Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH2:17]O)=[CH:14][C:13]=2[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH2:17][N:24]3[C:20](=[O:30])[C:21]4[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:23]3=[O:25])=[CH:14][C:13]=2[CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1cc2cc(OCc3ccccc3)ccc2o1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1cc2cc(OCc3ccccc3)ccc2o1
Temperature: 25 °C
Reaction time: 9 h
Yield: 74.9 %

Procedure:
To a tetrahydrofuran (10 mL) solution of (5-benzyloxy-benzofuran-2-yl)-methanol (561 mg, 2.21 mmol) described in Production Example 7-1-4 were added phthalimide (358 mg, 2.43 mmol), triphenylphosphine (696 mg, 2.65 mmol) and diethylazodicarboxylate (1.21 mL, 2.65 mmol) at 0° C., which was stirred at room temperature for 9 hours. Water was added to the reaction solution at room temperature followed by extraction with ethyl acetate. The organic layer was washed with sat. NaCl followed by drying over anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=7:3) to obtain the title compound (635 mg, 75%) as a white solid.
Reaction SMILES: [C:1]1(=[O:32])[N:5]([CH:6]2[C:25](=[O:26])[N:8]3[C:9]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:10]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[CH2:11][S:12][C@H:7]23)[C:4](=[O:27])[C:3]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:2]12.C1C[O:36]CC1.[OH-].[Na+].O>C(OCC)(=O)C>[C:1]([C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[C:4]([NH:5][CH:6]1[C:25](=[O:26])[N:8]2[C:9]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])=[C:10]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[CH2:11][S:12][C@H:7]12)=[O:27])([OH:36])=[O:32]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N3C(=O)c4ccccc4C3=O)[C@H]2SC1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)c3ccccc3C(=O)O)[C@H]2SC1
Reaction time: 0.08 h
Yield: 83 %

Procedure:
A solution of 458 mg. (1 mmol.) of t-butyl 7-phthalimido-3-acetoxymethyl-3-cephem-4-carboxylate in 10 ml. of THF was cooled in an ice water bath, and 1.1 ml. of 1N NaOH were then added. After stirring for 5 min., 10 ml. of water and 30 ml. of ethyl acetate were added. The ethyl acetate layer was separated, and 70 mg. of starting material were recovered therefrom. The aqueous layer was acidified to pH 4.0, and the acidified layer was extracted with ethyl acetate. After workup, 330 mg. (83%) of the desired phthalamic acid were obtained [α] + 26.37 (MeCN); λEtOH 260 mμ (ε 8800)D ; ir (CHCl3) 1785, 1730 and 1685 cm-1 ; nmr (CDCl3) δ 1.55 (s, 9, t-Bu), 2.05 (s, 3, Ac), 3.3 and 3.6 (ABq, 2, J = 17 Hz), 4.72 and 5.2 (ABq, 2, J = 14 Hz), 4.98 (d, 1, J = 4.5 Hz), 5.9 (dd, 1, J = 4.5 and 9 Hz), and 7.5-8 (m, 4, ArH).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]3[CH:15]=[C:14]([C@H:16]([NH:18]C(=O)OC(C)(C)C)[CH3:17])[O:13][N:12]=3)[NH:8][C:7]=2[CH:26]=1>C(O)(C(F)(F)F)=O>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]3[CH:15]=[C:14]([C@H:16]([NH2:18])[CH3:17])[O:13][N:12]=3)[NH:8][C:7]=2[CH:26]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1cc(-c2nc3ccc(C(F)(F)F)cc3[nH]2)no1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N)c1cc(-c2nc3ccc(C(F)(F)F)cc3[nH]2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
A mixture of (R)-tert-butyl 1-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)isoxazol-5-yl)ethylcarbamate (86.5 g, 0.22 mol) in TFA (300 mL) was stirred at RT for 2 hr. The reaction mixture was concentrated in vacuo and re-dissolved in ethyl acetate. The ethyl acetate solution was washed with K2CO3 and water, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography to afford compound Na, (R)-1-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)isoxazol-5-yl)ethanamine (30.2 g, 46.7%). 1H NMR (DMSO-d6) δ 7.98 (s, 1H), 7.78 (d, 1 H), 7.56 (d, 1H), 6.94 (s, 1H), 4.16 (q, 1H), 1.36 (d, 3H).
Reaction SMILES: [CH2:1]([NH:3][NH2:4])[CH3:2].[CH3:5][C:6]1[S:10][C:9]([N:11]=[C:12]=[O:13])=[N:8][N:7]=1.NN>C(Cl)Cl>[CH2:1]([N:3]([C:12]([NH:11][C:9]1[S:10][C:6]([CH3:5])=[N:7][N:8]=1)=[O:13])[NH2:4])[CH3:2]
Reactant: Cc1nnc(N=C=O)s1
Reactant: CCNN
Agent: NN
Solvent: ClCCl
Product: CCN(N)C(=O)Nc1nnc(C)s1
Temperature: 25 °C

