Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:17]CCCOS(C)(=O)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16]
Reactant: C=CCCCCCCCCCCCCCCOCCCOS(C)(=O)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCCCCCCCCCCCO
Temperature: 97.5 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
Substitution of (32) with Bz-c-CDV. 1.7 g (4.6 mmol) of Bz-c-CDV was dissolved in 10 mL of NMP and 1.2 mL (7 mmol) of DIPEA was added to it followed by 9 g (23.9 mmol) of 32. The reaction was heated at 95-100° C. for 24 h at which time the TLC showed the product together with some Bz-c-CDV. At this stage the reaction was allowed to proceed for an additional 4 h, but as the TLC did not show much progress, the reaction mixture was cooled to room temperature and the solvent was evaporated under high vacuum. The residue was purified by combiflash using chloroform/MeOH as eluent to furnish 1.33 g of target product 26 as yellow oil in 45% yield.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].CC(C)([O-])C.[K+].C(O)(=O)C>C1COCC1>[CH:6]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]2[C:4](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3][CH2:2][O:1]1
Reactant: CCOC(=O)C=Cc1ccccc1CCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)CC1OCCc2ccccc21
Reaction time: 0.08 h

Procedure:
Ethyl 2-(2-hydroxyethyl)cinnamate (CXXX, EXAMPLE 112, theoretically 2.40 moles) is dissolved in THF (2.4 liters) and cooled to 0°. Potassium t-butoxide (5 mol %, 120 ml of a 1 molar THF solution) is added via syringe. After 5 min HPLC shows the cyclization is completed. Acetic acid (6 mol %, 8.2 ml, 144 mmol) is added. The slurry is filtered through approximately 300 g of 200 mesh silica gel. The solvent is Diatomaceous earth (100 g) is added followed by hexane (4.5 liters). This slurry is filtered through 200 mesh silica gel (400 g), washing with THF/hexane (1/9) until TLC shows no remaining product. Solvent removal gives the title compound. This material is filtered through silica gel more carefully, giving an analytical sample of the title compound, NMR (300 MHz, CDCl3) 7.1-7.2, 7.05, 5.26, 4.23, 4.12, 3.83, 3.0-2.7, 1.28; high resolution MS calculated for 220.1099, found 220.1105.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[CH2:16])[C:6]=2[CH:17]=1.C12BC(CCC1)CCC2.[O:27]1CCCC1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([CH2:16][OH:27])[C:6]=2[CH:17]=1
Reactant: C1CCOC1
Reactant: C=C1c2ccccc2C=Cc2ccc(Br)cc21
Agent: B1C2CCCC1CCC2
Product: OCC1c2ccccc2C=Cc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-bromo-5-methylene-dibenzo[a,d]cycloheptene (3.8 g) in dry tetrahydrofuran (20 ml). under an inert atmosphere. was added 9-borabicyclo [3.3,1 ]nonane (30 ml of a 0.5 molar solution in tetrahydrofuran) at ambient temperature and the reaction mixture was refluxed for 3 h. After cooling in an ice bath the reaction was quenched by the slow addition of 2N sodium hydroxide solution (100 ml) and 30% hydrogen peroxide (20 ml). After stirring vigorously at 0° C. for 45 minutes the reaction mixture was allowed to warm to room temperature over a 2 hour period then extracted with diethyl ether (3×200 ml). The combined organic layers were washed with brine (1×100 ml), dried (Na2SO4) filtered and concentrated in vacuo to leave a residue which was purified by chromatography on flash silica with 30% ethyl acetate in hexane as eluent to give the title compound (2.3 g) as a colourless oil. δ (CDCl3, 360 MHz) 3.83 (2H, d, J=7.9 Hz, CH2OH), 4.13 (1H, t, J=7.9 Hz, CH--CH2OH), 6.78 (1H, d, J=12 Hz, CHA =CHB), 6.87 (1H, d, J=12 Hz, CHA =CHB), 7.17-7.50 (7H, m, ArH). m/e 302 and 300 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=1.[Li+].CCC[CH2-].CN([CH:22]=[O:23])C>C1COCC1>[CH:22]([C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=1)=[O:23]
Reactant: CN(C)C=O
Reactant: CC(=O)N[C@@H](C)c1ccc(Br)cc1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](C)c1ccc(C=O)cc1
Reaction time: 1 h

