Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([C:30]2[CH:34]=[CH:33][O:32][N:31]=2)[CH2:14][C:15]([N:17]2[C@@H:21]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:20][O:19][C:18]2=[O:29])=[O:16])=[CH:9][CH:8]=1.[F:38][C:39]([F:50])([F:49])[C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:22]([C@H:21]1[CH2:20][O:19][C:18](=[O:29])[N:17]1[C:15](=[O:16])[CH2:14][C@@H:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:3]=[C:2]([NH:1][C:44](=[O:45])[C:43]3[CH:47]=[CH:48][C:40]([C:39]([F:38])([F:49])[F:50])=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)=[CH:8][CH:9]=1)[C:30]1[CH:34]=[CH:33][O:32][N:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1cccc(COc2ccc([C@H](CC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)c3ccon3)cc2)c1
Solvent: ClCCl
Product: O=C(Nc1cccc(COc2ccc([C@H](CC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)c3ccon3)cc2)c1)c1ccc(C(F)(F)F)cc1
Reaction time: 16 h
Yield: 107.5 %

Procedure:
To a solution of substituted aniline 27.3 (0.050 g, 0.100 mmol) in DCM (1 mL), was added TEA (14.1 μL, 0.100 mmol) and 4-(trifluoromethyl)benzoyl chloride (15.0 μL, 0.100 mmol). The reaction mixture was stirred for 16 hours and then concentrated to dryness under reduced pressure. The residue was purified by medium pressure chromatography (silica gel, 0 to 30% EtOAc:DCM) to give 27.4 (72 mg). MS ESI (pos.) m/e 670.2 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)#[N:2].N1C=CC=CC1=O.P(Cl)(Cl)(Cl)(Cl)[Cl:21]>>[Cl:21][C:4]1[C:3]([C:1]#[N:2])=[CH:8][C:7]([C:9]([F:12])([F:10])[F:11])=[CH:6][N:5]=1
Reactant: N#Cc1cncc(C(F)(F)F)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: O=c1cccc[nH]1
Product: N#Cc1cc(C(F)(F)F)cnc1Cl
Temperature: 25 °C

Procedure:
A mixture of 3-cyano-5-trifluoromethylpyrdine-2-pyridone (250 mg), phosphorus pentachloride (550 mgs) and phosphonylchloride (0.62 ml) were heated at the reflux temperature for 8 hours. After cooling to ambient temperature (ca 28° C.) the reaction mixture was poured into ice/water and rigourously extracted with ethylacetate. The combined organic layers were washed with aqueous sodium bicarbonate solution followed by brine, and finally dried over anhydrous magnesium sulphate. Removal of the solvent by evaporation under reduced pressure gave 2-chloro-3-cyano-5trifluoromethyl-pyridine as an off-white solid which was used without further purification. The compound showed (CDC13) 8.89 (1H,d) 8.28 (1H,d).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[NH:5][C:6](=[O:11])[CH2:7][C:8](=[O:10])[CH3:9].[CH:15]([O-])([O-])OC.N1C2C(=CC=CC=2)C=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[NH:5][C:6](=[O:11])/[CH:7]=[C:8](\[O:10][CH3:15])/[CH3:9]
Reactant: CC(=O)CC(=O)Nc1cccc(Br)c1
Reactant: COC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: CO/C(C)=C\C(=O)Nc1cccc(Br)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
A mixture of 68.5 g of m-bromo-acetylacetanilide, 39.6 g of methyl orthoformate, 160 ml of methanol and 0.5 g of p-toluene sulfonic acid was stirred for 2 hours at 20° C and after the addition of 1 ml of quinoline, the mixture was evaporated to dryness under reduced pressure. The 83 g of colorless oil residue was taken up in 400 ml of toluene and the mixture was heated at 140° C for 4 hours while distilling the toluene-methanol azeotrope formed. After cooling, the toluene was evaporated under reduced pressure and the residue was chromatographed over silica gel. The product was eluted with a 9-1 mixture of methylene chloride and ethyl acetate and the fraction with an Rf = 0.65 was taken up in isopropyl ether to obtain 44 g of m-bromo-3-methoxy-crotonanilide melting at 110° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([C:12](=[N:14][OH:15])[NH2:13])=[CH:10][CH:11]=1)=[O:4].N.[C:17](OC(=O)C)(=O)[CH3:18]>O>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[N:13]=[C:17]([CH3:18])[O:15][N:14]=2)=[CH:10][CH:11]=1)=[O:4]
Reactant: NC(=NO)c1ccc(NC(=O)CCl)cn1
Reactant: CC(=O)OC(C)=O
Agent: N
Solvent: O
Product: Cc1nc(-c2ccc(NC(=O)CCl)cn2)no1

