Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][CH:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:20][C:21]1([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH2:23][CH2:22]1>>[F:15][C:11]1([F:14])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:9]([C:16](=[O:18])[NH:20][C:21]2([C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=3)[CH2:23][CH2:22]2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(F)CC1C(=O)O
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)C3CC(F)(F)CCN3C(=O)OC(C)(C)C)CC2)cc1
Yield: 69.4 %

Procedure:
The title compound (D68) (688 mg) was prepared according to the general procedure for amides preparation (Method C) starting from 1-(tert-butoxycarbonyl)-4,4-difluoropiperidine-2-carboxylic acid (600 mg; described in WO2010148197) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (566.5 mg). Reaction time: 5 hrs
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:18]C(NCCN)=S)=[C:16]([CH3:17])[C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(Cl)Cl>CO>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:18][N:10]3[CH2:11][CH2:12][N:8]=[CH:9]3)=[C:16]([CH3:17])[C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(NC(=S)NCCN)ccc2c1ncn2C(=O)OC(C)(C)C
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1c(NN2C=NCC2)ccc2c1ncn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of N-(1-tert-butoxycarbonyl-4-methyl-5-benzimidazolyl)-N'-2-aminoethylthiourea (2.89 g) and mercuric acetate (3.32 g) in methanol (200 mL)/chloroform (100 mL) is stirred at room temperature for 2 hours. The resulting black mixture is filtered on Celite and the filtrate rotary evaporated. The residue is purified by flash chromatography on a short pad of silica gel, eluting with 10% methanol/chloroform containing 1% ammonium hydroxide. The product-containing fractions are collected and rotary evaporated to afford 1-tert-butoxycarbonyl-4-methyl-5-(2-imidazolinylamino)benzimidazole as a white solid.
Reaction SMILES: [CH3:1][Sn:2]([CH3:15])([CH3:14])[C:3]1[CH:12]=[N:11][C:10]2[NH:9][C:8](=[O:13])[CH2:7][O:6][C:5]=2[CH:4]=1.[Li]N([Si](C)(C)C)[Si](C)(C)[CH3:19].S(O)(O)(=O)=O.COS(OC)(=O)=O>C1COCC1>[CH3:19][N:9]1[C:8](=[O:13])[CH2:7][O:6][C:5]2[CH:4]=[C:3]([Sn:2]([CH3:15])([CH3:14])[CH3:1])[CH:12]=[N:11][C:10]1=2
Reactant: C[Sn](C)(C)c1cnc2c(c1)OCC(=O)N2
Reactant: [Li]N([Si](C)(C)C)[Si](C)(C)C
Agent: O=S(=O)(O)O
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: CN1C(=O)COc2cc([Sn](C)(C)C)cnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 680 mg of 7-trimethylstannyl-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (0.0022 mole) in 10 ml of THF is added 2.4 ml of LiN(TMS)2 (0.0024 mole) in THF. The homogenous solution is maintained under nitrogen at room temperature for 20 min , 300 mg (0.0024 mole) of dimethylsulfate sulfate is added and the reaction mixture allowed to stir overnight. The reaction mixture is then quenched with 10 ml of sat. ammonium chloride and extracted with 3×50 ml ethyl acetate. The ethyl acetate is then washed with 3×10 ml sat. ammonium chloride, dried over sodium sulfate and concentrated to obtain off white product whish is used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[CH:6][C:5]([N:14]=[C:15]=[O:16])=[C:4]([F:17])[CH:3]=1.[NH:18]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:19]1[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[CH:6][C:5]([NH:14][C:15]([N:18]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:19]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:16])=[C:4]([F:17])[CH:3]=1
Reactant: CCOC(=O)C1CCCCN1
