Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([Mg]Cl)(C)C.[I:15]I.CCOC(C)=O>C1COCC1>[I:15][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N+:4]=1[O-:9]
Reactant: Cc1cc(C)c[n+]([O-])c1
Reactant: II
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(I)[n+]([O-])c1
Reaction time: 2 h
Yield: 36.4 %

Procedure:
To a solution of 3,5-dimethylpyridine 1-oxide (92 g, 0.75 mol) in THF (1300 mL) was added dropwise i-PrMgCl (600 mL, 1.2 mol) at −72° C. After stirring for 2 hr at the same temperature, a solution of iodine (350 g, 1.38 mol) in THF (500 mL) was added dropwise. After stirring for 1 hr, TLC (petroleum ether:EtOAc=1:4) showed the starting material was consumed almost. After quenching with Na2S2O3(aq.) (400 mL), THF was removed in vacuo and the residue was diluted with EtOAc (1500 mL). The solution was washed with water (400 mL) and brine (400 mL) and dried over Na2SO4. The resulting material was concentrated in vacuo to give crude material which was purified by chromatography on silica gel with petroleum ether:EtOAc=1:4 to afford 2-iodo-3,5-dimethylpyridine 1-oxide (68 g, 36.3%) as white solid.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].Cl[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1>>[C:10]1([CH2:9][CH2:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH2:5][CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: ClCc1cccc2ccccc12
Reactant: CC(=O)CC(C)=O
Product: O=C(CCc1cccc2ccccc12)CC(=O)CCc1cccc2ccccc12

Procedure:
Using 2,4-pentanedione (59.6 g, 0.595 mol) and 1-chloromethylnaphthalene (245 g), the reaction was carried out in the same manner as described in Example 17, (1), and the residual oil (200 g) was chromatographed on silica gel (Wako Gel C-200) with n-hexane/benzene (1:4) as eluent to give the title compound as a yellow oil which was an ca 1:6 mixture of Keto/Enol as seen by the methylene singlet at δ3.33 ppm and the methine singlet at δ5.27 ppm in the 1HNMR spectrum; yield: 71 g.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH2:25]1[C:28]2([CH2:31][NH:30][CH2:29]2)[CH2:27][O:26]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(#N)C.CN(C=O)C.[OH-].[Na+]>[CH2:25]1[C:28]2([CH2:31][N:30]([C:19]([C:18]3[CH:22]=[CH:23][C:15]([N:12]4[C:13]([OH:14])=[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=5[CH3:24])[CH:10]=[N:11]4)=[N:16][CH:17]=3)=[O:20])[CH2:29]2)[CH2:27][O:26]1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: C1NCC12COC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CC4(COC4)C3)cn2)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.7 %

Procedure:
Combined 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (27 mg, 0.084 mmol) and 2-oxa-6-azaspiro[3.3]heptane (12.53 mg, 0.126 mmol) in acetonitrile (1 mL) and DMF (0.5 mL). Then triethylamine (0.035 mL, 0.253 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19.39 mg, 0.101 mmol) were added and the reaction was stirred at room temperature overnight. A few drops of 1N NaOH solution were added to give a clear solution, and then the mixture was diluted in ACN and purified by HPLC (Waters SunFire C18, 5 μm, ID 30×75 mm, 35-65% ACN/water+0.05% TFA) to give the title compound (3.6 mg, 10.64% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.43 (s, 3H) 4.23-4.30 (m, 2H) 4.53-4.60 (m, 2H) 4.65-4.74 (m, 3H) 7.61-7.88 (m, 4H) 8.24 (br. s., 2H) 8.49-8.78 (m, 2H) 13.27 (br. s., 2H). MS m/z [M+H]+ 402.1.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][Br:10].[O:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16]>CN(C)C=O>[Br:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][N:13]1[CH2:14][CH2:15][O:11][C:12]1=[O:16]
Reactant: O=C1NCCO1
Reactant: BrCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1OCCN1CCCCCCBr
Yield: 7.9 %

