Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([O:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C([O:12][C@@H:13]1[C@H:17]([O:18]C(=O)C)[C@@H:16]([CH2:22][O:23]C(=O)C)[O:15][C@H:14]1[N:27]1[CH:35]=[N:34][C:33]2[C:28]1=[N:29][C:30]([CH3:37])=[N:31][C:32]=2Cl)(=O)C.C(N(CC)CC)C>O1CCOCC1>[CH:2]1([O:7][NH:8][C:32]2[C:33]3[N:34]=[CH:35][N:27]([C:28]=3[N:29]=[C:30]([CH3:37])[N:31]=2)[C@@H:14]2[O:15][C@H:16]([CH2:22][OH:23])[C@@H:17]([OH:18])[C@H:13]2[OH:12])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NOC1CCCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1nc(NOC2CCCC2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 100 °C

Procedure:
O-Cyclopentylhydroxylamine hydrochloride (0.52 g, 3.75 mmol) was reacted with 9-(2,3,5-triO-acetyl-β-D-ribofuranosyl)-6-chloro-2-methyl-9H-purine (1.07 g, 2.5 mmol) [prepared from 2-methylinosine (Journal of Organic Chemistry, 1967, 32, 3258-3260) by standard acylation and chlorination steps] in dioxan (40 ml) in the presence of triethylamine (0.63 g, 6.25 mmol). The reaction mixture was heated at 100° C. for 70 h, before being filtered and evaporated. The product (after purification by chromatography), followed by debenzoylation using methanolic ammonia to provide the title N-cyclopentoxy-2-methyladenosine (after column chromatography) as a foam 1H NMR (DMSO-d6)γ 1.47-1.93 (8H, m,--CH2CH2CH2CH2 --), 2.32 (3H, s,--CH3), 4.59 (1H, br m,--O--CH--), 5.88 (1H, d, H-1').
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][OH:14])[CH2:10][C:11]#[N:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[O:23][N:22]=[C:21](O)[C:20]=2[CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:10][C:11]#[N:12])[CH2:13][O:14][C:21]1[C:20]2[CH:25]=[C:16]([Cl:15])[CH:17]=[CH:18][C:19]=2[O:23][N:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(CO)CC#N
Reactant: Oc1noc2ccc(Cl)cc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CC#N)COc1noc2ccc(Cl)cc12
Yield: 73.4 %

Procedure:
To a solution of 1.0 g of 3-tert-butoxycarbonylamino-4-hydroxybutyronitrile in 15 ml of tetrahydrofuran are added 0.85 g of 5-chloro-3-hydroxy-1,2-benzoisoxazole, 1.71 g of triphenylphosphine and 1.14 g of diethyl azodicarboxylate with ice-cooling, and they are subjected to reaction at room temperature for 24 hours. Thereafter, the solvent is removed by distillation under reduced pressure. The residue obtained is purified by a column chromatography [eluant:n-hexane:ethyl acetate=5:1], to obtain 1.29 g of 3-(2-tert-butoxycarbonylamino-3-cyanopropoxy)-5-chloro-1,2-benzoisoxazole having a melting point of 147.2°-147.9° C.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[CH3:12][C:13]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:16]=[CH:15][CH:14]=1.CC(=O)OCC>>[CH3:12][C:13]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:2][C:3]3[S:4][C:5]4[C:10]([N:11]=3)=[CH:9][CH:8]=[CH:7][N:6]=4)[CH2:21][CH2:20]2)[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cccc(N2CCNCC2)n1
Reactant: ClCc1nc2cccnc2s1
Solvent: CCOC(C)=O
Product: Cc1cccc(N2CCN(Cc3nc4cccnc4s3)CC2)n1

