Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[F:26][C:27]1([F:38])[O:31][C:30]2[CH:32]=[CH:33][CH:34]=[C:35]([NH:36]N)[C:29]=2[O:28]1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[F:38][C:27]1([F:26])[O:31][C:30]2[CH:32]=[CH:33][CH:34]=[C:35]([N:36]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)[C:29]=2[O:28]1
Reactant: NNc1cccc2c1OC(F)(F)O2
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1cccc2c1OC(F)(F)O2

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and 2,2-difluoro-benzo[1,3]dioxol-4-yl-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for example 91. MS: M=479.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:21])[N:4]([CH3:20])[C:5]2[CH2:6][CH:7]([C:14]3[CH:18]=[CH:17][S:16][C:15]=3[Cl:19])[CH2:8][C:9](=O)[C:10]=2[C:11]=1[CH3:12].[C:22]([NH:25][NH2:26])([NH2:24])=[NH:23].Cl.C(OCCO)C.Cl>>[ClH:1].[Cl:1][C:2]1[C:3](=[O:21])[N:4]([CH3:20])[C:5]2[CH2:6][CH:7]([C:14]3[CH:18]=[CH:17][S:16][C:15]=3[Cl:19])[CH2:8][C:9](=[N:26][NH:25][C:22]([NH2:24])=[NH:23])[C:10]=2[C:11]=1[CH3:12]
Reactant: Cc1c2c(n(C)c(=O)c1Cl)CC(c1ccsc1Cl)CC2=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCOCCO
Product: Cc1c2c(n(C)c(=O)c1Cl)CC(c1ccsc1Cl)CC2=NNC(=N)N
Temperature: 135 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To a mixture of 3-chloro-7-(2-chlorothiophen-3-yl)-1,4-dimethyl-1,2,5,6,7,8-hexahydroquinoline-2,5-dione (0.098 g) and aminoguanidine hydrochloride (32 mg) were added 2-ethoxyethanol (1.5 ml) and concentrated hydrochloric acid (0.05 ml), and the mixture was stirred at 135° C. for 1 hour and cooled. Precipitated crystals were filtered, washed with methanol and dried to give 3-chloro-7-(2-chlorothiophen-3-yl)-5-guanidinoimino-1,4-dimethyl-1,2,5,6,7,8-hexahydroquinolin-2-one hydrochloride (Compound 140) (0.04 g) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:38][CH3:39])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:37]=[CH:36][C:22]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([C:34]#[N:35])=[CH:31][CH:32]=5)[N:27]=[CH:26][CH:25]=4)=[CH:21][CH:20]=3)=[N:10][N:9]=2)[CH:7]=1.C(=O)(O)[O-:41].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:38][CH3:39])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:37]=[CH:36][C:22]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([C:34]([NH2:35])=[O:41])=[CH:31][CH:32]=5)[N:27]=[CH:26][CH:25]=4)=[CH:21][CH:20]=3)=[N:10][N:9]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1nnc(Nc2ccc(Oc3ccnc4cc(C#N)ccc34)cc2)c2ccccc12
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(F)cc1-c1nnc(Nc2ccc(Oc3ccnc4cc(C(N)=O)ccc34)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A sealed tube was charged with 4-(4-(4-(5-fluoro-2-methoxyphenyl)phthalazin-1-ylamino)phenoxy)quinoline-7-carbonitrile (150 mg, 0.529 mmol) in neat concentrated sulfuric acid (3 mL). The tube was sealed and placed in a preheated oil bath at 80° C. for 1 h, at which point the reaction was determined complete by LCMS. The reaction was cooled to RT and added drop-wise to sat. sodium bicarbonate in an ice bath. Neutralized the mixture with 2N NaOH to a pH of 7 and extracted with ethyl acetate (3×). Organic layers were dried over magnesium sulfate, filtered and concentrated. The crude was purified via silica gel chromatography using a slow gradient of 90:10:1 (DCM:methanol:ammonium hydroxide) in DCM. Fractions contained the desired material were pooled and concentrated in vacuo to afford 4-(4-(4-(5-fluoro-2-methoxyphenyl)phthalazin-1-ylamino)phenoxy)quinoline-7-carboxamide as a tan solid. MS m/z=532 [M+H]+. Calc'd for C31H22FN5O3: 531.54.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].CC(C)=O.[OH:9][N:10]=[C:11]([CH3:26])[CH2:12][N:13]([S:22]([CH3:25])(=[O:24])=[O:23])[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21]>C(N(CC)CC)C>[CH3:1][NH:2][C:3]([O:9][N:10]=[C:11]([CH3:26])[CH2:12][N:13]([S:22]([CH3:25])(=[O:24])=[O:23])[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])=[O:4]
Reactant: CC(CN(c1c(C)cccc1C)S(C)(=O)=O)=NO
Reactant: CN=C=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CNC(=O)ON=C(C)CN(c1c(C)cccc1C)S(C)(=O)=O
Reaction time: 8 h