Procedure:
By the procedure of Example 1, sodium hydride (3.85 g of 50% dispersion in oil, 0.0804 mole), 1,6-dibromohexane (24.5 ml, 0.16 mole) and 2-oxazolidinone (7.0 g, 0.0804 mole) in dimethylformamide (180 ml total) were reacted and the reaction mixture concentrated to one tenth volume. Hexane (200 ml) was added, salts were removed by filtration, and the heavy, oily layer separated from the filtrate. This heavy layer was chromatographed on silica gel with ethyl acetate as eluant and tlc monitoring. Clean product-containing fractions were combined and evaporated to yield the title product as an oil [1.59 g; Rf 0.5 (ethyl acetate)].
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18][CH2:19][CH2:20][CH3:21])[N:15]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[C:14]=2[CH:29]=1.[CH3:31][O:32][CH2:33][CH2:34][CH2:35][NH2:36]>>[CH3:31][O:32][CH2:33][CH2:34][CH2:35][NH:36][C:3](=[O:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18][CH2:19][CH2:20][CH3:21])[N:15]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[C:14]=2[CH:29]=1
Reactant: COCCCN
Reactant: CCCSc1nc2ccc(OCCCCCC(=O)OC)cc2n1-c1ccc(C)cc1
Product: CCCSc1nc2ccc(OCCCCCC(=O)NCCCOC)cc2n1-c1ccc(C)cc1

Procedure:
100 mg of 6-[[1-(4-methylphenyl)-2-propylmercapto-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was reacted with 3-methoxypropylamine according to general operating instructions 4. 38 mg was obtained.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[CH:6][S:7][CH:8]=1.C([O-])(O)=O.[Na+].[C:14]([C:16]1[CH:17]=[C:18]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]1[CH2:23][CH2:22][CH:21]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH2:20][C:19]2=1)#[N:15].[H-].[Na+]>CN(C=O)C.CCOC(C)=O.CCOCC>[C:14]([C:16]1[CH:17]=[C:18]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH2:3][C:4]1[N:5]=[CH:6][S:7][CH:8]=1)[C:24]1[CH2:23][CH2:22][CH:21]([NH:29][C:30](=[O:34])[CH:31]([CH3:32])[CH3:33])[CH2:20][C:19]2=1)#[N:15]
Reactant: ClCc1cscn1
Reactant: CC(C)C(=O)NC1CCc2[nH]c3ccc(C#N)cc3c2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)C(=O)NC1CCc2c(c3cc(C#N)ccc3n2Cc2cscn2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
Partition 4-chloromethyl-thiazole hydrochloride (199 mg, 1.17 mmol) between Et2O (20 mL) and saturated aqueous NaHCO3 (20 mL). Separate the layers and dry the ether layer over MgSO4. Add DMF (3 mL) to the ether layer and concentrate in vacuo to remove the ether. Add this solution to a slurry of N-(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (Preparation 3) (300 mg, 1.07 mmol) and sodium hydride (60% suspension in mineral oil, 47 mg, 1.17 mmol) in DMF (3 mL) which has stirred for 30 min at room temperature. Stir the reaction at room temperature for 2 h, then add aqueous NaHCO3 (30 mL) and EtOAc (50 mL). Separate the layers and wash the organic portion with aqueous NaHCO3 (2×30 mL). Dry the organic layer (MgSO4). Filter and concentrate in vacuo to obtain 487 mg crude yellow solid. Recrystallize the material from boiling toluene (10 mL) to afford 296 mg (73%) of the title compound as a yellow solid. MS (ES): m/z 379 (M+1), 377 (M−1); 1H NMR (DMSO-d6): δ 9.01 (d, 1H, J=1.8 Hz), 7.90 (d, 1H, J=1.3 Hz), 7.84 (d, 1H, J=7.9 Hz), 7.69 (d, 1H, J=8.4 Hz), 7.56 (d, 1H, J=1.8 Hz), 7.40 (dd, 1H, J=8.6, 1.5 Hz), 5.47 (s, 2H), 3.99 (m, 1H), 3.03-2.81 (m, 3H), 2.49 (m, 1H), 2.37 (m, 1H), 1.98 (m, 1H), 1.80 (m, 1H), 0.99 (d, 6H, J=7.0 Hz); HPLC (Method A): Rt=1.93 min, (97%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[C:7](=[O:16])[CH:6]3[CH2:17][O:18][CH2:19][CH2:20][N:5]3[C:4]=2[N:3]=1.IC.[CH3:23]C([O-])(C)C.[Na+]>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][CH:13]3[CH2:14][CH2:15]3)[C:7](=[O:16])[C:6]3([CH3:23])[CH2:17][O:18][CH2:19][CH2:20][N:5]3[C:4]=2[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1C2COCCN2c2nc(Cl)ncc2N1CC1CC1
Agent: [Na+]
Solvent: CI
Solvent: CS(C)=O
Product: CC12COCCN1c1nc(Cl)ncc1N(CC1CC1)C2=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
To a round-bottomed flask equipped with a magnetic stirrer was added 2-chloro-5-(cyclopropylmethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (745 mg, 2.53 mmol), DMSO (10 ml), iodomethane (0.189 ml, 3.03 mmol). The suspension was cooled to 0° C. and sodium 2-methylpropan-2-olate (292 mg, 3.03 mmol) was added. The reaction was removed from the ice-bath and stirred at 20° C. for 16 hours. The reaction solution was poured into water, extracted with ethyl acetate 3 times and the organic layer washed with saturated NaCl. The organic layer was collected, dried with Na2SO4, filtered and the filtrate concentrated in vacuo to furnish a light-brown solid. The solid was washed with a small amount of ethanol followed by diethyl ether to afford 2-chloro-5-(cyclopropylmethyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (641 mg, 2.228 mmol, 82% yield) as white solid. MS [M+H] found 309.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1.[CH:14]1([CH2:17][NH2:18])[CH2:16][CH2:15]1>ClCCl>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9]([NH:18][CH2:17][CH:14]2[CH2:16][CH2:15]2)(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Reactant: NCC1CC1
Solvent: ClCCl
Product: O=S(=O)(NCC1CC1)c1cc(F)c(Br)cc1F