Procedure:
The product from Example 38A (50 mg, 0.81 mmol), 1-(6-methyl-2-pyridinyl)piperazine (160 mg, 0.98 mmol), and D1 EA (280 μL, 1.6 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR 1H NMR (300 MHz, DMSO-d6) δ 2.68 (m, 4H) 3.32 (s, 3H) 3.53 (m, 4H) 4.04 (s, 2H) 6.54 (m, 1H) 6.61 (d, J=8.48 Hz, 1H) 7.40 (m, 1H) 7.56 (dd, J=8.31, 4.58 Hz, 1H) 8.33 (dd, J=8.31, 1.53 Hz, 1H); (ESI) m/z 326 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][O:5][C:6]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1.Cl>O1CCOCC1>[C:18]1([C:6]2([O:5][CH2:4][C:3]([O:2][CH3:1])=[O:24])[CH2:10][CH2:9][NH:8][CH2:7]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)COC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)COC1(c2ccccc2)CCNC1
Reaction time: 1 h

Procedure:
To tert-butyl 3-(2-methoxy-2-oxoethoxy)-3-phenylpyrrolidine-1-carboxylate (160 mg, 0.00048 mol) was added 4 M of hydrogen chloride in 1,4-dioxane (1 mL) and the resulting solution was stirred for 1 h. The reaction mixture was then concentrated in-vacuo and the crude product was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[CH3:18])=[CH:4][N:3]=1.[H][H]>[Pd].C(OCC)(=O)C.C(O)C>[CH3:18][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][C:9]=1[O:8][C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][CH:6]=1)[NH2:15]
Reactant: [H][H]
Reactant: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2C)cn1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2ccc(N)cc2C)cn1
Reaction time: 5 h
Yield: 97 %

Procedure:
A mixture of 2-methyl-5-(2-methyl-4-nitrophenoxy)pyridine (141 g, 0.58 mol) and 10% palladium on charcoal (13 g) in ethyl acetate (200 ml) and ethanol (700 ml) was stirred under an atmosphere of hydrogen (1.2 bar) for 5 hours. After reaction completion (the reaction being complete when 3 mole equivalents of hydrogen have been reacted), the mixture was purged with nitrogen and the catalyst was filtered off. The filtrate was evaporated to dryness to give 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline as a white solid (120.6 g, 98%); NMR Spectrum (CDCl3): 2.11 (s, 3H), 2.50 (s, 3H), 6.51 (d, 1H), 6.58 (s, 1H), 6.75 (d, 1H), 6.98-7.03 (m, 2H), 8.18 (s, 1H); Mass spectrum: MH+ 215.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C1C(=O)N([Br:17])C(=O)C1.[O-]S([O-])(=S)=O.[Na+].[Na+]>CC#N>[Br:17][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([CH3:9])[C:2]=1[Cl:1]
Reactant: Cc1c(N)cccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: Cc1c(N)ccc(Br)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
To a solution of 3-chloro-2-methylaniline (30 g, 0.212 mol) in CH3CN (300 mL) was added NBS (45.2 g, 0.254 mol) in portions at 10° C. The resulting mixture was stirred at room temperature for 30 minutes. Upon completion, saturated Na2S2O3 (500 mL) was added slowly into the reaction mixture at 10° C. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was washed with petroleum ether to afford the title compound (30 g), which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3): δ 7.24 (d, 1H), 6.48 (d, 1H), 3.70 (br, 2H), 2.28 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=2)[CH:12]=[C:11]([CH2:20][OH:21])[C:10]=1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=2)[CH:12]=[C:11]([CH:20]=[O:21])[C:10]=1[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(CO)cc2ccc(F)cc2c1OCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1c(C=O)cc2ccc(F)cc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.4 %