Procedure:
A solution of ethylhydrazine (0.3 mole) in methylene chloride (150 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 5-Methyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.1 mole) is then added, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 4 hours. After this time the reaction mixture is stripped of solvent and excess hydrazine to yield the desired product 2-ethyl-4-(5-methyl-1,3,4-thiadiazol-2-yl)semicarbazide as the residue.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl.CCN(C(C)C)C(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[Cl:59][C:60]1[CH:65]=[CH:64][C:63](B(O)O)=[CH:62][CH:61]=1>C(Cl)Cl.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.O>[CH2:17]([O:16][C:14]([C:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C:10]=1[C:63]1[CH:64]=[CH:65][C:60]([Cl:59])=[CH:61][CH:62]=1)=[O:15])[CH3:18]
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1=C(c2ccc(Cl)cc2)CN(Cc2ccccc2)CC1
Temperature: -30 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
In a 1500 mL four necked flask (with mechanical stirrer) 22 g (84.2 mmol) ethyl N-benzyl-3-oxo-4-piperidine-carboxylate (from the HCl-salt by aq.Na2CO3/CH2Cl2-extraction) and 43.5 mL (252 mmol) DIPEA were dissolved in 300 mL DCM. The amber solution was cooled to −20° C. to −30° C. 28.5 g (101 mmol) trifluoromethanesulfonic anhydride were added drop wise over a period of 45 min. The dark brown solution was stirred for 2 h at −20° C./−30° C. 300 mL water and 300 mL 10% Na2CO3 aq. was added and the mixture was stirred for 15 min at 5-10° C. The organic layer was separated and the aqueous layer was extracted twice with 150 mL DCM. The combined organic layers were dried over Na2SO4 and filtered. The filtrate was evaporated to dryness and dissolved in 500 mL dioxane. 15.8 g (101 mmol) 4-chlorophenylboronic acid, 93 mL Na2CO3 aq. (2M) and 3.8 g (3.36 mmol) tetrakis(triphenylphosphine)palladium(0) was added and the mixture was heated to reflux over night. After cooling to room temperature, the mixture was diluted with 400 g ice-water and extracted twice with 400 mL ethyl acetate. The organic layers were extracted once with 500 mL brine. After drying over Na2SO4 the filtrate was evaporated to dryness. The black oil was absorbed on 60 g isolute HM-N and purified by column chromatography to yield 14.6 g (48%) of the title compound as viscous yellow oil. MS (m/e): 356.3 [(M+H)+].
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.[C:11]([C:13]1[CH:14]=[C:15]([C:19](=[O:21])[CH3:20])[CH:16]=[CH:17][CH:18]=1)#[CH:12].N>>[N:5]1[CH:6]=[CH:7][N:8]=[CH:9][C:4]=1[C:3]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]([C:19](=[O:21])[CH3:20])[CH:16]=[CH:17][CH:18]=2)[O:1][N:2]=1
Reactant: ON=C(Cl)c1cnccn1
Reactant: C#Cc1cccc(C(C)=O)c1
Agent: N
Product: CC(=O)c1cccc(-c2cc(-c3cnccn3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 83D (79 mg, 0.5 mmol) and 1-(3-ethynylphenyl)ethanone (GFS Chemicals, 72 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 2.70 (s, 3H), 7.55 (s, 1H), 7.71 (t, J=7.8 Hz, 1H), 8.07-8.23 (m, 2H), 8.52 (t, J=1.7 Hz, 1H), 8.70 (d, J=2.7 Hz, 1H), 8.74-8.82 (m, 1H), 9.31 (d, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 266 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:27][CH3:28])[N:13]2[CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C2CCOCC2)=[C:9]([NH2:29])[N:8]=1)[CH2:3][CH2:4][CH3:5].ClCCCCN1C(OC)=NC2C1=NC(O[C@@H](C)CCC)=NC=2N.[O:53]1[CH2:58][CH2:57][CH:56]([CH2:59]N)[CH2:55][CH2:54]1>>[CH3:1][C@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:27][CH3:28])[N:13]2[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:59][CH:56]2[CH2:57][CH2:58][O:53][CH2:54][CH2:55]2)=[C:9]([NH2:29])[N:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCNC3CCOCC3)c2n1
Reactant: NCC1CCOCC1
Agent: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCNCC3CCOCC3)c2n1

