[NH3:32]>CCO>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([S:19]([NH:18][C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[N:9]2[CH:10]=[C:6]([C:4]([NH2:32])=[O:5])[N:7]=[N:8]2)(=[O:20])=[O:21])=[CH:23][CH:24]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: N
Reactant: CCOC(=O)c1cn(-c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nn1
Solvent: CCO
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2cc(C(N)=O)nn2)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A 4 mL scintillation vial was charged with 1-[2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-phenyl]-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (synthesized according to general procedure G, 10 mg, 0.02 mmol) and 2 M NH3 in EtOH (1 mL). The reaction was heated to 100° C. and stirred overnight. The following day, the volatiles were removed in vacuo and the residue was purified by preparative TLC chromatography to afford 1-[2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-phenyl]-1H-[1,2,3]triazole-4-carboxylic acid amide: MS (ES) M+H expected 434.1, found 434.0.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1>C(O)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH2:11][NH:10]2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(-c2cnccn2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(C2CNCCN2)cc1
Reaction time: 4 h

Procedure:
The pyrazine from Step 1 (13 g, 0.058 mol) was dissolved in acetic acid (100 mL) and palladium acetate added. This mixture was hydrogenated at 45 psi for 4 h., then filtered to remove catalyst and the filtrate concentrated in vacuo to give the product as brown solid. 1H NMR (500 MHz, CD3OD): δ 1.98 (6H, s), 2.93 (1H, t, J 11.9), 3.03-3.15 (2H, m), 3.26-3.32 (3H, m), 4.09 (1H, dd, J 2.7, 11.2), 7.65 (2H, d, J 8.3), 7.72 (2H, d, J 8.2).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[OH:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)C>[CH2:2]([O:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=1)[CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCCOc1ccc(C(=O)OCC)cc1
Yield: 33 %

Procedure:
A mixture of 50 parts of 4-bromo-1-butene, 58 parts of ethyl 4-hydroxybenzoate, 55.2 parts of potassium carbonate and 320 parts of 2-propanone was refluxed for 68 hours. The reaction mixture was evaporated and the residue was dissolved in methylbenzene. The organic solution was washed with a diluted sodium hydroxide solution. The separated organic layer was dried, filtered and evaporated, yielding 25 parts (33%) of ethyl 4-(3-butenyloxy)benzoate as an oily residue (interm. 14).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH2:33])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2].[CH3:35][C:36]1[CH:37]=[C:38]([S:42](Cl)(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=1>>[CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH:33][S:42]([C:38]2[CH:39]=[CH:40][CH:41]=[C:36]([CH3:35])[CH:37]=2)(=[O:44])=[O:43])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:17]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2]
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)OC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccccc1
Product: Cc1cccc(S(=O)(=O)Nc2cc3nc(-c4ccccc4)n(-c4ccccc4)c3cc2OCCCCCC(=O)OC(C)C)c1

Procedure:
6-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid isopropyl ester was reacted according to general operating instructions 13 with 3-methylbenzenesulfonic acid chloride.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]([NH:21][OH:22])=[NH:20])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CO[C:27](=O)[CH2:28][N:29]([CH3:31])[CH3:30].[ClH:33]>O1CCCC1.C(O)(C)C>[ClH:33].[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]3[N:20]=[C:27]([CH2:28][N:29]([CH3:31])[CH3:30])[O:22][N:21]=3)=[CH:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)CN(C)C
Reactant: COc1cccc2c(C(=N)NO)cn(CC3CCCCC3)c12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COc1cccc2c(-c3noc(CN(C)C)n3)cn(CC3CCCCC3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Molecular sieves (4 Å, powdered, 200 mg) were added to a suspension of 1-(cyclohexyl)methyl-N-hydroxy-7-methoxy-1H-indole-3-carboxamidine (250 mg, 0.829 mmol) in tetrahydrofuran (6 ml) under nitrogen, and the mixture was stirred at room temperature for 30 min. Sodium hydride (60% suspension in oil, 36 mg, 0.900 mmol) was added, then the resulting mixture was stirred at 60° C. for 20 min. The reaction mixture was cooled to room temperature and N,N-dimethylglycine methyl ester (194 mg, 1.66 mmol) was added to the mixture. The resulting mixture was stirred at reflux temperature for 2 h and then concentrated in vacuo. The obtained residue was mixed with dichloromethane (200 ml), washed with 5% aqueous sodium carbonate, dried over magnesium sulfate and concentrated in vacuo. The obtained oil was purified by flash column chromatography eluting with 0.6% (v/v) methanol in dichloromethane to afford an oil. This oil was dissolved in isopropanol (3 ml), then hydrogen chloride (1M solution in diethyl ether; 3 ml) was added to the solution. The resulting mixture was concentrated in vacuo to afford the title compound (1:1 hydrochloride salt) (66 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]2[CH:27]=[CH:26][C:25]([N+]([O-])=O)=[C:24]3[C:19]=2[CH:20]=[CH:21][N:22]=[CH:23]3)[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[OH:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]2[CH:27]=[CH:26][C:25]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:24]3[C:19]=2[CH:20]=[CH:21][N:22]=[CH:23]3)[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: OCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(-c2cc(-c3ccccc3F)nc3ncccc23)c2ccncc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Fc1ccccc1-c1cc(-c2ccc(OCCN3CCOCC3)c3cnccc23)c2cccnc2n1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
A solution of 198 mg (0.50 mmol) 2-(2-fluoro-phenyl)-4-(8-nitro-isoquinolin-5-yl)-[1,8]naphthyridine (synthesis see example 6) and 131 mg (1.00 mmol) 4-(2-hydroxyethyl)morpholine in 1 ml dioxane was treated with 326 mg (1.00 mmol) cesium carbonate (3.0 mmol). The resulting slurry was stirred at 80° C. for three days. The reaction mixture was cooled to room temperature and partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column with dichloromethane/methanol as eluent yielding 2-(2-fluoro-phenyl)-4-[8-(2-morpholin-4-yl-ethoxy)-isoquinolin-5-yl]-[1,8]naphthyridine as colourless solid; HPLC/MS: 1.37 min, [M+H] 481.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[O:19])[CH2:11][CH2:10]2)[N:3]=1.[CH3:27][C:28](=O)[C:29](=O)[CH3:30]>CO>[CH3:27][C:28]1[N:8]=[C:7]2[CH:6]=[CH:5][C:4]([N:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[O:19])[CH2:11][CH2:10]3)=[N:3][C:2]2=[N:1][C:29]=1[CH3:30]
Reactant: Nc1ccc(N2CCN(CCCC(=O)c3ccc(F)cc3)CC2)nc1N
Reactant: CC(=O)C(C)=O
Solvent: CO
Product: Cc1nc2ccc(N3CCN(CCCC(=O)c4ccc(F)cc4)CC3)nc2nc1C

