Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3]([O:15][CH3:16])[C:4]1[C:9](CO)=[CH:8][C:7]2[O:12][CH2:13][O:14][C:6]=2[CH:5]=1.[CH3:17][O:18][C:19]([C:21]#[C:22][C:23]([O:25][CH3:26])=[O:24])=[O:20].CC(O)=O>>[O:15]1[CH:16]2[C:9]3[C:4]([CH:3]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:19]([O:18][CH3:17])=[O:20])=[CH:5][C:6]1[O:14][CH2:13][O:12][C:7]=1[CH:8]=3
Reactant: COC(=O)C#CC(=O)OC
Reactant: COC(OC)c1cc2c(cc1CO)OCO2
Solvent: CC(=O)O
Product: COC(=O)C1=C(C(=O)OC)C2OC1c1cc3c(cc12)OCO3
Yield: 176.5 %

Procedure:
The substrate 2 (23.7 g, 105 mmol) was dissolved in excess DMAD (251 g, 1.76 mol) and glacial AcOH (23.2 mL, 0.4 mol), and the mixture was stirred for 2 h at 80° C. Excess DMAD was removed by vacuum distillation, and flash chromatography (30% EtOAc/hexanes) gave 3 (56.4 g, 90%) as a yellow solid. On a smaller scale, 2 (5.53 g, 24.1 mmol) gave 3 in 92% yield (13.6 g): mp 117-119° C.; 1H NMR (300 MHz, CDCl3) δ 3.79 (s, 6H), 5.86 (s, 2H), 5.90 (d, J=1 Hz, 1H), 5.95 (d, J=1 Hz, 1H), 6.95 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 53.0, 85.7, 102.2, 105.2, 141.4, 146.2, 152.5, 163.5. Anal. Calculated for C15H12O7: C, 59.21; H, 3.98. Found: C, 59.27; H, 4.11.
Reaction SMILES: [Br:1][C:2]1[C:6]2=[CH:7][C:8]([Cl:30])=[C:9]3[C:14]([C:13](=[O:15])[O:12][C:11]([C:16]4[N:17]([C:23]5[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=5)[N:18]=[C:19]([O:21][CH3:22])[CH:20]=4)=[N:10]3)=[C:5]2[NH:4][N:3]=1.C(#N)C.O.[CH:35]([NH2:38])([CH3:37])[CH3:36]>[Cl-].[Na+].O>[CH:35]([NH:38][C:13]([C:14]1[C:9]([NH:10][C:11]([C:16]2[N:17]([C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=3)[N:18]=[C:19]([O:21][CH3:22])[CH:20]=2)=[O:12])=[C:8]([Cl:30])[CH:7]=[C:6]2[C:5]=1[NH:4][N:3]=[C:2]2[Br:1])=[O:15])([CH3:37])[CH3:36]
Reactant: CC(C)N
Reactant: COc1cc(-c2nc3c(Cl)cc4c(Br)n[nH]c4c3c(=O)o2)n(-c2ncccc2Cl)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(=O)Nc2c(Cl)cc3c(Br)n[nH]c3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.1 %

Procedure:
To a suspension of 120 mg (0.24 mmol) of the above 3-bromo-5-chloro-7-[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazol-3-yl]-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 2.4 mL of a mixture acetonitrile:H2O 4:2 (v/v) is added 60 μL (0.71 mmol) of isopropylamine. The reaction mixture is stirred for 6 hours at ambient temperature. Brine is then added to the mixture and the product is extracted with ethyl acetate (3 times). The regrouped organic phases are dried on Na2SO4, filtrated and evaporated. The purification of the residue by flash chromatography (SiO2, heptane/ethyl acetate 1:2) affords 56 mg (42%) of a white solid; LC/MS:568/570 (M+H)+, m.p.: 217-218° C.
Reaction SMILES: C([N:8]1[CH2:19][CH2:18][N:17](CC2C=CC=CC=2)[CH2:16][CH2:15][N:14](CC2C=CC=CC=2)[CH2:13][CH2:12][N:11]([CH2:34][C:35](=[O:82])[NH:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][NH:45][C:46](=[O:81])[CH2:47][N:48]2[CH2:59][CH2:58][N:57](CC3C=CC=CC=3)[CH2:56][CH2:55][N:54](CC3C=CC=CC=3)[CH2:53][CH2:52][N:51](CC3C=CC=CC=3)[CH2:50][CH2:49]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[N:11]1([CH2:34][C:35](=[O:82])[NH:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][NH:45][C:46](=[O:81])[CH2:47][N:48]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][NH:8][CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: O=C(CN1CCN(Cc2ccccc2)CCN(Cc2ccccc2)CCN(Cc2ccccc2)CC1)NCCOCCOCCNC(=O)CN1CCN(Cc2ccccc2)CCN(Cc2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C(CN1CCNCCNCCNCC1)NCCOCCOCCNC(=O)CN1CCNCCNCCNCC1

