Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH2:1].O(C)[Na].[NH2:5][C:6]1[C:7]2[C:14]([C:15]#[N:16])=[CH:13][N:12]([CH2:17][O:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])[C:8]=2[N:9]=[CH:10][N:11]=1>>[NH2:5][C:6]1[C:7]2[C:14]([C:15](=[S:1])[NH2:16])=[CH:13][N:12]([CH2:17][O:18][CH:19]([CH2:20][OH:21])[CH2:22][OH:23])[C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: S
Reactant: N#Cc1cn(COC(CO)CO)c2ncnc(N)c12
Agent: CO[Na]
Product: NC(=S)c1cn(COC(CO)CO)c2ncnc(N)c12
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Dry H2S was passed through a NaOCH3 solution (1 M) (6 mL) with magnetic stirring and cooling at 0° C. for 10 minutes. Compound 18a (0.13 g; 0.5 mmole) was then added in one portion to the stirred solution of NaSH which had been generated in situ as described above. The mixture was stirred at room temperature for 4 hours and then allowed to stand at 0° C. for an additional 12 hours. The mixture was filtered and the filtrate conc. in vacuo. The residue was purified by a column (2×40 cm; prepacked in CH2Cl2) of silica gel (20 g; 70-230 mesh). Elution of the column with CH2Cl2 :CH3OH (94:6) gave the title compound, which was crystallized from H2O to afford pure 18c (0.04 g; yield 28%); m.p. 180°-181° C.; IR (KBr) γ3400 and 3180 (NH2, OH), 1640 cm-1 ; UVλmax nm: (pH 1), 241 (2750) 301 (1220); MeOH, 283 (5387); pH 11, 216 (26200) 278 (5806); 1H NMR (DMSO-d6): δ3.3-3.45 (m, 4H, H-3', H-4'), 3.60 (m, 1H, H-4'), 4.62 (t, 2H, OH), 5.65 (s, 2H, H-1'), 7.9 (s, 1H, C6 --H), 7.98 (brs, 2H, D2O exchangeable, NH2), 8.15 (s, 1H, C2 --H), 9.45 and 9.60 (brs, 1 each, D2O exchangeable, CSNH2). Anal. (C11H15N5O3S.H2O). (C,H,N).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](Cl)(=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.C(Cl)Cl>O>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:25])=[CH:18][CH:19]=1
Reactant: c1ccc(-c2cc3ccccc3o2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (ice bath) mixture of 7.81 g. (0.040 mol.) of 2-phenylbenzofuran and 7.0 g. (0.041 mol.) of p-anisoyl chloride in 100 ml. of methylene chloride is added dropwise 28.7 g. (0.11 mol.) of stannic chloride. The reaction mixture is allowed to warm to ambient temperature, then stirred for 2 hours. Water is slowly added to the mixture and it is stirred an additional 30 minutes. The layers are separated and the organic phase is washed with water until the washings are neutral, dried (MgSO4) and concentrated to give 3-(4-methoxybenzoyl)-2-phenylbenzofuran.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]([CH:12]3[C:21](=[O:22])[CH2:20][CH2:19][C:14]4([O:18][CH2:17][CH2:16][O:15]4)[CH2:13]3)=[O:11])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[O-:23][CH2:24][CH3:25].[Na+]>C(O)C>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][CH2:19][C:14]1([CH2:13][CH2:12][C:10]([C:7]2[CH:8]=[CH:9][C:4]3[N:3]=[CH:2][S:1][C:5]=3[CH:6]=2)=[O:11])[O:18][CH2:17][CH2:16][O:15]1)[CH3:25]
Reactant: CC[O-]
Reactant: O=C1CCC2(CC1C(=O)c1ccc3ncsc3c1)OCCO2
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCC1(CCC(=O)c2ccc3ncsc3c2)OCCO1
Reaction time: 12 h

Procedure:
Under a nitrogen atmosphere, 7-(Benzothiazole-6-carbonyl)-1,4-dioxa-spiro[4.5]decan-8-one (271 mg, 0.85 mmol) was dissolved in ethanol (1 mL). 2.43 M sodium ethoxide solution (0.01 mL, 0.03 mmol) was added. After 12 hrs, reaction was concentrated in vacuo. The residue was diluted with 10 mL EtOAc/5 mL 10% citric acid. The layers were separated. The aqueous layer was further extracted with EtOAc (3×3 mL). The combined organic layers were washed with water (5 mL) and brine (5 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column (40% EtOAc/hexanes) to yield 3-[2-(3-Benzothiazol-6-yl-3-oxo-propyl)-[1,3]dioxolan-2-yl]-propionic acid ethyl ester (19C) (100 mg, 38%, light yellow oil).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:25])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([OH:23])=[CH:18][CH:19]=4)[C:14]3=[O:24])[CH:7]=2)[CH2:3][CH2:2]1.C1(N[S:33]([C:36]([F:39])([F:38])[F:37])(=[O:35])=[O:34])C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C(OCC)(=O)C>[F:37][C:36]([F:39])([F:38])[S:33]([O:23][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[CH:22][N:13]([C:8]3[CH:7]=[C:6]([C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:25])[CH:11]=[CH:10][C:9]=3[CH3:12])[C:14]2=[O:24])=[CH:19][CH:18]=1)(=[O:35])=[O:34]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(O)cc2c1=O
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1=O
Temperature: 120 °C

Procedure:
N-Cyclopropyl-3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzamide (250 mg), N-phenyltrifluoromethanesulfonamide (267 mg) and potassium carbonate (311 mg) were stirred in THF (6 ml) and heated under microwave irradiation (Personal Chemistry Emrys Optimizer with 300 W magnetron) at 120° C. for 10 minutes. The reaction mixture was diluted with ethyl acetate and washed with water (2×), brine, dried (magnesium sulfate) and concentrated. Purification by column chromatography with a gradient of iso-hexane to 70% ethyl acetate/iso-hexane yielded 2-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-1-oxo-1,2-dihydroisoquinolin-7-yl trifluoromethanesulfonate as a cream coloured solid (264 mg); NMR Spectrum: (DMSOd6) 0.53 (m, 2H), 0.67 (m, 2H), 2.10 (s, 3H), 2.83 (m, 1H), 6.87 (d, 1H), 7.49 (m, 2H), 7.76 (s, 1H), 7.86 (d, 1H), 7.93 (d, 1H), 8.00 (d, 1H), 8.19 (s, 1H), 8.42 (d, 1H); Mass Spectrum: M+Na+ 489.
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[S:30][C:29]([CH3:31])=[N:28][CH:27]=1)=[O:23])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[OH:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:20])([CH3:21])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[S:30][C:29]([CH3:31])=[N:28][CH:27]=1)=[O:23]
Reactant: Cc1ncc(CNC(=O)c2nc3n(c(=O)c2OCc2ccccc2)CCOC3(C)C)s1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ncc(CNC(=O)c2nc3n(c(=O)c2O)CCOC3(C)C)s1
Yield: 92.1 %

Procedure:
A solution of 3-(benzyloxy)-9,9-dimethyl-N-((2-methylthiazol-5-yl)methyl)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.210 g, 0.477 mmol) in a mixture of ethyl acetate (200 ml) and ethanol (50 ml) at 25° C. was hydrogenated over 10% palladium on activated carbon (0.25 g) and under one atmosphere of hydrogen for two hours to give 0.154 g (92% yield) of the title compound as white crystals; mp 245° C. (ethanol). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.60 (6H, s, 2×CH3), 2.71 (3H, s, CH3), 4.04 (4H, s, 2×CH2), 4.76 (2H, d, J=6.1 Hz, NCH2), 7.57 (1H, s, CH), 7.82 (1H, broad t, NH), 11.83 (1H, s, OH). Anal. Calcd for C15H18N4O4S: C 51.41; H, 5.17; N, 15.99; Found: C, 51.47; H, 5.29; N, 15.76.