Procedure:
Methyl isocyanate (1.2 ml) was added to an acetone solution of N-[2-hydroxyiminopropyl]-2',6'-dimethylmethanesulphonanilide (2.7 g) containing triethylamine (0.05 ml). The mixture was allowed to stand at room temperature overnight, then evaporated to a viscous oil which slowly solidified on standing. Recrystallisation from ethylacetate/60°-80° petrol gave colourless crystals of N-[2-(methylcarbamoyloxyimino)propyl]-2',6'-dimethylmethanesulphonanilide. Yield 3.0 g (91%). Melting point 130°-134°.
Reaction SMILES: [N:1]([C:4]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=O)=[N+]=[N-].O=P(Cl)(Cl)[Cl:23]>>[Br:20][C:18]1[CH:17]=[CH:16][C:5]2[C:4]([CH:19]=1)=[N:1][N:8]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[C:6]=2[Cl:23]
Reactant: [N-]=[N+]=Nc1cc(Br)ccc1C(=O)Nc1ccc(F)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc(-n2nc3cc(Br)ccc3c2Cl)cc1
Temperature: 95 °C
Yield: 64 %

Procedure:
A mixture of compound (xii) (6.44 g, 19.20 mmol) and POCl3 (50 mL) was heated at 95° C. for 6 h. The volatiles were removed under reduced pressure and the residue was basified by the addition of an ice-cold saturated solution of sodium carbonate. The solid obtained was filtered and dried (Na2SO4) to give the crude product which was purified by column chromatography on 100-200 mesh silica gel eluting with EtOAc/hexane (3-5%) to give 6-bromo-3-chloro-2-(4-fluorophenyl)-2H-indazole (xiii) (4 g, 64%) as a white solid. ESI-MS m/z calculated for [M+H]+: 326.95; found: 326.95.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][C:6](=O)[CH2:5][CH2:4][S:3]1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:31]=1)[NH:28][CH:27]=[CH:26]2.C([SiH](CC)CC)C>C(Cl)Cl>[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:31]=1)[NH:28][CH:27]=[C:26]2[CH:6]1[CH2:5][CH2:4][S:3][C:2]([CH3:9])([CH3:1])[CH2:7]1
Reactant: CC1(C)CC(=O)CCS1
Reactant: CCOC(=O)c1cc(Br)cc2cc[nH]c12
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)cc2c(C3CCSC(C)(C)C3)c[nH]c12
Temperature: 0 °C
Yield: 114 %

Procedure:
2,2-Dimethyltetrahydro-4H-thiopyran-4-one (0.675 g, 4.68 mmol) was placed in a dried flask fitted up with an addition funnel, a septum and an argon inlet, and dissolved in dry DCM (15 mL), cooled to 0° C., stirred, and then trimethylsilyl trifluoromethanesulfonate (1.692 mL, 9.36 mmol) was added dropwise through the addition funnel over 10 minutes. DCM (5 mL) was used to wash the addition funnel walls. To this mixture was added dropwise ethyl 5-bromo-1H-indole-7-carboxylate (1.341 g, 5 mmol) in DCM (15 mL) over 2 hours. Then triethylsilane (2.98 mL, 18.73 mmol) was added in one portion. The mixture was stirred 2 h at 0° C., and left stirring at 23° C. overnight. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate, and the resulting biphasic mixture extracted with DCM to give 2.115 g of the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[CH3:22])/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CCO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:14]=1
Reactant: CCOC(=O)/C(C)=C/c1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The reaction mixture compound 12.2 (2.80 g, 9.45 mmol) and Pd/C (0.40 g, wt 10% on activated carbon) in EtOH (35 mL) was purged with hydrogen three times and stirred under hydrogen at ambient temperature overnight. The catalyst was removed by filtration. The filtrate was evaporated to give the crude compound 12.3 which was used in the next step without further purification. MS ESI (pos.) m/e: 209 (M+H). 1H NMR (CDCl3) δ 7.02(d, 2H), 6.75(d, 2H), 4.11(q, 2H), 2.93(dd, 1H), 2.68(m, 2H), 1.21(t, 3H), 1.16(d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:14][C:15]([OH:17])=[O:16])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: O=C(O)CC(=O)O
Reactant: COc1cc(C=O)cc(OC)c1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1cc(C=CC(=O)O)cc(OC)c1
Temperature: 100 °C
Yield: 70.7 %