Procedure:
To 20.0 g (74.3 mmol) (S)—N-(1-(4-bromophenyl)ethyl)acetamid (WO 2012/01107) in 300 mL THF are added dropwise 75.0 mL (187 mmol)N-butyllithium (2.5 M in THF) at −78° C. and stirred for 1 h. 10.0 mL (124 mmol) DMF are added dropwise to the mixture at −78° C. and stirred for 2 h. After that aq. NH4CI solution is added and extracted with EtOAc. The organic layer is dried over Na2SO4, filtered and concentrated by evaporation. The residue is purified by column chromatography (silica gel, MeOH:DCM).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=S)[NH:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.O>O1CCCC1>[O:17]1[CH2:18][CH2:19][N:14]([C:10]2[O:11][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:8]=3[N:9]=2)[CH2:15][CH2:16]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc2oc(=S)[nH]c2c1
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2oc(N3CCOCC3)nc2c1
Yield: 92.3 %

Procedure:
5-nitrobenzo[d]oxazole-2(3H)-thione (98.1 mg, 0.5 mmol) and morpholine (66 μL, 0.75 mmol) in tetrahydrofuran (3 mL) were heated at 150° C. for 15 min in the microwave. After cooling, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4 and absorbed on silica. Purification by column chromatography, eluting with ethyl acetate/hexanes 25:75 v/v affords 115 mg (92%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][C:4]1[N:8]=[C:7]([C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[N+:16]([O-])=O)[O:6][N:5]=1.O.O.O.O.O.O.O.O.O.[S-][S-].[Na+].[Na+]>O1CCOCC1.O>[CH3:19][N:2]([CH2:3][C:4]1[N:8]=[C:7]([C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[NH2:16])[O:6][N:5]=1)[CH3:1]
Reactant: Cc1ccc([N+](=O)[O-])c(-c2nc(CN(C)C)no2)c1
Agent: [Na+]
Agent: [S-][S-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(N)c(-c2nc(CN(C)C)no2)c1
Temperature: 80 °C

Procedure:
To a solution of N,N-dimethyl-1-(5-(5-methyl-2-nitrophenyl)-1,2,4-oxadiazol-3-yl)methanamine (38 mg, 0.15 mmol) in dioxane (1 mL) at 80° C. was added a hot solution (80° C.) of sodium disulfide nonahydrate (70 mg, 0.29 mmol) in water (1 mL). The reaction was heated at 80° C. for 30 min resulting in clean conversion to the desired product. The reaction was diluted with dichloromethane then washed with 50% saturated NaHCO3 (2×20 mL) and brine. The solution was dried over Na2SO4, filtered and dried down to provide 2-(3-((dimethylamino)methyl)-1,2,4-oxadiazol-5-yl)-4-methylaniline as a light orange oil (29 mg, 86% yield). LC/MS m/z 233.2 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[C:9]([Cl:10])=[CH:8][NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:11]=[O:12].C(N(CC)CC)C>CC(C)=O>[C:1]([C:5]1[C:9]([Cl:10])=[CH:8][N:7]([CH2:11][OH:12])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1n[nH]cc1Cl
Reactant: C=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nn(CO)cc1Cl
Temperature: 130 °C
Reaction time: 7 h
Yield: 111.2 %

