Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][O:19][NH2:20])=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][O:19][NH:20][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])=[CH:16][CH:15]=1
Reactant: COc1ccc(CON)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(CONS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A solution of tosyl chloride (156.7 g) in pyridine (240 ml) was added dropwise to a solution of p-methoxybenzyloxyamine (102.3 g) in pyridine (210 ml) for 2.5 hours under cooling at 0°~5° C. and the mixture was stirred overnight at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate (1 l). The insoluble substances were filtered off, and the filtrate was washed three times with 2N hydrochloric acid, twice with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give crystalline product, which was recrystallized from a mixture of ethylacetate and petroleum ether to give N-(p-methoxybenzyloxy)-p-toluenesulfonamide (162.2 g) in the form of crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1>C(OCC)(=O)C.[Ni]>[F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:8][CH3:9])=[CH:6][CH:7]=1
Reactant: CNc1ccc(F)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CNc1ccc(F)cc1N
Reaction time: 4.5 h
Yield: 76.4 %

Procedure:
6.2 g (4-fluoro-2-nitrophenyl)-methylamine are suspended in 200 ml of ethyl acetate and hydrogenated with 1 g Raney nickel at a pressure of 5 bar and ambient temperature. After 4.5 hours the catalyst is suction filtered and the filtrate is evaporated to dryness. 3.9 g product are obtained as an oil.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][C:7]#[N:8])[C:3]#[N:4].[NH3:9]>[Pd]>[CH3:1][C:2]1[C:3]([NH2:9])=[N:4][C:7]([NH2:8])=[CH:6][CH:5]=1
Reactant: N
Reactant: CC(C#N)CCC#N
Agent: [Pd]
Product: Cc1ccc(N)nc1N
Temperature: 200 °C

Procedure:
2-Methylglutaronitrile was combined with Pd.C (5 mol % of 10 wt % Pd on carbon) in a 10 mL Hastelloy shaker autoclave to which liquid NH3 was added. The mixture was heated at 200° C. for 45 h. The mixture was cooled to ambient temperature and the excess NH3 removed by N2 purge. The crude mixture was suspended in 10 mL anhydrous methanol, the catalyst was removed by syringe filtration, and the crude reaction mixture was concentrated in vacuo. 2-Methylglutaronitrile conversion was 100% to give 0.02 mmol of 3-methylpyridine-2,6-diamine in 2.3% net yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[C:35](=[O:36])[N:34]([CH2:37][CH3:38])[C:15]2[N:16]=[C:17]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)=[CH:23][CH:22]=3)[N:18]=[CH:19][C:14]=2[CH:13]=1)[C:5]([NH:7][NH2:8])=[O:6].F[C:40](F)(F)C(O)=O>C(OCC)(OCC)OCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][CH:40]=[N:8][N:7]=2)[CH:9]=[CH:10][C:11]=1[C:12]1[C:35](=[O:36])[N:34]([CH2:37][CH3:38])[C:15]2[N:16]=[C:17]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)=[CH:25][CH:26]=3)[N:18]=[CH:19][C:14]=2[CH:13]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CCn1c(=O)c(-c2ccc(C(=O)NN)cc2Cl)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Solvent: CCOC(OCC)OCC
Product: CCn1c(=O)c(-c2ccc(-c3nnco3)cc2Cl)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Temperature: 130 °C
Yield: 50 %

Procedure:
3-Chloro-4-{8-ethyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl}benzoic acid hydrazide (7, 30 mg, 0.06 mmol) was suspended in triethyl orthoformate (5 mL) to which was added trifluoroacetic acid (1 mL). The resulting reaction mixture was heated at 130° C. for 2 h. The volatiles were removed and the residue was taken up in dichloromethane (1×20 mL) and washed with 10% sodium hydroxide solution (2×10 mL). The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography using dichloromethane:methanol (95:5). The title compound (18 mg, 0.03 mmol, 50%) was obtained as a yellow solid. ESMS m/z 543 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.57 (s, 1H) 8.50 (s, 1H) 8.21 (d, J=1.5 Hz, 1H) 8.04 (dd, J=8.0, 1.5 Hz, 1H) 7.62 (s, 1H) 7.52-7.60 (m, 3H) 7.29 (br. s., 1H) 6.98 (d, J=9.0 Hz, 2H) 4.50 (q, J=6.8 Hz, 2H) 3.16-3.27 (m, 4H) 2.56-2.65 (m, 4H) 2.37 (s, 3H) 1.39 (d, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@H:12]([O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:11]([CH2:22]Br)[O:10][C@H:7]([O:8][CH3:9])[CH2:6]1)(=[O:3])[CH3:2].C1C=CC=CC=1.CC(C)=O.CCOCC>N1C=CC=CC=1.[Ag]F>[C:1]([NH:4][C@@H:5]1[C@H:12]([O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11](=[CH2:22])[O:10][C@H:7]([O:8][CH3:9])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CO[C@@H]1C[C@H](NC(C)=O)[C@H](OC(=O)c2ccccc2)[C@@H](CBr)O1
Agent: F[Ag]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: c1ccncc1
Product: C=C1O[C@H](OC)C[C@H](NC(C)=O)[C@@H]1OC(=O)c1ccccc1