Procedure:
Compound of example 4 (5.5 g, 24 mmol) was refluxed in acetic anhydride (10 mL) at a temperature in the range of 115-120° C. for 2 hours. The black colored reaction mixture was cooled, diluted with water, basified with ammonia solution, and extracted with ethyl acetate (3×100 mL). The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude product obtained was purified over silica gel using ethyl acetate/petroleum ether (25%-50%) as eluent and the semipurified fractions were further purified using methanol/chloroform (0.5% -1%) as eluent. Pure fractions were concentrated and crystallized using chloroform/petroleum ether, to obtain the title compound.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.[C:13](OC)(=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17]>C1COCC1>[O:18]=[C:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: CCCCC(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC(=O)CP(=O)(OC)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
To a solution of dimethyl methylphosphonate (3.25 mL, 30 mmol) in anhydrous THF (30 mL), cooled at −78° C. was added n-BuLi (1.6 M in hexane, 20.6 mL, 33 mmol). The mixture was stirred for 30 minutes at this temperature under nitrogen. Methyl valerate (2.0 mL, 15 mmol) was added dropwise for 10 minutes. The mixture was stirred for 2 hours at −78° C., gradually was warm to room temperature. The mixture was quenched with addition of 1N HCl to pH 4-5. The organic layer was separated, washed with brine and dried over MgSO4. The residue was purified through flash chromatography on silica gel (MeOH/DCM 2/98) to give the product (3.0 g) with colorless oil in 96% yield. 1H NMR (CDCl3) δ 0.848 (t, J=7.3 Hz, 3H), 1.28 (m, 2H), 1.52 (m, 2H), 2.57 (t, J=2.4 Hz, 2H) 3.074 (d, J=21 Hz, 2H), 3.760 (s, 3H), 3.762 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:29][CH2:28][NH:27][C:26]3=[O:30])=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].O>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:29][CH2:28][N:27]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:26]3=[O:30])=[CH:21][CH:20]=2)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(N3CCNC3=O)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN1CCN(c2ccc(C(=O)N3CCN(c4ccccc4C(C)(C)C)CC3)cc2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(4-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}phenyl)imidazolidin-2-one (1.0 g, 2.46 mmol) and sodium hydride (0.16 g, 4.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 0° C. for 1 h. tert-Butyl bromoacetate was added to the reaction mixture and the mixture was stirred at room temperature for 3 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a solid (1.3 g, quant.).
Reaction SMILES: O[N:2]=[C:3]([C:5]1[C:6]([OH:32])=[CH:7][C:8]2[O:31][CH2:30][C:11]3([C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[C:12]3=[O:29])[C:9]=2[CH:10]=1)[NH2:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH-].[Na+]>O1CCCC1>[NH2:4][C:3]1[C:5]2[CH:10]=[C:9]3[C:11]4([C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:13]([CH2:20][C:21]5[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=5)[C:12]4=[O:29])[CH2:30][O:31][C:8]3=[CH:7][C:6]=2[O:32][N:2]=1
Reactant: COc1ccc(CN2C(=O)C3(COc4cc(O)c(C(N)=NO)cc43)c3ccccc32)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)C3(COc4cc5onc(N)c5cc43)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.4 %

