Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:2]=[C:3]([S:10][C:11]2[CH:12]=[CH:13][C:14]3[N:15]([CH:17]=[C:18]([NH:20]C(=O)OC(C)(C)C)[N:19]=3)[N:16]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl.C(O)(C(F)(F)F)=O>O1CCOCC1>[N:1]1[N:2]=[C:3]([S:10][C:11]2[CH:12]=[CH:13][C:14]3[N:15]([CH:17]=[C:18]([NH2:20])[N:19]=3)[N:16]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)Nc1cn2nc(Sc3nnc4ccccn34)ccc2n1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: Nc1cn2nc(Sc3nnc4ccccn34)ccc2n1
Yield: 91 %

Procedure:
A solution of tert-butyl 6-([1,2,4]triazolo[4,3-a]pyridin-3-ylthio)imidazo[1,2-b]pyridazin-2-ylcarbamate (300 mg, 0.78 mmol) in dioxane (5 ml) was treated with 4M HCl in dioxane (5 ml) at 80° C. for 1 hr. The mixture was concentrated and purified by LCMS to give the title compound, 6-([1,2,4]triazolo[4,3-a]pyridin-3-ylthio)imidazo[1,2-b]pyridazin-2-amine (201 mg, 68% yield) as the TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.00 (d, J=9.35 Hz, 1 H) 7.16 (t, J=6.44 Hz, 1 H) 7.22 (s, 1 H) 7.54-7.65 (m, 1 H) 7.73 (d, J=9.35 Hz, 1 H) 8.00 (d, J=9.09 Hz, 1 H) 8.47 (d, J=6.82 Hz, 1 H). ESI-MS:m/z 284.2 (M+H)+.
Reaction SMILES: C(OCCC[N:7]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:19]=3)=[CH:17][C:12]=2[CH:11]=[C:10]([C:31](O)=[O:32])[CH2:9][CH2:8]1)C.S(Cl)(Cl)=O.C[N:39](C=O)C>C1COCC1>[CH2:28]([O:27][CH2:26][CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]2[CH:15]=[CH:14][C:13]3[NH:7][CH2:8][CH2:9][C:10]([C:31]([NH2:39])=[O:32])=[CH:11][C:12]=3[CH:17]=2)=[CH:19][CH:20]=1)[CH2:29][CH3:30]
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CCCOCC)cc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(N)=O)CCN3)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 1-(3-ethoxypropyl)-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (250 mg) in THF (10 ml) were added thionyl chloride (0.080 ml) and DMF (one droplet) at room temperature, and the mixture was stirred for 1.5 hours. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in THF (20 ml), which was added dropwise to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (133 mg) and triethylamine (0.46 ml) in THF (3 ml) at 0° C. The mixture was stirred at room temperature for 2.5 hours, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with magnesium sulfate. After concentration under reduced pressure, the residue was purified with column chromatography (ethanol:ethyl acetate=1:9→1:3), and the resulting crystals were purified by recrystallization (hexane-ethyl acetate) to give 1-(3-ethoxypropyl)-N-[4-[[N-methyl-N-tetrahydropyran-4-yl)amino]methyl]phenyl]-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 105) (242 mg) as yellow crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([S:12][C:8]2[C:6]3[N:7]=[C:2]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:3]=[C:4]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:5]=3[N:11]=[CH:10][N:9]=2)=[CH:14][CH:15]=1
Reactant: C1CNCCN1
Reactant: Clc1ccc(Sc2ncnc3c(N4CCOCC4)nc(Cl)nc23)cc1
Product: Clc1ccc(Sc2ncnc3c(N4CCOCC4)nc(N4CCNCC4)nc23)cc1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(4-chlorophenyl-thio)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 208°-210° C.) and piperazine.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Br>>[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][N:4]1[CH:5]=[CH:6][C:2]([NH2:1])=[N:3]1
Reactant: Nc1cc[nH]n1
Reactant: Clc1cccc(CBr)c1
Product: Nc1ccn(Cc2cccc(Cl)c2)n1

Procedure:
Prepared in analogy to example 10a) starting with 3-amino-1H-pyrazole and 3-chlorobenzyl bromide. The title compound was obtained as a brown oil (Yield=11%). MS ISP (m/e): 208.0 (100) [(M+H)+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5](Br)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2].[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([NH:18][C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CC(C)(C)N
Reactant: CCOC(=O)C(Br)c1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(NC(C)(C)C)c1cccnc1
Yield: 41.2 %