Procedure:
According to general procedure C, 4-Bromo-2,5-difluorobenzenesulfonyl chloride (0.20 g, 0.68 mmol) and cyclopropylmethylamine were stirred together in dichloromethane (1 mL) for 16 hours. The reaction afforded 4-bromo-N-(cyclopropylmethyl)-2,5-difluorobenzenesulfonamide (0.17 g) after purification. HPLC purity 95.0% at 210-370 nm, 9.3 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min. HRMS: calcd for C10H10BrF2NO2S−H+, 323.95109; found (ESI-FTMS, [M−H]1−), 323.95103
Reaction SMILES: Br[C:2]1[N:7]=[CH: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.C([N:32]1[CH:36]([CH3:37])[CH2:35][NH:34][C:33]1=[O:38])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].CNCCNC>[Cu]I.O.O1CCOCC1>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:34]4[CH2:35][CH:36]([CH3:37])[NH:32][C:33]4=[O:38])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: CC1CNC(=O)N1C(=O)c1ccccc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)NC4=O)nc3)CC2)c(C)c1
Yield: 43.1 %

Procedure:
To a mixture of (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 127, 1-benzoyl-5-methylimidazolidin-2-one (105 mg) described in Preparation Example 56, cesium carbonate (260 mg) and copper(I) iodide (38 mg) were added 1,4-dioxane (8 mL) and N,N′-dimethylethylenediamine (43 μL), and the mixture was stirred with heating under reflux for 18 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (68 mg) produced by debenzoylation that simultaneously proceeded during the reaction.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[NH:16][CH2:17][CH3:18].[Li+].[OH-]>>[CH2:17]([NH:16][C:7]1[CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=[CH:11][C:6]=1[CH:5]=[CH:4][C:3]([OH:19])=[O:2])[CH3:18]
Reactant: CCNc1cc(C(F)(F)F)ccc1C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCNc1cc(C(F)(F)F)ccc1C=CC(=O)O

