Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[CH:12]=[CH:13][N:14]=[C:15]([O:16]CC)[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]=1.ClC1C2C=CN=C(Cl)C=2C2C(=CC=NC=2)N=1.[Cl:35][C:36]1[CH:42]=[C:41]([I:43])[CH:40]=[C:39]([Cl:44])[C:37]=1[NH2:38]>>[Cl:35][C:36]1[CH:42]=[C:41]([I:43])[CH:40]=[C:39]([Cl:44])[C:37]=1[NH:38][C:2]1[C:11]2[CH:12]=[CH:13][NH:14][C:15](=[O:16])[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]=1
Reactant: Nc1c(Cl)cc(I)cc1Cl
Reactant: CCOc1nccc2c(Cl)nc3ccncc3c12
Agent: Clc1nc2ccncc2c2c(Cl)nccc12
Product: O=c1[nH]ccc2c(Nc3c(Cl)cc(I)cc3Cl)nc3ccncc3c12

Procedure:
The title compound was synthesized following the procedure in Example 155, Steps 1, 2, and 3 using 6-chloro-10-ethoxypyrido[4,3-c]-1,6-naphthyridine (Example 133, Step 3), 6,10-dichloropyrido[4,3-c]-1,6-naphthyridine (124 mg, 0.495 mmol) (Example 133, Step 3), and 2,6-dichloro-4-iodoaniline as the starting materials.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([C:16]#[N:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:20](B(O)O)=[CH:21][C:22]([F:25])=[N:23][CH:24]=1.C(Cl)Cl>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].COCCOC>[Cl:18][C:19]1[C:20]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([NH:8][CH2:9][C:10]3([C:16]#[N:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:7]=2)=[CH:21][C:22]([F:25])=[N:23][CH:24]=1
Reactant: N#CC1(CNc2cccc(Br)n2)CCOCC1
Reactant: OB(O)c1cc(F)ncc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: COCCOC
Product: N#CC1(CNc2cccc(-c3cc(F)ncc3Cl)n2)CCOCC1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
A mixture of 4-((6-bromopyridin-2-yl-amino)methyl)tetrahydro-2H-pyran-4-carbonitrile (Intermediate S, 410 mg, 1.384 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (362.2 mg, 2.07 mmol), PdCl2(dppf).CH2Cl2 adduct (113 mg, 0.14 mmol), DME (5 Ml) and 2 M aqueous Na2CO2 (1.75 Ml, 3.5 mmol) was sealed and stirred at 110° C. for 20 min using microwave reactor. After cooling to room temperature the mixture was extracted with EtOAc (35 Ml), filtered and concentrated in vacuo. The crude material was purified by column chromatography [silica gel, 24 g, EtOAc/hexane=5/100 to 50/50] to provide 4-((5′-chloro-2′-fluoro-2,4′-bipyridin-6-ylamino)methyl)tetrahydro-2H-pyran-4-carbonitrile (360 mg, 75% yield). LCMS (m/z): 347 [M+H]+; retention time=0.814 min.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]([SiH2:12][O:13][C:14]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:15]([CH:22]=[CH2:23])[C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])([CH3:11])([CH3:10])[CH3:9].C(O)(=O)C>C1(C)C=CC=CC=1.CO>[CH3:1][O:18][C:17](=[O:19])[C:16]([CH3:21])([CH3:20])[CH:15]([C:14]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[O:13][SiH2:12][C:8]([CH3:9])([CH3:10])[CH3:11])[CH:22]=[CH2:23]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C=CC(C(C)(C)C(=O)O)C(O[SiH2]C(C)(C)C)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C=CC(C(C)(C)C(=O)OC)C(O[SiH2]C(C)(C)C)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
Trimethylsilyl diazomethane (29 mL, 2 M in hexanes, 57.78 mmol) was added to a stirred solution of Example 5G (15.58 g, 39.3 mmol) in toluene (100 mL) and methanol (20 mL). After one hour at room temperature, acetic acid (1.5 mL) was added to quench the excess reagent. The solvent was evaporated and the crude product was dissolved in diethyl ether and washed with NaHCO3 solution brine, dried (MgSO4), filtered, and evaporated. The title compound was isolated as an oil and used without further purification.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][C:7]1[NH:8][C:9]([CH3:32])=[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[H-].[Na+].ClCOCC=C>C(O)(=O)C>[CH2:2]([O:1][CH2:5][N:8]1[C:9]([CH3:32])=[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]1[CH3:6])[CH:3]=[CH2:4]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reactant: C1CCOC1
Agent: C=CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C=CCOCN1C(C)=C(C(=O)OCC)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC)=C1C
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
In 10 ml. of tetrahydrofuran was dissolved 1.0 g. of diethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and after adding to the solution 0.2 g. of a 50% oil dispersion of sodium hydride, the mixture was stirred for 30 minutes at room temperature. After cooling the mixture to -10° C., 0.5 ml. of 3-chloromethoxy-1-propene was added thereto, the temperature was elevated to room temperature over a period of about 20 minutes, and then after 15 minutes the mixture was cooled again to -10° C. After adding to the reaction product 0.5 ml. of glacial acetic acid and 20 ml. of water, the product was extracted three times each time with 5 ml. of ether at room temperature. The extracts were combined, washed with 5 ml. of saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and then ether was distilled away. The residue was subjected to a silica gel column chromatography using benzene as an eluant. The effluent was then subjected to a thin layer chromatography, and then the effluent or the main fraction was concentrated to provide a white crystalline material. By recrystallizing the crystals from benzene-hexane, 0.74 g. of diethyl 1-allyloxymethyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate melting at 111°-112° C. were obtained.
Reaction SMILES: CS[C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.FC1C2SC([I:24])=NC=2C=CC=1>>[I:24][C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CSc1nc2cccc(C#N)c2s1
Reactant: Fc1cccc2nc(I)sc12
Product: N#Cc1cccc2nc(I)sc12