Reactant: CC(C)OC(=O)c1cc(N=C=O)c(F)cc1Cl
Solvent: c1ccccc1
Product: CCOC(=O)C1CCCCN1C(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F
Temperature: 25 °C
Yield: 83.2 %

Procedure:
5.15 g (0.02 mol) of 4-chloro-2-fluoro-5-isopropoxycarbonylphenyl isocyanate were added to a solution of 3.31 g (0.02 mol) of ethyl pipecolate (95% purity) dissolved in 30 ml of benzene. The mixture was stirred at room temperature for an hour, washed with water, dried over anhydrous sodium sulfate, and then concentrated. The resulting crystal was recrystallized from a mixed solvent of hexane, toluene and ethyl acetate to give 6.9 g (yield 83.2%) of the desired product as white crystals with a melting point of 83°-85° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[C:15]1[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[C:18]([NH2:19])=[C:17]([CH:25]([CH3:27])[CH3:26])[CH:16]=1.CN1C=CN=C1>Cl[Cu].C(OCC)C.O.C1(C)C=CC=CC=1.CC1C=CC=CC=1C>[CH:22]([C:20]1[CH:21]=[C:15]([O:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:16]=[C:17]([CH:25]([CH3:27])[CH3:26])[C:18]=1[NH2:19])([CH3:24])[CH3:23]
Reactant: Oc1ccccc1
Reactant: CC(C)c1cc(Br)cc(C(C)C)c1N
Agent: Cl[Cu]
Agent: Cn1ccnc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)c1cc(Oc2ccccc2)cc(C(C)C)c1N
Yield: 99 %

Procedure:
To 32.4 g (0.234 mol) K2CO3, 0.58 g (5.8 mmol) CuCl, 13.2 g (0.14 mol) phenol, and 30 g (0.117 mol) 4-bromo-2,6-di-iso-propylaniline 2 in a 250 mL three-necked bulb with argon inlet, reflux condenser and stopper 4.7 mL (58 mmol) 1-methylimidazole and 100 mL o-xylene were added under argon atmosphere. The mixture was stirred and heated to 140° C., until thin layer chromatography (eluent toluene) showed no residual starting material 4-bromo-2,6-di-iso-propylaniline (ca. 30 h). After cooling, water and diethyl ether were added, the organic phase was washed with 10% K2CO3 solution, water and brine and dried over Na2SO4. After evaporation of the solvents, an aliquot part of the dark oily material was filtered through a short silica gel plug with toluene as solvent to give, after removal of the solvent and drying in vacuum, a dark solid. The purity is determined to 95% by gc, The calculated yield is 99%
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[C:16]([F:17])=[CH:15][C:11]([C:12](N)=[O:13])=[CH:10][C:9]=2[F:18])=[CH:5][C:4]=1[C:21]([F:24])([F:23])[F:22].[O:25]1CCOCC1>>[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[C:16]([F:17])=[CH:15][C:11]([C:12]([OH:25])=[O:13])=[CH:10][C:9]=2[F:18])=[CH:5][C:4]=1[C:21]([F:24])([F:23])[F:22]
Reactant: C1COCCO1
Reactant: NC(=O)c1cc(F)c(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Agent: Cl
Product: O=C(O)c1cc(F)c(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Temperature: 120 °C
Reaction time: 5 h
Yield: 59 %

Procedure:
Hydrochloric acid (6M, 20 mL) was added to a solution of 4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorobenzamide (Preparation 86, 440 mg, 1.25 mmol) in dioxan (10 mL). The reaction mixture was stirred at 120° C. for 5 h. After cooling the solvent was removed in vacuo and the aqueous residue was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (1×20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with dichloromethane:methanol (from 98:2 to 85:15) then triturated with heptane to yield the title compound as a white solid (259 mg, 59%)
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]([C:14]1[S:18][C:17]([NH2:19])=[N:16][CH:15]=1)=[O:13].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:10][O:11][C:12]([C:14]1[S:18][C:17]([NH:19][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:16][CH:15]=1)=[O:13]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1cnc(N)s1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(NC(=O)c2ccccc2)s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 78 %