Procedure:
2-Ethylamino-4-trifluoromethyl-benzaldehyde (22 mg) was reacted with methyl (triphenylphosphoranylidene)acetate (49 mg, 0.14 mmol) at 110° C. overnight as described above to yield 3-(2-ethylamino-4-trifluoromethyl-phenyl)-acrylic acid methyl ester. 3-(2-Ethylamino-4-trifluoromethyl-phenyl)-acrylic acid methyl ester was reacted with 1N LiOH (5 ml) as described above to yield the title compound (20.2 mg)
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[CH3:9][CH:10]([N:17]1[CH2:20][CH:19]([OH:21])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H-].[Na+].[Cl:24][C:25]1[CH:26]=[C:27](F)[CH:28]=[CH:29][CH:30]=1.[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34]>[OH-].[K+].C1C=CC=CC=1.CN(C)C=O>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[Cl:24][C:25]1[CH:30]=[C:29]([CH:28]=[CH:27][CH:26]=1)[O:21][CH:19]1[CH2:20][N:17]([CH:10]([CH3:9])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:18]1
Reactant: Fc1cccc(Cl)c1
Reactant: CC(c1ccccc1)N1CC(O)C1
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C(O)C(=O)O
Agent: [H-]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(c1ccccc1)N1CC(Oc2cccc(Cl)c2)C1
Temperature: 90 °C

Procedure:
1-(α-Methylbenzyl)-3-hydroxyazetidine maleate (393 g., 1.3 moles) was partitioned in dilute potassium hydroxide-benzene. The separated dried benzene solution was concentrated, the residual oil dissolved in 250 ml. of dimethylformamide and added dropwise to a stirred suspension of 53 g. (1.1 moles) of 50% sodium hydride in 750 ml. of dimethylformamide at 90° C. The mixture was heated at 90° C. for 1 hr. and 130.5 g. (1 mole) of 3-chlorofluorobenzene added dropwise at 90° C. The mixture was refluxed for 3 hrs., cooled and partitioned between isopropyl ether and dilute sodium hydroxide. The isopropyl ether solution was dried, concentrated, and the residue added to 1200 ml. of isopropyl alcohol containing 90 g. (1 mole) of oxalic acid. The oxalate salt was recrystallized from ethanol. Yield 263 g. (69%); m.p. 141°-144° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](S(C)=O)[N:8]([CH3:15])[C:7]2=[O:16].IC1C=CC=C2C=1N=C(S(C)(=O)=[O:29])N(C)C2=O.O[Li].O>C1COCC1.O>[OH:29][C:9]1[N:8]([CH3:15])[C:7](=[O:16])[C:6]2[C:11](=[C:2]([I:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: Cn1c(S(C)(=O)=O)nc2c(I)cccc2c1=O
Reactant: Cn1c(S(C)=O)nc2c(I)cccc2c1=O
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(O)nc2c(I)cccc2c1=O
Temperature: 75 °C
Reaction time: 2.5 h
Yield: 94 %