Procedure:
The title compound was prepared from 2-methylsulfanyl-1,3-benzothiazole-7-carbonitrile as described for 7-fluoro-2-iodo-1,3-benzothiazole.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[S:15][CH2:14][CH2:13][CH2:12][S:11]2)[CH3:9])=[CH:4][CH:3]=1.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.C(OCC)(=O)C>O1CCCC1.C1CCCCC1>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[S:15][CH2:14][CH2:13][CH2:12][S:11]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: BrCCCCBr
Reactant: CC(c1ccc(Br)cc1)C1SCCCS1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC(c1ccc(CCCCBr)cc1)C1SCCCS1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-bromo-1-(1,3-dithian-2-yl)ethylbenzene (27.2 g, 94 mmol) in tetrahydrofuran (200 ml) was charged with sec-butyl]ithium (99 ml, 1.3M in cyclohexane, 0.13 mole) dropwise at -78° C. under nitrogen. The mixture was stirred at ambient temperature for 1.5 hours, and then quenched with 1,4-dibromobutane (42 g, 0.2 mole). After being stirred for 3 hours, the mixture was poured into ethyl acetate, and then washed with water and brine. The organic solution was then dried (Na2SO4) and concentrated to an oil. The crude product was purified by flash chromatography over a silica gel column. The 4-(4-bromobutyl)-1-(l,3-dithian-2-yl)-ethylbenzene thus purified was a light oil, 22.3 g.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]([C:11]([F:14])([F:13])[F:12])=[CH:5][C:6]([O:8]CC)=O.[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=1[CH2:24][N:25]=[C:26]=[O:27].O>CN(C)C=O>[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=1[CH2:24][N:25]1[C:6](=[O:8])[CH:5]=[C:4]([C:11]([F:12])([F:13])[F:14])[NH:3][C:26]1=[O:27]
Reactant: CCOC(=O)C=C(N)C(F)(F)F
Reactant: O=C=NCc1cc(Cl)cc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1Cc1cc(Cl)cc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 53.4 %