Procedure:
A mixture of Compound VI (5 g, 13 mmoles) and dry, technical-grade silver fluoride (5 g, 22.1 mmoles) in dry pyridine (90 ml) was stirred for 14 hours at 25° C, after which time, t.l.c. (2:3 benzene-acetone) showed that all of Compound VI had reacted. The dark solution was poured into ether (500 ml), and the resultant mixture was filtered. The filtrate was evaporated at ≤40° C, and then three 25-ml portions of toluene were added to and evaporated from the residue (to remove all of the pyridine). The resultant syrup was taken up in ether, and the suspension filtered through a small column (250 × 20 mm) of silica get to remove residual silver salts. The effluent was evaporated in vacuo to give the pure Compound VII as a syrup; yield 4 g (100%), [α]D23 +55.2° (c, 1.4, chloroform); νmaxfilm 3420-3290 (NH), 1725 (ester CO), 1660 (Amide I, C=C), 1600, 1585 (monosubstituted phenyl), and 1525 cm-1 (Amide II).
Reaction SMILES: N[C:2]1[S:3][C:4]([I:12])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.C(ON=O)(C)(C)C>CN(C=O)C.[Cl-].[Na+].O>[CH2:10]([O:9][C:7]([C:5]1[N:6]=[CH:2][S:3][C:4]=1[I:12])=[O:8])[CH3:11]
Reactant: CCOC(=O)c1nc(N)sc1I
Agent: CC(C)(C)ON=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ncsc1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
A solution of 10.68 g of 2-amino-4-ethoxycarbonyl-5-iodothiazole in 140 ml of DMF was cooled in ice under an argon atmosphere. t-Butylnitrite (6.15 ml) was added to the cooled solution, and the mixture was stirred at room temperature for 30 min. The reaction solution was poured into brine, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, followed by washing three times with brine. The organic layer was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1 to 3:1) to give 5.08 g of 4-ethoxycarbonyl-5-iodothiazole.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:33])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].[OH:34]N1C(=O)C2=CC=CC=C2C1=O>C(C(C)=O)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:1]([O:4][CH:5]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C:7](=[CH:8][C:9](=[O:34])[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:33])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([O:17][Si:18]([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](C(C)O[Si](C)(C)C(C)(C)C)[C@@]4(C)CC[C@@H]32)C1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCC(C)=O
Product: CC(=O)OC1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H](C(C)O[Si](C)(C)C(C)(C)C)[C@@]4(C)CC[C@@H]32)C1
Temperature: 40 °C
Reaction time: 5 h
Yield: 31.9 %