Procedure:
A 100 mL Autoclave pressure reactor was charged with 9.2 g (8.3 mmol) of 8, 50 mL of ethanol and 3 g of 10% Pd/C. The reactor was pressurized to 220 psig with hydrogen for 3 hours at 80° C. The mixture was filtered and the filtrate was concentrated to a slightly yellow oil. 1H NMR, 13C NMR, and mass spectroscopy data were consistent with 9. The yield of 9 was essentially quantitative.
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:33])[C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:10](=[O:34])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>N1C=CC=CC=1>[C:35]([N:20]([CH2:19][CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][CH2:12][N:11]1[C:10](=[O:34])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(NCCCNCCCCNCCCn1c(=O)[nH]c2ccccc2c1=O)c1ccc(O)cc1
Solvent: c1ccncc1
Product: CC(=O)N(CCCCNCCCn1c(=O)[nH]c2ccccc2c1=O)CCCNC(=O)c1ccc(O)cc1
Reaction time: 2 h

Procedure:
N-(3-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butylamino}propyl)-4-hydroxybenzamide(1.27 g, 2.72 mmol) was dissolved in 10 mL pyridine and acetic anhydride (0.4 mL, 4.07 mmol) was added thereto. After 2 hours, pyridine was removed by distillation under reduced pressure and dichloromethane and water were added thereto. The organic layer was separated and removed. After concentration under reduced pressure, the remaining residue was treated by silica gel column-chromatography and ion exchange resin to give the title compound of oil form (0.06 g, 4.3%).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH:17]O>O1CCCC1.[Pt]>[CH2:10]([N+:8]([O-:17])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH3:9])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: OO
Reactant: CCCCCCCN(C)CCCCCCC
Agent: [Pt]
Solvent: C1CCOC1
Product: CCCCCCC[N+](C)([O-])CCCCCCC
Temperature: 25 °C

Procedure:
To a solution of 6.6 g of diheptylmethyl amine in 25 ml tetrahydrofuran (THF) was added 12 ml 30% hydrogen peroxide. The reaction mixture was refluxed for 24 hours, cooled to room temperature and then stirred with 0.2 mg platinum black overnight. After filtering the reaction mixture through Hyflo® filter-aid, the THF was removed in vacuo. The aqueous solution was extracted with 100 ml ether. The aqueous portion of the extraction was allowed to stand for several days to allow most of the water to evaporate. The resulting solution was found to be 40% water and 60% diheptylmethyl amine oxide by NMR analysis.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH:24]=[O:25])[CH:7]=1)[CH3:2].CO.[BH4-].[Na+]>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24][OH:25])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CO)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To [3-(2-formyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (1 equivalent methanol was added sodium borohydride (1.2 equivalents), and the reaction was stirred at room temperature for 15 minutes. The mixture was then concentrated and partitioned between EtOAc and H2O. The aqueous layer was separated and extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [Br:1]Br.[O:3]=[C:4]1[CH2:13][CH2:12][CH2:11][C:10]2[CH:9]=[C:8]([C:14]#[N:15])[CH:7]=[CH:6][C:5]1=2>C(Cl)Cl>[Br:1][CH:13]1[CH2:12][CH2:11][C:10]2[CH:9]=[C:8]([C:14]#[N:15])[CH:7]=[CH:6][C:5]=2[C:4]1=[O:3]
Reactant: N#Cc1ccc2c(c1)CCCC2=O
Reactant: BrBr
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CCC(Br)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
Bromine (0.8 mL, 15.7 mmol) was added to a solution of 5-oxo-5,6,7,8-tetrahydro-naphthalene-2-carbonitrile (2.7 g, 15.7 mmol), prepared in the previous step, in dry methylene chloride (55 mL) at 0° C. The reaction was warmed to room temperature. After 2 h, the reaction was diluted with methylene chloride and washed with 5% sodium thiosulfate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 4.3 g of crude product. Purification of the crude product on silica gel using 10% ethyl acetate:hexane as the eluent gave 6-bromo-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (3.2 g, 81%), MS(ES) m/z 251 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])[CH:2]([CH3:4])[CH3:3].[C:13](Cl)(=[O:17])[C:14](Cl)=[O:15]>C(N(CC)CC)C>[CH2:1]([C:5]1[CH:11]=[CH:10][C:8]2[O:9][C:13](=[O:17])[C:14](=[O:15])[O:12][C:7]=2[CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)Cc1ccc(O)c(O)c1
Solvent: CCN(CC)CC
Product: CC(C)Cc1ccc2oc(=O)c(=O)oc2c1