Procedure:
Under a nitrogen atmosphere, a stirred suspension of 0.62 gram (0.015 mole) of 60% sodium hydride (in mineral oil) in 30 mL of N,N-dimethylformamide was cooled to below 7° C., and a solution of 2.8 grams (0.015 mole) of ethyl 3-amino-4,4,4-trifluoro-2-butenoate in 15 mL of N,N-dimethylformamide was added dropwise at a rate to maintain the reaction mixture below 7° C. Upon completion of the addition the reaction mixture was stirred for about 45 minutes, during which time the reaction mixture temperature was about 2°-4° C. After this time a solution of 3.2 grams of 2,3,5-trichlorophenylmethyl isocyanate in 10 mL of N,N-dimethylformamide was added dropwise at a rate to maintain the reaction mixture temperature at about 2°-4° C. Upon completion of the addition the reaction mixture was stirred for about 10 minutes at 2°-4° C. and then warmed to 70°-85° C., where it was stirred for 3 hours. After this time the reaction mixture was allowed to cool to ambient temperature, where it stirred for about 16 hours. The reaction mixture was then poured into water, and the mixture was extracted with ethyl acetate. The extract was then washed with one portion of water. The water layer and the wash were combined and acidified with concentrated hydrochloric acid. The resultant solid was collected by filtration, yielding, when dried, 0.5 gram of solid. To collect additional product, the ethyl acetate extract was again washed, this time with five 150 mL portions of water. The combined washes were acidified with concentrated hydrochloric acid. The resultant solid was collected by filtration. The solid was dissolved in ethyl acetate and washed with water. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding a solid residue. The solid was combined with the 0.5 gram of material collected above, yielding 2.7 grams of 3-(2,3,5-trichlorophenylmethyl)-6-trifluoromethyluracil, mp 199°-202° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(#N)C.Br[CH2:5][C:6]([NH:8][CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12][CH2:11][CH2:10]1)=[O:7].[O:20]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(N(CC)CC)C>[O:20]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][CH2:37][N:36]([CH2:5][C:6]([NH:8][CH:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[O:13][CH2:12][CH2:11][CH2:10]3)=[O:7])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Reactant: O=C(CBr)NC1CCCOc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(CN1CCC(c2ccc(Oc3ccccc3)cc2)CC1)NC1CCCOc2ccccc21
Temperature: 0 °C
Yield: 98 %

Procedure:
To a 5 ml acetonitrile solution of 190 mg of the compound (8) synthesized in Reference Example 8 were added 184 mg of the compound (4) synthesized in Reference Example 4 and 0.14 ml of triethylamine. This was heated at reflux for 3 hours. To the reaction was added 10 ml of ice water, then extraction was performed with ethyl acetate. The extract was dried, filtered, then concentrated under reduced pressure to obtain a residue which was then purified by silica gel column chromatography (methylene chloride:methanol=25:1) to obtain the above-identified compound (28) in an amount of 300 mg (yield of 98%).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[N:6]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C)C=O>[CH2:23]([O:2][C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[N:6]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:8]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)n1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)cc(C(=O)OC)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 100 g of dimethyl 4-hydroxypyridine-2,6-dicarboxylate hydrochloride dissolved in 500 ml of N,N-dimethylformamide, 122 g of potassium carbonate was added, and the mixture was stirred at room temperature for 1 hour. 52.5 ml of benzyl bromide was added to the resulting reaction mixture, and it was stirred at 50° C. overnight. The reaction mixture was poured into water; and then the resulting white solid was collected after filtration, washed with water, and dried in vacuo to afford the title compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3]1.Cl[C:10]1[N:15]2[N:16]=[C:17]([NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=3)[N:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C.C>CC(O)(C)C>[OH:8][CH:4]1[CH2:5][CH2:6][CH2:7][CH:2]([NH:1][C:10]2[N:15]3[N:16]=[C:17]([NH:19][C:20](=[O:27])[C:21]4[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=4)[N:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)[CH2:3]1
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1cccnc1
Reactant: NC1CCCC(O)C1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc2cccc(NC3CCCC(O)C3)n2n1)c1cccnc1
Temperature: 200 °C
Reaction time: 0.08 h

Procedure:
3-amino-cyclohexanol (Betapharma, 67.33 mg; 0.58 mmol; 2.0 eq.) was added to a mixture of N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B4), 80 mg; 0.29 mmol; 1.0 eq.), DIEA (76 mg; 0.58 mmol; 2.0 eq.) and activated Charcoal (8 mg) in tBuOH (0.8 mL). The reaction mixture was heated at 200° C. for 2×30 min under microwave irradiation. After this time, it was filtered on a celite pad and the cake was washed with ACN. The filtrate was directly purified by RP-HPLC (Starting with 15% ACN in water for 5 min, then up to 30% in 10 min.). The title compound was isolated after lyophilisation as a white powder (51 mg, 49%). HPLC, Rt: 2.14 min. (purity 98.0%). LC/MS, M+(ESI): 353.0, M−(ESI): 351.0.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:24]([NH:32][NH2:33])(=[O:31])[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=[N:33][NH:32][C:24](=[O:31])[C:25]5[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=5)[CH3:22])=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: NNC(=O)c1ccncc1
Solvent: CCO
Product: CC(=NNC(=O)c1ccncc1)c1ccc2nnn(Cc3ccc4ncccc4c3)c2n1