Procedure:
To a solution of N′,6-dihydroxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carboximidamide (0.90 g, 2.1 mmol) and triphenylphosphine (0.71 g, 2.7 mmol) in tetrahydrofuran (30 mL) was added diethyl azodicarboxylate (0.43 mL, 2.7 mmol) at 0° C. The reaction mixture was allowed to warm to ambient temperature and was stirred for 16 h. 10% w/v aqueous sodium hydroxide (10 mL) was added and the mixture was stirred for 3 h. Most of the tetrahydrofuran was removed in vacuo and the resultant mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography to afford 3-amino-1′-(4-methoxybenzyl)spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one (0.16 g, 19%): mp 214-216° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.29-7.20 (m, 5H), 7.14-7.12 (m, 1H), 7.05 (s, 1H), 7.02-6.98 (m, 2H), 6.90-6.87 (m, 2H), 6.29 (s, 1H), 4.92-4.69 (m, 4H), 3.69 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 177.3, 162.8, 159.1, 155.3, 148.8, 142.6, 138.1, 132.5, 129.1, 128.7, 124.5, 124.1, 123.4, 114.5, 109.9, 109.2, 93.0, 79.9, 57.9, 55.5, 42.9; MS (ES+) m/z 413.9 (M+1).
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=[C:3]([F:15])[CH:2]=1.[OH:16]S(O)(=O)=O.C1(C)C=CC=CC=1>O.O=[Mn]=O>[F:15][C:3]1[CH:2]=[CH:1][C:6]([C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[O:16])=[CH:5][CH:4]=1
Reactant: Fc1ccc(Cc2ccc(F)cc2)cc1
Reactant: O=S(=O)(O)O
Agent: O=[Mn]=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 125 °C
Yield: 69.2 %

Procedure:
To a 250 mL round bottomed flask equipped with a heating mantle, overhead agitator, thermometer, condenser, and addition funnel with a tube protruding below the liquid level was added 10.6 g 4,4'-difluorodiphenylmethane (0.051 moles). Agitation was begun and a slurry of 20.5 g MnO2 (0.195 moles) in 30 g water was added to the flask. About 30 g of water were used to wash the MnO2 beaker and were added to the flask. The mixture was allowed to reach about 100° C. at which point 50 g H2SO4 (0.487 moles) were added to the addition funnel. The H2SO4 was then added dropwise into the flask and the reaction temperature slowly rose to about 125° C. when all of the acid had been added. The mixture was heated to maintain the temperature at about 125° C. until gas chromatography showed complete conversion after approximately 12 hours. The reaction mixture was allowed to cool to 100° C. and 50 g toluene were added to the mixture. A slurry of 6 g diatomaceous earth in 30 g water was poured into a vacuum Buchner funnel fitted with No. 42 filter paper to form a filter pre-coat. The contents of the round bottomed flask were then vacuum filtered. 10 g toluene was used to wash the flask and, subsequently, the filter cake. The filter cake was then washed with 100 g toluene heated to about 50° to 70° C. and the filtrate phase separated. The toluene was removed from the organic phase by heating to approximately 65° C. at 10 mm Hg. The 10 g yellow solids assayed as 95% pure 4,4'-difluorobenzophenone for an 84% yield. The solids were recrystallized from a hexane solvent leaving 7.7 g crystalline 4,4'-difluorobenzophenone for a 68% yield.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11]/[C:12](=[C:19]3\[C:20](=[O:31])[NH:21][C:22]4[C:27]\3=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.Cl.[C:33](OC(=O)C)(=[O:35])[CH3:34].CCN(C(C)C)C(C)C>C(O)(=O)C.O>[C:33]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([NH:11]/[C:12](=[C:19]3\[C:20](=[O:31])[NH:21][C:22]4[C:27]\3=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=2)[CH2:1]1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc2c(c1)CCNC2)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)N1CCc2cc(N/C(=C3\C(=O)Nc4ccc([N+](=O)[O-])cc43)c3ccccc3)ccc2C1

