Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.[NH2:9][NH2:10]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:9][NH2:10])[N:3]=1
Reactant: NN
Reactant: Fc1cccc(Br)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NNc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-6-fluoropyridine (2-1) (1.0 g, 5.68 mmol) in THF (10 mL) was added hydrazine (0.91 g, 0.89 mL, 28.4 mmol). After stirring for 1 h room temperature, the mixture was heated at 65° C. for 1 h. The mixture was cooled, diluted with EtOAc (200 mL), washed with water (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude product (2-2) was used in the subsequent step without further purification. 1H NMR (300 MHz, CHCl3-d): δ 7.32 (app t, J=7.8 Hz, 1H), 6.82 (dd, J=7.8, 0.6 Hz, 1H), 6.67 (dd, J=7.8, 0.6 Hz, 1H), 5.93 (s, 1H), 3.80 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([N:30]2[CH:34]=[CH:33][C:32]([CH3:35])=[N:31]2)=[C:26]([CH:29]=1)[CH:27]=O.OOS([O-])=O.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.O>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:27]1[C:26]1[CH:29]=[C:22]([O:21][CH3:20])[CH:23]=[CH:24][C:25]=1[N:30]1[CH:34]=[CH:33][C:32]([CH3:35])=[N:31]1)([CH3:16])([CH3:18])[CH3:17]
Reactant: COc1ccc(-n2ccc(C)n2)c(C=O)c1
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Agent: O=S([O-])([O-])=S
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-n2ccc(C)n2)c(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Reaction time: 12 h
Yield: 37.7 %

Procedure:
To a solution of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (100 mg, 0.38 mmol) in DMF (3 mL) is added 5-methoxy-2-(3-methyl-pyrazol-1-yl)-benzaldehyde (90 mg, 0.42 mmol) at room temperature. Oxone (230 mg, 0.38 mmol) in H2O (1 mL) is added and the solution is stirred at the same temperature for 12 hours. The reaction is poured into water (25 mL) and sodium thiosulfate (sat., 20 mL). The product is extracted into EtOAc (3×) and the combined organics are then dried (MgSO4), filtered, and concentrated. Purification via flash chromatography (silica gel, 0-8% MeOH/CH2Cl2) affords the title compound (65 mg, 38%). LCMS (ESMS): m/z 454.20 (M++1)
Reaction SMILES: [CH3:1][CH:2]1[N:15]2[C:6]([CH2:7][O:8][C:9]3[C:14]2=[CH:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH:10]=3)=[N:5][NH:4][C:3]1=[O:25].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=2Br)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Na+].[Na+]>CCO.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=2[C:11]2[CH:10]=[C:9]3[C:14]([N:15]4[C:6]([CH2:7][O:8]3)=[N:5][NH:4][C:3](=[O:25])[CH:2]4[CH3:1])=[CH:13][CH:12]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC1C(=O)NN=C2COc3cc(B4OC(C)(C)C(C)(C)O4)ccc3N21
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(F)c2Br)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: CC1C(=O)NN=C2COc3cc(-c4c(F)cccc4N4CCN(C(=O)OC(C)(C)C)CC4)ccc3N21
Temperature: 100 °C
Reaction time: 4 h
Yield: 46.4 %