Procedure:
The same procedures as described in Example 8 were carried out by using 4.16 g (25 mM) of 4-isobutylcatechol, 5.06 g (50 mM) of triethylamine and 3.50 g (28 mM) of oxalyl chloride. 6-iso-Butyl-1,4-benzodioxine- 2,3-dione 2/5 hydrate was obtained in the yield of 5.11 g (22.5 mM) as colorless crystals having a melting point of 92°-97° C.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][NH:9][CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-])=O.O.NN>CCO.[Ni]>[N:12]1([CH2:11][CH2:10][NH:9][CH2:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:18][CH:17]=2)[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=[N+]([O-])c1ccc(CNCCN2CCCC2)cc1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc(CNCCN2CCCC2)cc1
Temperature: 65 °C
Reaction time: 0.75 h
Yield: 75.2 %

Procedure:
The (4-Nitro-benzyl)-(2-pyrrolidin-1-yl-ethyl)-amine (0.503 g, 2.02 mmol) was dissolved in EtOH (10 mL) under Ar(g), and hydrazine hydrate (0.439 mL, 14.14 mmol) was added. Subsequently, excess RaNi was added in dropwise until the solution stopped bubbling. The suspension was then allowed to stir for an additional 45 minutes at 65° C. The suspension was cooled to r.t. and then filtered over celite. The celite was washed with MeOH and the combined organic solutions were then concentrated in vacuo affording a pure 4-[(2-Pyrrolidin-1-yl-ethylamino)-methyl]-phenylamine as a light purple oil (0.331 g, 1.52 mmol, 75% yield).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[C:5]1[C:10]([C:11]([NH:13][C:14]2[C:15]([Cl:25])=[N:16][C:17]([CH3:24])=[CH:18][C:19]=2[C:20]([F:23])([F:22])[F:21])=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[Cl:25][C:15]1[C:14]([NH:13][C:11]([C:10]2[C:5]([NH:3][CH2:1][CH3:2])=[N:6][CH:7]=[CH:8][CH:9]=2)=[O:12])=[C:19]([C:20]([F:23])([F:22])[F:21])[CH:18]=[C:17]([CH3:24])[N:16]=1
Reactant: Cc1cc(C(F)(F)F)c(NC(=O)c2cccnc2Cl)c(Cl)n1
Reactant: CCN
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCNc1ncccc1C(=O)Nc1c(C(F)(F)F)cc(C)nc1Cl
Temperature: 160 °C
Yield: 37.5 %