Procedure:
The mixture of 0.62 g of 3-t-butyl-4-chloro-1H-pyrazole, 0.24 g of paraformaldehyde and 0.10 g of triethylamine was stirred at 130° C. for 7 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. Hexane was added to the residue obtained by concentration of the filtrate under reduced pressure, as a result, a crystal was formed. The crystal was collected to obtain 0.82 g of 3-t-butyl-4-chloro-1H-pyrazole-1-ylmethanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19](O)[CH2:20][OH:21].CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH3:16])[O:21][CH2:20][CH2:19][O:17]2)=[CH:11][C:10]=1[F:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(c2ccc(OCc3ccccc3)c(F)c2)OCCO1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 1-(4-(benzyloxy)-3-fluorophenyl)ethanone 22 (23.8 g, 97.5 mmol), ethylene glycol (16.4 mL, 293 mmol), p-TsOH (930 mg, 4.88 mmol) and toluene (400 mL) was stirred under reflux conditions for 4 days, azeotropically removing water with a Dean-Stark trap. The mixture was cooled to room temperature and quenched by addition of saturated sodium bicarbonate solution (200 mL). The aqueous phase was back-extracted with toluene (3×200 mL). The combined organic phases were washed with brine (200 mL), dried over sodium sulfate, filtered and the solvent removed under reduced pressure to give 28.7 g (103%) of crude 23 as a yellow solid. Crude 23 was used without further purification. 1H NMR (CDCl3) δ: 7.39 (m, 5H), 7.22 (dd, 1H), 7.16 (dd, 1H), 6.95 (t, 1H), 5.12 (s, 2H), 4.12 (dd, 2H), 3.77 (dd, 2H), 1.62 (s, 3H). LCMS m/z=289.1 (M+H).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[N:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[S:10][CH2:11][CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22]>C(N(CC)CC)C.C(Cl)Cl>[CH2:14]([N:13]([C:26](=[O:27])[NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])[C:9](=[N:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[S:10][CH2:11][CH3:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CC(C)(C)N=C=O
Reactant: CCCCCCCN=C(NCCCCCCC)SCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCN=C(SCC)N(CCCCCCC)C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The equipment was the same as used in Example 26. 3.0 g (0.01 mole) 1,3-di-n-heptyl-2-S-ethyl isothiourea was mixed with 30 ml of methylene chloride. Two drops of triethylamine and 1 drop of dibutyltindilaurate were added to the mixture followed by 1.0 g (0.01 mole) tert-butyl isocyanate. The temperature rose from 24° to 39° C. The reaction mixture was stirred overnight at ambient temperature and then heated for one-half hour at 35° to 40° C. to complete the reaction. The reaction mixture was vacuum evaporated to produce 3.83 g (96 weight percent of theory yield) of a clear liquid having a nD30 of 1.4750. The product was identified as the title product by IR and NMR spectra analyses. Compound No. 40 in Table I.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7])#[N:2].[F:11][C:12]([F:27])([F:26])[C:13]1[CH:14]=[C:15]([NH:20][CH2:21][CH:22](O)[CH2:23][CH3:24])[CH:16]=[CH:17][C:18]=1[Cl:19].O>C1(C)C=CC=CC=1.CS(O)(=O)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]2[N:20]([C:15]3[CH:16]=[CH:17][C:18]([Cl:19])=[C:13]([C:12]([F:27])([F:11])[F:26])[CH:14]=3)[CH2:21][CH:22]([CH2:23][CH3:24])[O:7]2)[CH:8]=[CH:9][CH:10]=1)#[N:2]
Reactant: N#Cc1cccc(C=O)c1
Reactant: CCC(O)CNc1ccc(Cl)c(C(F)(F)F)c1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1CN(c2ccc(Cl)c(C(F)(F)F)c2)C(c2cccc(C#N)c2)O1

Procedure:
Meta-cyanobenzaldehyde (2.1 g, 0.016 mole) was added to 4.3 g of 1-(3-trifluoromethyl-4-chlorophenylamino)-2-butanol in 50 ml of toluene and 2-3 drops of methane sulfonic acid was added. The mixture was refluxed under a modified Dean-Stark apparatus until no more water came off and the mixture was stripped on a rotary evaporator. Yield was 6 g of product, nD30 1.5774. It was characterized by IR and NMR.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11].[C:31](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][N:27]([CH3:31])[CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11]
Reactant: O=C([O-])[O-]
Reactant: CC(Oc1cc(-c2cn(C3CCNCC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(Oc1cc(-c2cn(C3CCN(C)CC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 8 h

Procedure:
3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-2-aminopyridine (451 mg, 1 mmol) in the above mentioned Example 2 was added to N,N-dimethyl formamide (10 mL), potassium carbonate (276 mg, 2 mmol) and iodomethane (425.7 mg, 3 mmol) were added, and the reaction was performed overnight at room temperature. The resultant mixture was washed with water for several times, dried over anhydrous sodium sulfate, filtered, the filtrate was rotatedly concentrated to dryness to yield a solid, which was purified via silica gel column chromatography (dichloromethane/methanol=10:1) to yield the target product as white solid powder.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([NH:21][C:22]([NH:24][C:25]1([C:42]2[CH:47]=[C:46]([Br:48])[CH:45]=[CH:44][C:43]=2[F:49])[CH:29]([CH2:30]O)[CH2:28][N:27]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:26]1)=[S:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1.O>[C:13]([NH:21][C:22]1[S:23][CH2:30][CH:29]2[CH2:28][N:27]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[O:33])[CH2:26][C:25]2([C:42]2[CH:47]=[C:46]([Br:48])[CH:45]=[CH:44][C:43]=2[F:49])[N:24]=1)(=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(NC(=S)NC1(c2cc(Br)ccc2F)CN(C(=O)OCc2ccccc2)CC1CO)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC1=NC2(c3cc(Br)ccc3F)CN(C(=O)OCc3ccccc3)CC2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.2 %

