Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][C:20]#[N:21]>CN(C=O)C.[Cl-].[Na+].O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:18][CH2:19][C:20]#[N:21])[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: Ic1ccc(Nc2ncccn2)cc1
Reactant: N#CCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCN(c1ccc(I)cc1)c1ncccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, a solution of N-(4-iodophenyl)pyrimidin-2-amine (100 mg) in anhydrous DMF (1.0 ml) was added to a suspension of sodium hydride (16 mg) in anhydrous DMF (1.0 ml), and the resulting mixture was stirred at room temperature for 30 minutes. To the reaction solution, a solution of 3-bromopropionitrile (0.04 ml) in anhydrous DMF (0.5 ml) was added, and the resulting mixture was stirred at room temperature overnight. Saturated brine was added to the reaction solution and the resulting mixture was extracted with chloroform. Organic layer was dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/chloroform=1/10) to obtain 3-(N-(4-iodophenyl)-N-(pyrimidin-2-yl)amino)propanenitrile (94 mg). NMR (H1, CDCl3): δ 2.82(2H, t, J=6.8 Hz), 4.24 (2H, t, J=6.8 Hz), 6.68 (1H, t, J=4.9 Hz), 7.06-7.10 (2H, m), 7.74-7.78 (2H, m), 8.35 (2H, d, J=4.9 Hz)
Reaction SMILES: C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.[CH3:19][O:20][C:21]1[N:26]=[C:25]([CH2:27][CH2:28]O)[CH:24]=[CH:23][CH:22]=1.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.C(P(CCCC)CCCC)CCC>C(OCC)(=O)C.C1COCC1>[CH3:19][O:20][C:21]1[N:26]=[C:25]([CH2:27][CH2:28][N:34]2[C:30](=[O:40])[C:31]3[C:32](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:33]2=[O:35])[CH:24]=[CH:23][CH:22]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1cccc(CCO)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(CCN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
ADDP (49.0 g, 194.09 mmol) was added to a mixture of 2-(6-methoxypyridin-2-yl)ethanol (22.87 g, 149.30 mmol), phthalimide (24.16 g, 164.23 mmol), tributylphosphine (48.5 mL, 194.09 mmol) and THF (340 mL) at 0° C. under argon atmosphere to give a solution. The solution was stirred at room temperature for 16 hr, to the reaction mixture was added ethyl acetate (about 500 mL), and the mixture was stirred at 0° C. for 20 min. The insoluble substance was removed by filtration with ethyl acetate, and washed with ethyl acetate. The filtrate was poured into water (1000 mL), and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5→20% ethyl acetate/hexane), and the precipitate was collected by filtration with hexane to give 2-(2-(6-methoxypyridin-2-yl)ethyl)isoindoline-1,3-dione (29.03 g, 103 mmol, 69%) as an off-white powder.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:17](=[O:27])[CH:18]([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[CH3:19]>CS(C)=O>[O:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH:21]1[O:20][CH:18]([C:17]1([C:11]2[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=2[F:9])[CH2:4][O:27]1)[CH3:19]
Reactant: CC(OC1CCCCO1)C(=O)c1ccc(F)cc1F
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(OC1CCCCO1)C1(c2ccc(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.7 %

Procedure:
To dimethyl sulfoxide (650 ml) was added, at room temperature, 60% sodium hydride in oil (15.2 g) by portions during 10 minutes. The mixture was stirred for 10 minutes at room temperature, to which was added by portions trimethylsulfoxonium iodide (83.7 g) during one hour. To the resultant mixture was added dropwise during one hour a solution of 2',4'-difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (86.5 g) in dimethyl sulfoxide (150 ml). The mixture was stirred for 3 hours at room temperature, then the reaction mixture was poured into ice-water (1.5 l), which was subjected to extraction 5 times with ethyl acetate (300 ml). The ethyl acetate layer was washed with water (300 ml) for four times, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to leave 2-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyl]-2-(2,4-difluorophenyl)oxirane (83.4 g) as a pale yellow oily product.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6])=O.[C:11]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:13][CH2:14][CH3:15])=[O:12]>C1(C)C=CC=CC=1>[C:5]([C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1/[CH:1]=[CH:16]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:6]
Reactant: N#Cc1ccccc1C=O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1ccccc1C#N
Temperature: 110 °C