Procedure:
Prepared from 3-{(Z)-1-[(1,2,3,4-tetrahydro-isoquinolin-6-yl)-amino]-1-phenylmethylidene}-5-nitro-2-indolinone×HCl×H2O in glacial acetic acid with acetic anhydride in the presence of Hunig's base.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[C:22](=[O:23])[C:14]3=[CH:15][N:16]4[C:21]([CH2:20][CH2:19][CH2:18][CH2:17]4)=[C:13]3[CH:12]=[N:11]2)[N:5]=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:50]=[C:44]3[CH2:45][N:46]([CH3:49])[CH2:47][CH2:48][N:43]3[N:42]=2)[C:26]1=[O:51].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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].O.C(#N)C>[CH3:24][N:25]1[C:26](=[O:51])[C:27]([NH:40][C:41]2[CH:50]=[C:44]3[CH2:45][N:46]([CH3:49])[CH2:47][CH2:48][N:43]3[N:42]=2)=[CH:28][C:29]([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([N:10]3[C:22](=[O:23])[C:14]4=[CH:15][N:16]5[C:21]([CH2:20][CH2:19][CH2:18][CH2:17]5)=[C:13]4[CH:12]=[N:11]3)[N:5]=[CH:4][CH:3]=2)=[CH:30]1
Reactant: O=Cc1c(Cl)ccnc1-n1ncc2c3n(cc2c1=O)CCCC3
Reactant: CN1CCn2nc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)cc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CN1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6c7n(cc6c5=O)CCCC7)c4C=O)cn(C)c3=O)cc2C1
Temperature: 100 °C
Yield: 61.9 %

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 4-chloro-2-(4-oxo-7,8,9,10-tetrahydropyridazino[4,5-a]indolizin-3(4H)-yl)nicotinaldehyde 192c (200 mg, 0.60 mmol), 1-methyl-3-(5-methyl-4,5,6,7-tetrahydropyra-zolo[1,5-a]pyrazin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 135a (230 mg, 0.60 mmol), sodium acetate (100 mg, 1.2 mmol), K3PO4 (320 mg, 1.2 mmol), PdCl2(dppf) (50 mg, 0.060 mmol), acetonitrile (25 mL), and water (1 mL). After bubbling nitrogen through the mixture for 30 minutes, it was heated at 100° C. for 3 hours under N2 protection. The reaction was cooled to room temperature and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 25:1 methylene chloride/methanol to afford 202a (205 mg, 62%) as a brown solid. MS-ESI: [M+H]+ 552.3.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:24]2[CH2:28][C:27]([CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[O:26][N:25]=2)[CH:12]=[C:13](/[CH:15]=[CH:16]/[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]=1)C1C=CC=CC=1>[Pd].C1COCC1>[C:40]([O:39][C:37](=[O:38])[CH2:36][C:27]1([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[O:26][N:25]=[C:24]([C:11]2[CH:10]=[C:9]([OH:8])[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH:12]=2)[CH2:28]1)([CH3:41])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)/C=C/c1cc(OCc2ccccc2)cc(C2=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1cc(O)cc(C2=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.1 %

Procedure:
A mixture of tert-butyl 3-(3-(benzyloxy)-5-((1E)-3-tert-butoxy-3-oxoprop-1-en-1-yl)phenyl)-5-(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (272 mg), 10% Pd/C (containing about 55% water, 27 mg), and THF (3 mL) was stirred at room temperature for 3 hours under a hydrogen atmosphere. The catalyst was filtered off, and then, the filtrate was concentrated under reduced pressure. The residue was combined with 10% Pd/C (containing about 55% water, 54 mg) and THF (3 mL), and the obtained mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The catalyst was filtered off, and then, the filtrate was concentrated under reduced pressure. The residue was combined with 10% Pd/C (containing about 55% water, 81 mg) and THF (3 mL), and the obtained mixture was stirred overnight at room temperature under a hydrogen atmosphere. The catalyst was filtered off, and then, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (167 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([CH:9]([CH:13]1[CH2:18][N:17]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:15][NH:14]1)[C:10]([O-])=[O:11])C.[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.O>[CH2:19]([N:17]1[CH2:16][CH2:15][NH:14][CH:13]([CH2:9][CH2:10][OH:11])[CH2:18]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCC(C(=O)[O-])C1CN(Cc2ccccc2)CCN1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCCC1CN(Cc2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.3 %