Procedure:
To a solution of 3,5-dimethoxybenzaldehyde (12.5 g) in pyridine (20 ml) was added malonic acid (8.61 g) and piperidine (1 ml). The resulting solution was heated at 100° C. for 16 hours, cooled to room temperature, poured onto ice and acidified using conc. HCl. The resulting precipitate was collected, extracted into sodium bicarbonate solution and washed with isohexane. The aqueous phase was acidified using conc. HCl to yield a white precipitate which was filtered off, washed with water and dried to afford the subtitle compound (11.07 g).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].CN(C)C1C=CC=CC=1.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])=[O:22])[CH3:25]
Reactant: O=C(O)c1ccccc1O
Reactant: CCOC(=O)Cl
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)Oc1ccccc1C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 41.7 %

Procedure:
60 g (434 mmol) of salicylic acid and 111 ml of N,N-dimethylaniline are dissolved in 360 ml of toluene. The medium is cooled to 0° C. and then 41.5 ml (434 mmol) of ethyl chloroformate are added dropwise. After stirring for 2 hours at ambient temperature, the mixture is washed with a 1N aqueous hydrochloric acid solution and then with a saturated sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and concentrated. The residue is taken up in dichloromethane and precipitated from heptane. The solid is filtered off and then dried. 38 g of 2-(ethoxycarbonyloxy)benzoic acid are obtained in the form of a white solid with a yield of 42%.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: NS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (337 mg, 1.0 mmol) and commercially available 3-bromobenzene-1-sulfonamide [CAS 89599-01-9] (307 mg, 1.3 mmol) according to general procedure II. Obtained as a yellow solid (150 mg, 31%). MS (ISP) 493.0[(M+H)+]; mp 246-247° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([Br:12])[C:9]2[C:4](=[C:5]([Br:22])[CH:6]=[C:7]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:14])[CH:8]=2)[N:3]=1.[CH3:23][C:24]([O-:27])([CH3:26])[CH3:25].[K+]>C1(C)C=CC=CC=1.[Cl-].[Na+]>[Br:12][C:10]1[C:9]2[C:4](=[C:5]([Br:22])[CH:6]=[C:7]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:14])[CH:8]=2)[N:3]=[C:2]([O:27][C:24]([CH3:26])([CH3:25])[CH3:23])[CH:11]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C(c1ccc(Cl)cc1)c1cc(Br)c2nc(Br)cc(Br)c2c1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)Oc1cc(Br)c2cc(C(=O)c3ccc(Cl)cc3)cc(Br)c2n1
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2,4,8-tribromo-6-[(4-chlorophenyl)carbonyl]quinoline (1.0 g, 1.98 mmol, 1.00 equip) in toluene (30 mL), and KOt-Bu (2.18 mL, 1.10 equip). The resulting solution was stirred for 1.5 h at 65° C. The resulting solution was diluted with saturated sodium chloride (50 mL). The resulting solution was extracted with ethyl acetate (2×100 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (5:95) to yield 4,8-dibromo-2-(tert-butoxy)-6-[(4-chlorophenyl)carbonyl]quinoline as a yellow solid. LCMS (ES, m/z) 498 [M+H]+
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13]
Reactant: COC(=O)c1ccc(C)c(I)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C)c(C#C[Si](C)(C)C)c1
Temperature: 50 °C