Procedure:
2-Formylbenzonitrile (5 g, 38.1 mmol) was added to a round bottom flask, equipped with a stir bar, and dissolved in toluene (50 mL). (Carbethoxymethylene)triphenylphosphorane (14.6 g, 41.9 mmol) was then added to the mixture. The reaction was heated at 110° C. for 20 hours. The solution was concentrated under vacuum, and the residue was redissolved in dichloromethane. The solution was passed though a plug of silica (dichloromethane eluent) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.37 (t, 3H, J=7.12 Hz), 4.30 (q, 2H, J=7.12 Hz), 6.61 (d, 1H, J=15.94 Hz), 7.47 (dt, 1H, J=7.71 Hz, J=1.19 Hz), 7.62 (dt, 1H, J=7.80 Hz, J=1.36 Hz), 7.7-7.75 (m, 2H), 7.97 (d, 1H, J=15.94 Hz); MS (DCI+) m/z 218.9 [M+NH3]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[I:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][C:50]=1[CH3:51])[NH2:47].CCN(C(C)C)C(C)C>CN(C=O)C>[I:43][C:44]1[CH:45]=[C:46]([NH:47][C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[O:8])[CH:48]=[CH:49][C:50]=1[CH3:51]
Reactant: Cc1ccc(N)cc1I
Reactant: O=C(O)c1ccsc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccsc2)cc1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Thiophene-3-carboxylic acid (2.75 g, 21.45 mmol) and HATU (8.15 g, 21.45 mmol) in DMF (25 ml) were stirred at room temperature for l5 mins. HOBT (2.9 g, 21.45 mmol), 3-iodo-4-methylaniline (5.0 g, 21.45 mmol) and DIPEA (11.2 ml, 64.35 mmol) were added and the reaction stirred at room temperature for 16 hrs. The solvent was evaporated under vacuum and the residue partitioned between ethyl acetate (100 ml) and aqueous sodium carbonate (10%, 100 ml). The aqueous layer was extracted with ethyl acetate (50 ml) and the combined organic phases washed with hydrochloric acid (2N, 75 ml), water (75 ml) and brine (75 ml). The organic phase was dried (magnesium sulphate) and absorbed onto silica. The silica was applied to a flash silica column and eluted with cyclohexane/ethyl acetate (4:1). The solvent was evaporated from the product fractions under vacuum to give N-(3-iodo-4-methylphenyl)thiophene-3-amide. LCMS: retention time 3.69 min, MH+ 344. NMR: δH [2H6]-DMSO 10.06,(1H, b), 8.34,(1H, m), 8.29,(1H, d), 7.70,(1H, dd), 7.66,(1H, dd), 7.62,(1H, dd), 7.30,(1H, d), 2.34,(3H, s).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH:15]=[C:14]([OH:16])[C:13](=[O:17])[CH:12]=[C:11]3[CH3:18])[C:4]=2[N:3]=[CH:2]1.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:21]=1[CH2:22]Br>CN(C=O)C>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:21]=1[CH2:22][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH:15]=[C:14]([OH:16])[C:13](=[O:17])[CH:12]=[C:11]3[CH3:18])[C:4]=2[N:3]=[CH:2]1
Reactant: Cc1cc(=O)c(O)cn1-c1cccc2[nH]cnc12
Reactant: Fc1cccc(Cl)c1CBr
Solvent: CN(C)C=O
Product: Cc1cc(=O)c(O)cn1-c1cccc2c1ncn2Cc1c(F)cccc1Cl
Temperature: 100 °C
Reaction time: 3 h

Procedure:
1-(1H-Benzimidazol-4-yl)-5-hydroxy-2-methylpyridin-4(1H)-one (30 mg, 0.124 mmol) and 2-chloro-6-fluorobenzyl bromide (20 μl, 0.146 mmol) were combined in DMF (0.5 ml) then heated to 100° C. After 3 h LC/MS indicated the reaction was incomplete. The mixture was cooled to RT and 10 μL of 2-chloro-6-fluorobenzyl bromide was added. The mixture was heated to 100° C. After 1 hr the mixture was cooled to RT and purified directly by preparative reversed-phase HPLC (20×150 mm Waters Sunfire (0.1% TFA), 5-40% ACN/water over 20 min at 20 mL/min). Fractions containing the product were pooled then applied to a Phenomenex Strata-X—C ion exchange column. The column was washed with H2O and MeOH (discard) then with 10% concentrated NH4OH in MeOH (collect). The collected fraction was concentrated to give 1-[1-(2-Chloro-6-fluorobenzyl)-1H-benzimidazol-4-yl]-5-hydroxy-2-methylpyridin-4(1H)-one as an off-white solid. 1H NMR (500 MHz, d6-DMSO) δ 8.43 (s, 1 H), 7.66 (d, J=8.3 Hz, 1 H), 7.52-7.29 (m, 6 H), 6.24 (s, 1 H), 5.70 (s, 2 H), 1.90 (s, 3 H). HRMS (ESI) Calc (M+H)=384.0910. Found 384.0913.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([OH:8])[N:5]2[N:9]=[C:10]([C:21]([F:24])([F:23])[F:22])[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[Cl:20])=[C:4]2[N:3]=1.[CH3:25][CH:26]1[O:31][CH2:30][CH2:29][NH:28][CH2:27]1>C(O)C.C(OCC)(=O)C>[Cl:20][C:14]1[C:15]([Cl:19])=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][C:11]1[C:10]([C:21]([F:24])([F:23])[F:22])=[N:9][N:5]2[C:6]([OH:8])=[CH:7][C:2]([N:28]3[CH2:29][CH2:30][O:31][CH:26]([CH3:25])[CH2:27]3)=[N:3][C:4]=12
Reactant: CC1CNCCO1
Reactant: Oc1cc(Cl)nc2c(Cc3cccc(Cl)c3Cl)c(C(F)(F)F)nn12
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1CN(c2cc(O)n3nc(C(F)(F)F)c(Cc4cccc(Cl)c4Cl)c3n2)CCO1