Procedure:
A suspension of 8-iodo-3-methyl-2-(methylthio)quinazolin-4(3H)-one (700a; 15 g, 45.2 mmol) in 400 mL of DCM was set stirring at 0° C. before adding 3-chlorobenzoperoxoic acid (15.59 g of 77% max. Aldrich, 70 mmol) portion wise over 10 min. The ice bath was removed; and the reaction mixture was stirred at RT for 30 min. It was diluted with 200 mL of DCM, washed sequentially with ice cold 2×50 mL of saturated Na2CO3 followed by sat. Na2SO3 solution and 15 mL of brine. The organic solution was dried over Na2SO4, filtered, and concentrated under reduced pressure to give yellow crystalline solid (700b) containing a mixture of 8-iodo-3-methyl-2-(methylsulfinyl)quinazolin-4(3H)-one and 8-iodo-3-methyl-2-(methylsulfonyl)quinazolin-4(3H)-on. The crude material of yellow crystalline solid (700b) in 40 mL of THF and 40 mL of water at RT was treated with LiOH—H2O (6.60 g, 275 mmol). The reaction mixture was stirred in an oil bath at 75° C. for 2.5 h. It was concentrated to half of its volume under reduced pressure. The precipitated solid was filtered, rinsed with 2×5 mL of water followed by 2×5 mL of ether. The off-white crystalline solid was dried in a vacuum oven at 45° C. for 48 h to give 2-hydroxy-8-iodo-3-methylquinazolin-4(3H)-one (700c; 12.79 g, 42.3 mmol, 94% yield). The crude material was used in the next step. m/z (ES, +ve) 302.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[F:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:22]([F:21])[CH:23]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: Nc1cccc(F)c1
Product: O=C(Nc1cccc(F)c1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 3-fluoro-aniline (43 mg, 0.39 mmol). The title compound was obtained as a solid (75 mg, 52% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.68 (1H, s), 9.01 (2H, s), 8.71 (1H, s), 7.61 (1H, m), 7.42 (1H, m), 6.97 (1H, m). MS m/z: 442.07, 444.05 [M+H]+.
Reaction SMILES: [ClH:1].[CH:2]([N:5]([C:14](=[O:21])[NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])[NH:6]C(=O)OC(C)(C)C)([CH3:4])[CH3:3]>O1CCOCC1>[ClH:1].[CH:2]([N:5]([C:14]([NH:15][CH2:16][C:17]([F:18])([F:19])[F:20])=[O:21])[NH2:6])([CH3:4])[CH3:3]
Reactant: CC(C)N(NC(=O)OC(C)(C)C)C(=O)NCC(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)N(N)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HCl (4 M in dioxane, 10 mL) was added to a stirred solution of tert-butyl N-[isopropyl(2,2,2-trifluoroethylcarbamoyl)amino]carbamate (530 mg, 1.77 mmol) in 1,4-dioxane (5 mL) at 0° C. and the reaction mixture was stirred at ambient temperature for 2 h. The volatiles were evaporated and the residue was washed with pentane to afford the title compound as a pale yellow solid. (360 mg, crude): 1H NMR (300 MHz, DMSO-d6) δ 11.2 (bs, 2H), 9.81 (s, 1H), 6.98 (t, J=6.3 Hz, 1H), 3.90-3.80 (m, 2H), 3.07-3.03 (m, 1H), 1.18 (d, J=6.6 Hz, 6H); 13C NMR (300 MHz, DMSO-d6) δ 157.06, 126.90, 52.25, 45.33, 17.49; 19F NMR (300 MHz, DMSO-d6) δ −71.52; ESIMS m/z 200.0 ([M−HCl]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([N:11]([CH2:15][C:16]1[N:20]([CH2:21][CH2:22][CH3:23])[C:19]2[CH:24]=[CH:25][C:26]([CH2:28]Cl)=[CH:27][C:18]=2[N:17]=1)[CH2:12][CH2:13][CH3:14])=[O:10].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CN1CCCC1=O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([N:11]([CH2:15][C:16]1[N:20]([CH2:21][CH2:22][CH3:23])[C:19]2[CH:24]=[CH:25][C:26]([CH2:28][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:27][C:18]=2[N:17]=1)[CH2:12][CH2:13][CH3:14])=[O:10]
Reactant: C1COCCN1
Reactant: CCCN(Cc1nc2cc(CCl)ccc2n1CCC)C(=O)c1cc(F)ccc1F
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: CCCN(Cc1nc2cc(CN3CCOCC3)ccc2n1CCC)C(=O)c1cc(F)ccc1F
Yield: 70 %