Procedure:
Ethylamine (0.4 g) was added to a suspension of 1.3 g of 2-chloro-N-(2-chloro-6-methyl-4-trifluoromethyl-3-pyridinyl)-3-pyridinecarboxamide in 5 ml of xylene, and the resulting mixture heated in a pressure tube for 30 min. at 160° C. The cooled mixture was diluted with ethyl acetate, washed, dried, and concentrated. Column chromatography over silica gel (ethyl acetate/hexane, 1:1) gave 0.5 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:9](=[O:19])[CH:8]([NH:20][C:21](=[O:41])[C@H:22]([NH:27][C:28](=[O:40])[C:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:31])[CH3:30])[CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:7]2.[CH:42](=O)[CH3:43].C(#N)C.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH2:42]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:9](=[O:19])[CH:8]([NH:20][C:21](=[O:41])[C@H:22]([NH:27][C:28](=[O:40])[C:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:30])[CH3:31])[CH2:23][CH:24]([CH3:25])[CH3:26])[CH2:7]2)[CH3:43]
Reactant: CC=O
Reactant: CC(C)C[C@@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N)c2N(Cc2ccccn2)C1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCNc1cccc2c1N(Cc1ccccn1)C(=O)C(NC(=O)[C@@H](CC(C)C)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2
Reaction time: 0.08 h

Procedure:
tert-Butyl 1-((2R)-1-(8-amino-2-oxo-1-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-ylamino)-4-methyl-1-oxopentan-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (59 mg) and acetaldehyde (29 μL) were sequentially added to acetonitrile (730 μL), and sodium cyanoborohydride (7 mg) and acetic acid (18 μL) were added to the mixture under cooling on ice, followed by stirring for 5 minutes. The resultant mixture was extracted with ethyl acetate and saturated aqueous sodium bicarbonate solution, and the aqueous layer was further extracted with ethyl acetate. The organic layers were combined, and the combined organic layer was washed with saturated aqueous sodium chloride solution, followed by drying over sodium sulfate. The solvent was evaporated under reduced pressure, and the thus-recovered residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:1), whereby the title compound (58 mg) was yielded.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].[Br:10]N1C(=O)CCC1=O>CC#N>[Br:10][C:8]1[C:7]([F:9])=[CH:6][C:4]([NH2:5])=[CH:3][C:2]=1[Cl:1]
Reactant: Nc1cc(F)cc(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1cc(F)c(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
To a cooled (0° C.) solution of 3-chloro-5-fluoroaniline (5.0 g, 33 mmol) in MeCN (50 ml) was added a suspension of N-bromosuccinimide (5.9 g, 33 mmol) in MeCN (10 ml). After being stirred for 2 h at RT the reaction was quenched by adding 10% NaHSO3 (50 ml). The mixture was concentrated to about half of the volume, diluted with water (50 ml) and extracted with EtOAc (3×50 ml). Combined organic phases were dried over Na2SO4 and evaporated to give crude product, which was purified by CombiFlash (column: silica, eluent: 0-100% EtOAc in heptane) to yield 5.5 g (74%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 5.88 (bs, 2H), 6.45 (dd, 1H), 6.64 (m, 1H).
Reaction SMILES: [CH:1]1([CH2:4][C:5]([O:10][C:11]2[CH:33]=[CH:32][C:14]3[C:15]4[N:19]([CH2:20][CH2:21][O:22][C:13]=3[CH:12]=2)[CH:18]=[C:17]([C:23]2[N:24]([CH:29]([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[N:27]=2)[N:16]=4)([CH2:8][OH:9])[CH2:6][OH:7])[CH2:3][CH2:2]1.CCN(CC)CC.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[CH:1]1([CH2:4][C:5]([O:10][C:11]2[CH:33]=[CH:32][C:14]3[C:15]4[N:19]([CH2:20][CH2:21][O:22][C:13]=3[CH:12]=2)[CH:18]=[C:17]([C:23]2[N:24]([CH:29]([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[N:27]=2)[N:16]=4)([CH2:6][O:7][S:42]([CH3:41])(=[O:44])=[O:43])[CH2:8][O:9][S:42]([CH3:41])(=[O:44])=[O:43])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(CO)(CO)CC4CC4)cc2OCC3)n(C(C)C)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(COS(C)(=O)=O)(COS(C)(=O)=O)CC4CC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.2 %

