Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:41][O:42][NH:43][CH3:44]>C(Cl)Cl>[CH3:41][O:42][N:43]([CH3:44])[C:10](=[O:12])[CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
8.75 g (50 mmol) of BOC-glycine dissolved in 150 ml DCM and 6.95 ml (50 mmol) of TEA was added to the solution, and stirred. 17.42 g (50 mmol) BOP reagent (Richelieu Biotechnologies, QC, Canada) was added, followed a few minutes later with O,N-dimethylhydroxylamine hydrochloride (5.6 g, 55 mmol) and TEA (7.67 g, 55 mmol). The reaction was complete in 60 min, and the result was verified by TLC monitoring. A small amount of TEA was used to neutralize the mixture (adjust the pH to above 7.0) in order to allow the reaction go to completion. The mixture was diluted to 500 ml with DCM. The solution was washed in turn with 3N HCl (3×100 ml), saturated NaHCO3 (3×100 ml), and brine (3×100 ml). The DCM layer was dried over MgSO4 and concentrated to obtain the crude product. Recrystallization from water afforded 5.85 g Nα -(BOC)-glycine N-methoxy-N-methylamide (m.p. 92°-95° C.). This product was dried thoroughly in vacuo over P2O5 before use in the following reaction.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:15])=[C:11]([Cl:14])[CH:12]=2)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>N1C=CC=CC=1>[ClH:14].[OH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:12]=2)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]1
Reactant: O=C(O)c1cn(CCO)c2cc(Cl)c(F)cc2c1=O
Reactant: C1CNCCN1
Solvent: c1ccncc1
Product: Cl
Product: O=C(O)c1cn(CCO)c2cc(N3CCNCC3)c(F)cc2c1=O
Yield: 51.1 %

Procedure:
A mixture of 1-(2-hydroxyethyl)-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 2.85 g (0.01 mole), piperazine 4.3 g (0.05 mole) and pyridine 4 ml was refluxed at 135°-145° C. for 8 hours by heating. After cooling, the reaction mixture was evaporated under vacuum. The residue was acidified with acetic acid and the insoluble matters were removed by filtration. The filtrate was neutralized with an aqueous solution of caustic soda. The precipitated crystals were collected by filtration, washed with water and dried. The crystals were dissolved in hot diluted hydrochloric acid, ethanol was added and the solution was cooled to precipitate crystals. The precipitated crystals were collected by filtration, washed with ethanol, dried, and recrystallized from ethanol to obtain 1.9 g (51%) of 1-(2-hydroxyethyl)-6-fluoro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride. Colorless powders.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[O:11][C:10](C(O)=O)=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]>N1C2C(=CC=CC=2)C=CC=1.O.[Cu]=O>[N+:1]([C:4]1[C:12]2[O:11][CH:10]=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc2cccc([N+](=O)[O-])c2o1
Agent: O=[Cu]
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: O=[N+]([O-])c1cccc2ccoc12
Temperature: 170 °C
Yield: 91.8 %

Procedure:
A mixture of 7-nitrobenzofuran-2-carboxylic acid (3.54 g, 17.1 mmol) and copper(II) oxide (0.16 g, 2 mmol) in quinoline (30 mL) was heated at 170° C. for 1 hour. Cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed by brine, dried over anhydrous sodium sulfate, evaporated and purified by silica gel chromatography (petroleum ether/dichloromethane 2/3) to afford the product 7-nitrobenzofuran (2.56 g, yield 92%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.27-8.28 (d, 1H, J=2.0 Hz), 8.12-8.17 (m, 2H), 7.46-7.50 (t, 1H, J=8.0 Hz), 7.215-7.220 (d, 1H, J=2.0 Hz).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.[Cl:14]N1C(=O)CCC1=O.Cl.CCOCC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:14][C:2]1[NH:1][C:9]2[C:4]([C:3]=1[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COC(=O)c1c(Cl)[nH]c2ccccc12
Yield: 47.7 %