Procedure:
To a solution of 5-chloro-3-[(2,3-dichlorophenyl)methyl]-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-7-ol (79 mg, 0.2 mmol), prepared as described in Example 7 step b, in ethanol (2 mL) was added 2-methylmorpholine (101 mg, 1.0 mmol) in a microwave reaction vessel. It was sealed and irradiated (microwave) at 150° C. for seven hours. The reaction mixture was diluted with ethyl acetate (20 mL), washed with 5% HCl solution (5 mL). Organic layer was dried, filtered, and concentrated. The crude product was purified by reverse-phase HPLC to provide the titled compound. (17 mg, 18%); LC/MS: MS (ES+) m/e 461 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (d, J=6.32 Hz, 3H) 2.68 (m, 1H) 2.96 (m, 1H) 3.56 (m, 2H) 3.71 (m, 2H) 3.88 (m, 1H) 4.20 (s, 2H) 5.23 (s, 1H) 6.85 (s, 1H) 7.25 (t, J=7.96 Hz, 1H) 7.53 (d, J=7.58 Hz, 1H) 11.24 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:4][CH:3]=1.[N:24]#[C:25][NH2:26]>C(O)C>[NH2:26][C:25]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])=[CH:22][CH:23]=1)=[NH:24]
Reactant: N#CN
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(N)cc1)C(=O)OC(C)(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N(Cc1ccc(NC(=N)N)cc1)C(=O)OC(C)(C)C

Procedure:
10 mmol of di-(tert-butyl) 4-aminobenzylimidodicarbonate and 100 mmol of cyanamide are heated at reflux for 2 days in 80 ml of anhydrous ethanol. Removal of the ethanol by evaporation, and purification by chromatography on silica, yield the expected product.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@H:4](/[CH:5]=[C:6]2/[C:7](=[O:11])[O:8][CH2:9][CH2:10]/2)[C@H:3]1[C:12]([OH:14])=[O:13].[CH:16](NC(=NC(C)C)OC)(C)C>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:15])[C@H:4](/[CH:5]=[C:6]2/[C:7](=[O:11])[O:8][CH2:9][CH2:10]/2)[C@H:3]1[C:12]([O:14][CH3:16])=[O:13]
Reactant: COC(=NC(C)C)NC(C)C
Reactant: CC1(C)[C@H](/C=C2\CCOC2=O)[C@H]1C(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1[C@@H](/C=C2\CCOC2=O)C1(C)C
Yield: 55.8 %

Procedure:
A mixture of 4.2 g of (1R,trans) 2,2-dimethyl-3-[(E) (dihydro-2-oxo-3-(2H)-furanylidene)-methyl]-cyclopropane-1-carboxylic acid, 3.5 g of methyl N,N'-diisopropyl-carbamimidate and about 20 ml of ethyl acetate was refluxed for 2 hours and was cooled and evaporated to dryness. The residue was chromatographed over silica gel and was eluted with a 6-4 cyclohexane-ethyl acetate mixture to obtain 2.5 g of methyl (1R,trans) 2,2-dimethyl-3-[(E) (dihydro-2-oxo-3-(2H)-furanylidene)-methyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+65°±2.5° (c=0.6% in ethanol).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([OH:14])[CH:8]=[CH:7]2.[CH2:15](I)[CH3:16].O>CN(C=O)C>[Br:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH2:15][CH3:16])[CH:10]=2)[CH:5]=1
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc2cc(Br)ccc2c1
Yield: 60 %