Procedure:
To a solution of (4-benzyloxy-6-fluoro-3-methyl-naphthalen-2-yl)-methanol (180 mg, 0.6 mmol) in dichloromethane (10 mL) was added pyridinium chlorochromate (260 mg, 1.2 mmol) in portions. After being stirred at room temperature for 3 hours, the resulting dark mixture was diluted with diethyl ether, and stirred at room temperature for 10 minutes. The mixture was filtered through a short silica gel column. The filtrate was concentrated in vacuo to give 4-benzyloxy-6-fluoro-3-methyl-naphthalene-2-carbaldehyde (165 mg, 93%) as a white solid, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 10.31 (s, 1H), 8.16 (s, 1H), 8.00 (dd, J=8.84, 5.56 Hz, 1H), 7.73 (dd, J=10.48, 2.40 Hz, 1H), 7.55 (d, J=6.82 Hz, 2H), 7.39-7.49 (m, 2H), 7.32 (td, J=8.65, 2.65 Hz, 1H), 4.99 (s, 2H), 2.75 (s, 3H).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[C:9]([C:11](=[N:17]O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10]>O.C(=O)([O-])O.[Na+]>[NH2:17][CH:11]([C:9]#[N:10])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(C#N)=NO
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(N)C#N
Temperature: 35 °C
Yield: 37.4 %

Procedure:
119 g of sodium dithionite are added in portions (15 min) at room temperature to 35 g (0.246 mol) of ethyl 2-cyanoglyoxylate-2-oxime in 350 ml of H2O and 280 ml of saturated sodium hydrogen carbonate solution. The mixture is then warmed at 35° C. for 1 hour; it is then saturated with NaCl and extracted 5 times with dichloromethane. After drying with calcium chloride, the organic phase is concentrated. 11.8 g of the title compound are obtained as an oil.
Reaction SMILES: [Cl-].[NH4+].C(O)C.[Br:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[NH:17][C:18](=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-])=O>O.[Fe]>[NH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]([NH:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[N:9]=[CH:8][C:7]([Br:6])=[CH:16]2)=[O:28]
Reactant: O=C(Nc1cccc2cc(Br)cnc12)c1ccccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccccc1C(=O)Nc1cccc2cc(Br)cnc12
Temperature: 50 °C
Yield: 86.6 %

Procedure:
To a solution of ammonium chloride (50.9 mg) in water (2 ml) was added ethanol (10 ml), and the mixture was stirred at 50° C. To the mixture were added 3-bromo-8-(2-nitrobenzoylamino)quinoline (590 mg) and iron (531 mg), and the mixture was refluxed for 1 hour. After filtration, the filtrate was concentrated in vacuo, and the residue was suspended in hot 80% ethanol and allowed to cool to ambient temperature. The resulting precipitates were collected by filtration to give 8-(2-aminobenzoylamino)-3-bromoquinoline (470 mg) as pale tan solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:42])[CH2:10][C:11]1[CH:41]=[CH:40][CH:39]=[CH:38][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][C:23]2[CH:37]=[CH:36][C:26]([CH2:27][NH:28]C(=O)OC(C)(C)C)=[CH:25][CH:24]=2)[N:16]=1>C(Cl)Cl>[NH2:28][CH2:27][C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:17]2[N:16]=[C:15]([CH2:14][CH2:13][C:12]3[CH:38]=[CH:39][CH:40]=[CH:41][C:11]=3[CH2:10][C:9]([NH2:8])=[O:42])[C:20]([CH3:21])=[CH:19][N:18]=2)=[CH:37][CH:36]=1
Reactant: Cc1cnc(Nc2ccc(CNC(=O)OC(C)(C)C)cc2)nc1CCc1ccccc1CC(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc(Nc2ccc(CN)cc2)nc1CCc1ccccc1CC(N)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.9 %