Procedure:
Prepared similarly to Intermediate 36 from 9-(4-chlorobutyl)-2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-6-amine and (tetrahydro-2H-pyran-4-ylmethyl)amine.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH3:19][C:20]1[CH:29]=[C:28]([C:30]#[C:31][Si](C)(C)C)[CH:27]=[CH:26][C:21]=1[O:22][CH2:23][CH2:24][OH:25].CCOC(C)=O>C1COCC1>[C:30]([C:28]1[CH:27]=[CH:26][C:21]([O:22][CH2:23][CH2:24][OH:25])=[C:20]([CH3:19])[CH:29]=1)#[CH:31]
Reactant: Cc1cc(C#C[Si](C)(C)C)ccc1OCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#Cc1ccc(OCCO)c(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
20.8 g (74.4 mmol) of TBAF was added at RT to a solution of 16.8 g (67.6 mmol) of 2-(2-methyl-4-trimethylsilanylethynylphenoxy)ethanol in 500 mL of THF and the mixture was stirred for 3 hours at RT. The reaction mixture was evaporated down in vacuo and the residue dissolved in EtOAc. The organic phase was washed with water and saturated aqueous NaCl solution, dried over sodium sulfate, and evaporated down in vacuo. The crude product was used in the next reaction step without further purification. Yield: 12.0 g (quant. yield); C11H12O2 (M=176.212); calc.: molpeak (M)+: 176; found: molpeak (M)+: 176; Rf value: 0.24 (silica gel, cyc/EtOAc 2:1).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].Cl.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:33]3[CH2:34][CH2:35][CH:30]([C:27]4[CH:26]=[CH:25][C:24]([NH2:23])=[CH:29][CH:28]=4)[CH2:31][CH2:32]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: Nc1ccc(C2CCNCC2)cc1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: Cl
Product: Nc1ccc(C2CCN(C(=O)Oc3ccc(Oc4ccc(C(F)(F)F)cn4)cc3)CC2)cc1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 4-(4-aminophenyl)piperidine, hydrochloride, preparative HPLC (Method C) (30%, light yellow crystals). HPLC-MS m/z=458.2 (M+1), Rt: 3.42 min.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[C:18](I)[N:17]=2)=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:30]1([CH2:36]/[CH:37]=[CH:38]/B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>COC.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]>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[C:18](/[CH:38]=[CH:37]/[CH2:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:17]=2)=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2cncc(I)n2)sc1C(=O)NCc1ccccc1
Reactant: OB(O)/C=C/Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: COC
Solvent: O
Product: Cc1nc(-c2cncc(/C=C/Cc3ccccc3)n2)sc1C(=O)NCc1ccccc1
Reaction time: 3 h
Yield: 50.8 %