Procedure:
A stirred suspension of methyl indole-3-carboxylate (6.0 g, 0.034 mole) in chloroform (200 ml) was treated with N-chlorosuccinimide (5.04 g, 0.038 mole) to afford a clear solution within 15 minutes. After 2 h at room temperature this was treated with 1M HCl/ether (34 ml, 0.034 mole) and allowed to stir for a further 1h, then treated with excess 10% Na2CO3 solution and the chloroform layer separated, dried (Na2SO4) and concentrated in vacuo. The residual yellow solid was recrystallised from chloroform/60-80 petrol to afford the title compound (D11a) as a beige solid (3.4 g, 48%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[N:11]=[C:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[CH:21]=2)=[N:14][CH:15]=1.O.C(Cl)Cl>CN(C=O)C>[NH2:9][C:10]1[N:11]=[C:12]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:13]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[CH:21]=2)=[N:14][C:15]=1[Br:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)n1cc(-c2ncc(N)nc2-c2ccccc2)ccc1=O
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1cc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Reaction time: 2 h
Yield: 79.5 %

Procedure:
Under ice-bath cooling, N-bromosuccinimide (1.83 g) was added to a solution of 5-(5-amino-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (3.0 g) in DMF (90 ml). The mixture was stirred at the same temperature for 2 hours. Water and CH2Cl2 were poured into the mixture and the organic layer was separated, washed with sat. aq. sodium thiosulfate solution, sat. aq. NaHCO3 solution, water, and brine, and dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by column chromatography (silica-gel, toluene-EtOAc), recrystallized from EtOH, and dried in vacuo to give 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (3.0 g).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9](N(C)C=O)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:33]([N:35](CC)[CH2:36]C)C>ClCCl.O>[C:1]1([C:7]2[N:8]=[C:9]([CH2:36][N+:35]#[C-:33])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCN(CC)CC
Reactant: CN(C=O)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: [C-]#[N+]Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
4,5-Diphenyl-2-oxazolyl-methylformamide (14 g, 0.05 mol) was dissolved in dichloromethane (70 mL)/triethylamine (16 mL) and cooled to about 0° C. under N2. Upon dropwise addition of phosphorous oxychloride (4.7 mL, 0.05 mol), the reaction mixture was warmed to about 25° C. and stirred about 1 hour. A 40% sodium carbonate solution (50 mL) was added and after about 15 minutes the reaction mixture was diluted with water (1 vol), extracted with dichloromethane, washed with saturated sodium carbonate solution, brine and dried (Na2SO4) to give 13 g (98%) of 27 as a white solid. Recrystallization from ether gave light amber colored crystals, mp 95°-96° C. IR (KBr, cm-1) 2970, 2956, 2160 (NC), 1604, 1594, 1502, 1446, 1338, 1212, 1054, 1026, 954, 916, 778, 764, 712, 694, 674, 654, 526. 1H NMR (300 MHz, CDCl3) δ 4.81 (2H, s), 7.31 to 7.41 (7H, m),7.57 to 7.66 (5H, m). 13C NMR (75 MHz, CDCl3) ppm 39.03, 126.78, 127.86, 128.04, 128.58, 128.73, 128.83, 129.25, 131.53, 135.77, 147.28, 153.17, 160.84. m/e 261 (MH+).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][SH:3].[C:8]([O:12][C:13](=[O:38])[NH:14][CH2:15][CH2:16][NH:17][C:18]1[C:23]([C:24](=[O:33])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:22][N:21]=[C:20](S(C)(=O)=O)[N:19]=1)([CH3:11])([CH3:10])[CH3:9].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][S:3][C:20]1[N:19]=[C:18]([NH:17][CH2:16][CH2:15][NH:14][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:38])[C:23]([C:24](=[O:33])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:22][N:21]=1)[CH3:7]
Reactant: CC(C)(C)OC(=O)NCCNc1nc(S(C)(=O)=O)ncc1C(=O)Nc1ccc(F)cc1
Reactant: CCOC(=O)CS
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CSc1ncc(C(=O)Nc2ccc(F)cc2)c(NCCNC(=O)OC(C)(C)C)n1
Reaction time: 8 h
Yield: 58.3 %