Procedure:
A 1M solution of lithium aluminium hydride in tetrahydrofuran (32.8 ml) was added dropwise to a stirred solution of (RS)-ethyl-(4-benzylpiperazin-2-yl)acetate (D3) (4.3 g, 16.41 mmol) in anhydrous tetrahydrofuran (100 ml) under argon, maintaining the temperature below 10° C. The resultant was stirred for a further 0.25 h, warmed to room temperature and stirred for 2.5 h. Water (8.2 ml), 2N sodium hydroxide (10.2 ml), and water (8.2 ml) were added dropwise sequentially with ice cooling. After 0.2 h sodium sulfate was added, the mixture stirred for 0.2 h then filtered through a short pad of celite. The filtrate was evaporated in vacuo to give the title compound as a pale orange oil (3.3 g, 91%). Mass spectrum (AP+): Found 221 (MH+). C13H20N2O requires 220.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:10]1[N:15]=[C:14]([N:16]2[C:20]([C:21]([F:24])([F:23])[F:22])=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:18]=[N:17]2)[CH:13]=[C:12]([N+:30]([O-])=O)[CH:11]=1.O.O.[Sn](Cl)Cl.NO.[Sn](Cl)Cl>CCOC(C)=O.[Pd].O.CN(C=O)C>[NH2:30][C:12]1[CH:11]=[C:10]([C:4]2[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:15]=[C:14]([N:16]2[C:20]([C:21]([F:24])([F:23])[F:22])=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:18]=[N:17]2)[CH:13]=1
Reactant: CCOC(=O)c1cnn(-c2cc([N+](=O)[O-])cc(-c3cc(C)ccc3OC)n2)c1C(F)(F)F
Agent: [Pd]
Agent: Cl[Sn]Cl
Agent: NO
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2cc(N)cc(-c3cc(C)ccc3OC)n2)c1C(F)(F)F
Temperature: 70 °C

Procedure:
A mixture of the title compound from Example 19 Step D (1.2 g, 2.7 mmol), DMF (15 mL), water (1.5 mL) and tin (II) chloride dihydrate (1.8 g, 7.9 mmol) was heated at 70° C. for 1.5 h, leading to reduction of the nitro group to the corresponding hydroxylamine. A second addition of tin (II) chloride dehydrate (2.4 g, 10.6 mmol) followed by heating at 100° C. overnight led to little progress. Water was added, and the reaction mixture was extracted with hexanes-EtOAc. The organic phase was separated and passed through a pad of silica gel. Hydrogenation using Pd-black (450 mg, 4.2 mmol) in EtOAc:EtOH (100 mL, 1:1 v/v) under 50 psi H2, followed by filtration and concentration, provided the title compound: LCMS m/z 421.6 [M+H]+; 1H NMR (400 MHz, acetone-d6) δ 8.09 (s, 1H), 7.71 (d, J=2.1 Hz, 1H), 7.45 (d, J=1.9 Hz, 1H), 7.13 (dd, J=8.4 Hz, 2.1 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 6.84 (d, J=1.9 Hz, 1H), 4.31 (q, J=7.1 Hz, 2H), 3.82 (s, 3H), 2.26 (s, 3H), 1.34 (t, J=7.1 Hz, 3H).
Reaction SMILES: C([O:3][P:4]([C:9]([P:30](=[O:37])([O:34]CC)[O:31]CC)=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.O1CCCC1.O>C(Cl)Cl.[2H]C([2H])(Cl)Cl>[C:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:10]=[C:9]([P:30](=[O:31])([OH:34])[OH:37])[P:4](=[O:3])([OH:5])[OH:8])#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCC#Cc1ccccc1C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Agent: C[Si](C)(C)Br
Agent: [2H]C([2H])(Cl)Cl
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCC#Cc1ccccc1C=C(P(=O)(O)O)P(=O)(O)O
Reaction time: 5 h
Yield: 78.5 %