Procedure:
Bromo-pyridin-3-yl-acetic acid ethyl ester (2.4 g; 9.8 mmol) was reacted in refluxing CH2Cl2, overnight with tert-butylamine (6.2 mL; 55.8 mmol; 6 equiv) and Et3N (2.8 mL; 19.6 mmol; 2 equiv). The reaction solution was evaporated to dryness, dissolved in CH2Cl2, washed six times with saturated NaHCO3 (aq), washed once with saturated NaCl (aq), dried with Na2SO4, filtered, and concentrated in vacuo. The resulting brown oil was purified with silica gel chromatography in a 6×8 cm glass column using a 30% EtOAc/hexanes (v/v) mobile phase. A total of 955 mg desired product was isolated (41% yield). MS(ES) calc'd: [M+H]+=237.1 m/z. Found: 237.1 m/z.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-:3])=[O:2].C(Cl)(Cl)(Cl)Cl.O.[Br:17]Br>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][Br:17])([O-:3])=[O:2]
Reactant: Cc1ccccc1[N+](=O)[O-]
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: O=[N+]([O-])c1ccccc1CBr
Yield: 45 %

Procedure:
Even the side-chain brominations of o-nitrotoluene in a carbon tetrachloride/water mixture using elementary bromine and under UV-irradiation, which have been described recently in German Democratic Republic patent specifications Nos. 74279 and 82463, provide only o-nitrobenzyl bromide in a yield of 45 to 55%. Continuation of the bromination did not prove advantageous. The process described in German Democratic Republic patent specification No. 118609 affords a somewhat better yield when o-nitrotoluene is brominated in carbon tetrachloride under irradiation with visible or ultra-violet light or using peroxide as catalyst; but in this process too it was not possible to obtain either a benzal bromide or a complete bromination of o-nitrotoluene as starting material to benzyl bromide.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:18])[N:3]=1.[OH-].[NH4+:20].O.C(OCC)(=O)C>O1CCOCC1>[NH2:20][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:18])[N:3]=1
Reactant: COc1ccccc1C(=O)c1ccc(Cl)nc1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1C(=O)c1ccc(Cl)nc1N
Temperature: 150 °C
Yield: 50.7 %

Procedure:
A solution of (2,6-Dichloro-pyridin-3-yl)-(2-methoxy-phenyl)-methanone (50.3 mg, 0.178 mmol, Example 4) in 1,4-dioxane (2 mL) was treated with concentrated ammonium hydroxide (0.24 mL, 29.4%) and heated to 150° C. in the microwave for 3 hrs. The resulting mixture was treated with water and ethyl acetate, washed with saturated sodium chloride, dried over sodium sulfate and evaporated in vacuo. The residue was purified on silica gel with hexanes/ethyl acetate to give (2-Amino-6-chloro-pyridin-3-yl)-(2-methoxy-phenyl)-methanone as a off-white solid (23.7 mg, 50.7% yield). HRMS, observed: 262.0502, Calcd for M+: 262.0509.
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]\[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])([O-])=[O:11].[K+].[K+].CC(O)=O.OOS([O-])=O.[K+].C([O-])([O-])=O.[K+].[K+]>C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O>[CH3:1][C@H:2]1[O:11][C@H:3]1[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C/C=C\c1ccccc1
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=S(=O)([O-])O
Solvent: CC(=O)O
Product: C[C@H]1O[C@H]1c1ccccc1
Temperature: -10 °C
Yield: 87 %

Procedure:
To a solution of cis-β-methyl styrene (0.059 g, 0.5 mmol) and ketone IVd (0.026 g, 0.075 mmol) in DME-DMM (3:1, v/v) (7.5 mL) were added buffer (0.2 M K2CO3—AcOH in 4×10−4 M aqueous EDTA, buffer pH=8.0) (5 mL) and Bu4NHSO4 (0.0075 g, 0.02 mmol) with stirring. After the mixture was cooled to about −10° C. (bath temperature) via a NaCl-ice bath, a solution of Oxone® (0.212 M in 4×10−4 M aqueous EDTA, 4.2 mL) (0.548 g, 0.89 mmol) and K2CO3 (0.479 M in 4×10−4 M aqueous EDTA, 4.2 mL) (0.278 g, 2.01 mmol) were added dropwise separately over a period of 3.5 h via a syringe pump. The reaction was then quenched with the addition of pentane and extracted with pentane. The combined organic layers were washed with brine, dried (Na2SO4), filtered, concentrated, and purified by flash chromatography (the silica gel was buffered with 1% Et3N in pentane; pentane-ether (1/0 to 50/1 was used as eluent) to give cis-β-methylstyrene oxide as a colorless liquid (0.58 g, 87% yield, 91% ee).
Reaction SMILES: [CH2:1]([Sn:5]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12][CH2:13][CH2:14][CH3:15])[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].ClC1C=C(C=CC=1)C(OO)=[O:25]>C(Cl)(Cl)Cl>[CH2:16]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:12][CH2:13][CH2:14][CH3:15])[C:6]1[CH:11]=[CH:10][N+:9]([O-:25])=[CH:8][CH:7]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCCC[Sn](CCCC)(CCCC)c1cc[n+]([O-])cc1
Yield: 63.9 %