Procedure:
1,1′-carbonyldiimidazole (2.87 g, 17.7 mmol) is added to a solution of benzyl 3-(benzoylcarbamothioylamino)-3-(5-bromo-2-fluoro-phenyl)-4-(hydroxymethyl)pyrrolidine-1-carboxylate (5.198 g, 8.86 mmol) in tetrahydrofuran (52 mL). The mixture is stirred for 1.5 hours at room temperature and then the reaction is heated at reflux overnight under nitrogen. The reaction is cooled, diluted with water, and extracted with ethyl acetate (3×). The organic layers are combined, dried over sodium sulfate, filtered, and the solvent removed in vacuo. The crude product is purified over silica gel with a 30 minute 5% to 100% EtOAc in hexanes gradient to give the title compound (2.93 g, 58%). ES/MS (m/e): (79Br/81Br). 568/570 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11](N)[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.O.CCOC(C)=O.[BrH:21]>>[Br:21][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: Br
Reactant: COc1cc(N)c2ncccc2c1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(Br)c2ncccc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
To 5.05 g (29.0 mmol) 6-methoxy-quinolin-8-yl-amine in 25 mL of 48% HBr at 0° C. is added a solution of 2.60 g (37.7 mmol) and 20 mL H2O. After stirring at 0° C. for 15 min, the resulting mixture is added dropwise to a 75° C. solution of 5.0 g (34.8 mmol) CuBr and 60 mL of 48% HBr. After 5.5 h, the reaction mixture is neutralized with 150 mL of ice cold 5N NaOH, the resulting mixture is stirred with 300 mL EtOAc and filtered through a pad of celite. This mixture is extracted 2×100 mL EtOAc, and the combined organics are washed with 1×200 mL H2O, 1×200 mL brine, dried over Na2SO4, filtered, and the volatiles are evaporated. Flash chromatography on SiO2 gel, eluting with hexanes/EtOAc (4/1 to 1/1), gives 4.23 g (17.8 mmol, a 61% yield) of the title compound as a brown oil. MS (ES) m/z 239 (MH)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:35])[N:11]([CH2:20][CH2:21][CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].C([S:38]P([O-])(OCC)=S)C.O>C1COCC1>[C:29]1([CH:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:21][CH2:20][N:11]([CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:10](=[O:35])[NH:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]([NH2:2])=[S:38])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: N#Cc1cccc(NC(=O)N(CCC(c2ccccc2)c2ccccc2)CCN2CCOCC2)c1
Reactant: CCOP([O-])(=S)SCC
Solvent: C1CCOC1
Solvent: O
Product: NC(=S)c1cccc(NC(=O)N(CCC(c2ccccc2)c2ccccc2)CCN2CCOCC2)c1
Temperature: 40 °C
Reaction time: 27 h

Procedure:
70 mg (0.15 mmol, 1 eq.) of 3-(3-cyanophenyl)-1-(3,3-diphenylpropyl)-1-(2-morpholin-4-ylethyl)urea (obtained in Example 19) are dissolved in 0.5 mL of THF under argon. 142 μL (0.90 mmol, 6 eq.) of diethyldithiophosphate and 50 μL (0.01 mmol, 0.1 eq.) of water are added. The mixture is stirred for 27 hours at 40° C. Water is added to the medium and the aqueous phase is extracted with dichloromethane, washed twice with water then brine, dried over MgSO4, filtered and concentrated. The oil obtained is subjected to chromatography over silica gel (eluent: 97/3 dichloromethane/methanol) in order to obtain the expected product in the form of a yellow powder (55 mg, yield=73%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15](O)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:52][C:53]([F:62])([F:61])[C:54]1[CH:55]=[C:56]([CH:58]=[CH:59][CH:60]=1)[NH2:57]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:57][C:56]3[CH:58]=[CH:59][CH:60]=[C:54]([C:53]([F:52])([F:61])[F:62])[CH:55]=3)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncc2c(n1)CCN(c1cccc(C(=O)Nc3cccc(C(F)(F)F)c3)c1)C2
Temperature: 40 °C
Reaction time: 16 h

Procedure:
A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (162 mg, 0.60 mmol), triethylamine (0.335 mL, 2.4 mmol), and HBTU (250 mg, 0.66 mmol) in 4.0 mL DMF was briefly warmed to approx. 40° C. to dissolve solids. After 3 minutes 3-(trifluoromethyl)aniline (0.149 mL, 1.2 mmol) was added and the reaction stirred at 50° C. for 3 hours, at rt for 16 hours, then an additional 1 hour at 50° C. The reaction mixture was partitioned between EtOAc and aqueous NaHCO3 solution, the EtOAc layer washed with brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting oily solid was chromatographed eluting with CHCl3, warm EtOAc, CHCl3:EtOAc (1:1), then 5% MeOH in CHCl3:EtOAc (1:1) giving a pale yellow solid. This solid was recrystallized from EtOAc giving a white solid (100 mg, 40%). 1H NMR (DMSO-d6) δ: 10.46 (s, 1H), 8.25 (s, 1H), 8.13 (s, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.53 (s, 1H), 7.34-7.48 (m, 3H), 7.22-7.27 (m, 1H), 6.41 (s, 2H), 4.30 (s, 2H), 3.66 (t, J=6.0 Hz, 2H), 2.77 (t, J=5.9 Hz, 2H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[C:11]([NH2:13])[C:10]([N+:14]([O-])=O)=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CO>[Pd].C1COCC1>[O:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:8]=[CH:9][C:10]([NH2:14])=[C:11]([NH2:13])[CH:12]=2)[CH2:2][CH2:3]1
Reactant: Nc1cc(N2CCOCC2)ncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cnc(N2CCOCC2)cc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.4 %