Procedure:
To a solution of example 208 (0.065 g, 0.214 mmol) in ethanol (1.5 ml), isonicotinic hydrazide (0.050 g, 0.428 mmol) was added refluxed for 12 h. The reaction mixture was concentrated and the residue was washed with water, ethyl acetate and dried under vacuum to afford the title compound as a single isomer and as a pale yellow solid (0.070 g, 77%). M.P.: 239-241° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 11.24 (s, 1H), 8.88 (dd, J=4.1, 2.5 Hz, 1H), 8.77 (s, 2H), 8.60 (br s, 1H), 8.37 (d, J=8.0 Hz, 2H), 8.02 (d, J=8.8 Hz, 2H), 7.82 (d, J=7.1 Hz, 2H), 7.71 (m, 1H), 7.54 (dd, J=8.3, 4.2 Hz, 1H), 6.18 (s, 2H), 2.55 (s, 3H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[O:13]=[C:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)=[C:18]([CH2:35][CH2:36][CH3:37])[N:17]2[N:38]=[CH:39][N:40]=[C:16]2[N:15]1[C@H:41]1[CH2:46][CH2:45][C@H:44]([O:47][CH2:48][C:49]([OH:55])([CH3:54])[C:50]([F:53])([F:52])[F:51])[CH2:43][CH2:42]1>O.C(OCC)(=O)C>[O:7]=[C:4]1[O:5][N:3]=[C:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:19]3[C:14](=[O:13])[N:15]([C@H:41]4[CH2:46][CH2:45][C@H:44]([O:47][CH2:48][C:49]([OH:55])([CH3:54])[C:50]([F:52])([F:53])[F:51])[CH2:43][CH2:42]4)[C:16]4[N:17]([N:38]=[CH:39][N:40]=4)[C:18]=3[CH2:35][CH2:36][CH3:37])=[CH:22][CH:23]=2)[NH:34]1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(O)C(F)(F)F)CC2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(O)C(F)(F)F)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.16 g), sodium hydrogen carbonate (0.26 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C. for 30 min, 4′-({5-oxo-7-propyl-4-[trans-4-(3,3,3-trifluoro-2-hydroxy-2-methylpropoxy)cyclohexyl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.092 g) was added, and the mixture was stirred at 90° C. for 19 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.031 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.028 mL) were added, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was diluted with ethyl acetate, 1 M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.063 g, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:11])[C:9]=1[OH:10])[CH2:5][OH:6].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:19]([C:25]1[CH:30]=[CH:29][C:28]2[O:31][CH2:32][O:33][C:27]=2[CH:26]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([Cl:11])[C:9]=1[O:10][CH:19]([C:25]1[CH:30]=[CH:29][C:28]2[O:31][CH2:32][O:33][C:27]=2[CH:26]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C(Br)c1ccc2c(c1)OCO2
Reactant: OCc1cc(Cl)c(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1c(Cl)cc(CO)cc1Cl)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
To a solution of 0.120 g (0.62 mmol) of 3,5-dichloro-4-hydroxybenzyl alcohol in 1.5 mL DMF was added 0.223 g (0.68 mmol) of cesium carbonate and the reaction was magnetically stirred at room temperature for 15 minutes. A solution of 0.196 g (0.68 mmol) of ethyl α-bromo-3,4-methylenedioxyphenylacetate in 0.5 mL DMF was added and the reaction was stirred an additional 30 minutes at room temperature. The reaction mixture was partitioned between EtOAc and 5% aqueous citric acid, extracted, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 30% EtOAc-hexane, and evaporation of the purified fractions afforded 0.214 g (86%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:24]([O:25]C)=[CH:23][C:5]2[NH:6][C:7]([C:9]3[C:21]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14](=[O:22])[C:13]=4[CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.B(Br)(Br)Br.O>ClCCl>[F:1][C:2]1[C:24]([OH:25])=[CH:23][C:5]2[NH:6][C:7]([C:9]3[C:21]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14](=[O:22])[C:13]=4[CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: COc1cc2[nH]c(-c3cccc4c3-c3ccccc3C4=O)nc2cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C1c2ccccc2-c2c1cccc2-c1nc2cc(F)c(O)cc2[nH]1
Temperature: 0 °C
Reaction time: 20 h
Yield: 89 %