Procedure:
A mixture of methyl 3-iodo-4-methylbenzoate (2.0 g, 7 mmol), trimethylsilylacetylene (1.2 ml, 8 mmol), Pd(PPh3)4 (0.42 g, 0.3 mmol), CuI (0.137 g, 0.7 mmol) and diisopropylethylamine (2.5 ml, 11.4 mmol) in THF (20 ml) was heated at 50° C. for 12 hrs under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and filtered through a Celite® bed. The clear filtrate was concentrated and the residue purified by flash chromatography on silica gel (elution with 2% ethyl acetate in n-hexane) to provide methyl 4-methyl-3-[(trimethylsilyl)ethynyl]benzoate.
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:35])[C@H:20]2[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([S:47]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:44][C@H:43]1[CH2:67][CH:68]1[NH:72][C:71](=[O:73])[NH:70][C:69]1=[O:74])=[O:41])[CH:37]=[CH2:38]>>[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([S:47][C:18]2[C@H:19]([CH3:35])[C@@H:20]3[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:21]3[C:22]=2[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH2:44][C@H:43]1[CH2:67][CH:68]1[NH:72][C:71](=[O:73])[NH:70][C:69]1=[O:74])=[O:41])[CH:37]=[CH2:38]
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CC1NC(=O)NC1=O
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CC3NC(=O)NC3=O)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 26 %

Procedure:
The same procedure as in Example 8-1 was carried out by using allyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (220 mg, 0.440 mmol) and (2R,4S)-N-allyloxycarbonyl-2-(2,4-dioxoimidazolidin-5-ylmethyl)-4-tritylthiopyrrolidine diastereomer A (270 mg, 0.498 mmol, compound of Reference Example 29) to obtain allyl (1R,5S,6S)-2-[(2R,4S)-N-allyloxycarbonyl-2-(2,4-dioxoimidazolidin-5-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate diastereomer A (70 mg, yield: 26%).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:26]=[C:25]([CH3:27])[CH:24]=[N:23][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([C:21]3[N:28]=[N:29][NH:30][N:22]=3)[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:26]=[C:25]([CH3:27])[CH:24]=[N:23][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCS(=O)(=O)c1cccc(-c2cc(C#N)cc3[nH]c4ncc(C)cc4c23)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1cccc(-c2cc(-c3nn[nH]n3)cc3[nH]c4ncc(C)cc4c23)c1
Temperature: 158 °C
Yield: 77.5 %

Procedure:
Compound 126 (14 mg, 0.037 mmol), sodium azide (9.7 mg, 0.15 mmol), and ammonium chloride (8.0 mg, 0.15 mmol) were combined in DMF (1 mL) and heated at 158° C. in the microwave for 1 h. Purification by prep-HPLC gave 12 mg (77%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 8.35 (s, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 8.02-8.11 (m, 2H), 7.94 (t, 1H, J=5.6 Hz), 7.83 (s, 1H), 7.54 (s, 1H), 3.44 (q, 2H, J=7.2 Hz), 2.27 (s, 3H), 1.17 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C21H18N6O2S, 419; found 419.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]3([CH2:31]I)[CH2:29][O:28][C:27](=[O:30])[NH:26]3)=[C:18]([Cl:33])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:34](OCC)([O:38]CC)[O:35][CH2:36][CH3:37]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]3([CH:31]=[P:34]([O:35][CH2:36][CH3:37])=[O:38])[CH2:29][O:28][C:27](=[O:30])[NH:26]3)=[C:18]([Cl:33])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(CI)(CCCc2ccc(Sc3cccc(OCc4ccccc4)c3)cc2Cl)CO1
Reactant: CCOP(OCC)OCC
Product: CCO[P+]([O-])=CC1(CCCc2ccc(Sc3cccc(OCc4ccccc4)c3)cc2Cl)COC(=O)N1

Procedure:
The compound of Example 188 (330 mg) was dissolved in triethyl phosphite (120 μL) and the solution was refluxed for 3 hours. Subsequently, the reaction mixture was purified on a silica gel column chromatography (hexane:ethyl acetate=1:1 to 1:5) to give the desired product as a pale yellow oil (320 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH:8]=[CH:7]2.[H][H]>[Pd].C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2
Reactant: [H][H]
Reactant: Cc1nc(-c2ccccc2)cc2cc[nH]c(=O)c12
Agent: [Pd]
Solvent: CCO
Product: Cc1nc(-c2ccccc2)cc2c1C(=O)NCC2
Yield: 91.6 %