Reaction SMILES: CC([N:4]1[C:12]2[C:11]([O:13][CH3:14])=[CH:10][CH:9]=[C:8]([C:15]([OH:17])=O)[C:7]=2[CH:6]=[CH:5]1)C.[NH2:18][CH2:19][C:20]1[C:21](=[O:30])[NH:22][C:23]([CH3:29])=[CH:24][C:25]=1[CH2:26][CH2:27][CH3:28].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>O.CS(C)=O>[CH3:29][C:23]1[NH:22][C:21](=[O:30])[C:20]([CH2:19][NH:18][C:15]([C:8]2[C:7]3[CH:6]=[CH:5][NH:4][C:12]=3[C:11]([O:13][CH3:14])=[CH:10][CH:9]=2)=[O:17])=[C:25]([CH2:26][CH2:27][CH3:28])[CH:24]=1
Reactant: COc1ccc(C(=O)O)c2ccn(C(C)C)c12
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1ccc(OC)c2[nH]ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Added 1-(1-methylethyl)-7-(methyloxy)-1H-indole-4-carboxylic acid (160 mg, 0.686 mmol), 3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone (186 mg, 0.857 mmol), 1-hydroxy-7-azabenzotriazole (187 mg, 1.372 mmol), EDC (263 mg, 1.372 mmol) and N-methylmorpholine (0.302 mL, 2.74 mmol) to DMSO (10 mL) and stirred mixture at RT for 16 h. Added 25 ml of water and stirred for 10 minutes. Filtered off solids and dried in vacuo. The solids were purified by column chromatography (Biotage; 0% to 15% gradient MeOH:DCM; 10 g-HP-silica gel column) to give 165 mg of 141-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-7-(methyloxy)-1H-indole-4-carboxamide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.01 (t, 3 H), 1.45 (d, J=6.57 Hz, 6 H), 1.63 (m, J=7.45, 7.45, 7.45, 7.45, 7.33 Hz, 2 H), 2.24 (s, 3 H), 2.74 (t, J=7.58 Hz, 2 H), 3.96 (s, 3 H), 4.64 (br. s., 2 H), 5.45 (quin, J=6.63 Hz, 1 H), 5.97 (s, 1 H), 6.62 (d, J=8.08 Hz, 1 H), 6.94 (d, J=3.28 Hz, 1 H), 7.24 (d, J=3.28 Hz, 1 H), 7.53 (d, J=8.08 Hz, 1 H), 7.74 (br. s., 1 H), 12.46 (br. s., 1 H). MS(ES) [M+H]+ 395.7.
Reaction SMILES: [CH:1]1([CH2:5][N:6]2[CH2:24][CH2:23][C@:13]34[C:14]5[C:15]6[O:22][CH:12]3[C:11]3(OCC[O:25]3)[CH2:10][CH2:9][C@@:8]4([F:29])[C@H:7]2[CH2:20][C:19]=5[CH:18]=[CH:17][C:16]=6[OH:21])[CH2:4][CH2:3][CH2:2]1.N>C(O)(=O)C(O)=O>[CH:1]1([CH2:5][N:6]2[CH2:24][CH2:23][C@:13]34[C:14]5[C:15]6[O:22][CH:12]3[C:11](=[O:25])[CH2:10][CH2:9][C@@:8]4([F:29])[C@H:7]2[CH2:20][C:19]=5[CH:18]=[CH:17][C:16]=6[OH:21])[CH2:2][CH2:3][CH2:4]1
Reactant: Oc1ccc2c3c1OC1C4(CC[C@@]5(F)[C@@H](C2)N(CC2CCC2)CC[C@]315)OCCO4
Agent: N
Agent: O=C(O)C(=O)O
Product: O=C1CC[C@@]2(F)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CCC2)C1O5

Procedure:
17'-(Cyclobutylmethyl)-4',5'-epoxy-14'-fluorospiro-[1,3-dioxolane-2,6'-morphinan]-3'-ol (1.3 g) was added to a solution of oxalic acid (4.8 g in 80 ml of water) and heated at reflux for a period of 18 hours. The reaction mixture was cooled, and then basified with ammonia to pH 9.2. The precipitated solids were collected by filtration, washed with water, and air dried. The crude material melted at 100° with slight softening and sintering at 93°. The infrared spectrum indicated the presence of a carbonyl group (C=O), 1700 cm-1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.ClC(Cl)C.C(OCC)C.[NH2:22][C:23]1[CH:42]=[CH:41][C:26]([CH2:27][N:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)=[CH:25][CH:24]=1.C(N(CC)CC)C>[Cl-].[Zn+2].[Cl-].C(O)(C)(C)C>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([CH2:27][N:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:30][CH2:29]3)=[CH:41][CH:42]=2)[N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N)cc2)CC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(Cl)Cl