Procedure:
Into a 50-mL round-bottom flask were placed 2-(morpholin-4-yl)-5-nitropyridin-4-amine (compound 151.1, 350 mg, 1.56 mmol), methanol (20 mL), THF (10 mL), and Pd/C (35 mg). The above solution was purged with N2 and then H2. The reaction mixture was stirred for 4 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under reduced pressure. This resulted in 280 mg (92%) of the title compound as a pink solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH2:16])=[C:11]([O:17][CH2:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=C)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:36]C1C=CC(C=O)=C(O)C=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].BrCC(C1C=CC(OC)=CC=1)=O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH2:16])=[C:11]([CH:10]=1)[O:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(OCc2ccccc2)cc1OCC(=C)c1ccc(OC)cc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Agent: CC(C)(C)[O-]
Agent: COc1ccc(C(=O)CBr)cc1
Agent: [K+]
Product: C=Cc1ccc(OCc2ccccc2)cc1OCC(=O)c1ccc(OC)cc1
Yield: 74 %

Procedure:
Alternatively, the compound 2 can be obtained by reacting 4-benzyloxy-2-hydroxybenzaldehyde with a mixture of MTPPB and t-BuOK, followed by reaction with 2-bromo-4′-methoxyacetophenone, and the resultant mixture, instead of being subjected to purification to afford compound 2a, was continuously reacted with a mixture of MTPPB and t-BuOK in THF, giving a one pot yield of 74%.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:11]([C:12]([OH:14])=[O:13])[C:10]([OH:16])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17](O)[CH3:18].S(=O)(=O)(O)O.Cl.C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:15]=[C:11]([C:12]([O:14][CH2:17][CH3:18])=[O:13])[C:10]([OH:16])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cc(-c2ccccc2)ccc1O
Reactant: CCO
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(-c2ccccc2)ccc1O
Yield: 55 %

Procedure:
To 18.58 g of 5-phenylsalicylic acid, 350 ml of ethanol, 100 ml of toluene and 42 ml of concentrated sulfuric acid were added. The mixture was heated under reflux for 14 hours. After it was confirmed with TLC that the starting materials were almost disappeared, the reaction liquid was poured into a mixed medium of diluted hydrochloric acid-ethyl acetate. The mixture was extracted, and the organic phase was collected and washed with saturated sodium chloride aqueous solution. After dried with magnesium sulfate, the liquid was concentrated to form a crude product. The product was recrystallized from ethanol to obtain 11.53 g of ethyl 5-phenylsalicylate in the form of colorless crystallites. The yield was 55%. The product was confirmed with NMR and mass spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[N:22]=[C:21]([C:23]([NH:25]N)=[O:24])[O:20][N:19]=2)=[CH:4][CH:3]=1.ClC1C=CC(C2N=C3C=CC([F:42])=CN3C=2CC2N=C(C(OCC)=O)ON=2)=CC=1.N>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([F:42])=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[N:22]=[C:21]([C:23]([NH2:25])=[O:24])[O:20][N:19]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)no1
Reactant: CCOC(=O)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccc(F)cn23)no1
Agent: N
Solvent: CO
Product: NC(=O)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccc(F)cn23)no1

Procedure:
The title compound was prepared in the same fashion as that for compound 215 from ethyl 3-((2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylate and saturated ammonia in MeOH. (47 mg, 90.0%), as a white solid. m/e+=372 (M+H+). 1H NMR (300 MHz, in DMSO-d6): δ 8.68 (2H, D, brd, NH2), δ 8.39 (1H, D, s, ArH), δ 7.82-7.80 (2H, D, d, J=8.4 Hz, ArH), δ 7.75-7.71 (1H, D, dd, J=9.6, 5.2 Hz, ArH), δ 7.55-7.53 (2H, D, d, J=8.4 Hz, ArH), δ 7.47-7.44 (1H, D, m, ArH), and δ 4.74 (2H, D, s, CH2).