Procedure:
Benzoyl chloride (0.44 g, 0.37 mL) was added to a mixture of 2-aminothiazole-5-carboxylic acid methyl ester (0.50 g, 3.16 mmol), 4-dimethylaminopyridine (0.050 g, 0.41 mmol) and pyridine (2.5 mL, 31.60 mmol) in N,N-dimethylformamide (20 mL) at ambient temperature. The reaction mixture was stirred at ambient temperature for 12 h, and concentrated in vacuo. The residue was purified by column chromatography to yield 2-benzoylaminothiazole-5-carboxylic acid methyl ester in 78% yield (0.654 g); MS (ES+) m/z 263.2 (M+1).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][C:6]1([CH3:12])[N:10]=[C:9]([CH3:11])[CH2:8][S:7]1.C(O)(=O)C.C(OC(=O)C)(=O)C.[OH-].[Na+]>O.C1(C)C=CC=CC=1>[N:1](=[C:8]1[S:7][C:6]([CH3:12])([CH3:5])[N:10]=[C:9]1[CH3:11])[OH:3]
Reactant: CC1=NC(C)(C)SC1
Reactant: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC1=NC(C)(C)SC1=NO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
7.0 g (0.1 mol) of solid sodium nitrite are added portionwise while stirring well to a mixture of 12.9 g (0.1 mol) of 2,2,4-trimethyl-3-thiazoline, 12.0 g (0.2 mol) of acetic acid, 10.2 g (0.1mol) of acetic anhydride and 35 g of toluene at 10° C. The temperature of the mixture is allowed to rise to room temperature over 2 hours and the mixture is stirred at this temperature for an additional 16 hours. An ice-cold solution of 16 g (0.4 mol) of sodium hydroxide in 120 ml of water is then added dropwise to the mixture, a pH of about 11 being attained. The water insoluble portion is separated with 50 ml of diethyl ether. The aqueous phase is subsequently neutralized with concentrated hydrochloric acid. Almost colorless crystals precipitate when the mixture has a pH of about 6. The mixture is filtered and the crystals are washed with water and then dried at 40° C. under reduced pressure to yield 5-oxo-2,2,4-trimethyl-3-thiazoline oxime; m.p. 161°-162° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[C:7]([CH3:17])=[CH:6]2.C(N(CC)CC)C.ClCCl>O>[CH:2]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[C:7]([CH3:17])=[CH:6]2)=[O:1]
Reactant: COC(=O)c1nc2ccc(CO)cc2cc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1nc2ccc(C=O)cc2cc1C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To a mixture of methyl 6-hydroxymethyl-3-methylquinoline-2-carboxylate (193 mg), triethylamine (422 mg) dimethyl sulfoxide (2 ml) and dichloromethane (2 ml) was added portionwise sulfur trioxide pyridine complex (266 mg) in water bath and the mixture was stirred for 2 hours at the same temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (n-hexane:ethyl acetate=1:1, V/V) to give methyl 6-formyl-3-methylquinoline-2-carboxylate (149 mg).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].[F:51][C:52]1[CH:57]=[CH:56][C:55]([Mg]Br)=[CH:54][CH:53]=1>C1COCC1>[F:51][C:52]1[CH:57]=[CH:56][C:55]([C:13]2([OH:43])[C:12]3[CH:11]=[C:10]4[C:19]([C:20](=[O:27])[C@@:21]5([O:25][CH3:26])[C@@:8]([OH:45])([C:9]4=[O:44])[C:7]4[C:2]([OH:1])=[C:3]([C:47]([O:49][CH3:50])=[O:48])[C:4]([CH3:46])=[CH:5][C:6]=4[CH2:23][C@H:22]5[OH:24])=[C:18]([OH:28])[C:17]=3[C:16](=[O:29])[CH:15]=[C:14]2[NH:30][C@@H:31]2[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]2)=[CH:54][CH:53]=1
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4(O)c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