Procedure:
A solution of 0.2 mL of 0.2M (2,5-difluorophenyl)-N-{[5-(chloromethyl)-1-propylbenzimidazol-2-yl]methyl}-N-propylcarboxamide in 1-methyl-2-pyrrolidinone is treated at room temperature for 16 hr with 0.3 mL of 0.2M solution of morpholine in toluene. The resulting mixture is diluted with 2 mL of ethyl acetate and washed 2×2 mL of water 1×2 mL brine. The ethyl acetate layer is dried over anhydrous Na2SO4 and concentrated in vacuo to afford 70% of (2,5-difluorophenyl)-N-{[5-(morpholin-4-ylmethyl)-1-propylbenzimidazol-2-yl]methyl}-N-propylcarboxamide.
Reaction SMILES: [CH3:1][C:2]1[N:11]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:10](=[O:20])[C:9]2[C:4](=[CH:5][C:6]3[CH2:23][CH2:22][C:21](=O)[C:7]=3[CH:8]=2)[N:3]=1.[NH2:25][C:26]1[CH:47]=[CH:46][C:29]([C:30]([NH:32][C@H:33]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:31])=[CH:28][CH:27]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.COCCOC>[CH3:1][C:2]1[N:11]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:16])[CH3:17])[C:10](=[O:20])[C:9]2[C:4](=[CH:5][C:6]3[CH2:23][CH2:22][CH:21]([NH:25][C:26]4[CH:27]=[CH:28][C:29]([C:30]([NH:32][C@H:33]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:31])=[CH:46][CH:47]=4)[C:7]=3[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)cc1)C(=O)OCC
Reactant: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(=O)CC3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: COCCOC
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(NC2CCc3cc4nc(C)n(COC(=O)C(C)(C)C)c(=O)c4cc32)cc1)C(=O)OCC
Temperature: 25 °C
Yield: 44.2 %

Procedure:
A reaction flask was charged with 2-methyl-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4,6-dione (3.332 g, 10.15 mmol), diethyl p-aminobenzoyl-L-glutamate (6.54 g, 20.3 mmol), prepared as described in the Journal of Medicinal Chemistry, 1985, 28, 1428, p-toluenesulphonic acid monohydrate (0.12 g, 0.6 mmol), and dry 1,2-dimethoxyethane (100 ml), and fitted with a pressure equalising dropping funnel containing activated 3A molecular sieve beads (4-8 mesh; 41 g). A reflux condenser was fitted to the top of the dropping funnel and the mixture was stirred and heated under reflux under nitrogen for 4 hours. The apparatus enabled solvent vapour to pass up the side tube of the dropping funnel and condense in the reflux condenser, and the condensed solvent to percolate through the molecular sieves before returning to the reaction flask. The mixture was cooled to ambient temperature and a solution of sodium cyanoborohydride (1.0 g, 15.9 mmol) in methanol (18 ml) was added, followed immediately by acetic acid (1.0 ml). The mixture was stirred at ambient temperature for 18 hours and concentrated. The residue was partitioned between saturated aqueous sodium hydrogen carbonate (150 ml) and ethyl acetate (150 ml). The aqueous layer was extracted with ethyl acetate (3×25 ml) and the combined organic solution washed with brine (5×25 ml), dried (MgSO4) and concentrated to dryness. The residue was fractionated by chromatography with increasingly polar mixtures of dichloromethane and ethanol (ratio 100:0 to 100:4 v/v) as eluant. The appropriate fractions were combined and evaporated and the residue triturated with diethyl ether to give diethyl N-{p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]-benzoyl}-L-glutamate (2.847 g, 44%), m.p. 171° C.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[CH:12]([CH2:13][C@@H:14]2[O:22][C@@H:15]2[CH2:16]1)[CH2:11][CH2:10]3.O.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>ClCCl>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[CH:12]([CH2:13][C@H:14]([OH:22])[C@@H:15]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:16]1)[CH2:11][CH2:10]3
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CCC4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3CC[C@]12C
Reactant: C1CNCCN1
Solvent: O
Solvent: ClCCl
Product: CO[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](O)[C@@H](N5CCNCC5)C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 150 °C
Yield: 69.8 %

Procedure:
To compound 35 (100 mg, 0.33 mmol) was added water (1 mL) and piperazine (3.5g, 41 mmol). The solution was subsequently heated at 150° C. over a period of 24 h. The resulting mixture was diluted with dichloromethane (50 mL) and washed with water, dried with Na2SO4, filtered and evaporated under reduced pressure. The crude compound was purified by flash chromatography (DCM/MeOH: 9:1 containing 0.5% of TEA) to yield compound 36 (90 mg, 70%). 1H NMR (CDCl3) δ: 0.72 (s, 18-CH3), 0.82 (s, 19-CH3), 0.65-2.05 (residual CH and CH2), 2.38, 2.60 and 2.86 (3m, 4×CH2N and 2α-CH), 3.18 (t, J=8.2 Hz, 17α-CH), 3.31 (s, OCH3), 3.82 (m, 3β-CH).