Procedure:
9 g 4-[4-(2,3-Diamino-pyridin-6-yl)-1-piperazinyl]-1-(4-fluorophenyl)-1-butanone and 2.6 g butane-2,3-dione in 250 ml methanol are stirred under reflux for 1 hour. The solvent is evaporated. The residue is dissolved in hot ethyl acetate and treated with active charcoal, filtered and cooled to give the title compound, m.p. 155°-156°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CCc1ccc(OC)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(O)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
To a 25 mL RB flask fitted with magnetic stirrer was charged with 10 mL of dichloromethane. To the stirred solvent was added ethyl 3-(2-fluoro-4-methoxyphenyl)propanoate (0.45 g, 2 mmol). The reaction mixture was cooled to 0° C. and boron tribromide (0.45 mL) was added drop wise. After stirred for 30 minutes, the reaction mixture was quenched with ethanol (1 mL) at 0° C. by slow addition. The reaction mixture was concentrated to distill off the solvent; ethyl acetate (10 mL) was added. The organic layer was washed with saturated NaHCO3 solution (10 mL), followed by brine solution (10 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as colorless oil (0.421 g, yield: 99.75%). 1H NMR (300 MHz, CDCl3): δ 6.93-6.99 (t, 1H), 6.43-6.48 (m, 2H), 5.54 (s, 1H), 4.02-4.09 (q, 2H), 2.79-2.85 (t, 2H), 2.50-2.55 (t, 2H), 1.14-1.19 (t, 3H).
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[C:3](=[O:11])[CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[NH4+].[Cl-].O>CO.[Fe]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:2]([CH3:1])[C:3](=[O:11])[CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:13][CH:14]=1
Reactant: CN(C(=O)CN1CCCCC1)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CN(C(=O)CN1CCCCC1)c1ccc(N)cc1
Yield: 84.4 %

Procedure:
A mixture of 3.12 g (11.3 mmol) of N-Methyl-N-(4-nitrophenyl)-2-piperidin-1-yl-acetamide, 2.52 g (45.1 mmol) of Fe powder and 2.99 g (56.5 mmol) of NH4Cl in 65 mL of MeOH+25 mL of H2O is stirred and refluxed for 3.5 h. The cooled reaction is filtered, the precipitate is washed with MeOH and the filtrate and wash were combined and evaporated. The residue is redissolved in H2O, neutralized with K2CO3 and extracted with EtOAc. The combined extracts were treated with Darco, dried (MgSO4), evaporated and dried in vacuo to give 2.36 g (85%) of brown oil. 1H NMR (DMSO-d6 δ 6.85 (d, 2H, J=7.1 Hz), 6.51 (d, 2H, J=7.1 Hz), 3.30 (s, 2H), 2.78 (s, 3H), 2.24 (s, 4H), 1.50 (m, 6H); MS (ESI) m/z 248.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[CH:13][NH:14][C:15](=O)[C:16]=3[N:17]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:30])=O>C1(C)C=CC=CC=1>[Cl:30][C:15]1[C:16]2[N:17]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:9]=[CH:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2ccc(-c3ccc(F)cc3)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2ccc3ncnc(Cl)c3n2)cc1
Yield: 96.3 %

Procedure:
To a mixture of 6-(4-fluorophenyl)-pyrido[3,2-d]-pyrimidin-4(3H)one (482 mg, 2 mmol) in toluene (20 ml), was added diisopropylethylamine (1.0 ml, 6 mmol) and phosphorus oxychloride (0.56 ml, 6 mmol). The reaction mixture was refluxed for 1 hour. After concentration under reduced pressure, the residue was extracted with dichloromethane (100 ml), and washed with ice water till pH 6-7. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure yielding the title compound as a yellowish solid (0.50 g, yield 96%) which was characterised as follows: Rf=0.90 (MeOH/CH2Cl2=1/9).