Procedure:
8-methyl-6-phenyl-2H-[2,7]naphtyridine-1-on (500 mg, 2.116 mmol) was suspended in anhydrou ethanol, added with 5% Pd/C (400 mg) and then stirred at room temperature under the hydrogen atmosphere for about 72 hours. The mixture was filtered and then concentrated under reduced pressure. A silica gel column chromatography (2% MeOH/MC) was performed on the resulting residue and obtained 462 mg (92%) of 8-methyl-6-phenyl-3,4-dihydro-2H-[2,7]naphtyridine-1-on in white solid.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7](CC(N3CCOCC3)=S)[CH:8]=[CH:9][C:2]1=2.[C:19]([OH:22])(=[O:21])[CH3:20].S(=O)(=O)(O)O>O>[S:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([CH2:20][C:19]([OH:22])=[O:21])[CH:8]=[CH:9][C:2]1=2
Reactant: CC(=O)O
Reactant: S=C(Cc1ccc2c(c1)CCS2)N1CCOCC1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)CCS2
Temperature: 100 °C
Yield: 41 %

Procedure:
In a round bottom flask with a reflux condenser was placed 2-(2,3-dihydro-benzo[b]thiophen-5-yl)-1-morpholin-4-yl-ethanethione (1.85 g, 6.62 mmol) and to it was added acetic acid (7.7 mL), concentrated sulfuric acid (1.1 mL) and water (2 mL). The reaction mixture was then heated at 100° C. for 4 h. After this time the solution was added to water (40 mL) and extracted with ethyl acetate (3×50 mL). The organics were dried over sodium sulfate, filtered and concentrated in vacuo. Purified using reverse phase HPLC to afford (2,3-dihydro-benzo[b]thiophen-5-yl)-acetic acid (525 mg, 41%) as a white solid.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:13]([NH:15][CH2:16][CH2:17][NH2:18])C.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH3:13][NH:15][CH2:16][CH2:17][NH:18][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1F
Reactant: CCNCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CNCCNc1cc([N+](=O)[O-])ccc1C#N
Reaction time: 16 h

Procedure:
A mixture of 2-fluoro-4-nitrobenzonitrile (13.2 g), N-ethylethylenediamine (16 mL) and potassium carbonate (10 g) in acetonitrile (250 mL) was vigorously stirred for 16 hours resulting in the formation of an orange solid. The mixture was diluted with water and filtered. The precipitate was washed with water and dried to provide 2-(2-methylamino-ethylamino)-4-nitro-benzonitrile (10 g): 1H NMR (300 MHz, CDCl3) δ 7.65 (d, 1H), 7.55 (m, 2H), 5.8 (br, 1H), 3.4 (q, 2H), 3.1 (m, 2H), 2.8 (q, 2H), 1.2 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24](OC)=[C:23]([O:29]C)[CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([C:31]([F:34])([F:33])[F:32])[NH:11]1.B(Br)(Br)Br>C(Cl)Cl>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:29])[CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([C:31]([F:33])([F:32])[F:34])[NH:11]1
Reactant: COc1ccc(Cc2nc3n(-c4c(Cl)cc(Cl)cc4Cl)[nH]c(C(F)(F)F)c-3c(=O)n2)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1nc(Cc2cccc(O)c2)nc2n(-c3c(Cl)cc(Cl)cc3Cl)[nH]c(C(F)(F)F)c1-2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 60 mg (0.12 mmol) of 1-(2,4,6-trichlorophenyl)-3-trifluoromethyl-6-(3-methoxy-4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 2 mL of CH2Cl2 was added 2 mL of a 1M solution of BBr3 in CH2Cl2. The solution was stirred 2.5 h at RT and quenched with 1 N aq. HCl. The mixture was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried (MgSO4), and concentrated under reduced pressure. The crude product was chromatographed on silica gel (elution with 1:1 hexanes-THF, then THF) to afford 1-(2,4,6-trichlorophenyl)-3-trifluoromethyl-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one, as an off-white solid. Mass spec.: 487(M−H)−.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:35])[CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:24]1[CH:23]=[C:22]([C:21]2[CH2:20][C:19](=[O:35])[NH:18][C:9]3[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccccn3)c2)=Nc2ccc(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {2-[3-oxo-3-(3-pyridin-2-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M30) (275 mg, 0.551 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (141 mg).