Procedure:
Ethyl thioglycolate (73 μL, 0.66 mmol) was added to a solution of {2-[5-(4-fluorophenylcarbamoyl)-2-methylsulfonyl-pyrimidin-4-ylamino]-ethyl}carbamic acid tert-butyl ester (0.30 g, 0.66 mmol) and DIPEA (117 μL, 0.66 mmol) in DMF (1.5 mL). The resulting solution was stirred under N2 overnight. The reaction mixture was then diluted with ethyl acetate (20 mL) and washed with water (10 mL), 1 N HCl (3×10 mL), water (10 mL), saturated NaHCO3 (3×10 mL), water (10 mL), saturated NaCl (20 mL) and dried over MgSO4. Following filtration, the solvent was removed by rotary evaporation to yield the titled product (0.19 g, 58%) as an off-white solid. 1H NMR: (d6-DMSO) δ 10.25 (s, 1H), 8.63 (m, 1H), 8.57 (s, 1H), 7.65 (m, 2H), 7.16 (m, 2H), 6.91 (t, 1H), 4.08 (q, 2H), 3.96 (s, 2H), 3.44 (m, 2H), 3.08 (m, 2H), 1.31 (s, 9H), 1.16 (t, 3H); HPLC: Rt=4.41 min; MS (ESI): m/z 492.44 (M−H)−.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[C:30]([C@H:31](O)[CH3:32])=[CH:29][C:28]2[C:23](=[C:24]([F:34])[CH:25]=[CH:26][CH:27]=2)[N:22]=1.C1(P([N:49]=[N+:50]=[N-:51])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[N:49]([C@H:31]([C:30]1[C:21]([Cl:20])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][C:24]=2[F:34])[CH3:32])=[N+:50]=[N-:51]
Reactant: C[C@@H](O)c1cc2cccc(F)c2nc1Cl
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](N=[N+]=[N-])c1cc2cccc(F)c2nc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triphenylphosphine (1.81 g, 6.9 mmol, 1.2 eq) was dissolved in anhydrous THF (30 mL) and cooled to 0° C. To this solution was added diispropylazodicarboxylate (1.36 mL, 6.9 mmol, 1.2 eq). The reaction was stirred for 30 minutes at 0° C. and (R)-1-(2-chloro-8-fluoroquinolin-3-yl)ethanol (1.3 g, 5.7 mmol) in 30 mL of THF was added, followed by diphenylphosphoryl azide (1.37 mL, 6.3 mmol, 1.1 eq). The reaction was allowed to warm to rt and stir at rt overnight. The reaction was deposited on silica gel and concentrated. Purification by column chromato-graphy (3% etoac in hexanes) afforded (S)-3-(1-azidoethyl)-2-chloro-8-fluoro-quinoline. 1H NMR (400 MHz, CDCl3) δ ppm 8.30 (d, J=1.2 Hz, 1H), 7.67 (br d, J=8.22 Hz, 1H), 7.54 (td, J=7.8, 4.7 Hz, 1H), 7.45 (ddd, J=10.2, 7.8, 1.2 Hz) 5.22 (q, J=6.7 Hz, 1H), 1.68 (d, J=6.7 Hz, 3H). Mass Spectrum (ESI) m/e=250.9 (M+1).
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]([C:17]([F:20])([F:19])[F:18])([C:13]([F:16])([F:15])[F:14])[C:8]([O:10]CC)=[O:9])=[CH:4][CH:3]=1.O(C(C(F)(F)F)(C(F)(F)F)C(OCC)=O)C1C=CC=CC=1>>[O:6]([C:7]([C:13]([F:14])([F:15])[F:16])([C:17]([F:18])([F:19])[F:20])[C:8]([OH:10])=[O:9])[C:5]1[CH:4]=[CH:3][CH:2]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(Oc1ccc(Cl)cc1)(C(F)(F)F)C(F)(F)F
Agent: CCOC(=O)C(Oc1ccccc1)(C(F)(F)F)C(F)(F)F
Product: O=C(O)C(Oc1ccccc1)(C(F)(F)F)C(F)(F)F