Procedure:
Part A. To a solution of 2-(6-iodo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid benzylamide (80 mg, 0.18 mmol, 1.0 equiv) in dimethyl ether (1 mL) was added Na2CO3 (38 mg, 0.36 mmol, 2.0 equiv), trans-3-phenylpropen-1-yl boronic acid (73 mg, 0.45 mmol, 2.5 equiv), PdCl2(dppf) (1.3 mg, 0.02 mmol, 0.1 equiv) and water (0.1 mL) in a sealed tube. The reaction vessel was immersed in an oil bath preheated to 60° C. After stirring for 3 hr, the reaction mixture was cooled and the solvent was removed in vacuo. The crude product was purified by column chromatography [SiO2, methanol/dichloromethane, 0:100 to 10:90, v/v] to give 4-methyl-2-[6-((E)-3-phenyl-propenyl)-pyrazin-2-yl]-thiazole-5-carboxylic acid benzylamide (39 mg, 50%); MS (M+H)+=427.1, Rt=1.70 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[Cl:16][CH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O>O1CCCC1.C(=O)([O-])[O-].[K+].[K+].[Zn]>[Cl:16][CH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: O=C(CCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Zn]
Solvent: C1CCOC1
Product: Nc1ccc(C(=C(CCCl)c2ccccc2)c2ccccc2)cc1
Temperature: -10 °C
Reaction time: 3.5 h

Procedure:
Zinc (10.0 g, 0.154 mol) and tetrahydrofuran (THF) (120 ml) is added to the reaction vessel and cooled to −10° C. To the mixture is added dropwise titan tetrachloride (1 4.4 g, 0.076 mol) at about −10° C. After the addition is completed the mixture is refluxed for two hours. Then it is cooled to 40° C. and (4-Amino-phenyl)phenyl-methanone (5.1 g, 0.0258 mol) and 3-chloropropiophenone (4.36 g, 0.0258 mol) are dissolved in THF (50 ml) and added to the mixture. Refluxingis continued for additional 3.5 hours. The cooled reaction mixture is poured in aqueous potassium carbonate solution (14 g K2CO3+140 ml water) and allowed to stand over night. The mixture is filtered and the precipitate is washed three times with THF. The filtrate is evaporated to dryness. The residue is dissolved in ethyl acetate and washed with water. Yield 9.6 g Z-isomer being the only isomer.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:30])[C@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.N1C=CC=CC=1.[C:39]([NH:42][C:43]1[CH:44]=[C:45]2[C:50](=[CH:51][CH:52]=1)[CH:49]=[C:48]([S:53](Cl)(=[O:55])=[O:54])[CH:47]=[CH:46]2)(=[O:41])[CH3:40]>CC(C)=O>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:14](=[O:30])[C:13]=1[C:8]1[NH:7][C:6]2[CH:31]=[CH:32][C:3]([NH:2][S:53]([C:48]3[CH:49]=[C:50]4[C:45](=[CH:46][CH:47]=3)[CH:44]=[C:43]([NH:42][C:39](=[O:41])[CH3:40])[CH:52]=[CH:51]4)(=[O:55])=[O:54])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CC(=O)Nc1ccc2cc(S(=O)(=O)Cl)ccc2c1
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC(=O)Nc1ccc2cc(S(=O)(=O)Nc3ccc4c(c3)S(=O)(=O)N=C(C3=C(O)c5ccccc5[C@@](C)(CCC(C)C)C3=O)N4)ccc2c1
Yield: 61 %