Procedure:
To a solution of 2-cyclopropylmethyl-2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-propane-1,3-diol (200 mg, 0.441 mmol) and Et3N (184 μL, 1.32 mmol) in DCM (20 mL) cooled at 0° C. was added methanesulfonyl chloride (86 μL, 1.10 mmol) and stirring at RT was continued for 1.5 h. The mixture was diluted with DCM, washed with a saturated solution of NaHCO3, followed by water, then dried (Na2SO4) and concentrated in vacuo affording the title compound as a colourless solid (264 mg, 98%). LCMS (Method B): RT 3.34 min [M+H]+ 610
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[NH2:14][C:15]1[C:16](=[O:23])[C:17](=[O:22])[C:18]=1OCC.O>N1C=CC=CC=1>[NH2:14][C:15]1[C:16](=[O:23])[C:17](=[O:22])[C:18]=1[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOc1c(N)c(=O)c1=O
Reactant: Nc1ccc(-c2cccnc2)cc1
Solvent: O
Solvent: c1ccncc1
Product: Nc1c(Nc2ccc(-c3cccnc3)cc2)c(=O)c1=O
Yield: 41.8 %

Procedure:
A solution of 3-(4-aminophenyl)pyridine (0.51 g) and 3-amino-4-ethoxy-3-cyclobutene 1,2-dione (0.42 g) in pyridine (2 ml) is stirred at 80° for 20 hours. The cool mixture is treated with water (15 ml), and the solid filtered off and washed with water and hot methanol. Recrystallation from dimethylformamide gives 0.33 g of the title compound, mp 3224° C. dec.
Reaction SMILES: [Br:1][C:2]1[N:6]([C@@H:7]2[O:24][CH2:23][C@@H:18]([O:19]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.[Li+].[OH-]>O1CCOCC1>[Br:1][C:2]1[N:6]([C@@H:7]2[O:24][CH2:23][C@@H:18]([OH:19])[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: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1c(Br)nc2cc(Cl)c(Cl)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O[C@@H]1[C@H](O)[C@H](O)CO[C@H]1n1c(Br)nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
3.0 g (5.7 mmol) 2-Bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-β-D-ribopyranosyl)-1H-benzimidazole was deprotected as using the general procedure summarized in the foregoing description by being dissolved in 60 ml dioxane and the resultant solution cooled in an ice bath between 0 and 5° C. To this solution was added all at once, 22 ml (22 mmol) of 1 M aq. LiOH. The mixture was removed from the ice bath and allowed to stir at ambient temperature for 1 h. The mixture was diluted with 120 ml of pH 7 phosphate buffer and extracted with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate (anhyd.), filtered and solvents evaporated. The residue was triturated in dichloromethane and 1.7 g (4.3 mmol, 75% yield) of 2-bromo-5,6-dichloro-1-β-D-ribopyranosyl-1H-benzimidazole was collected by vacuum filtration. The product was dried in a vacuum oven at 50° C. overnight; m.p. 175° C. (decomposes); 1H NMR (DMSO-d6) δ 7.96 (s, 1H), 7.07 (s, 1H), 5.64-5.62 (d, J=9.2 Hz), 5.19-5.17 (d, 1H, J=6.4 Hz), 5.13-5.12 (d, 1H, J=3.2 Hz), 4.86-4.84 (d, 1H, J=6.5 Hz), 4.12-4.06 (m, 1H), 3.98-3.92 (m, 2H), 3.68-3.63 (m, 2H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:20]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[C:26]2[CH2:32][CH2:33]O)([O-:22])=[O:21].C(Br)(Br)(Br)[Br:36]>C(#N)C.C(OCC)(=O)C>[N+:20]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[C:26]2[CH2:32][CH2:33][Br:36])([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc2[nH]cc(CCO)c2c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2[nH]cc(CCBr)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