Procedure:
TFA (1 mL) was added to a solution of tert-butyl 4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)benzylcarbamate (A114) (0.043 g, 0.090 mmol) in DCM (3 mL) and the resulting solution stirred at room temperature for 4 hours. The volatiles were removed in vacuo then 2 M aqueous K2CO3 (5 mL) and water (15 mL) were added to the residue. The resulting suspension was sonicated for 1 minute, filtered and the filter cake dried to give the title compound 27 as a light tan solid (0.028 g, 82%); 1H NMR (300 MHz, d6-DMSO) δ 9.30 (s, 1H), 8.16 (s, 1H), 7.70 (d, J=8.5 Hz, 2H), 7.43 (s, 1H), 7.12-7.27 (m, 6H), 6.93 (s, 1H), 3.64 (s, 2H), 3.49 (s, 2H), 3.34 (brs, 2H), 3.02-3.07 (m, 2H), 2.85-2.90 (m, 2H), 2.06 (s, 3H). LCMS-B: rt 4.666 min; m/z 376 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7]1>C1COCC1>[CH2:1]([NH:3][C:4]([N:7]1[C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:6]1)=[O:5])[CH3:2]
Reactant: CCN=C=O
Reactant: O=c1[nH]oc2ccccc12
Solvent: C1CCOC1
Product: CCNC(=O)n1oc2ccccc2c1=O
Yield: 75 %

Procedure:
Ethyl isocyanate (92.4 mg, 1.30 mmol) is added to a stirred solution of benzo[d]isoxazol-3-one (150 mg; 1.10 mmol) in anhydrous THF (4 mL) at ambient temperature under nitrogen. The resultant mixture is heated in an oil bath at 70° C. for 2 hr. After concentration and subsequent flash chromatography on silica (15% hexane in CH2Cl2), 6-1 is obtained as a white solid (170 mg, 75% yield). mp 112.0–113.0° C.; 1H-NMR (CDCl3) δ1.28 (t, J=7.3 Hz, 3H), 3.43–3.51 (m, 2H), 7.21–7.29 (m, 3H), 8.04 (br s, 1H), 8.07 (d, J=6.8 Hz, 1H); ESIMS m/e 207 (M+H)+. Analysis for C10H10N2O3: calcd: C, 58.25; H, 4.89; N, 13.59; found: C, 58.04; H, 4.82; N, 13.41.
Reaction SMILES: [CH3:1][C:2](=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:10][P:11]=[O:12]>CO>[OH:9][C:2]([P:11]([OH:12])[OH:10])([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=PO
Reactant: CCCCCCC(C)=O
Solvent: CO
Product: CCCCCCC(C)(O)P(O)O
Temperature: 25 °C

Procedure:
A mixture of octan-2-one (3.76 g, 0.29M) and hypophosphorus acid (91.5%, 2.09 g, 0.029M) is heated at 100° C. for 12 hours in the presence of Dowex 50W×2 ion exchange resin (1 ml, aqueous slurry). The mixture is cooled to room temperature, methanol (50 ml) is added and the Dowex is removed by filtration. The filtrate is evaporated to an oily residue, which is dissolved in ethyl acetate, washed with water, brine, then dried (MgSO4). Removal of the solvent gives 1-hydroxy-1-methylheptylphosphonous acid.
Reaction SMILES: Br[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([NH:12][C:13](=[O:15])[CH3:14])=[C:4]([F:16])[CH:3]=1.[C:17]([Cu])#[N:18].CCOC(C)=O>CN(C=O)C>[C:17]([C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([NH:12][C:13](=[O:15])[CH3:14])=[C:4]([F:16])[CH:3]=1)#[N:18]
Reactant: N#C[Cu]
Reactant: CC(=O)Nc1cc(C(F)(F)F)c(Br)cc1F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(C(F)(F)F)c(C#N)cc1F
Temperature: 150 °C
Yield: 56.9 %