Procedure:
To a solution of 3-acetoxy-20-tert-butyldimethylsilyloxy-pregn-5-ene (337 gm, 0.71 mol) in methyl ethyl ketone (4 L) was added N-hydroxyphthalimide (115.8 gm, 0.71 mol) and dibenzoyl peroxide (1.1 gm, 4.4 mmol). Air was bubbled through the reaction as the reaction was refluxed for 7.5 hr. Additional N-hydroxyphthalimide (9 gm) and dibenzoyl peroxide (0.1 gm) was added and reflux continued for 5 hr. The solvent was removed by rotoevaporation and methylene chloride (0.7 L) was added and warmed to 40° C. Upon cooling to room temperature, the suspension was filtered and the filtrate washed with methylene chloride (0.2 L). The filtrate was rotoevaporated and treated with pyridine (1.35 L) and acetic anhydride (135 mL). After stirring overnight, the solvent was removed by rotoevaporation and the dark orange oil dissolved in methanol (0.6 L). The mixture was heated to 50° C. and then cooled to room temperature. The solution was allowed to stand for 3 days and then cooled in an ice bath. The precipitant was filtered, washed with methanol, and dried to yield the title compound (110.6 gm, 32% yield). The filtrate was rotoevaporated to a dry gum to yield 253 gm of the crude product.
Reaction SMILES: [Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCCCC.C([Li])CCC.[CH:32]12[CH2:37][CH:36]1[CH2:35][CH:34]([OH:38])[CH2:33]2.[CH:39]12C[CH:43]1[CH2:42][CH2:41][CH:40]2[OH:45]>CCCCCC.C1C=CC=CC=1>[O:45]1[CH2:39][CH2:43][CH2:42][CH2:41][CH:40]1[O:38][CH:34]1[CH2:35][CH:36]2[CH:32]([CH2:37]2)[CH2:33]1
Reactant: OC1CC2CC2C1
Reactant: OC1CCC2CC12
Agent: CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: c1ccccc1
Product: C1CCC(OC2CC3CC3C2)OC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of hexyltriphenylphosphonium bromide (102 g.) and benzene (1200 ml.) is stirred under nitrogen during addition of a solution of butyl lithium in hexane (146 ml. of a 15% solution -w/v). The resulting mixture is stirred 30 minutes. Then a solution of the mixture (27 g.) of products obtained according to Preparation 4 in 300 ml. of benzene is added dropwise with stirring during 30 minutes. The mixture is heated and stirred at 70° C. for 2.5 hours, and then is cooled to 25° C. The resulting precipitate is collected by filtration and washed with benzene. The filtrate and benzene wash are combined, washed with water, dried, and evaporated to give 58 g. of a mixture of the tetrahydropyranyl ethers of endo-6-(cis- and trans-1-heptenyl)bicyclo[3.1.0]hexan-3-ol and endo-6-(cis- and trans-1-heptneyl)bicyclo[ 3.1.0]hexan-2-ol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=O.C(Cl)(=O)C([Cl:16])=O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([Cl:16])=[O:12]
Reactant: O=C(O)CCc1ccccc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)CCc1ccccc1F
Temperature: 25 °C

Procedure:
To a mixture of 3-(2-fluorophenyl)propionic acid (18.64 g, 0.111 mol) and dimethylformamide (5 drops) at room temperature was added dropwise oxalyl chloride (60 mL). The mixture was stirred at room temperature until gas evolution had ceased. The excess oxalyl chloride was removed by distillation to give 3-(2-fluorophenyl)propionyl chloride. A solution of the 3-(2-fluorophenyl)propionyl chloride in dichloromethane (230 mL) was added dropwise to a mixture of aluminum chloride (16.25 g, 0.12 mol) in dichloromethane (230 mL), and the mixture was refluxed for 3.5 h. The reaction mixture was poured into ice water (1200 mL), and the two phases were separated. The dichloromethane phase was washed successively with 0.1N aqueous sodium hydroxide (2×100 mL), water (200 mL), and brine (200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residual oil was chromatographed on silica gel eluting with hexane:dichloromethane (9:1) to give 11.0 g of crude 4-fluoro-1-indanone as a yellow solid. Recrystallization from acetone:water mixtures gave 8.02 g (48%) of 4-fluoro-1-indanone as a pale yellow solid: m.p., 71-72° C.; NMR (DMSO-d6): d 7.51 (m, 3H, Ar), 3.13 (t, 2H, CH2), 2.74 (t, 2H, CH2).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=CN2)=[C:4](NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1.Cl[C:27]1[N:35]=[C:34]2[C:30]([N:31]=[CH:32][N:33]2[C@@H:36]2[CH2:40][C@H:39]([NH:41][C:42](=[O:51])[CH2:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C@@H:38]([OH:52])[C@H:37]2[OH:53])=[C:29]([NH:54][CH2:55][CH:56]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[N:28]=1.N1CC[C@@H](N)C1.[I-].[Na+].N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](NC(=O)CC4C=CC=CC=4)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1>>[NH2:6][C@@H:5]1[CH2:4][CH2:2][N:10]([C:27]2[N:35]=[C:34]3[C:30]([N:31]=[CH:32][N:33]3[C@@H:36]3[CH2:40][C@H:39]([NH:41][C:42](=[O:51])[CH2:43][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C@@H:38]([OH:52])[C@H:37]3[OH:53])=[C:29]([NH:54][CH2:55][CH:56]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[N:28]=2)[CH2:9]1
Reactant: Clc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Reactant: O=C(CCc1ccccc1)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)Cc5ccccc5)[C@@H](O)[C@H]4O)c3n2)C1
Agent: N[C@@H]1CCNC1
Agent: [I-]
Product: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CCc5ccccc5)[C@@H](O)[C@H]4O)c3n2)C1

