Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O[C@H:12]1[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C@H:14]([CH2:27]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:13]1)(C1C=CC(C)=CC=1)(=O)=O.[S-2:39].[Na+].[Na+].CCOC(C)=O>CS(C)=O>[C@H:12]12[CH2:13][C@H:14]([N:15]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:16]1)[CH2:27][S:39]2
Reactant: [S-2]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OS(=O)(=O)c3ccc(C)cc3)CN2C(=O)OCc2ccccc2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1C[C@@H]2C[C@H]1CS2
Temperature: 110 °C
Reaction time: 17 h
Yield: 60.6 %

Procedure:
(2S,4R)-benzyl 4-(tosyloxy)-2-((tosyloxy)methyl)pyrrolidine-1-carboxylate (10 g, 17.87 mmol) and sodium sulfide (1.125 mL, 26.8 mmol) were combined in DMSO (80 mL) in a 150 mL medium pressure flask. The reaction mixture was purged with N2 (g) and the resulting slurry was heated to 110° C. under a N2 (g) atmosphere. The reaction became deep blue immediately. After 17 h, the resulting black reaction mixture was cooled to rt, diluted with 1:1 EtOAc:Et2O (150 mL) and washed with H2O (100 mL). The aqueous layer was extracted with 1:1 EtOAc:Et2O (100 mL). The combined organic layer was washed with 1N HCl (100 mL), brine, dried over MgSO4, filtered and concentrated to give dark red viscous oil. The crude material was loaded onto a silica gel column (60 g) and eluted with 3:1 hex:EtOAc to give (1S,4S)-benzyl 2-thia-5-azabicyclo[2.2.1]heptane-5-carboxylate (2.7 g, 61% yield) as red viscous oil. LC/MS: m/e 250.0 (M+H)+, 2.22 min (method 3). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.39-7.31 (m, 5H), 5.18-5.06 (m, 2H), 4.79-4.65 (m, 1H), 3.64 (d, J=7.8 Hz, 2H), 3.59 (br. s., 1H), 3.22-3.04 (m, 1H), 3.04-2.96 (m, 1H), 2.16 (t, J=10.0 Hz, 1H), 1.88 (d, J=10.3 Hz, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=O)[C:11]([N:13]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14]2)=O)=[CH:2]1.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[OH:18][CH:15]1[CH2:16][CH2:17][N:13]([CH2:11][CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:14]1
Reactant: O=C(C(=O)N1CCC(O)C1)c1c[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OC1CCN(CCc2c[nH]c3ccccc23)C1

Procedure:
A suspension of 11 g. (0.043 mole) of 1-(indol-3-ylglyoxyloyl)-3-pyrrolidinol in 50 ml. of tetrahydrofuran was added dropwise, under nitrogen, to a stirred suspension of 9.8 g. (0.026 mole) of lithium aluminum hydride in 100 ml. of tetrahydrofuran. After addition, the mixture was refluxed for 2 hours, cooled, and treated with enough water to destroy the excess lithium aluminum hydride. The resulting aluminum hydroxide was filtered off and washed thoroughly with tetrahydrofuran. The filtrate was evaporated on a rotating evaporator to an oil which solidified on standing. Crystallization from acetonitrile gave a melting point of 144°-146° C.; yield 7.7 g. (78%).