Procedure:
4-Tributylstannylpyridine (3.00 g, 8.15 mmol) and 3-chloroperoxybenzoic acid (2.81 g, 16.3 mmol) in CHCl3 (60 ml) was stirred at 0° C. for 24 h. The mixture was washed with saturated aqueous NaHCO3 (2×200 ml). The organic layer was dried (Na2SO4), filtered, and evaporated in vacuo. Purification by chromatography (silica gel, 0–10% MeOH/EtOAc) gave 2.00 g (64%) of the title compound: 1H NMR (360 MHz, CDCl3) δ 0.80–1.60 (27H, m), 7.42 (2H, d, J 5.0), 8.35 (2H, d, J 5.0).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[O:17])[CH:11]=2)=[C:4]([CH3:18])[C:3]=1[CH3:19].CO.[BH4-].[Na+].Cl>O1CCCC1>[OH:17][CH2:16][C:12]1[CH:11]=[C:10]([C:5]2[C:4]([CH3:18])=[C:3]([CH3:19])[C:2]([OH:1])=[C:7]([CH3:8])[C:6]=2[CH3:9])[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1c(C)c(-c2cccc(C=O)c2)c(C)c(C)c1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C)c(-c2cccc(CO)c2)c(C)c(C)c1O
Reaction time: 2 h
Yield: 92.7 %

Procedure:
A solution of 4′-hydroxy-2′,3′,5′,6′-tetramethylbiphenyl-3-carbaldehyde (2.03 g, 8.00 mmol) in a mixed solvent of methanol (10 mL) and tetrahydrofuran (20 mL) was ice-cooled, sodium borohydride (90%, 0.336 g, 8.00 mmol) was added, and the mixture was stirred for 2 hr under nitrogen atmosphere. The reaction mixture was treated with diluted hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (1.90 g, yield 93%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([C:11]([O:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[O:12])[C:9]([CH3:18])=[N:8][C:5]2=[N:6][CH:7]=1.[CH3:19][C:20]([O:23][C:24]([N:26]1[CH2:32][C:31]2[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:30]=2[O:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])[CH3:21].C([O-])(=O)C.[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:18][C:9]1[N:10]([C:11]([O:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[O:12])[C:4]2[C:5]([N:8]=1)=[N:6][CH:7]=[C:2]([C:34]1[CH:35]=[CH:36][C:30]3[O:29][CH2:28][CH2:27][N:26]([C:24]([O:23][C:20]([CH3:21])([CH3:19])[CH3:22])=[O:25])[CH2:32][C:31]=3[CH:33]=1)[CH:3]=2
Reactant: Cc1nc2ncc(Br)cc2n1C(=O)OCC(C)C
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B(O)O)cc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: Cc1nc2ncc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CCO4)cc2n1C(=O)OCC(C)C
Temperature: 95 °C
Reaction time: 29 h
Yield: 32.2 %

Procedure:
A mixture of isobutyl 6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine-1-carboxylate (2.2 g, 7.1 mmol) (reagent preparation 19), (4-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (2.7 g, 9.2 mmol, example 1, step 2), potassium acetate (2.8 g, 28.3 mmol), and dichloro[1,1-bis(diphenylphosphino]-ferrocenepalladium (II) dichloromethane adduct (0.78 g, 1.1 mmol) in dioxane (50 ml) was stirred at 95° C. under nitrogen for 29 h. The mixture was cooled to room temperature, filtered through celite, and the filter cake was washed with ethyl acetate (100 ml). The filtrate was concentrated and purified by column chromatography on silica (0-100% ethyl acetate in hexanes) to give 1,1-dimethylethyl 7-(2-methyl-1-{[(2-methylpropyl)oxy]carbonyl}-1H-imidazo[4,5-b]pyridine-6-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)carboxylate (1.1 g, 33% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3): 8.74 (d, 1H), 8.39 (s, 1H), 7.47 (d, 1H), 7.43 (s, 1H), 7.14 (d, 1H), 4.50 (s, 2H), 4.34 (d, 2H), 4.12 (m, 2H), 3.88 (m, 2H), 2.96 (s, 3H), 2.22 (m, 1H), 1.42 (s, 9H), 1.21 (d, 6H); MS (EI) for C26H32N4O5: 481 (MH+).
Reaction SMILES: [C:1]1([CH:7](O)[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1(C)C=CC=CC=1>[CH3:9][CH:8]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(O)c1ccccc1
Solvent: Cc1ccccc1
Product: CC=Cc1ccccc1
Yield: 93.6 %