Procedure:
The above process is repeated except that the ethyl 2-(4-chlorophenoxy)-3,3,3-trifluoro-2-trifluoromethylpropionate is replaced by ethyl 2-phenoxy-3,3,3-trifluoro-2-trifluoromethylpropionate (13 g.) and the residue obtained by evaporation of the ethereal extract is purified by distillation at 10-3 mm. pressure, crystallisation from petrol (b.p. 30°-40° C.) at -65° C. and redistillation to give 2-phenoxy-3,3,3-trifluoro-2-trifluoromethylpropionic acid, b.p. 68°-70° C, at 10-3 mm., m.p. 6°-8° c. (8 g.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH:19]=O>>[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1/[CH:19]=[C:6]1/[C:7](=[O:11])[C:8]2[C:4]([CH2:5]/1)=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=2
Reactant: Cc1ccc2c(c1)CCC2=O
Reactant: O=Cc1ccncc1Br
Product: Cc1ccc2c(c1)C/C(=C\c1ccncc1Br)C2=O

Procedure:
The title compound 90 is prepared according to the procedure reported in Example 34.1 with 5-methyl-1-indanone (0.73 g, 5 mmol) and 3-bromo-4-pyridinecarboxaldehyde (0.93 g, 5 mmol) as reactants. White solid. (Yield 1.24 g, 79%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:13][CH2:12][CH2:11]CO1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(=O)(O)[O-:27].[Na+]>C(Cl)Cl>[CH3:21][S:22]([O:24][CH2:11][C:12]#[C:13][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)(=[O:27])=[O:23]
Reactant: O=C([O-])O
Reactant: C1CCC(OC2CCCCO2)OC1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC#CCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 15 g (0.088 mol) of the foregoing monotetrahydropyranyl ether and 19.79 ml (14.25 g, 0.141 mol) of triethylamine in 250 ml of anhydrous methylene chloride, there were added dropwise 10.24 ml (15.15 g, 0.1323 mol) of methanesulfonyl chloride, at such a rate to maintain the reaction temperature at 0° C., stirring the reaction mixture for 30 minute further at 0° C. It was then poured into aqueous saturated sodium bicarbonate solution and extracted with methylene chloride. The combined organic extracts were dried and evaporated, to yield 4-tetrahydropyranyloxybut-2-yn-1-ol methanesulfonate, in almost quantitative yield. This crude product was dissolved in 50 ml of acetone and treated with a solution of 40.34 g (0.4636 mol) of lithium bromide in 200 ml of acetone, stirring the reaction mixture at room temperature for 1 hour. The solvent was then evaporated and the residue diluted with water and extracted with methylene chloride, the organic extracts were dried and evaporated in vacuo. The crude material was purified by silica gel column chromatography using hexane-ethyl acetate (95:5) as eluant, to yield 1-bromobut-2-yn-4-ol-tetrahydropyranyl ether, as an oil.
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.I[CH2:15][CH2:16][OH:17].[C:18]([O:42][CH:43]1[CH2:48][C:47]([CH3:50])([CH3:49])[N:46]([OH:51])[C:45]([CH3:53])([CH3:52])[CH2:44]1)(=[O:41])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH:30]1[CH2:35][C:34]([CH3:37])([CH3:36])[N:33]([OH:38])[C:32]([CH3:40])([CH3:39])[CH2:31]1)=[O:28].CCCCCCC.CCCCCCC.[C:68](OCC)(=[O:70])[CH3:69]>ClC1C=CC=CC=1>[OH:17][CH2:16][CH2:15][O:38][N:33]1[C:32]([CH3:39])([CH3:40])[CH2:31][CH:30]([O:29][C:27](=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]([O:42][CH:43]2[CH2:44][C:45]([CH3:53])([CH3:52])[N:46]([O:51][CH2:69][CH2:68][OH:70])[C:47]([CH3:50])([CH3:49])[CH2:48]2)=[O:41])[CH2:35][C:34]1([CH3:36])[CH3:37]
Reactant: CCOC(C)=O
Reactant: OCCI
Reactant: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CCCCCCC
Solvent: Clc1ccccc1
Product: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(OCCO)C(C)(C)C2)CC(C)(C)N1OCCO