Reaction SMILES: [CH:1](=[CH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1(=[O:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[OH-].[Na+]>C(O)C>[C:2]1([CH:1]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C:17]2=[O:23])[CH2:8][C:9](=[O:10])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(CC(c1ccccc1)C1CCCCC1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ten parts of benzalacetophenone and 5 parts of cyclohexanone was dissolved in 200 mL of ethyl alcohol and a solution of 5 parts of sodium hydroxide in 100 ml of ethanol was added to the reaction mixture. After 30 minutes the solution became cloudy and white solid was appeared. The reaction mixture was stirred for 10 hours at room temperature and solid was filtered, washed with water and then with 100 ml of ethyl alcohol. The white solid was dried under reduced pressure,with a yield of 12 parts. The reaction proceeded as follows:
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N+:12]([O-])=[C:11]([CH3:16])[C:10]=2[CH3:17])[CH2:4][O:3]1.C(OC(=O)C)(=[O:21])C>>[CH3:1][C:2]1([CH3:18])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:16][OH:21])[C:10]=2[CH3:17])[CH2:4][O:3]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(OC[C@@H]2COC(C)(C)O2)cc[n+]([O-])c1C
Product: Cc1c(OC[C@@H]2COC(C)(C)O2)ccnc1CO
Temperature: 80 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
The 4-(((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2,3-dimethylpyridine1-oxide (10.5 g, 41.5 mmol) obtained in the step (14a) was mixed with acetic anhydride (20 ml). The mixture was stirred at 80° C. for one hour. After cooled to room temperature, the reaction mixture was concentrated under reduced pressure. To the residue, methanol (40 ml) and a 5N aqueous sodium hydroxide solution (20 ml) were added and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated and the residue was partitioned between a saturated saline solution and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol) to obtain the title compound (3.77 g, yield: 41.9%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:10]([OH:12])=O)[CH2:2][CH:3]([CH3:5])[CH3:4].CN(C)C=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:31]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][C:44]([O:46][CH2:47][CH2:48][CH:49]([CH3:51])[CH3:50])=[O:45])[CH2:32][CH:33]([CH3:35])[CH3:34]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:10]([C:40]1[CH:41]=[CH:42][C:37]([O:36][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[C:38]([CH2:43][C:44]([O:46][CH2:47][CH2:48][CH:49]([CH3:50])[CH3:51])=[O:45])[CH:39]=1)=[O:12])[CH2:2][CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)CCOC(=O)Cc1ccccc1OCCC(C)C
Reactant: CC(C)CCOc1ccc(C(=O)O)cc1OCCC(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)CCOC(=O)Cc1cc(C(=O)c2ccc(OCCC(C)C)c(OCCC(C)C)c2)ccc1OCCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
In 8 ml of methylene chloride is dissolved 0.80 g of 3,4-diisopentyloxybenzoic acid. Then, 20 μl of N,N-dimethylformamide is added, and the mixture thus obtained is stirred at ambient temperature for one hour. To the mixture thus obtained are successively added 1.10 g of aluminum chloride and 0.95 g of isopentyl 2-(2-isopentyloxyphenyl)acetate at 5-10° C., and the mixture thus obtained is stirred at 5-10° C. for 10 minutes. The reaction mixture is added to a mixture of chloroform and ice water, and the organic layer is separated. After washing the organic layer with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography [eluent; hexane:ethyl acetate=10:1] to obtain 1.20 g of isopentyl 2-[5-(3,4-diisopentyloxybenzoyl)-2-isopentyloxyphenyl]-acetate as a yellow oily product.
Reaction SMILES: C([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH2:11][CH2:12][NH2:13])(OC(C)(C)C)=O.F[C:18]1[CH:19]=[C:20]([CH3:27])[CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25].C(O)C.[OH-].[Na+]>Cl.C(O)(=O)C.O>[NH2:8][C@@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:18]1[CH:19]=[C:20]([CH3:27])[CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[C:14]([OH:16])=[O:15]
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc([N+](=O)[O-])c(NCCC[C@H](N)C(=O)O)c1
Reaction time: 2 h
Yield: 56 %

Procedure:
A mixture of 474 mg (2 mmol) of Noc-BOC-L-ornithine (supplier BAChem) and 314 mg (2 mmol) of 3-fluoro-4-nitrotoluene (Aldrich Chemical Co.)in 2 mL of ethanol and 2 mL of 1N NaOH was heated at reflux for 12 hours. Another 2 mmol each of NaOH and 3-fluoro-4-nitrotoluene was added and the reaction was continued another two hours. The solution was poured into 50 mL of water and extracted with dichloromethane (2×80 mL). The organic phase was dried and concentrated to give a solid residue, which was stirred in 20 mL of 4N HCl in 33% acetic acid for four hours, filtered and concentrated to leave a yellow solid, which was recrystallized from ethanol/water to afford 296 mg (56% yield) of the title product as an amorphous orange powder. mp 263°-264° (decomp.); MS M/Z 268 [M+H], 285 [M+NH4 ]; 1H NMR (300 MHz, D2O/NaOD) δ: 1.64 (m, 4H)2.18 (s, 3H), 3.12 (m, 2H), 3.30 (t, J=4.5 Hz, 1H), 6.22 (d, J=8.1 Hz, 1H), 6.43 (s, 1H), 7.58 (d, J=8.1 Hz, 1H); 13C NMR (75.5 MHz, D2O/NaOD) δ: 185.88, 158.28, 148.71, 130.81,128.71,120.22, 116.11, 58.73, 45.24, 35.40, 27.73, 24.24; Analysis calc'd for C12H17N3O4.0.4 HCl: C, 50.81; H, 6.25; N, 14.81; found: C, 50.79; H, 6.27; N, 14.73.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH2:19][N:18]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([NH2:25])=[O:24])[C:17](=[O:29])[CH2:16]2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>CCO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH2:19][N:18]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([NH2:25])=[O:24])[C:17](=[O:29])[CH2:16]2)[CH:12]=[CH:13][CH:14]=1
Reactant: NC(=O)c1cccc(N2CC(c3cccc(OCc4ccccc4)c3)CC2=O)c1
Agent: [Pd]
Solvent: CCO
Product: NC(=O)c1cccc(N2CC(c3cccc(O)c3)CC2=O)c1
Reaction time: 4 h
Yield: 86.9 %

Procedure:
To a solution of 3-[4-(3-benzyloxyphenyl)-2-oxo-pyrrolidin-1-yl]benzamide (1.2 g) in 50 mL EtOH was added 10% Pd/C (100 mg). The resulting mixture was stirred under H2 for 4 h, filtered, and concentrated under reduced pressure to give 0.8 g of crude product.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.C(OC(=O)[N:34]([CH2:50][CH3:51])[C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=1)(C)(C)C>>[CH2:50]([NH:34][C:35]1[CH:40]=[CH:39][C:38]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[CH:10]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)[S:8][C:6]=3[N:7]=2)=[CH:37][N:36]=1)[CH3:51]
Reactant: CCN(C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: CCNc1ccc(-c2nc(N3CCOCC3)c3cc(CN4CCN(S(C)(=O)=O)CC4)sc3n2)cn1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine was reacted with ethyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-carbamic acid tert-butyl ester in General Procedure A. Purification on silica yielded 365. NMR: (CDCl3): 1.31 (3 H, t, J 7.2, Me), 2.65-2.68 (4 H, m), 2.82 (3 H, s, Me), 3.28-3.31 (4 H, m), 3.38-3.44 (2 H, m, CH2), 3.81 (2 H, s, CH2), 3.88-3.90 (4 H, m), 3.94-3.97 (4 H, m), 4.71-4.74 (1 H, m, NH), 6.45 (1 H, d, J 8.7, Ar), 7.12 (1 H, s, Ar), 8.46 (1 H, dd, J 8.7 and 2.3, Ar) and 9.19 (1 H, d, J 2.3, Ar). MS: (ESI+): MH+=518.22
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([C:12]1[N:13]=[C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[S:15][CH:16]=1)[C:9]([OH:11])=O.CN(CC1C=CC=CC=1)C.ClC(OCCCC)=O.[CH3:40][N:41]1[C:45]([S:46][CH2:47][C:48]2[CH2:49][S:50][C@@H:51]3[CH:58]([NH2:59])[C:57](=[O:60])[N:52]3[C:53]=2[C:54]([OH:56])=[O:55])=[N:44][N:43]=[N:42]1>O1CCCC1.C(N(CC)CC)C>[CH3:40][N:41]1[C:45]([S:46][CH2:47][C:48]2[CH2:49][S:50][C@@H:51]3[CH:58]([NH:59][C:9](=[O:11])[CH:8]([O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[C:12]4[N:13]=[C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[S:15][CH:16]=4)[C:57](=[O:60])[N:52]3[C:53]=2[C:54]([OH:56])=[O:55])=[N:44][N:43]=[N:42]1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CS(=O)(=O)Nc1nc(C(OC2CCCCO2)C(=O)O)cs1
Agent: CCCCOC(=O)Cl
Agent: CN(C)Cc1ccccc1
Agent: CS(=O)(=O)N=c1[nH]c(C(OC2CCCCO2)C(=O)O)cs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(OC3CCCCO3)c3csc(NS(C)(=O)=O)n3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-(2-tetrahydropyranyl)oxy-2-(2-mesylamino-1,3-thiazol-4-yl)acetic acid, which can be represented as 2-(2-tetrahydropyranyl)oxy-2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)acetic acid, (350 mg.), triethylamine (96 mg.), N,N,-dimethylbenzylamine (half drop) and tetrahydrofuran (7 ml.) was dropwise added a mixture of butyl chloroformate (130 mg.) and tetrahydrofuran (1 ml.) over 1 minute at -15° C., and then the mixture was stirred for 30 minutes at -15° to -10° C. To the mixture was added all at once a mixture of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-amino-3-cephem-4-carboxylic acid (224 mg.), triethylamine (80 mg.) and 50% tetrahydrofuran aqueous solution (10 ml.) which was cooled at 0° C., and the mixture was stirred for 30 minutes under ice-cooling and further stirred for 2 hours at room temperature. After the reaction, the reaction mixture was concentrated. The residue was adjusted to pH 8 with 5% sodium bicarbonate aqueous solution and washed with ethyl acetate. Thus obtained aqueous layer was adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. After distillation of the solvent from the extract, the residue was pulverized in diethyl ether, collected by filtration and dried to give pale brown powder of 3-(1-methyl1H-tetrazol-5-yl)thiomethyl-7-[2-(2-tetrahydropyranyl)oxy-2-(2-mesylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-tetrahydropyranyl)oxy-2-(2-mesylimino-2,3-dihydro1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (270 mg.).