Procedure:
To a solution of 4-methyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Preparation #19, 0.057 g, 0.174 mmol), 4-(2-bromo-3-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.06 g, 0.174 mmol) and Pd(dppf)Cl2 (0.012 g, 0.017 mmol) in EtOH (4 mL) and water (1 mL) was added sodium carbonate (0.036 g, 0.34 mmol) and the reaction mixture was stirred at 100° C. for 4 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 30% EtOAc in petroleum ether) to give 4-[3-fluoro-2-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-7-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (0.040 g, 58%). LC/MS (Table 1, Method 25) Rt=0.920 min; MS m/z: 496 [M+H]+
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].Cl[CH2:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22].C(N(CC)CC)C>C(OCC)C>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CC(=O)CCCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)CCCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The thiol of Example 2 (5.0 g, 0.021 M) was reacted with 5-chloro-2-pentanone (2.87 ml) and triethylamine (3.0 ml) in ethyl ether (50 ml) by the method of Example 8 to give the title compound, m.p. ca. 65°-67° C. Analysis calc. for C19H30O2S(322.49):
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=[C:11]3[C:20]2[CH:25]=[CH:24][CH:23]=[C:22](I)[CH:21]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31].[Al].[I-]>C(NCC)C.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.[Cu].CN(C)C=O>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=[C:11]3[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:34]#[C:33][Si:30]([CH3:32])([CH3:31])[CH3:29])[CH:21]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cn1c(=O)cc(-c2cccc(I)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]
Agent: [Al]
Solvent: CN(C)C=O
Solvent: CCNCC
Product: Cn1c(=O)cc(-c2cccc(C#C[Si](C)(C)C)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(4-Chloro-benzoyl)4-(3-iodo-phenyl)-1-methyl-1H-quinolin-2-one (9.98 g, 20.0 mMol) was suspended in diethylamine (300 mL). To this solution was added 50 mL of anhydrous N,N-dimethylformamide (DMF), (trimethylsilyl)acetylene (8.5 mL) and bis(triphenylphosphine)-palladium(II) chloride (1.40 g, 2.00 mMol). The flask was covered with aluminum foil and then copper(l) iodide (780 mg, 4.09 mMol) was added causing the reaction mixture to exotherm. After stirring overnight under an atmosphere of dry N2 at ambient temperature, the reaction mixture was concentrated under vacuum and the residue was chromatographed on flash silica gel eluting with a gradient of DCM to MeOH/DCM (2:98) to give 8.55 g of the titled product as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[O:8][C:9]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:10]=2[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2].[H][H]>C(O)C.[Pt]=O>[CH2:1]([O:3][C:4]([CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:9]=2[O:8][C:7]1=[O:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2oc1=O
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CCOC(=O)C1C(=O)Oc2ccc(Cl)cc2C1c1ccccc1
Yield: 50.6 %

Procedure:
To a solution of 6-chloro-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxylic acid ethyl ester (4.4 g) in ethanol (300 ml) was added platinum oxide (0.30 g), followed by stirring at room temperature in a hydrogen atmosphere (3 to 4 atm) for 3 hours. After the catalyst was filtered off, the filtrate was distilled to remove the solvent, followed by treatment of the residue with isopropyl ether, to yield 6-chloro-3,4-dihydro-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxylic acid ethyl ester as colorless crystals (2.24 g).
Reaction SMILES: [C:1]1([CH:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:8][CH2:9][O:10][C:11]([C:13]2[CH:14]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=3)[C:15]([C:21]([O:23]CCC#N)=[O:22])=[C:16]([CH3:20])[NH:17][C:18]=2[CH3:19])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO>[C:35]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][O:10][C:11]([C:13]2[CH:14]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=3)[C:15]([C:21]([OH:23])=[O:22])=[C:16]([CH3:20])[NH:17][C:18]=2[CH3:19])=[O:12])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)OCCC(c2ccccc2)c2ccccc2)=C(C)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C(C(=O)OCCC(c2ccccc2)c2ccccc2)=C(C)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
808 mg (1.46 mmol) of 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-cyanoethyl) ester 5-(3,3-diphenylpropyl) ester was dissolved in 15 ml of methanol. 3 ml of 1 N aqueous sodium hydroxide solution was added and stirred at room temperature for 2 hours. After adding 2 N hydrochloric acid, methanol was evaporated under reduced pressure. Water was added thereto and the solid substance was filtered. The obtained substance was washed with water and then hexane/ethyl acetate (3/1) and dried under reduced pressure to obtain the title compound.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1C=C(C2(O)CCC(CC)CC2CCN2CCN(C)CC2)C=CC=1.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]([C:43]2([OH:51])[CH2:48][CH2:47][CH:46]([CH2:49][CH3:50])[CH2:45][CH2:44]2)[CH2:36][N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:32]=[CH:33][CH:34]=1>>[ClH:3].[ClH:28].[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]([C:43]2([OH:51])[CH2:48][CH2:47][CH:46]([CH2:49][CH3:50])[CH2:45][CH2:44]2)[CH2:36][N:37]2[CH2:42][CH2:41][N:40]([CH3:4])[CH2:39][CH2:38]2)[CH:32]=[CH:33][CH:34]=1
Reactant: CCC1CCC(O)(c2cccc(Cl)c2)C(CCN2CCN(C)CC2)C1
Reactant: CCC1CCC(O)(C(CN2CCNCC2)c2cccc(Cl)c2)CC1
Agent: Cl
Product: CCC1CCC(O)(C(CN2CCN(C)CC2)c2cccc(Cl)c2)CC1