Procedure:
The filtered catalyst above was added to 1-phenyl-1-propanol (0.16 g) in toluene (1 ml). The same procedure as above was followed to afford β-methyl styrene as a colourless oil (0.13 g, 92%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=S)=[CH:15][CH:14]=1>CO.O=[Hg]>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[O:7][C:6]([C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=3)=[N:8][N:9]=2)=[CH:15][CH:14]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: NNC(=O)c1ccc(O)cc1
Agent: O=[Hg]
Solvent: CO
Product: Oc1ccc(-c2nnc(Nc3ccc(Cl)cc3)o2)cc1
Temperature: 25 °C

Procedure:
Mercury (II) oxide yellow (6.38 g, 29.47 mmol) was suspended in ca. 70 mL of anhydrous methanol. 4-Hydroxybenzoic acid hydrazide (4.48 g, 29.47 mmol) was added to this bright-orange suspension, followed by 4-chlorophenylisothiocyanate (5.0 g, 29.47 mmol). The reaction mixture was brought to reflux and refluxed for 2 hours. The reaction mixture turned pitch-black in color and formed black precipitate. Then it was cooled down to ambient temperature and filtered through a short pad of Celite, then through a short pad of silica gel. Then methanol was removed in vacuo and the resulting grey precipitate was re-crystallized from ca. 40 mL of EtOAc. The formed white precipitate was filtered, washed with a small amount of EtOAc and dried in vacuo to give the title product as a white powder.
Reaction SMILES: CS(O[CH:6]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][CH2:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:12](=[O:25])[CH2:11][CH2:10]1)(=O)=O.[S-:31][C:32]#[N:33].[K+]>CN(C)C=O>[O:25]=[C:12]1[CH2:11][CH2:10][C@H:9]([CH2:8][CH2:7][CH:6]([S:31][C:32]#[N:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C@H:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC)OS(C)(=O)=O
Reactant: N#C[S-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC)SC#N

Procedure:
A solution of 1 g. of ethyl 15-methanesulfonyloxy-9-oxo-prostanoate (Example 90) and 1 g. of dry potassium thiocyanate in 30 ml. of N,N-dimethylformamide is heated on the steam bath for 18 hours. The resulting mixture is poured into 150 ml. of water and extracted with ether. The extract is washed with water, dried with anhydrous magnesium sulfate and taken to dryness. Silica gel chromatography of the residue gives 462 mg. of oil; λmax. 4.67 (thiocyanate group) and 5.78 μ (carbonyl groups).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15]([O:17][CH2:18]Cl)[CH3:16]>CC(C)=O>[Br:1][C:2]1[C:7]([O:8][CH2:18][O:17][CH2:15][CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Br
Reactant: CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOCOc1cccnc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
To a RBF was added 2-bromo-3-pyridinol (6.0 g, 34.5 mmol) and potassium carbonate (11.91 g, 86 mmol) in Acetone (50 mL). The suspension was stirred at ambient temperature for 30 min and then treated with the drop-wise addition of chloromethyl ethyl ether (3.34 mL, 36.7 mmol) via addition funnel. The mixture was stirred at ambient temperature overnight. The mixture was filtered and the filtrate partitioned between EtOAc and water. The combined organic layers were washed with water, saturated solution of sodium bicarbonate and brine, then dried over Mg2SO4 to afford 7.12 g of desired product as a clear oil which was used without further purification.
Reaction SMILES: Cl.Cl.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][O:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)[O:17][C:16]3=[O:27])=[CH:11][C:10]=2[F:28])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>N1C=CC=CC=1.ClCCl>[CH3:36][S:37]([N:6]1[CH2:5][CH2:4][N:3]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][O:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)[O:17][C:16]3=[O:27])=[CH:11][C:10]=2[F:28])[CH2:8][CH2:7]1)(=[O:39])=[O:38]
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCNCC2)c(F)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CS(=O)(=O)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one dihydrochloride (433 mg, 1 mmol) in pyridine (15 ml) and dichloromethane (15 ml) was treated with triethylarnine (353 mg, 3.5 mmol) and stirred for 30 minutes at ambient temperature. Methanesulfonyl chloride (138 mg, 1.2 mmol) was added and the mixture stirred for 18 hours. The mixture was diluted with dichloromethane (50 ml), washed with water (2×25 ml), saturated brine (25 ml), and dried (magnesium sulfate). After evaporation to dryness and azeotroping with toluene (10 ml), the residue was triturated with diethyl ether to give the desired product (365 mg).
Reaction SMILES: CS([C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[N:9]=1)=O.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCCCCC>C(OCC)(=O)C>[C:22]1([NH:21][C:4]2[N:5]=[CH:6][C:7]3[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:8]=3[N:9]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CS(=O)c1ncc2ccc(=O)n(-c3ccccc3)c2n1
Reactant: Nc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=c1ccc2cnc(Nc3ccccc3)nc2n1-c1ccccc1
Temperature: 175 °C
Yield: 39 %