To a solution of (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (200 mg, 0.28 mmol) in THF (5 mL) was added 4-fluorophenylmagnesium bromide (4.30 mL, 1.0 M solution in THF, 4.30 mmol) at −30° C. The mixture was stirred under nitrogen for 30 min. The reaction mixture was quenched with water (0.30 mL), the reaction was brought to room temperature and pH was adjusted to 7 with 1N HCl. The reaction mixture was extracted with dichloromethane (3×50 mL). The combined organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by preparative HPLC (10:90 acetonitrile/water to 60:40 acetonitrile/water with 0.05% TFA over 10 min, then isocratic) to afford (6R,6aS,14aR)-methyl 12-(4-fluorophenyl)-1,6,8,12,14a-pentahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate as a diastereomer A (13 mg, 7%) and as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 7.58-7.55 (m, 2H), 7.53 (s, 1H), 7.13-7.07 (m, 2H), 6.60 (s, 1H), 5.69 (s, 1H), 4.93 (br s, 1H), 4.87 (s, 1H), 3.86 (s, 3H), 3.69-3.66 (m, 1H), 3.65 (s, 3H), 3.58-3.46 (m, 5H), 3.37-3.33 (m, 2H), 3.25-3.21 (m, 1H), 2.92 (t, J=9.0 Hz, 1H), 2.41 (s, 3H), 1.35-1.25 (m, 2H), 1.17 (d, J=6.5 Hz, 3H); MS (ESI+) m/z 794 (M+H); HPLC 95.4% (AUC), tR 13.49 min.
Reaction SMILES: C([Si:5]([CH3:8])([CH3:7])[CH3:6])(F)(F)F.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[OH2:27]>C1COCC1.C([O-])(O)=O.[Na+]>[Si:5]([O:27][Si:5]([CH3:8])([CH3:7])[CH3:6])([CH3:8])([CH3:7])[CH3:6]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: C[Si](C)(C)O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
This material was dissolved in THF (0.1 mL), cooled to at 0° C. and treated with 0.5 M CF3TMS in THF (30 μL, 15 mmol) followed by 0.05 M TBAF in THF (5 mL, 0.025 mmol). After stirring for 30 min, the reaction mixture was diluted with saturated aqueous NaHCO3 (2 mL) and H2O (1 mL), extracted with EtOAc (6×), dried over Na2SO4, filtered and concentrated to give the crude bis-TMS ether.
Reaction SMILES: [C:1]1(=[O:33])[N:5]([CH:6]2[C:26](=[O:27])[N:8]3[C:9]([C:14]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[O:15])=[C:10]([CH3:13])[CH2:11][S:12][C@H:7]23)[C:4](=[O:28])[C:3]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:2]12.C1C[O:37]CC1.OS(O)(=O)=O.C(O)(=O)C1C(=CC=CC=1)C(N)=O>C(Cl)(Cl)Cl.CC#N.C(OCC)(=O)C.O>[C:4]([C:3]1[CH:29]=[CH:30][CH:31]=[CH:32][C:2]=1[C:1]([NH:5][CH:6]1[C:26](=[O:27])[N:8]2[C:9]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)=[O:15])=[C:10]([CH3:13])[CH2:11][S:12][C@H:7]12)=[O:33])([OH:28])=[O:37]
Reactant: COc1ccc(COC(=O)C2=C(C)CS[C@@H]3C(N4C(=O)c5ccccc5C4=O)C(=O)N23)cc1
Reactant: C1CCOC1
Agent: NC(=O)c1ccccc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(COC(=O)C2=C(C)CS[C@@H]3C(NC(=O)c4ccccc4C(=O)O)C(=O)N23)cc1
Reaction time: 0.25 h

Procedure:
A solution of 930 mg. (2 mmol.) of p-methoxybenzyl 7-phthalimido-3-methyl-3-cephem-4-carboxylate in 25 ml. of THF and 8 ml. of water was cooled in an ice water bath, and 660 mg. of Na2S.9H2O were then added. The mixture was stirred for 15 min., and 10 ml. of water and 40 ml. of ethyl acetate were added. The layers were separated, and 140 mg. of a neutral material were obtained from the ethyl acetate layer. The aqueous layer was acidified to pH 4.3 with 1N H2SO4 and extracted twice with ethyl acetate. The ethyl acetate extract was washed, dried, and evaporated to give 660 mg. (68%) of the phthalamic acid as an amorphous solid, [α]D + 85.6° (MeCN); ir (CHCl3), 1781, 1740 and 1710 cm-1, nmr (CDCl3) δ 2.08 (s, 3, CH3), 3.1 and 3.43 (ABq, 2, J = 17 Hz), 3.79 (s, 3, CH3), 5.0 (d, 1, J = 4.5 Hz), 5.1 (s, 2, CH2), 5.8 (dd, 1, J = 4.5 Hz), 6.75-7.6 (m, 8).