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2,4-Dichloro-5-(trifluoromethyl)pyrimidine (0.546 g, 2.52 mmol) in 1:1 dichloroethane: tert-butanol was cooled to 0° C. under nitrogen. A 1.0 M solution of zinc(II) chloride in diethyl ether (3.43 mL, 3.34 mmol) was added, and the mixture stirred for one hour at 0° C. tert-Butyl 4-(4-aminobenzyl)piperazine-1-carboxylate (I93) (0.667 g, 2.29 mmol) in 1:1 dichloroethane:tert-butanol (20 mL) was added dropwise over thirty minutes, followed by triethylamine (0.351 mL, 2.52 mmol) in 1:1 dichloroethane:tert-butanol (10 mL). The mixture was stirred overnight, allowing the ice bath to come to room temperature over this time. The mixture was concentrated onto silica gel and chromatographed (40 g silica cartridge, 0-100% ethyl acetate/petroleum benzine 40-60° C.) to give a residue which was triturated with petroleum benzine 40-60° C. to give the title compound (I94) (0.976 g, 90%) as an off white solid; 1H NMR (400 MHz, dr MeOD) δ 8.68 (d, J=0.6 Hz, 1H), 7.85 (d, J=8.6 Hz, 2H), 7.51 (d, J=8.6 Hz, 2H), 4.30 (s, 2H), 3.27-3.00 (br, overlaps with solvent), 1.47 (s, 9H). LCMS Method C, 5.08 min; m/z 472.1 [M+H]+; m/z 470.1 [M−H]−
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15](Cl)[CH:14]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(CC)CC)C.[C:31]1([C:37]#[CH:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=[C:15]([C:38]#[C:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: C#Cc1ccccc1
Reactant: COc1ccc(Nc2nc(Cl)cc(-c3ccccc3)n2)cc1Cl
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Nc2nc(C#Cc3ccccc3)cc(-c3ccccc3)n2)cc1Cl
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of compound (3-chloro-4-methoxy-phenyl)-(4-chloro-6-phenyl-pyrimidin-2-yl)-amine (0.4 g, 1.15 mmol), (PPh3)4Pd (53 mg, 0.05 mmol), copper iodide (11 mg, 0.06 mmol) and triethylamine (0.93 g, 9.23 mmol) in dimethylformamide (10 mL) was stirred at 80° C. for 0.5 hour under nitrogen atmosphere. The mixture was cooled to temperature in the range of 20-40° C. and phenylacetylene (0.24 g, 2.30 mmol) was added to it. The mixture was stirred at 80° C. for 12 hours under nitrogen atmosphere. The mixture was cooled to temperature in the range of 20-40° C., diluted with water (20 mL) and extracted with ethyl acetate (3×15 mL). The organic layers were collected, combined, washed with water (10 mL), dried over anhydrous sodium sulphate and concentrated under vacuum. The residue was purified by column chromatography using ethyl acetate-petroleum ether to give the desired product.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[NH:17][CH:16]=[N:15][C:14]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][C:22]=1[CH3:33])=[O:19])=[O:12].[C:34]1([S:40](Cl)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCN(C(C)C)C(C)C>ClCCl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[NH:17][CH:16]=[N:15][C:14]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:28][CH2:29][N:30]([S:40]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)(=[O:42])=[O:41])[CH2:31][CH2:32]2)=[CH:23][C:22]=1[CH3:33])=[O:19])=[O:12]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(N2CCNCC2)ccc1NC(=O)c1nc[nH]c1C(=O)Nc1nc2ccccc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(N2CCN(S(=O)(=O)c3ccccc3)CC2)ccc1NC(=O)c1nc[nH]c1C(=O)Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