Procedure:
In an analogous manner to Example 24 1-[1-(3-chlorophenyl)-2-(4-methylpiperazin-1-ylethyl]-4-ethylcyclohexanol dihydrochloride was prepared from 1-[1-(3-chlorophenyl)-2-piperazin-1-ylethyl]-4-ethylcyclohexanol. MS (ES) m/z 365.4; HRMS: calcd for C21H33ClN2O+H, 365.23597; found (ESI, [M+H]+), 365.236.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:13]C2CCCCO2)[CH:5]([C:20]2[NH:21][CH2:22][CH2:23][N:24]=2)[O:4]1)[CH3:2].[ClH:25]>CO.C(OCC)C>[ClH:25].[NH:24]1[CH2:23][CH2:22][N:21]=[C:20]1[CH:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([OH:13])[C:11]=2[CH2:12][CH:3]([CH2:1][CH3:2])[O:4]1
Reactant: CCC1Cc2c(OC3CCCCO3)cccc2C(C2=NCCN2)O1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CCC1Cc2c(O)cccc2C(C2=NCCN2)O1

Procedure:
Methyl 3-ethyl-5-hydroxyisochroman-1-carboxylate (90 mg) was dissolved dichloromethane (1 mL) and 3,4-dihydro-2H-pyran (52 μL) and pyridinium p-toluenesulfonate (9.6 mg) were added. After 28 hours more 3,4-dihydro-2H-pyran (102 μL) and pyridinium p-toluenesulfonate (10 mg) were added and mixture was stirred for another 24 hours. 3,4-Dihydro-2H-pyran (200 μL) was then added and mixture was stirred overnight after which it was diluted with diethyl ether (5 ml) and washed with saturated NaHCO3-solution. Organic phase was dried with Na2SO4 and concentrated. Purification of the evaporation residue by column chromatography (ethyl acetate-heptane) afforded 37 mg of oil that was converted to 2-(3-ethyl-5-((tetrahydro-2H-pyran-2-yl)oxy)isochroman-1-yl)-4,5-dihydro-1H-imidazole (13 mg) using the synthesis method A3. The crude product of this procedure was dissolved in methanol (1 ml) and HCl solution in diethyl ether (2M, 39 μL) was added. After 2.5 hours reaction mixture was concentrated and the residue was taken in water (10 mL). The solution was washed with ethyl acetate and the water layer was concentrated in freeze dryer to afford the title compound. (Yield 6 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10]=O>>[CH2:10]=[C:4]1[CH:3]([OH:9])[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5]1
Reactant: Cc1ccc(O)c(C)c1
Reactant: C=O
Product: C=C1C=C(C)C=C(C)C1O
Temperature: 80 °C

Procedure:
To a 13 g aqueous solution (33%) of polyethyleneimine CORCAT 150 (from Cordova Chemical Company) containing 0.1 mole of available amine nitrogen is added 10.8 g of 2,4-dimethyl phenol (0.1 mole). The solution was maintained below 20° C., while a 37% aqueous formaldehyde solution (0.11 mole) was added slowly with stirring. The solution was allowed to stand for an hour at ambient temperature and then warmed to 80° C. for 2 hrs. The aqueous solution was used without purification in subsequent experiments.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[CH:13]=[C:14](Cl)[C:15]2[N:16]([CH:18]=[C:19]([CH3:21])[N:20]=2)[CH:17]=1.Cl>CN(C)C=O>[ClH:11].[CH2:3]([O:10][C:14]1[C:15]2[N:16]([CH:18]=[C:19]([CH3:21])[N:20]=2)[CH:17]=[C:12]([Cl:11])[CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cn2cc(Cl)cc(Cl)c2n1
Reactant: OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn2cc(Cl)cc(OCc3ccccc3)c2n1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
1.8 g commercial 80% sodium hydride in paraffin is added in small portions at room temperature to 5.4 ml benzyl alcohol dissolved in 300 ml dry dimethylformamide. The benzylate solution is stirred for a further 2 hours. Thereafter it is cooled to -40° C., mixed with 10.0 g 6,8-dichloro-2-methyl-imidazo[1,2-a]pyridine and stirred for a further 4 hours. The temperature is allowed to rise gradually to 12° C. and the mixture is stirred at this temperature for 48 hours. Thereafter the solution is poured onto 1.5 kg icewater, the solution brought to pH=7 with 1 N-HCl and extracted 3×with 100 ml ethyl acetate each time. The combined extracts are dried with sodium sulfate and evaporated to dryness on the rotary evaporator. After dissolution in 100 ml 2-propanol, the title compound is precipitated by addition of saturated HCl-ether solution. After the precipitate has been filtered off under suction, it is recrystallized twice from isopropanol, 4.5 g of the title compound of m.p. 180°-182° C. being obtained.
Reaction SMILES: [CH2:1]([N:8]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([C:22]([N:24]([CH2:45][CH3:46])[C@@H:25]3[C@@H:30]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=4)[CH2:29][CH2:28][N:27]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:26]3)=[O:23])[C:19]([F:21])=[CH:20][C:15]=2[O:14][C:13]([CH3:48])([CH3:47])[C:12]1=[O:49])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:57](=O)([O-])[O-].[K+].[K+].CI.[Cl-].[NH4+]>C(#N)C>[CH2:1]([N:8]([CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([C:22]([N:24]([CH2:45][CH3:46])[C@@H:25]3[C@@H:30]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:57])[CH:32]=4)[CH2:29][CH2:28][N:27]([C:38]([O:40][C:41]([CH3:44])([CH3:42])[CH3:43])=[O:39])[CH2:26]3)=[O:23])[C:19]([F:21])=[CH:20][C:15]=2[O:14][C:13]([CH3:47])([CH3:48])[C:12]1=[O:49])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCN(C(=O)c1cc2c(cc1F)OC(C)(C)C(=O)N2CCN(Cc1ccccc1)Cc1ccccc1)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1cccc(O)c1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: CC#N
Product: CCN(C(=O)c1cc2c(cc1F)OC(C)(C)C(=O)N2CCN(Cc1ccccc1)Cc1ccccc1)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1cccc(OC)c1
Yield: 81.7 %