Reaction SMILES: [CH3:1][C:2]1[C:6](/[CH:7]=[CH:8]/[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH3:14])[N:4]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:27][C:28]=3[CH3:29])=[CH:18][CH:17]=2)[N:3]=1.C(O)C>[C].[Pd].O1CCCC1>[CH3:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH3:14])[N:4]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[O:27][C:28]=3[CH3:29])=[CH:18][CH:17]=2)[N:3]=1
Reactant: CCOC(=O)/C=C/c1c(C)nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1C
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c(C)nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
A mixture of ethyl(E)-3-[3,5-dimethyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propenoate (800 mg), 5% palladium-carbon (400 mg), ethanol (30 ml), and tetrahydrofuran (10 ml) was stirred at room temperature for one hour under a hydrogen atmosphere. After removal of the catalyst by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3,5-dimethyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (770 mg, yield: 96%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[CH3:20][C:21]1[S:25][C:24]([C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[CH:28]=O)=[N:23][N:22]=1.OOS([O-])=O.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.O>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:28]1[C:27]1[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=1[C:24]1[S:25][C:21]([CH3:20])=[N:22][N:23]=1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Reactant: Cc1nnc(-c2ccccc2C=O)s1
Agent: O=S([O-])([O-])=S
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)s1
Reaction time: 3 h
Yield: 13.4 %

Procedure:
To a solution of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (100 mg, 0.39 mmol) in DMF (3 mL) is added 2-(5-methyl-1,3,4-thiadiazol-2-yl)-benzaldehyde (100 mg, 0.49 mmol) at room temperature. Oxone (240 mg, 0.39 mmol) in H2O (1 mL) is added and the solution is stirred at the same temperature for 3 hours. The reaction is poured into water (75 mL) and sodium thiosulfate (sat., 15 mL). The product is extracted into EtOAc (3×) and the combined organics are then dried (MgSO4), filtered, and concentrated. Purification via flash chromatography (12 g silica gel, 0-10% MeOH/CH2Cl2) gives impure product which is re-purified via preparative TLC (0.5 mm silica gel, 5% MeOH/CH2Cl2). The product band is isolated to give the title compound (23 mg, 13%). LCMS (ESMS): m/z 442.20 (M++1)
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][N:10]([CH2:11][CH3:12])[C:6]=2[N:5]=[C:4]2[C:13](=[O:22])[C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[CH2:16][CH2:17][C:3]=12.[Na].[CH2:24]([OH:26])[CH3:25]>>[CH2:24]([O:26][C:2]1[C:7]2[CH:8]=[N:9][N:10]([CH2:11][CH3:12])[C:6]=2[N:5]=[C:4]2[C:13](=[O:22])[C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[CH2:16][CH2:17][C:3]=12)[CH3:25]
Reactant: CCO
Reactant: CCn1ncc2c(Cl)c3c(nc21)C(=O)c1ccccc1CC3
Agent: [Na]
Product: CCOc1c2c(nc3c1cnn3CC)C(=O)c1ccccc1CC2

Procedure:
6.2 g. of 4-chloro-1-ethyl-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)-one (0.02 mol.), from example 1(e), are added to a solution of 0.5 g. of sodium (0.022 mol.) in 150 ml. of absolute ethanol. The mixture is heated at 120° (bath temperature) in an autoclave for four hours. After cooling, the crystallized 4-ethoxy-1-ethyl-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)-one is filtered off and washed with water; yield: 3.5 g. An additional crop of 2.1 g. is obtained by work up of the mother liquor, total yield: 5.6 g. (87.5%); m.p. 150°-152° (ethanol; refrigerator).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14]1([CH3:24])[CH:19]=CC(S(Cl)(=O)=O)=C[CH:15]=1.C(O)(C)(C)C>N1C=CC=CC=1>[NH2:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([O:6][C:14]([CH3:24])([CH3:19])[CH3:15])=[O:5])=[C:2]([CH3:1])[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: CC(C)(C)O
Solvent: c1ccncc1
Product: Cc1cc(N)ccc1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 104.4 %

Procedure:
2-Methyl-4-nitrobenzoic acid (700 mg, 3.86 mmol) was dissolved in pyridine (8 mL), p-toluenesulfonyl chloride (1.47 g, 7.74 mmol) was added, then tert-butanol (0.369 mL, 3.86 mmol) was added under ice cooling, and the mixture was stirred at 0° C. for 2 hours and at room temperature for 2 hours. tert-Butanol (0.369 mL, 3.86 mmol) was further added, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, water was added, then the mixture was extracted with ethyl acetate (×3), and the organic layer was washed with 1 N hydrochloric acid, a 1 N aqueous sodium hydroxide solution, water, and saturated sodium chloride solution. The organic layer was dried with anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, a solution of the resulting residue in ethyl acetate (40 mL) was added to 10% palladium-carbon (dry; 222 mg), the atmosphere in the system was replaced with a hydrogen atmosphere, and then the mixture was stirred at room temperature for 2 hours. The atmosphere in the system was replaced with a nitrogen atmosphere, and then the mixture was filtered through celite. The solvent was evaporated under reduced pressure to give the title compound (835 mg; yield, 100%) as a brown solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[S:23]1[C:27]([C:28](Cl)=[O:29])=[CH:26][C:25]2[CH:31]=[CH:32][CH:33]=[CH:34][C:24]1=2.CCN(C(C)C)C(C)C>CC#N>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:28]([C:27]4[S:23][C:24]5[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=5[CH:26]=4)=[O:29])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1cc2ccccc2s1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)c4cc5ccccc5s4)cc3C2=O)C(=O)N1
Reaction time: 1 h
Yield: 55.9 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and benzo[b]thiophene-2-carbonyl chloride (0.59 g, 3.00 mmol) in MeCN (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. After 1 h, the solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (2×150 mL), water (100 mL), dried (MgSO4) and then concentrated. The product was dried in vacuo to give benzo[b]thiophene-2-carboxylic acid[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.75 g, 56% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 7.03 min (96.23%); mp: 318-320° C.; 1H NMR (DMSO-d6) δ 1.96-2.17 (m, 1H, CHH), 2.54-2.68 (m, 2H, CHH, CHH), 2.78-3.00 (m, 1H, CHH), 4.68 (d, J=5.9 Hz, 2H, CH2), 5.15 (dd, J=5.4, 12.7 Hz, 1H, CH), 7.39-7.55 (m, 2H, Ar), 7.79-8.10 (m, 5H, Ar), 8.16 (s, 1H, Ar), 9.50 (t, J=5.9 Hz, 1H, NH), 11.13 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.93, 42.64, 49.01, 122.07, 122.83, 123.63, 124.97, 125.25, 126.32, 129.93, 131.66, 133.54, 139.10, 139.27, 140.25, 147.13, 161.80, 166.96, 167.10, 169.82, 172.73; LCMS: MH=448; Anal Calcd for C23H17N3O5S: C, 61.74; H, 3.83; N, 9.39. Found: C, 61.59; H, 3.53; N, 9.29.