Procedure:
A mixture of compound 23 (300 mg, 1 mmol), CuCN (355 mg, 4 mmol) in DMF (6 mL) was heated at 150° C. under N2 overnight. The reaction mixture was cooled to room temperature and then poured into ice water. EtOAc was added and the insoluble solid was filtered off (rinsed with EtOAc). The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with aq.NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified with silica gel chromatography (PE:EtOAc=4:1) to afford the title compound 24 (140 mg, 28%) as a white solid. 1H NMR (400 MHz, CDCl3) δ8.99 (d, 1H, J=7.2 Hz), 7.55 (d, 1H, J=10.0 Hz), 2.92 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=3)=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1.I[CH3:24]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=3)=[C:7]([CH3:11])[N:8]2[CH3:24])=[CH:4][CH:3]=1
Reactant: Cc1[nH]c2cc(Cl)ccc2c1Sc1ccc(CC(=O)O)cc1
Reactant: CI
Product: Cc1c(Sc2ccc(CC(=O)O)cc2)c2ccc(Cl)cc2n1C

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: [4-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid and iodomethane.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:10]([OH:12])=[CH:9][CH:8]=[CH:7][C:6]=2[O:5][CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Cl[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=1>CN(C)C=O>[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=2)[O:5][CH2:4][CH2:3]1
Reactant: CC1CCOc2cccc(O)c21
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CCOc2cccc(Oc3ccc([N+](=O)[O-])cn3)c21
Temperature: 110 °C
Yield: 37.7 %

Procedure:
In a 0.5-2 ml Microwave vial 4-methylchroman-5-ol (Intermediate 211, 38.7 mg, 0.212 mmol) K2CO3 (88 mg, 0.636 mmol) and 2-chloro-5-nitropyridine (33.6 mg, 0.212 mmol) were dissolved in N,N-dimethylformamide (DMF) (2 mL) to give a light brown solution. The reaction vessel was sealed and heated under microwave irradiation at 110° C. for 1 hour. After cooling the reaction was quenched with 5 mL of water and diluted with 10 mL of ethyl acetate. Phases were separated by a separating funnel. The aqueous phase was extracted with 3×10 mL of ethyl acetate. The collected organic layer was dried using a hydrophobic frit and evaporated in vacuo to give the title compound (22.9 mg) as a colorless oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:11][NH:10][CH2:9][C:7]=2[N:8]=1.Br[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=2)=[O:20])[CH:14]=1>>[CH:28]([C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:19]([C:15]2[CH:14]=[C:13]([N:10]3[CH2:11][C:6]4[CH:5]=[N:4][C:3]([S:2][CH3:1])=[N:8][C:7]=4[CH2:9]3)[CH:18]=[CH:17][N:16]=2)=[O:20])=[CH:27][CH:26]=1)([CH3:30])[CH3:29]
Reactant: CC(C)c1ccc(NC(=O)c2cc(Br)ccn2)cc1
Reactant: CSc1ncc2c(n1)CNC2
Product: CSc1ncc2c(n1)CN(c1ccnc(C(=O)Nc3ccc(C(C)C)cc3)c1)C2

Procedure:
In a manner similar to that describe in Example 126, 2-(methylthio)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine and 4-bromo-N-(4-isopropylphenyl)picolinamide were converted to the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:31])[C:13]([CH3:30])([CH3:29])[CH:14]([CH2:27][CH3:28])[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][C:18]=2[F:25])[CH2:8][CH2:7]1)[CH3:2].[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:31])[C:13]([CH3:30])([CH3:29])[CH:14]([CH2:27][CH3:28])[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[NH:24])=[CH:19][C:18]=2[F:25])[CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)c2ccc(C#N)cc2F)CC1
Reactant: C1CCNC1
Product: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)c2ccc(C(=N)N3CCCC3)cc2F)CC1
Yield: 25 %