Procedure:
The procedure used in stage 1 of Example 230 is followed. In a 50 ml round-bottomed flask under argon, dissolve 1.07 g of 4-(5-fluoro-6-methoxy-1H-benzimidazol-2-yl)-9H-fluoren-9-one, obtained in stage 3 of Example 268, in 20 ml of dichloromethane, cooled to 0° C. and add 7.8 ml of a molar solution of boron tribromide in dichloromethane. After stirring for 20 hours, the reaction mixture is poured into water, and the insoluble material is drained, washed with water and then dried. After purification by formation of a paste with diisopropyl ether, in this way we obtain 914 mg of 4-(5-fluoro-6-hydroxy-1H-benzimidazol-2-yl)-9H-fluoren-9-one, in the form of a brown powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][S:24]([CH3:23])(=[O:26])=[O:25])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: CS(=O)(=O)Cl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNS(C)(=O)=O

Procedure:
Using the general method of Example 242, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.53 g, 5.11 mmol) was reacted with methanesulfonyl chloride to provide 800 mg of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}methanesulfonamide as light yellow needles, m.p. 193-194° C. Analysis: Calculated for C17H23N5O3S: % C, 54.09; % H, 6.14; % N, 18.55; Found: % C, 54.09; % H, 5.93; % N, 18.49.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:18])=[C:10](S(CC)(=O)=O)[N:11]=2)[C:6](=[O:19])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1)[CH3:2].Cl.Cl.[N:25]12[CH2:32][CH:29]([CH2:30][CH2:31]1)[NH:28][CH2:27][CH2:26]2.N12CCCN=C1CCCCC2>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:18])=[C:10]([N:28]3[CH:29]4[CH2:32][N:25]([CH2:31][CH2:30]4)[CH2:26][CH2:27]3)[N:11]=2)[C:6](=[O:19])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(S(=O)(=O)CC)nc21
Reactant: C1CN2CCC(C2)N1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN4CCC3C4)nc21
Reaction time: 8 h
Yield: 18.4 %

Procedure:
A suspension of 2.06 g (6.28 mmol) 1-ethyl-7-ethanesulfonyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and 1.29 g (6.97 mmol) 1,4-diazabicyclo[3.2.1]octane dihydrochloride in 30 ml acetonitrile was treated with 3.10 g (20.4 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene. The resulting solution was stirred overnight and the precipitate which formed was filtered to afford 0.40 g of the title compound, mp 228°-229° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[CH2:14][CH2:13][C@@H:12]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][C:18]([O:23][CH3:24])=[CH:17][C:16]=2[O:25][CH3:26])[C@H:11]([OH:27])[CH2:10]1.CS(Cl)(=O)=O.C([O-])(O)=O.[Na+].[C:38]([O-])(=[O:40])[CH3:39].[Na+]>C(Cl)Cl.C(O)(C)C>[CH3:8][N:9]1[CH2:14][CH2:13][C@@H:12]([C:15]2[C:16]([O:25][CH3:26])=[CH:17][C:18]([O:23][CH3:24])=[CH:19][C:20]=2[O:21][CH3:22])[C@@H:10]1[CH2:11][O:27][C:38](=[O:40])[CH3:39]
Reactant: CC(=O)[O-]
Reactant: COc1cc(OC)c([C@@H]2CCN(C)C[C@H]2O)c(OC)c1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2COC(C)=O)c(OC)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Distilled triethyl amine (344 mL, 2.49 mol) was added slowly to a solution of compound of example 2 (350 g, 1.25 mol) in dry CH2Cl2 (2.5 L). To the reaction mixture methanesulfonyl chloride (122 mL, 171.1 g, 1.49 mol) was added with stirring, at 0° C., under an atmosphere of N2 and over a period of 20 min. The reaction mixture was further stirred for 1 h at 0° C. It was poured over saturated aqueous NaHCO3 solution (1.5 L). The organic layer was separated, washed with brine, dried (anhydrousNa2SO4) and concentrated to obtained a residue. This was dissolved in distilled isopropyl alcohol (1.5 L), anhydrous sodium acetate (408 g, 4.97 mmol) was added and the reaction mixture was refluxed for 1 h. It was cooled to room temperature. Sodium acetate was filtered off and washed with CHCl3. The filtrate was concentrated to obtain the title compound, which was purified using a silica gel column and 60% EtOAc+petroleum ether 60-80° C. as eluant.