Procedure:
A mixture of Example 39H (23.8 mg, 0.050 mmol), pyridine (31.6 mg, 0.40 mmol) and 6-acetylamino-2-naphthalenesulfonyl chloride (56.7 mg, 0.20 mmol, prepared by the procedure as described in J. Med. Chem., 1995, 38, 8, p. 1344-1354) in acetone (1.5 mL) was stirred at rt for 18 h. The reaction mixture was evaporated in vacuo and partitioned between ethyl acetate and 1 N HCl. The organic phase was separated, dried (MgSO4), filtered, and evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with 99:1 dichloromethane/methanol to provide the title compound (20.8 mg, 61% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.38 m, 1 H) 0.66 (d, J=7.35 Hz, 3 H) 0.68 (d, J=6.99 Hz, 3H) 0.80 m, 1 H) 1.30 m, 1 H) 1.53 (s, 3 H) 2.02 m, 1 H) 2.10 (s, 3 H) 2.18 (m, 1 H) 7.52 m, 4 H) 7.69 m, 4 H) 7.99 (d, J=8.82 Hz, 1 H) 8.07 (d, J=8.82 Hz, 1 H) 8.11 (d, J=8.09 Hz, 1H) 8.38 (s, 2 H) 10.32 (s, 1 H) 10.87 (s, 1 H) 13.72 (s, 1 H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:8]=2)[CH2:3]1.Br[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO.O>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:26]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)=[CH:25][C:10]([C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:24])[F:23])=[CH:18][CH:19]=3)=[O:12])=[CH:9][N:8]=2)[CH2:3]1
Reactant: Brc1ccccn1
Reactant: CC1(C)OB(c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccccn2)c1

Procedure:
(R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 40.1, 150 mg, 0.243 mmol), 2-bromopyridine (192 mg, 1.216 mmol), Pd(Ph3P)2Cl2 (17.07 mg, 0.024 mmol) and Na2CO3 (77 mg, 0.730 mmol) were added to a MW vial and treated with a mixture of DME (1032 μL), water (295 μL) and EtOH (147 μL). The vial was sealed, evacuated/purged with argon and subjected to MW irradiation at 125° C. for 20 min. The RM was diluted with DME (2 mL), treated with Si-Thiol (Silicycle, 1.43 mmol/g, 102 mg, 0.146 mmol), centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 12 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (9:1), from 25% to 100% EtOAc-EtOH+0.1% NH4OH (9:1)) and further purification by preparative HPLC (Condition 13, from 5% to 100% in 14 min) yielded the title compound as a yellow solid. UPLC-MS (condition 1) tR=1.85 min, m/z=445.2 [M+H]+, m/z=443.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.78 (m, 1H) 1.79-1.94 (m, 1H) 2.85 (d, J=11.49 Hz, 1H) 3.13-3.28 (m, 2H) 3.36-3.50 (m, 1H) 4.19 (d, J=2.20 Hz, 1H) 4.83 (d, J=3.18 Hz, 1H) 7.24-7.44 (m, 3H) 7.53 (d, J=7.82 Hz, 1H) 7.80-7.97 (m, 3H) 8.12 (d, J=2.20 Hz, 1H) 8.66 (dd, J=4.89, 0.73 Hz, 1H) 8.78 (d, J=2.45 Hz, 1H) 10.20 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][CH2:12][C:11]2=[C:15]([CH:19]=[CH2:20])[N:16]([CH3:18])[N:17]=[C:10]12.N(C([O-])=O)=NC([O-])=O.[K+].[K+].C(O)(=O)C>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][CH2:12][C:11]2=[C:15]([CH2:19][CH3:20])[N:16]([CH3:18])[N:17]=[C:10]12
Reactant: C=Cc1c2c(nn1C)N(c1ccc(Cl)cc1Cl)CCC2
Agent: O=C([O-])N=NC(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: CCc1c2c(nn1C)N(c1ccc(Cl)cc1Cl)CCC2
Reaction time: 3 h