Procedure:
Tributyltin hydride is added dropwise to a solution of 2-iodoethanol and excess bis(1-oxyl-2,2,6,6-tetramethylpiperidin4-yl) sebacate in chlorobenzene. The crude reaction mixture is passed through silica gel with heptane and then heptane/ethyl acetate to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:4]=2[N:3]=1.[NH3:31]>CO>[NH2:31][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:4]=2[N:3]=1
Reactant: N
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CO
Product: Nc1nc2cc(Cl)c(Cl)cc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2,5,6-Trichloro-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)benzimidazole (42, 0.48 g; I mmole) was dissolved in dry MeOH (10 ml). Liq. NH3 (10 ml) was added and the mixture heated in a steel bomb at 100° C. for 2 hr. This mixture was stirred at room temperature for 24 hr. Excess NH3 was allowed to evaporate and the solution evaporated to dryness, absorbed onto silica gel (2 g), and chromatographed on a silica gel column using silica gel (20 g; 60-200 mesh). Elution of the column with CH2 Cl2 :CH3OH (96:4) gave the desired compound 44 as the major nucleoside. Evaporation of the solvent and crystallization of the residue from EtOH gave 44 (0.02 g; yield 6.06%). mp. 145° C.; UV Imax. (MeOH): 259 (7941) and 301 (8348) nm; Imax (pH1): 215 (26000) and 292 (7520) nm; Imax (pH11): 257 (7967) and 298 (7107) nm. 1H NMR(DMSO-d6): d 8.70 (s,1H, C7 -H, 8.28(s,1H, C4 -H), 7.90 (bs,2H, D2O exchangeable, NH2), 6.75(d,C1'H, J1,2 =4.5 Hz) and the rest of the sugar protons.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[O:17]1[CH:19]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18]1>>[C:5]1([N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3][CH2:2][NH:1][CH2:18][CH:19]([OH:17])[CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NCCN(c1ccccc1)c1ccccc1
Reactant: c1ccc(OCC2CO2)cc1
Product: OC(CNCCN(c1ccccc1)c1ccccc1)COc1ccccc1

Procedure:
A mixture of 6.4 g. N-(2-aminoethyl)-diphenylamine and 4.7 g. 1,2-epoxy-3-phenoxy-propane was heated for 10 minutes at 160° C. The reaction product was triturated with ether and then recrystallized from isopropanol. 4.7 g. (43% of theory) of colorless crystals of 1-(2-diphenylaminoethylamino)-2-hydroxy-3-phenoxy-propane were obtained; m.p. 95°-96° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:17][O:18][C:19](=[O:38])[C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[C:22]([N+:35]([O-:37])=[O:36])[CH:21]=1>COCCOC.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>[CH3:17][O:18][C:19](=[O:38])[C:20]1[CH:21]=[C:22]([N+:35]([O-:37])=[O:36])[CH:23]=[C:24]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=2)[CH:25]=1
Reactant: Cc1ccc(Br)nc1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cc([N+](=O)[O-])c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(-c2ccc(C)cn2)cc([N+](=O)[O-])c1
Yield: 39.6 %