Procedure:
A mixture of 2-methanesulfinyl-8-phenyl-8H-pyrido[2,3-d]pyrimidin-7-one (197 mg, 0.69 mmol) and 1 mL of aniline was heated at 175° C. for 10 minutes then cooled to room temperature. Hexane and ethyl acetate were added, and the solid was collected by filtration and purified by flash chromatography eluting with ethyl acetate. The fractions containing product were concentrated, and the residue was recrystallized first from hexane and ethyl acetate then from chloroform and ethyl acetate to provide 85 mg (39%) of 2-phenylamino-8-phenyl-8H-pyrido[2,3-d]pyrimidin-7-one, mp 300-302° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[CH3:18])=[CH:5][CH:4]=1)#[N:2]>CO.ClCCl.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[C:10]([CH3:18])[CH:11]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1-c1ccc(C#N)cc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(N)ccc1-c1ccc(C#N)cc1
Yield: 29.5 %

Procedure:
1-(4-Cyanophenyl)-2-methyl-4-nitrobenzene (9.7 gm, 40.76 mmol) was dissolved in a mixture of methanol and dichloromethane (1:1, 400 mL) and hydrogenated over 10% palladium on charcoal (970 mg) at 3 bar and 20° C. for 18 h. The mixture was filtered through Arbocel filter aid and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with hexane:ethyl acetate 20:1 to 1:1) to give 4-amino-1-(4-cyanophenyl)-2-methylbenzene (2.5 gm, 30%) as a brown oil.
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[O:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1B(O)O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[O:31]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:43]=1[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: OB(O)c1ccccc1Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOC=C1c1ccccc1Oc1ccccc1
Yield: 25 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and 2-phenoxyphenylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a white solid (25% yield); 1H-NMR (d6-DMSO) 1.07 (9H, s), 3.09 (2H, m), 3.97 (2H, m), 6.19 (1H, s), 6.78 (2H, m), 6.97-7.04 (2H, m), 7.15-7.19 (1H, m), 7.26-7.32 (4H, m); MS ES(+) 298.0 (M+-tBu). IR λmax=1692 cm−1.
Reaction SMILES: [C@@H:1]12[C:10](=[O:11])[O:9][C:7](=[O:8])[C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.C1(C)C=CC=CC=1.[CH3:19][O:20]C1C=CC2N=CC=C([C@@H](O)[C@H]3N4C[C@H](C=C)[C@@H](CC4)C3)C=2C=1.CO>C(Cl)(Cl)(Cl)Cl>[CH3:19][O:20][C:7]([C@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]1[C:10]([OH:9])=[O:11])=[O:8]
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)[C@H]1CCCC[C@H]1C(=O)O
Temperature: -55 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
(1S,2R)-Cyclohexane-1,2-dicarboxylic acid monomethyl ester was prepared as described in J. Org. Chem. 2000, 65, 6984-6991. cis-1,2-Cyclohexanedicarboxylic anhydride (4.48 g, 29.1 mmol) was suspended in a 1:1 mixture of toluene and carbon tetrachloride (582 mL). The mixture was stirred for 20 min. Quinine (10.38 g, 32 mmol) was added and the flask was degassed and backfilled with nitrogen. The solution was cooled to −55° C. While stirring, methanol (3.55 mL, 87.3 mmol) was added dropwise. The mixture was stirred at −55° C. for 20 h. Upon warming to 25° C., the mixture was concentrated in vacuo to dryness. The resulting residue was dissolved in ethyl acetate (400 mL), washed with 3.0 M aqueous hydrochloric acid solution (2×150 mL), saturated aqueous brine solution (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the desired product, (1S,2R)-cyclohexane-1,2-dicarboxylic acid monomethyl ester (5.41 g, 29.1 mmol, 100%), as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ: 1.37-2.05 (8H, m), 2.84-2.86 (2H, m), 3.68 (3H, s), 11.47 (1H, s).