Procedure:
To a suspension of sodium hydride (800 mg, 60% oil dispersion) in DMF (20 ml) was added a solution of 6-Bromo-2-naphthol dropwise with stirring at 0°. After gas evolution had ceased, neat ethyl iodide (1.6 ml) was added dropwise to the stirred solution. The reaction was stirred overnight at rt. The reaction mixture was poured into water and extracted several times with tert-butyl methyl ether. The combined organic extracts were washed with water and brine, then dried over MgSO4, filtered and evaporated under reduced pressure to give tan solid. This was recrystallized from MeOH and dried under high vacuum to a constant wt. giving a white solid (3.11 g, 60%). 1H NMR(400 MHz, CDCl3) δ 7.92 (d, J=1.7 Hz, 1H), 7.65(d, J=8.9 Hz, 1H), 7.59 (d, J=8.7 Hz, 2H), 7.16 (dd, J=8.9 Hz, 2.48, 1H), 7.09 (d, J=2.4 Hz, 1H), 4.15 (q, 2H), 1.49 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH:11][S:12]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])(=[O:14])=[O:13])[CH:5]=1.Br[CH2:26][CH2:27]Br>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:27][CH2:26][N:11]([S:12]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[O:22][CH3:23])(=[O:13])=[O:14])[C:6]=2[CH:5]=1)=[O:24]
Reactant: COC(=O)c1ccc(O)c(NS(=O)(=O)c2cc(Cl)ccc2OC)c1
Reactant: BrCCBr
Product: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CCO2

Procedure:
The title compound, MS (ISP)=522.2 (M−H)−, was produced in analogy with example 36, steps 1-4. Step 1 was performed using 3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-benzoic acid methyl ester (example 30, step 1) and 1,2-dibromoethane, yielding 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester, which was hydrolyzed in step 2 to afford 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid. This was reacted with ethyl 2-amino-4-thiazoleacetate in step 3 to produce (2-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-acetic acid ethyl ester, which was hydrolyzed in step 4.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[CH3:17][C:18]1[C:22](/[CH:23]=[CH:24]/[C:25](O)=[O:26])=[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:20][N:19]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:12]([O:11][P:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:25](=[O:26])/[CH:24]=[CH:23]/[C:22]2[C:18]([CH3:17])=[N:19][O:20][C:21]=2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:16][CH:15]=1)([O:8][CH2:9][CH3:10])=[O:14])[CH3:13]
Reactant: Cc1noc(-c2ccccc2)c1/C=C/C(=O)O
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1ccc(NC(=O)/C=C/c2c(C)noc2-c2ccccc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
A mixture of diethyl 4-aminobenzylphosphonate (0.43 g), (E)-3-(3-methyl-5-phenyl-4-isoxazolyl)propenoic acid (0.50 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.38 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.45 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and (E)-N-(4-diethylphosphonomethylphenyl)-3-(3-methyl-5-phenyl-4-isoxazolyl)propenamide (0.71 g, yield 83%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 155–156° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[N:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:39]2[CH2:40][CH2:41][N:36]([C:31]4[N:30]=[CH:35][CH:34]=[CH:33][N:32]=4)[CH2:37][CH2:38]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCN(c4ncccn4)CC3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 1-(2-pyrimidyl)piperazine (33 mg, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-[4-(pyrimidin-2-yl)piperazin-1-ylmethyl]indol-2-yl)isoindolinone.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([CH2:11][CH2:12][OH:13])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[N-:20]=[N+:21]=[N-:22].[Na+]>CS(C)=O.O>[C:14]1([C:4]2[N:3]3[N:20]=[N:21][N:22]=[C:2]3[N:7]3[N:8]=[CH:9][N:10]=[C:6]3[C:5]=2[CH2:11][CH2:12][OH:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCc1c(-c2ccccc2)nc(Cl)n2ncnc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: OCCc1c(-c2ccccc2)n2nnnc2n2ncnc12
Reaction time: 5 h