Procedure:
The title compound is prepared using a method that is analogous to that used to prepare the compound of Example 22 using N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-3-phenyl-propionamide, (R)-pyrrolidin-3-ylamine (34 mg, 0.4 mmol) and sodium iodide (6 mg, 0.04 mmol) to give a mixture of two regioisomers which are purified by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water—0.1% TFA) to give a product which is predominantly N-{(1S,2R,3S,4R)-4-[2-((R)-3-Amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-phenyl-acetamide. LCMS (electrospray): m/z [MH+] 647.47
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.CCCCCC.CCOC(C)=O>[CH2:12]([O:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Cl)nc1OCc1ccccc1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
To a stirred mixture of 6-chloro-3-nitropyridin-2-ol (5 g, 0.0286 mol, Combi Blocks) in toluene (50.0 mL) in a 250 mL sealed tube, were added Ag2CO3 (11.84 g, 0.041 mol, Aldrich) and benzyl bromide (5.8 g, 0.033 mol) in one lot. The reaction mixture was capped, and the mixture was stirred for 12 h at 110° C. temperature. After completion of the reaction (monitored by TLC, 10% EtOAc in hexane), the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a brown solid which was further purified column chromatography, silica gel (60-120 mesh) using 2-6% EtOAc in petroleum ether as an eluent to obtain the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ: 8.30 (d, J=8.1 Hz, 1H), 7.54 (d, J=6.9 Hz, 2H), 7.42-7.26 (m, 3H), 7.09 (t, J=8.4 Hz, 1H), 5.58 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:5]=1[C:6]([OH:8])=[S:7])([O-:3])=[O:2].[N+](=[CH2:16])=[N-]>CO>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:5]=1[C:6]([O:8][CH3:16])=[S:7])([O-:3])=[O:2]
Reactant: Cc1ccc([N+](=O)[O-])c(C(O)=S)c1
Reactant: C=[N+]=[N-]
Solvent: CO
Product: COC(=S)c1cc(C)ccc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
To an ice cold solution of 52.1 g. of 2-nitro-5-methylthiobenzoic acid in 250 ml. of methanol was added an ethereal solution of diazomethane until thin layer chromatography indicated the reaction was complete. The resulting solution was evaporated to dryness and used as such. In one case the crude product was crystallized from methanol to give yellow needles of methyl 2-nitro-5-methylthiobenzoate, mp 53°-54°.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([C:43]#[N:44])=[N:41][CH:42]=2)O1>>[O:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9]([CH2:11][CH2:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:37]3[CH:38]=[CH:39][C:40]([C:43]#[N:44])=[N:41][CH:42]=3)=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: Brc1cnc(N2CCOCC2)c2nc(CCc3ccc4ccccc4n3)cn12
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Product: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(CCc4ccc5ccccc5n4)cn23)cn1
Yield: 82 %

Procedure:
Compound 3a (950 mg, 2.17 mmol) was subjected to Suzuki coupling conditions with compound 1f (prepared in Example 1, Step F) as described in Example 1, Step G to obtain compound 3b as a white solid (820 mg, 82% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C27H23N7O: 462.2 (M+H). found: 462.2.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22]Cl)([C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CCOCC>[O:27]1[CH2:28][CH2:29][N:24]([CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH2:25][CH2:26]1
Reactant: O=C(c1ccccc1)C(OCCCl)(OCCCl)c1ccccc1
Reactant: C1COCCN1
Solvent: CCOCC
Product: O=C(c1ccccc1)C(OCCN1CCOCC1)(OCCN1CCOCC1)c1ccccc1

Procedure:
With stirring, 35 g (0.1 mole) of benzil-di-(2-chloroethyl)ketal and 52 g (0.6 mole) of morpholine are kept for 6 hours at 110° C. After cooling, the product is taken up in ether. The ether layer is washed with water, dried over Na2SO4 and concentrated. The residual oil is dried in a high vacuum at 50°-60° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[N:9][N:10]=2)[CH:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>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.O>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[N:6]2[CH:7]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COc1ccccc1-c1nnc2ccc(Br)cn12
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccc3nnc(-c4ccccc4OC)n3c2)cc1
Temperature: 100 °C
Reaction time: 10 h
Yield: 84.5 %