Procedure:
The same procedure as in Example 45 was performed with ethyl-N-(N-(4-cyano-2-fluorobenzoyl)-β-ethyl-α,α-dimethyl-β-alanyl)-4-piperidineacetate (1.4 g, 3.1 mmol) by using pyrrolidine (2.6 ml) as an amine to yield the titled compound (398 mg, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2ncccn2)c1-c1ccc(Cl)cc1
Product: Cc1nnc(Cl)c(-c2ncccn2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
0.64 g of 5-(4-chlorophenyl)-6-methyl-4-(2-pyrimidinyl)-2H-pyridazin-3-one and 10.4 g of phosphorus oxychloride were mixed. The mixture was stirred for 2 hours under reflux with heating. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue was added ethyl acetate and ice-cooled sodium bicarbonate water was added. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.56 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.49 g of 3-chloro-5-(4-chlorophenyl)-6-methyl-4-(2-pyrimidinyl)pyridazine (hereinafter, described as compound (6) of the present invention (6).).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[C:16]2[C:15]([NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)=[N:14][CH:13]=[N:12][C:11]=2[S:10][C:9]=1[CH3:29]>>[CH3:1][C:2]1[N:3]([C:13]2[N:14]=[C:15]([NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:16]3[CH:8]=[C:9]([CH3:29])[S:10][C:11]=3[N:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1sc2ncnc(NCCc3ccc4c(c3)OCO4)c2c1Cl
Reactant: Cc1ncc[nH]1
Product: Cc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 5-chloro-6-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH:13]=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(OC(=O)C)(=O)C.Cl[C:24](Cl)([F:29])[C:25]([O:27][CH3:28])=[O:26]>[Zn].[Cu]Cl.O1CCCC1>[F:1][CH:2]([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH:13]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[O:26])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: COC(=O)C(F)(Cl)Cl
Reactant: O=CC1(c2ccc(OC(F)F)cc2)CC1
Agent: Cl[Cu]
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(F)=CC1(c2ccc(OC(F)F)cc2)CC1
Yield: 28 %

Procedure:
The method of Example 1 was repeated using zinc powder (2.8 g), copper (I) chloride (0.42 g), molecular sieve 4A (2.8 g) tetrahydrofuran (50 ml), 1-(4-difluoromethoxyphenyl)-1-formylcyclopropane, acetic anhydride (1.5 ml) and methyl dichlorofluoroacetate (3.6 g) to yield the title compound (0.79 g, 28%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9])=[O:5].S(Cl)([Cl:23])=O>ClCCl.CN(C=O)C>[F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:7]=1[C:8]([Cl:23])=[O:9])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)c(C(=O)c2ccccc2F)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)Cl)c(C(=O)c2ccccc2F)c1
Reaction time: 1 h

Procedure:
To a solution of 2-2-fluorobenzoyl)-4-methoxybenzoic acid (84) (2.05 g, 7.48 mmol) in 50 mL of dichloromethane was added thionyl chloride (2.40 mL, 14.9 mmol), followed by 3 drops of DMF. The reaction was warmed to reflux. After 1 hour, LC-MS (aliquot quenched with pyrrolidine/ACN/H2O) showed that the reaction was complete (ESI+MS for corresponding pyrrolidine amide: 328.2 [M+H]+). The reaction was concentrated in vacuo to provide an oil which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11](=[O:13])[CH3:12])=[N:9][NH:8][C:5]2=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].O>CC#N>[C:25]([O:24][C:22](=[O:23])[CH2:21][N:8]1[C:5]2=[CH:6][N:7]=[C:2]([CH3:1])[CH:3]=[C:4]2[C:10]([C:11](=[O:13])[CH3:12])=[N:9]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(=O)c1n[nH]c2cnc(C)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(=O)c1nn(CC(=O)OC(C)(C)C)c2cnc(C)cc12

Procedure:
To a solution of 1-(5-methyl-1H-pyrazolo[3,4-c]pyridin-3-yl)-ethanone (1 g, 5.71 mmol) in CH3CN (30 mL) were added potassium carbonate (1.81 g, 13.13 mmol) and tert-butyl bromoacetate (0.927 mL, 6.28 mmol). The reaction mixture was stirred at reflux for 1 h, then poured into water and extracted with EtOAc (×3). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:0 to 3:2). TLC, Rf (c-hexane/EtOAC 1:1)=0.25; MS (UPLC/MS): 290 [M+H]+; tR (HPLC conditions f): 1.50 min.