N5-(1H-Benzo[d]imidazol-2-yl)-N4-(2-methyl-4-(piperazin-1-yl)phenyl)-1H-imidazole-4,5-dicarboxamide (1 equivalent), dichloromethane, benzenesulfonyl chloride (1.5 equiv), and DIEA (1.5 equiv.) were added and stirred at room temperature. After 1 hour, LC-MS indicated the reaction was complete. The reaction mixture was evaporated under reduced pressure. The resulting crude product was purified by reverse phase HPLC (aqueous ammonium acetate/acetonitrile to give N5-1H-benzimidazol-2-yl-N4-{2-methyl-4-[4-(phenylsulfonyl)piperazin-1-yl]phenyl}-1H-imidazole-4,5-dicarboxamide in 43% yield. 1H-NMR (400 MHz, DMSO-d6): δ 10.9 (s, br, 1H), 8.36 (s, 1H), 7.80 (m, 2H), 7.73-7.64 (m, 4), 7.43 (m, 2H), 7.33 (m, br, 1H), 6.97 (m, br, 2H), 3.31 (s, br, 4H), 3.09 (s, br, 4H). 2.24 (s, 3H). MS (EI): 585 (MH+).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.Br[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[CH:34]=1>ClCCl.C(=O)([O-])O.[Na+]>[F:23][C:2]([F:22])([F:1])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]2[CH2:17][CH2:18][N:19]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[CH:34]=3)[CH2:20][CH2:21]2)=[CH:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: OC(c1ccc(CN2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(CN2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Reaction time: 20 h
Yield: 65.3 %

Procedure:
To a stirred mixture of 1,1,1,3,3,3-hexafluoro-2-(4-(piperazin-1-ylmethyl)phenyl)-propan-2-ol (3.21 mmol, 1.1 g) and triethylamine (3.21 mmol, 0.448 ml, 0.325 g) in dichloromethane was added 1-(bromomethyl)-3-nitrobenzene (3.21 mmol, 0.694 g). The reaction was stirred for 20 hours then was diluted with dichloromethane and sodium hydrogen carbonate (aqueous). The organic layer was separated and poured onto a SCX column. The column was eluted with 2M ammonia in methanol and concentrated under reduced pressure to give the title compound (1 g). MS (ESI) m/z 478.1 [M+H]+
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.[CH2:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:41])[C@@H:30]([NH2:40])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:25][CH2:24]1)=[O:22])[CH2:17][CH2:18][CH3:19].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:41])[C@@H:30]([NH:40][C:13]([C:4]2[CH:3]=[C:2]([OH:1])[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=2)=[O:15])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:25][CH2:24]1)=[O:22])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Reactant: Cc1ccc2c(O)cc(C(=O)O)nc2c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5.0 g of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid and 9.1 g of 4-((S)-2-Amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid butyl ester in 50 ml of DMF, 3.7 g of HOBT and 4.7 g of EDC was added and the reaction mixture was stirred for 4 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The isolated crude product was used in the next reaction step. Yield: 12.6 g.