Procedure:
Tetraethyl[2-[2-(1-tridecynyl)phenyl]ethenylidene]bisphosphonate (1.26 g, 2.28 mmol) prepared according to Example 9 was dissolved in a mixture of CH2Cl2 -CD2Cl2 (12 ml, 1.73:1). Trimethylsilyl bromide (1.3 ml, 9.85 mmol) was added, and the reaction was stirred for 5 hours. At this time additional trimethylsilyl bromide (0.2 ml, 1.5 mmol) was added. The progress of the reaction was monitored by 1H and 31P NMR, until no additional change occurred. 1H NMR was more useful in this regard, particularly the low field doublet of doublets. At the end of 8 hours, the solvent was removed under reduced pressure and the resulting oil was placed on the vacuum line. Tetrahydrofuran (10 ml) and water (0.25 ml, 13.9 mmol) were added and stirred for 20 hours, then removed under reduced pressure. NMR showed at least two species to be present, so the tetrahydrofuran-water treatment was repeated. After stripping, the residue was recrystallized from heptane as a white solid, 0.793 g, 1.79 mmol, 78.5% yield; mp 141°-142° C.; 1H NMR (CD3OD) ∂ 0.89 (m, 3H), 1.20 to 1.55 (m, 16H), 1.63 (quintet, J=7.4 Hz, 2H), 2.46 (t, J=7.1 Hz, 2H), 7.24 to 7.42 (m, 3H), 7.98 (m, 1H), 8.42 (dd, J=46.4, 29.0 Hz, 1H); FAB mass spectrum m/z 443 (M+H)+.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][C:9]=3[N:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16]Br.N>CO.C(Cl)Cl>[CH:1]1([N:6]2[C:10]3[CH:11]=[CH:12][C:13]([NH2:15])=[C:14]([Br:16])[C:9]=3[N:8]=[CH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: BrBr
Reactant: Nc1ccc2c(c1)ncn2C1CCCC1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc2c(ncn2C2CCCC2)c1Br
Yield: 35 %

Procedure:
To a solution of 1-cyclopentyl-5-aminobenzimidazole (1.1 g, 5.5 mmol) in 20 ml of ACOH was added solution of Br2 in. ACOH until it produces a precipitation. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CH2Cl2) to provide 0.54 g (1.9 mmol, 35%) of the product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[CH:16]=[CH:15][N:14](CC3C=CC(OC)=CC=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].[C:27]([O:30][C:31](=O)[CH3:32])(=O)C>C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:26][C:1](=[O:3])[CH3:2])=[C:8]2[CH:16]=[CH:15][N:14]([C:6]3[CH:4]=[CH:32][C:31]([O:30][CH3:27])=[CH:8][CH:7]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccc(OC)cc2)c1O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(C#N)c2c(ccn2-c2ccc(OC)cc2)c1OC(C)=O

Procedure:
Prepared in analogy to that of Example 120(a) from 7-cyano-4-hydroxy-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, acetic anhydride, and triethyl amine. The title compound, ESI MS (m/z): 380 (M+H)+.
Reaction SMILES: F[C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-:13].[Na+]>CN1CCN(C)C1=O>[F:11][C:9]1[CH:10]=[C:2]([OH:13])[C:3](=[CH:7][C:8]=1[F:12])[C:4]([OH:6])=[O:5]
Reactant: [OH-]
Reactant: O=C(O)c1cc(F)c(F)cc1F
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Product: O=C(O)c1cc(F)c(F)cc1O
Temperature: 130 °C
Reaction time: 3 h
Yield: 28.7 %

Procedure:
1.76 g (0.01 mole) of 2,4,5-trifluorobenzoic acid, 1.62 g (0.04 mole) of powdery 99% sodium hydroxide and 20 ml of 1,3-dimethyl-2-imidazolidinone were fed into a 100-ml four-necked flask provided with a thermometer, a stirrer and a reflux condenser. The mixture was stirred at 130° C. for 3 hours to give rise to a reaction. Then, the same post-treatment as in Example 1 was conducted to obtain 0.50 g of 4,5-difluorosalicylic acid. The isolated yield was 28.7% relative to the 2,4,5-trifluorobenzoic acid used.