Procedure:
To a solution containing 27.4 g of 5-chloro-7-phenyl[1,2,4]triazolo[1,5-c]pyrimidine-8-ethanol (0.1 mole) dissolved in 250 ml of dimethylsulfoxide is added 13 g of sodium azide (0.2 mole). The resulting reaction mixture is stirred for 5 hours at a temperature of 65°-70° C. and then stirred overnight at room temperature. The reaction mixture is poured in water with stirring. A precipitate forms and the mixture is filtered and the precipitate is washed with water and dried yielding a crude product. The crude product is recrystallized from diethyl ether to yield 5-phenyltetrazolo[1,5-a][1,2,4]triazolo[1,5-c]pyrimidine-6-ethanol having the structural formula ##STR22## and the azido tautomer thereof as a white solid having a melting point of 110° C. and the following elemental analysis:
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][C:13]3[N:22]=[C:21]([CH3:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[C:6]3=[N:24][CH2:25][CH2:26][N:5]3[C:4]=2[N:3]=1.CCN(C(C)C)C(C)C.Br[CH2:37][C:38]#[C:39][CH3:40]>CN(C=O)C>[Br:1][C:2]1[N:10]([CH2:37][C:38]#[C:39][CH3:40])[C:9]2[C:8](=[O:11])[N:7]([CH2:12][C:13]3[N:22]=[C:21]([CH3:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[C:6]3=[N:24][CH2:25][CH2:26][N:5]3[C:4]=2[N:3]=1
Reactant: Cc1nc(CN2C(=O)c3[nH]c(Br)nc3N3CCN=C23)nc2ccccc12
Reactant: CC#CCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC#CCn1c(Br)nc2c1C(=O)N(Cc1nc(C)c3ccccc3n1)C1=NCCN12

Procedure:
To 2-bromo-5-((4-methylquinazolin-2-yl)methyl)-7,8-dihydro-3H-imidazo[2,1-b]purin-4(5H)-one 15 (470 mg, 1.14 mmol) in DMF (5 ml) was added Hunig's base (0.3 ml, 1.71 mmol) and 1-bromo-2-butyne (0.145 ml, 1.6 mmol) at room temperature. The mixture was stirred over night. Another 0.103 ml (1.14 mmol) of 1-bromo-2-butyne was added and stirred over night. The reaction was extracted by DCM twice, washed with NaHCO3 and brine, dried (MgSO4) and concentrated. The crude product was purified by flash chromatography (MeOH/DCM) to afford 2-bromo-3-(but-2-ynyl)-5-((4-methylquinazolin-2-yl)methyl)-7,8-dihydro-3H-imidazo[2,1-b]purin-4(5H)-one 16. 1H NMR S 8.02 (d, J=7.81, 1H), 7.90 (d, J=7.81, 1H), 7.78 (t, J=8.59, 1H), 7.54 (t, J=8.59, 1H), 5.50 (s, 2H), 5.30 (s, 2H), 5.08 (q, J=2.34, 21-1), 4.12 (t, J=9.38, 2H), 3.92 (t, 0.1=9.38, 2H), 2.89 (s, 3H), 1.79 (t, J=2.34, 3H).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([O:26][C:27]2[CH:37]=[C:36]([CH3:38])[C:30]3[N:31]([CH3:35])[C:32](=[O:34])[O:33][C:29]=3[CH:28]=2)[CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:35][N:31]1[C:30]2[C:36]([CH3:38])=[CH:37][C:27]([O:26][C:22]3[N:23]=[CH:24][N:25]=[C:20]([N:3]4[CH2:4][CH2:5][CH:6]([N:9]5[C:17]6[C:12](=[N:13][CH:14]=[CH:15][CH:16]=6)[NH:11][C:10]5=[O:18])[CH2:7][CH2:8]4)[CH:21]=3)=[CH:28][C:29]=2[O:33][C:32]1=[O:34]
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
75 mg (0.34 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloride, 100 mg (0.34 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-3,4-dimethyl-3H-benzoxazol-2-one and 0.15 mL (0.86 mmol) DIPEA were combined in 1.8 mL DMF and stirred overnight at RT. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined, the acetonitrile was evaporated down and the precipitate was suction filtered and dried i. vac.
Reaction SMILES: CO.[F:3][C:4]1([F:24])[CH2:8][CH2:7][C@@H:6]([C@@:9]([OH:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([O:12][CH2:13][CH2:14][CH2:15][NH2:16])=[O:11])[CH2:5]1.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[BH4-].[Na+]>C(OCC)(=O)C>[F:3][C:4]1([F:24])[CH2:8][CH2:7][C@@H:6]([C@@:9]([OH:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([O:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:11])[CH2:5]1
Reactant: O=Cc1ccccc1
Reactant: NCCCOC(=O)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(OCCCNCc1ccccc1)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Reaction time: 0.5 h

Procedure:
To a methanol solution of 87 mg of 3-aminopropyl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, 35 mg of benzaldehyde was added at room temperature, stirred for 30 minutes at the same temperature, sodium borohydride was added, and further stirred for 30 minutes. The reaction liquid was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resulting residue was purified on silica gel column chromatography (eluent: chloroform/methanol=50/1), to provide the title compound.