Procedure:
To a solution of 2-bromo-5-methylpyridine (1.24 g, 7 mmol), Pd(PPh3)4 (226 mg, 0.2 mmol) and K3PO4 (2.76 g, 13 mmol) in DME/H2O (5 ml/1 ml) was added 3-nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (2.00 g, 6.5 mmol) under N2 atmosphere. The mixture was subjected to microwave radiation at 130° C. for 0.5 hours. The reaction mixture was cooled and solvent was evaporated under reduced pressure. The residue was purified by flash-chromatography (CH2Cl2/MeOH) to give 3-(5-methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester as a white solid (700 mg, 40%).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].C(Cl)Cl.[CH3:10][N:11]1C(C(O)=O)=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=2)[CH:13]=[N:12]1>CN(C)C=O>[CH3:10][N:11]1[C:1]([C:2]([Cl:4])=[O:3])=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=2)[CH:13]=[N:12]1
Reactant: Cc1cccc(-c2cnn(C)c2C(=O)O)n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cccc(-c2cnn(C)c2C(=O)Cl)n1
Reaction time: 2 h

Procedure:
Oxalyl chloride (0.85 ml) was added to a mixed solution of methylene chloride (5 ml) and N,N-dimethylformamide (5 μl) containing the 1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-5-carboxylic acid (210 mg) obtained in (Example 3.3) <Step 1>, and the obtained mixture was then stirred for 2 hours. Thereafter, the reaction solution was concentrated under reduced pressure to obtain a crude product (230 mg) of the title compound in the form of an orange solid.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12](S(O)(=O)=O)=[CH:11][CH:10]=1>O1CCCC1.CN(C)C=O>[CH2:1]([O:8][CH2:19][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a manner similar to that described in Example I, 0.68 ml of benzyl alcohol and 7 mg of p-toluenesulfonic acid are added to a solution of 350 mg of Compound Z-1 (DMTD) in a mixture of 7 ml of tetrahydrofuran and 3 ml of dimethylformamide and the mixture stirred at room temperature for 24 hours. At the end the volatiles are removed in vacuo to obtain a residue which is purified on a preparative HPLC column using water/acetonitrile (40/60) as eluant. The appropriate fractions are combined and lyophilized to obtain benzyl ether of Z-1 (DMTD).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29]C(=O)C)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].C(O)C>O>[OH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCCCCCCCOC(C)=O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(OCCCCCCCCCCO)cc2)cc1
Yield: 97.3 %

Procedure:
30 m moles (13.2 g) of the above 4'-(10-acetyloxydecyloxy) biphenyl-4-carboxylic acid ethyl ester and 10 g of sodium hydroxide were stirred for 10 min. at 70° C. in a mixed solvent of 40 ml of ethanol and 80 ml of water. After the reaction, the reaction solution was concentrated to obtain 10.8 g of 4'-(10-hydroxydecyloxy)biphenyl-4-carboxylic acid. (yield: 97%)
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([C:6]([C:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:19][CH2:20][CH2:21][O:22][C:23]1[C:24]2[CH:25]=[CH:26][NH:27][C:28]=2[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([C:6]([C:12]3[CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH2:21][O:22][C:23]4[CH:31]=[CH:30][CH:29]=[C:28]5[C:24]=4[CH:25]=[CH:26][NH:27]5)[CH2:16][CH:17]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccc2c(C3=CCN(CCCOc4cccc5[nH]ccc45)CC3)c[nH]c2c1Cl

Procedure:
The title compound was prepared in a fashion similar to that described in Example 192 from 6,7-dichloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.70 g, 2.6 mmol), 1-chloro-3-(1H-indole-4-oxy)propane (0.60 g, 2.9 mmol) and potassium carbonate (0.48 g, 3.5 mmol). The product was isolated as a white granular solid. Yield 220 mg (19%). mp 224°-227° C. FDMS m/e=439 (M+ of free base).