Procedure:
A flask was charged with 6-bromo-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine (151 mg, 0.5 mmol), 4-methoxyphenylboronic acid (80 mg, 0.5 mmol), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4, 5.8 mg, 0.005 mmol), cesium carbonate (Cs2CO3, 326 mg, 1.0 mmol), 1,4-dioxane (10 mL) and water (2 mL). The mixture was stirred at 100° C. under Argon for 10 h. The mixture was evaporated to afford the crude product. The crude product was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=1:1) to give the title compound (140 mg, 84.2% yield) as yellow solids. 1H NMR (DMSO-d6): 8.06 (m, 1H), 7.90 (dd, J=9.5 and 0.9 Hz, 1H), 7.75 (dd, J=9.6 and 1.8 Hz, 1H), 7.67-7.62 (m, 4H), 7.32 (d, J=8.1 Hz, 1H), 7.19 (t, J=7.5 Hz, 1H), 7.03 (d, J=8.7 Hz, 2H), 3.85 (s, 3H), 3.80 (s, 3H). MS: m/z 332.2 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH:16]=O.CO[Na].Cl>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH:9]=[CH:16][C:12]2[O:11][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: O=Cc1ccco1
Agent: CO[Na]
Agent: Cl
Solvent: CO
Product: O=C(C=Cc1ccco1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a solution of 4-bromophenylethanone (112.6 g, 570 mmol) and furan-2-carbaldehyde (58.5 g, 610 mmol) in methanol (1.5 L) was added CH3ONa (31 g, 570 mmol) over 10 min and the reaction solution was stirred at room temperature overnight. The reaction mixture was neutralized with conc. HCl to pH=7, and the solvent was removed under reduced pressure. To the resultant residue was added EA and water. The aqueous layer was extracted with EA for 3 times. The combined layers were washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (PE (petroleum ether): EA (ethyl acetate)=10:1) to afford 1-(4-bromophenyl)-3-(furan-2-yl)prop-2-en-1-one (5A) as a yellow solid (90.2 g, 65%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]([N:16]=[N+:17]=[N-:18])[C:13]([OH:15])=[O:14])=[CH:4][C:3]=1[CH3:21].Cl[CH2:23]Cl.CO>C[Si](C=[N+]=[N-])(C)C>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]([N:16]=[N+:17]=[N-:18])[C:13]([O:15][CH3:23])=[O:14])=[CH:4][C:3]=1[CH3:21]
Reactant: Cc1cc(COCCCC[C@@H](N=[N+]=[N-])C(=O)O)ccc1F
Reactant: ClCCl
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)[C@@H](CCCCOCc1ccc(F)c(C)c1)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of crude (R)-6-(4-fluoro-3-methylbenzyloxy)-2-azidohexanoic acid (0.163 g, 0.552 mmol) in 10 mL of dichloromethane/methanol (4:1), trimethylsilyldiazomethane was added dropwise until the solution became yellow. After stirred at room temperature under N2 for 30 min, the reaction mixture was concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-100% dichloromethane/hexanes to give the title compound as colorless oil (0.141 g, 83% yield)
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[N:13]([C@@H:14]3[O:20][C@H:19]([CH2:21][OH:22])[C@@H:17]([OH:18])[C@H:15]3[OH:16])[CH:12]=[N:11][C:10]=2[C:23]#[N:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:25]O>>[C:1]1([C:7]#[C:8][C:9]2[N:13]([C@@H:14]3[O:20][C@H:19]([CH2:21][OH:22])[C@@H:17]([OH:18])[C@H:15]3[OH:16])[CH:12]=[N:11][C:10]=2[C:23]([NH2:24])=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OO
Reactant: N#Cc1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1C#Cc1ccccc1
Product: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
To a solution of 10 mg (0.03 mmol) of 5-(phenylethyn-1-yl)-1-β-D-ribofuranosylimidazole-4-carbonitrile dissolved in 4 ml of aqueous ammoniamethanol (1:1 V/V) was added 0.2 ml of hydrogen peroxide, and the reaction was carried out with stirring at room temperature for 30 minutes. After the reaction, the solvent was evaporated and the residue was adsorbed onto a silica gel column (1.8×35 cm) and eluted with a 5-20% ethanol-chloroform solvent mixture to obtain 8.4. mg of 5-(phenylethyn-1-yl)-1-β-D-ribofuranosylimidazole-4-carboxamide (yield: 79.6%).