Procedure:
To a solution of 7-(2,4-dichloro-phenyl)-2-methyl-3-vinyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine (3-7; 0.046 g, 0.15 mmol) in 2 mL of methanol was added dipotassium azodicarboxylate (0.174 g, 0.90 mmol) [prepared according to D. J. Pasto and R. J. Taylor, Organic Reactions 1991 40:91]. To the yellow suspension was added acetic acid (0.102 mL, 1.80 mmol) in 2 mL of methanol over 40 minutes. The reaction mixture was again treated with dipotassium azodicarboxylate (0.087 g, 0.45 mmol) and then acetic acid (0.051 mL, 0.90 mmol) in 1 mL of methanol over 20 nm. After 3 h at room temperature, the solvent was evaporated, the residue was treated with 10 mL of saturated sodium bicarbonate solution, extracted three times with 25 mL portions of dichloromethane, dried over magnesium sulfate, and evaporated to afford 41 mg of crude product. The crude product was purified by silica gel column chromatography eluting with 0 to 15% ethyl acetate/hexane which afforded 30 mg (65% theory) of 4-6 as a colorless oil: ms (M+H)+=310.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]>N1C=CC=CC=1>[S:11]([O:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1ccc(O)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(O)cc2)cc1
Reaction time: 2 h
Yield: 55.4 %

Procedure:
4-Hydroxyphenethyl alcohol (3.2 g) was dissolved in 50 ml of pyridine, to which 4.0 g of tosyl chloride was added in small portions under ice cooling. The temperature of the reaction mixture was allowed to rise to room temperature, at which it was stirred for 2 hours. Then, insoluble matter was filtered off, and pyridine was distilled off under reduced pressure. The residue was isolated and purified by chromatography on a silica gel column (eluent: CHCl3), whereby 3.4 g of the compound (1) were obtained (yield: 59%).
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:18]=[C:17]4[C:13]([CH2:14][CH2:15][CH2:16]4)=[CH:12][C:9]=3[O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:19]([O-:24])([N+]([O-])=O)=[O:20]>C(Cl)(Cl)Cl>[N+:19]([C:11]1[O:10][C:9]2[CH:12]=[C:13]3[C:17](=[CH:18][C:8]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:16][CH2:15][CH2:14]3)([O-:24])=[O:20]
Reactant: c1ccc(-c2coc3cc4c(cc23)CCC4)cc1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1oc2cc3c(cc2c1-c1ccccc1)CCC3

Procedure:
To a solution of 2.3 g. (0.01 mole) of the product of step B in 100 ml. of chloroform is added 1.8 g. (0.02 mole) of dinitrogen tetraoxide, and the mixture is stirred at about 20° C. for 20 hours. The mixture is evaporated, and the residue is triturated with isopropyl ether to provide a precipitate. The precipitate is separated by filtration and recrystallized from methanol to provide 6,7-dihydro-2-nitro-3-phenyl-5H-indeno-[5,6-b]furan, m.p. 161°-164° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:26]=[C:25]([O:27][CH2:28][CH:29]=[CH2:30])[C:24]([CH2:31][C:32]#[C:33][CH3:34])=[CH:23][C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:12][CH:11]=1)=O)[CH:2]=[CH2:3].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:26]=[C:25]([O:27][CH2:28][CH:29]=[CH2:30])[C:24]([CH2:31][C:32]#[C:33][CH3:34])=[CH:23][C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:12][CH:11]=1)=[S:44])[CH:2]=[CH2:3]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C=CCOc1cc(OCC=C)c(C(=O)Nc2ccc(CN3CCOCC3)cc2)cc1CC#CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CCOc1cc(OCC=C)c(C(=S)Nc2ccc(CN3CCOCC3)cc2)cc1CC#CC

Procedure:
2,4-bis-allyloxy-5 (but-2-ynyl)-N-[4-(morpholin-4-ylmethyl)-phenyl]-benzamide (F470-IM09: 400 mg, 0.86 mmol) and Lawesson's reagent (352 mg, 0.86 mmol) were dissolved in toluene (20 mL), and the mixture was heated under reflux for 3 hours. The reaction mixture was mixed with saturated aqueous sodium carbonate (30 mL) and extracted twice with ethyl acetate (40 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the crude title compound (F470-IM10:240 mg).