Reaction SMILES: [C:1]([CH:5]=C1CCP(C2C=CC=CC=2)C1(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH3:4])=[O:2].[Br:29][C:30]1[C:35]([O:36][CH2:37][O:38][CH3:39])=[CH:34][C:33]([O:40][CH2:41][O:42][CH3:43])=[C:32]([C:44]2[O:45][C:46]([CH:49]=O)=[CH:47][CH:48]=2)[C:31]=1[CH2:51][C:52]([O:54][CH3:55])=[O:53]>C1(C)C=CC=CC=1>[Br:29][C:30]1[C:31]([CH2:51][C:52]([O:54][CH3:55])=[O:53])=[C:32]([C:44]2[O:45][C:46]([CH:49]=[CH:5][C:1]([O:3][CH3:4])=[O:2])=[CH:47][CH:48]=2)[C:33]([O:40][CH2:41][O:42][CH3:43])=[CH:34][C:35]=1[O:36][CH2:37][O:38][CH3:39]
Reactant: COC(=O)C=C1CCP(c2ccccc2)C1(c1ccccc1)c1ccccc1
Reactant: COCOc1cc(OCOC)c(-c2ccc(C=O)o2)c(CC(=O)OC)c1Br
Solvent: Cc1ccccc1
Product: COCOc1cc(OCOC)c(-c2ccc(C=CC(=O)OC)o2)c(CC(=O)OC)c1Br
Temperature: 60 °C
Reaction time: 4 h
Yield: 96.1 %

Procedure:
(Carbomethoxymethylene)triphenylphospholane (0.17 g, 0.51 mmol) was added to toluene (4.0 mL) solution of methyl 2-bromo-6-(5-formylfuran-2-yl)-3,5-bis(methoxymethoxy)phenylacetate (0.11 g, 0.25 mmol) obtained in the step 3 in Example 265, and stirred at 60° C. for 4 h ours. The reaction solution was cooled to room temperature, and then concentrated under reduced pressure. The resulting residue was purified through silica gel column chromatography (n-hexane to ethyl acetate/n-hexane=1/2) to obtain methyl 3-{5-[3-bromo-2-(methoxycarbonylmethyl)-4,6-bis(methoxymethoxy)phenyl]furan-2-yl}acrylate (0.12 g, 93%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH2:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][NH:20]1)[CH3:18].CCN(C(C)C)C(C)C>CS(C)=O>[CH2:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]1[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)[CH3:18]
Reactant: CCC1CCCCN1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCC1CCCCN1c1nc2cc(C(=O)OC)ccc2[nH]c1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (500 mg, crude) in DMSO (5 mL) was added 2-ethylpiperidine (475 mg, 4.20 mmol) and DIEA (542 mg, 4.19 mmol). The resulting solution was stirred overnight at 80° C. in an oil bath and then quenched by the addition of water (50 mL), extracted with dichloromethane (5×20 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (1%-10% ethyl acetate in petroleum ether) to afford methyl 3-(2-ethylpiperidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as yellow oil (150 mg).
Reaction SMILES: C([O:5][C:6](=[O:43])[C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:21]=2[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:10]=[C:9]([Br:42])[CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Br:42][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:21]=2[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:10]=1)[C:6]([OH:43])=[O:5]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)OC(C)(C)C)c2)c1CCC(=O)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)O)c2)c1CCC(=O)OCC
Reaction time: 4 h
Yield: 99.9 %

Procedure:
To a solution of 3-bromo-5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-benzoic acid tert-butyl ester (2.3 g, 3.46 mmol) in dichloromethane (25 mL) was added trifluoroacetic acid (10 mL) at room temperature. The resulting light brown solution was stirred for 4 h. Then, the dichloromethane and excess TFA was removed under reduced pressure and the residue was dissolved in toluene and again removed under reduced pressure to remove all TFA to obtain 3-bromo-5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-benzoic acid (2.1 g, 100%) as a light brown oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][CH:9]=[C:10]([C:12](OCC)=[O:13])[N:11]=2)[CH:2]=1.N1(C2C=CC(C(OCC)=O)=CC=2)C2C=CC=CC=2N=C1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=2)[CH:2]=1
Reactant: CCOC(=O)c1csc(-c2cccnc2)n1
Agent: CCOC(=O)c1ccc(-n2cnc3ccccc32)cc1
Product: OCc1csc(-c2cccnc2)n1
Yield: 30 %

Procedure:
Utilising the procedure described in Example 23(d) employing ethyl 2-(3-pyridyl)-4-thiazolylcarboxylate (commercially available) in lieu of ethyl 4-(1H-benzimidazyl)benzoate gave (2-(3-pyridyl)-4-thiazolyl)methanol (30%) as a yellow crystalline solid.