Procedure:
tert-Butyl (rac.)-(3R,4R)-3-[({4-[2-(dibenzylamino)ethyl]-7-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(ethyl)amino]-4-(3-hydroxyphenyl)piperidine-1-carboxylate (82.5 mg) was dissolved in acetonitrile (2 ml), and thereto were added potassium carbonate (29.8 mg) and methyl iodide (13.4 μl), and the mixture was refluxed for 3 hours. The reaction solution was cooled, and thereto was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/ethyl acetate=2/1) to give the title compound (68.6 mg).
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[NH2:21][CH2:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1.Cl>CO>[Cl:14][C:8]1[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]([NH:21][CH2:22][CH2:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1Cl
Reactant: NCCc1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(O)c1ccc(CCNc2c(C(=O)O)cc(Cl)cc2[N+](=O)[O-])cc1
Yield: 55.2 %

Procedure:
A mixture of 2,5-dichloro-3-nitrobenzoic acid (23.6 g, 100 mmol), powdered potassium carbonate (41.1 g, 300 mmol), and 4-(aminoethyl)benzoic acid (60.04 g, 400 mmol) in 250 ml of methanol was refluxed under argon for 18 hours. The reaction mixture was poured into 650 ml of 10% aqueous hydrochloric acid solution. The solid was collected and triturated with ethyl acetate. The ethyl acetate extract was decanted, dried with magnesium sulfate and concentrated in vacuo to give 20.15 g (57.5%) of the title compound; mp 255°-257° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]1[NH:21][C:22]([C:25]2[S:29][C:28]([C:30]3[S:31][C:32]([C:35]4[N:36]=[C:37]([C@@H:40]5[CH2:44][CH2:43][CH2:42][N:41]5C(OC(C)(C)C)=O)[NH:38][CH:39]=4)=[CH:33][N:34]=3)=[N:27][CH:26]=2)=[CH:23][N:24]=1)=O)(C)(C)C>ClCCl>[NH:41]1[CH2:42][CH2:43][CH2:44][C@H:40]1[C:37]1[NH:38][CH:39]=[C:35]([C:32]2[S:31][C:30]([C:28]3[S:29][C:25]([C:22]4[N:21]=[C:20]([C@@H:16]5[CH2:17][CH2:18][CH2:19][NH:15]5)[NH:24][CH:23]=4)=[CH:26][N:27]=3)=[N:34][CH:33]=2)[N:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2cnc(-c3ncc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]4)s3)s2)c[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1[nH]c([C@@H]2CCCN2)nc1-c1cnc(-c2ncc(-c3c[nH]c([C@@H]4CCCN4)n3)s2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
TFA (1.0 mL, 13 mmol) was added to a stirred solution of tert-butyl (2S)-2-(4-(5′-(2-((2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-2,2′-bi-1,3-thiazol-5-yl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate (55 mg, 0.086 mmol) in dichloromethane (5 mL) and the reaction mixture was stirred at room temperature for 2 h. The volatiles were removed under vacuum and the crude product was purified by preparative HPLC (Waters Sunfire C18 column 30×150 mm 5 u, eluted with a gradient of 10 to 100% acetonitrile/water/0.1% TFA). Fractions containing the desired product were filtered through a Strata XC MCX cartridge. The cartridge was washed with methanol and the compound was released from the cartridge by washing the column with a 2M ammonia in methanol solution. The filtrate was evaporated under reduced pressure to yield 5,5′-bis(2-((2S)-2-pyrrolidinyl)-1H-imidazol-4-yl)-2,2′-bi-1,3-thiazole (39 mg, 0.085 mmol, 99% yield) as an orange solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:10][O:11][C:12]1[C:20]2[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=2[CH:15]=[CH:14][CH:13]=1)[CH3:6])=[O:4].N1C=CC=CC=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>ClCCl>[C:34]([NH:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:10][O:11][C:12]1[C:20]2[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=2[CH:15]=[CH:14][CH:13]=1)[CH3:6])=[O:4])(=[O:36])[CH3:35]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccc3c2nc(C)n3C)c1Cl
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 4-[3-(N-glycyl-N-methylamino) -2,6-dichlorobenzyloxy]-1,2-dimethyl-1H-benzimidazole (80 mg) in dichloromethane (0.8 ml) were added pyridine (23.3 mg) and acetic anhydride (30.1 mg) at ambient temperature, and the mixture was stirred for 1 hour at the same temperature. The solvent was removed with toluene azeotropically three times. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=10:1, v/v) to give 4-[3-[N-(acetylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-1,2-dimethyl-1H-benzimidazole (75 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([O:12][C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:10]=2[N:11]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]([NH:33][S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:30]=[N:31][CH:32]=2)O1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([O:12][C:9]2[C:10]3[N:11]=[C:2]([C:27]4[CH:28]=[C:29]([NH:33][S:34]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)(=[O:35])=[O:36])[CH:30]=[N:31][CH:32]=4)[CH:3]=[CH:4][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:14]=1
Reactant: Clc1ccc2ncnc(Oc3cccnc3)c2n1
Reactant: CC1(C)OB(c2cncc(NS(=O)(=O)c3ccccc3)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cncc(-c2ccc3ncnc(Oc4cccnc4)c3n2)c1)c1ccccc1
Temperature: 25 °C
Yield: 125.9 %