To a solution of triphenylphosphine (2.83 g, 0.011 mol) in 100 mL of acetonitrile was added a solution of 5-nitro-3-(2-hydroxyethyl)indole (2.00 g, 0.0097 mol) in 25 mL of acetonitrile, followed by a solution of CBr4 (3.60 g, 0.011 mol) in 25 mL of acetonitrile, at 0° C. under Ar. The mixture was stirred at room temperature for 18 h and then another 0.283 g (1.1 mmol) of triphenylphosphine and 0.360 g (1.1 mmol) of CBr4 were added. After 2.5 h the mixture was diluted with ethyl acetate, washed (H2O, brine), dried (Na2SO4) and evaporated and the residue was chromatographed (SiO2 /ethyl acetate-hexane, 1:4) to give the title compound (2.27 g, 87%) as a yellow solid: IR (neat) 3370, 1334 cm-1 ; 1H NMR (DMSO-d6, 200 MHz) δ11.69 (s, 1H), 8.60 (d, J=2.1 Hz, 1H), 7.98 (dd, J=9.0, 2.2 Hz, 1H), 7.54-7.49 (m, 2H), 3.76 (t, J=7.2 Hz, 2H), 3.32 (t, J=7.2 Hz, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6](O)=[O:7].C(Cl)(=O)C([Cl:13])=O>ClCCl>[CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]([Cl:13])=[O:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)CCCC(=O)O
Solvent: ClCCl
Product: CC(C)CCCC(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-methylhexanoic acid (0.53 g, 4 mmole) in dichloromethane was added oxalyl chloride (0.77 g, 6 mmole). The reaction mixture was stirred at room temperature for 2 hours and then evaporated under vacuum to give crude 5-methylhexanoyl chloride. To a solution of 4,4-bis(trifluoromethyl)-2-(4-fluorophenyl)-4,5-dihydro-5-amine-N,N-1,5-dimethyl-1H-imidazole (0.60 g, 1.76 mmole) in dichloromethane (15 mL) was added 5-methylhexanoyl chloride and pyridine (0.42 g, 5 mmole). The reaction mixture was stirred overnight at room temperature under nitrogen. The crude reaction mixture was quenched with water and extracted with ether. The organic layer was washed successively with water, sodium hydroxide (1N) and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with hexane and hexane-ethyl acetate (20:1 to 50:50). The crude product (0.42 g, 85%) was treated with HCl in ether and recrystallized from dichloromethane-methanol-petroleum ether to give the title compound as a white solid: mp 112°-114°; MS m/e 456 (M+ +H); 1H NMR (CDCl3 /TMS) δ 0.90(s,3H,CH3), 0.93(s,3H,CH3), 1.27(m,2H,CH2), 1.67(m,3H,CH2CH), 2.47(m,2H,CH2), 3.00(s,3H,NCH3), 3.23(s,3H,NCH3), 7.03(s,1H,CH), 7.33(m,2H,Harom), 8.00(m,2H,Harom).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:5]=[N:6][N:7]2[C:12](I)=[CH:11][CH:10]=[CH:9][C:8]=12)[CH3:2].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[C:12]1[N:7]2[N:6]=[CH:5][C:4]([N:3]([CH2:14][CH3:15])[CH2:1][CH3:2])=[C:8]2[CH:9]=[CH:10][CH:11]=1
Reactant: CCN(CC)c1cnn2c(I)cccc12
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCN(CC)c1cnn2c(-c3ccc(Cl)cc3Cl)cccc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
A solution of 3-diethylamino-7-iodopyrazolo[1,5-a]pyridine (0.20 g, 0.63 mmol) and Pd(PPh3)4 (0.037 g, 0.03 mmol) in DME (5.0 mL) was stirred at room temperature for 10 minutes then treated with 2,4-dichlorophenylboronic acid (0.19 g, 1.27 mmol) and 2M Na2CO3 (3.0 mL). The reaction was heated at 80° C. for 16 hours and cooled down to room temperature. Additional Pd(PPh3)4 (0.037 mg, 0.03 mmol) and 2,4-dichlorophenylboronic acid (0.19 g, 1.27 mmol) were added and heating was continued at 80° C. for 2 hours. The reaction was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2×). The combined organic solutions was washed with brine, dried over MgSO4, and concentrated in vacuo to dryness. The residue was subjected to column chromatography (5% ethyl acetate/hexane) to give 0.17 g (79%) of a light yellow oil as the title compound: 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.66–7.63 (m, 2H), 7.50 (d, J=8.2 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.14–7.09 (m, 1H), 6.71 (d, J=6.7 Hz, 1H), 3.15 (q, J=7.1 Hz, 4H), 1.09 (t, J=7.1 Hz, 6H); IR (diffuse reflectance) 2968, 2935, 2814, 1487, 1461, 1377, 1334, 1314, 1149, 1096, 921, 881, 867, 827, 791 cm−1; MS (EI) m/z 333 (M+); Anal. Calcd for C17H17Cl2N3: C, 61.09; H, 5.13; N, 12.57. Found: C, 60.97; H, 5.02; N, 12.54.