Procedure:
A mixture of 6-chloro-4-(pyridin-3-yloxy)pyrido[3,2-d]pyrimidine (0.090 g, 0.348 mmol) (Intermediate 8), N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfon amide (0.150 g, 0.418 mmol) (Intermediate 2), PdCl2(dppf)-CH2Cl2Adduct (0.057 g, 0.070 mmol) and 1N aq. sodium bicarbonate (0.70 ml, 0.70 mmol) in dioxane (1.74 ml) was subjected to microwave irradiation for 30 min at 120° C., and cooled to room temperature. The reaction mixture was filtered through a Celite pad and washed with EtOAc. The filtrate was diluted water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (EtOAc only) to give N-(5-(4-(pyridin-3-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfon-amide (0.20 g, 13%) as a yellow solid. 1H-NMR (DMSO-d6, Varian 400 MHz) δ 7.45-7.49 (2H, m), 7.51-7.56 (1H, m), 7.61 (1H, dd, J=8.4 and 4.8 Hz), 7.84-7.87 (2H, m), 7.92-7.95 (1H, m), 8.38 (1H, d, J=2.8 Hz), 8.45 (1H, s), 8.49-8.51 (2H, m), 8.53 (1H, dd, J=4.8 and 1.2 Hz), 8.66 (1H, d, J=2.4 Hz), 8.73 (1H, s), 9.06 (1H, d, J=2.0 Hz). m/z=457 [M+1]+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[C:9]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[N:8]=1)C.C(O)(=O)C>[Pd].CCO>[CH3:27][O:26][C:19]1[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=1[CH2:17][NH:16][C:9]1[CH:10]=[CH:11][C:12]2[NH:13][C:4](=[O:3])[CH2:5][O:6][C:7]=2[N:8]=1
Reactant: CCOC(=O)COc1nc(NCc2ccc(OC)cc2OC)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(CNc2ccc3c(n2)OCC(=O)N3)c(OC)c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 73.6 %

Procedure:
[6-(2,4-Dimethoxy-benzylamino)-3-nitro-pyridin-2-yloxy]acetic acid ethyl ester (6.35 g, 16.2 mmol) and acetic acid (8 mL) were dissolved EtOH (160 mL). 10% Pd/C (635 mg) was added and the mixture was stirred under a hydrogen atmosphere for 24 hours after which time the product precipitated. The solid was collected by filtration, suspended in 1,4-dioxane (200 mL) and then heated briefly to ˜100° C. The mixture was allowed to cool and was then filtered while still luke-warm (to remove Pd/C). The filtrate was evaporated in vacuo to give 6-(2,4-dimethoxy-benzylamino)-1H-pyrido[2,3-b][1,4]oxazin-2-one (3.76 g) as a beige solid. MS: [M+H]+=316.