Reaction SMILES: [C:1]([NH:6][NH:7][C:8]([C:10]1[N:15]2[N:16]=[C:17]([NH2:19])[N:18]=[C:14]2[CH:13]=[C:12]([Br:20])[CH:11]=1)=[O:9])(=O)[CH:2]([CH3:4])[CH3:3]>O=P(Cl)(Cl)Cl>[Br:20][C:12]1[CH:11]=[C:10]([C:8]2[O:9][C:1]([CH:2]([CH3:4])[CH3:3])=[N:6][N:7]=2)[N:15]2[N:16]=[C:17]([NH2:19])[N:18]=[C:14]2[CH:13]=1
Reactant: CC(C)C(=O)NNC(=O)c1cc(Br)cc2nc(N)nn12
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1nnc(-c2cc(Br)cc3nc(N)nn23)o1
Temperature: 100 °C

Procedure:
The product of Step 1, 2-amino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid N′-isobutyryl-hydrazide (1.0 g, 2.9 mmol) was suspended in neat POCl3 (˜10 mL) and heated to 100° C. for one hour. The mixture was concentrated under reduced pressure and the residue was diluted with water. The pH of the aqueous mixture was made slightly basic by the addition of K2CO3, then extracted with a solution of 9:1 CH2Cl2/MeOH (50 mL). The organics were dried with MgSO4 and concentrated under reduced pressure to give a solid, which was triturated with ether and collected by filtration andried under vacuum to give 7-bromo-5-(5-isopropyl-[1,3,4]oxadiazol-2-yl)-[1,2,4]triazolo[1,5,a]pyridine-2-ylamine, that was used without further purification in Step 3. MS (APCI+): m/z 325.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][C:13]1[S:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=2)=[N:15][CH:14]=1)(=[O:10])=[O:9].[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)C(C)C)(C)C>ClCCl>[C:28]([N:11]([CH2:12][C:13]1[S:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:19]=2)=[N:15][CH:14]=1)[S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:10])=[O:9])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CS(=O)(=O)c1cccc(-c2ncc(CNS(=O)(=O)c3ccccc3Cl)s2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(-c2ncc(CN(C(=O)c3ccccc3)S(=O)(=O)c3ccccc3Cl)s2)c1

Procedure:
In analogy to example 6, 2-chloro-N-[2-(3-methanesulfonyl-phenyl)-thiazol-5-ylmethyl]-benzenesulfonamide (example 10, step 2) was reacted with benzoyl chloride and N,N-diisopropyl ethyl amine in dichloromethane to give N-benzoyl-2-chloro-N-[2-(3-methanesulfonyl-phenyl)-thiazol-5-ylmethyl]-benzenesulfonamide as a colorless solid. MS: 548.7 ([M+H]+)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])[C:5]([Cl:18])=[CH:4][N:3]=1.[CH3:19][N:20]1[C:24]([NH2:25])=[CH:23][C:22]([CH3:26])=[N:21]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:18][C:5]1[C:6]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[CH:7][C:2]([NH:25][C:24]2[N:20]([CH3:19])[N:21]=[C:22]([CH3:26])[CH:23]=2)=[N:3][CH:4]=1
Reactant: Cc1cc(N)n(C)n1
Reactant: O=C(O)c1ccccc1Nc1cc(Cl)ncc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(Nc3ccccc3C(=O)O)c(Cl)cn2)n(C)n1
Temperature: 120 °C
Yield: 22.6 %

Procedure:
A pressure tube was charged with 2-[(2,5-dichloro-4-pyridinyl)amino]benzoic acid (1.0 g, 3.53 mmol), 1,3-dimethyl-1H-pyrazol-5-amine(0.589 g, 5.30 mmol), (±)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene (0.330 g, 0.530 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3, 0.162 g, 0.177 mmol) and sodium tert-butoxide (0.849 g, 8.83 mmol) in 1,4-dioxane (30 mL). The tube was degassed with N2 and sealed and the reaction mixture was heated in an oil bath at 120° C. for 18 hours. The reaction mixture was evaporated to dryness under high vacuum. The residue was taken back in water solution and the pH was adjusted to ˜4 to 5 using 6.0 N hydrochloride acid. The reaction was concentrated to dryness and the resulting solid was dissolved in MeOH and purified by reverse-phase HPLC to give the title compound as a solid (285 mg, 21% yield). MS: M(C17H16ClN5O2)=357.79, (M+H)+=358, 360.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.OB(O)[C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.CN(C=O)C.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]>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)[CH:10]=2)[CH:6]=[CH:7]1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2ccc3cc[nH]c3c2)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 6-bromoindole (480 mg, 2.45 mmol), 4-(dihydroxyboryl)benzoic acid (406 mg, 2.45 mmol), Pd(dppf)Cl2.CH2Cl2 (10 Mg, 0.01 mmol), and 2M Na2CO3 (5.6 mL, 11.2 mmol) in a mixture of ethanol (4 mL) and DMF (7 mL) was heated to 100° C., stirred for 16 hours, filtered, and concentrated The concentrate was dissolved in ethyl acetate, washed sequentially with 1M H3PO4, water, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5% methanol/dichloromethane to provide the desired product. MS (ESI(−)) m/e 236 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:11](=[N:12][N:13](CC4C=CC(OC)=CC=4)[C:14]=3[CH3:16])[C:10](=[O:26])[N:9]2[C:27]2[CH:32]=[CH:31][C:30](=[O:33])[N:29]([CH3:34])[CH:28]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:11](=[N:12][NH:13][C:14]=3[CH3:16])[C:10](=[O:26])[N:9]2[C:27]2[CH:32]=[CH:31][C:30](=[O:33])[N:29]([CH3:34])[CH:28]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(Cn2nc3c(c2C)C(c2ccc(Cl)cc2)N(c2ccc(=O)n(C)c2)C3=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1[nH]nc2c1C(c1ccc(Cl)cc1)N(c1ccc(=O)n(C)c1)C2=O
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
In a 2-5 mL MW flask was introduced 4-(4-chlorophenyl)-2-(4-methoxybenzyl)-3-methyl-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-one (Example 1) (85 mg, 0.179 mmol) and TFA (1379 μL, 17.90 mmol). The reaction mixture was stirred for 30 min at 100° C. under MW irradiation, quenched with a saturated aq. NaHCO3 solution, and extracted with CH2Cl2. The combined organic layers were washed with a saturated aq. solution of NaHCO3, dried over Na2SO4, and evaporated. The crude material was purified by silica gel column chromatography (CH2Cl2/MeOH 1-8%) to afford the title compound (32 mg, 0.090 mmol, 50% yield) as a white solid. tR: 3.13 min (HPLC 1); tR: 0.69 min (LC-MS 2); ESI-MS: 355 [M+H]+ (LC-MS 2); Rf=0.40 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.03 (s, 3H) 3.34 (s, 3H) 6.09 (s, 1H) 6.30 (d, J=9.4 Hz, 1H) 7.22 (d, J=8.2 Hz, 2H) 7.35 (d, J=8.6 Hz, 2H) 7.44 (dd, J=9.8, 2.74 Hz, 1H) 7.88 (d, J=3.1 Hz, 1H) 13.35 (br. s., 1H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:14][CH2:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:18]([CH2:17][CH2:16][CH2:15][Cl:14])(=[O:20])=[O:19])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)CCCCl)CC1
Yield: 95.8 %

Procedure:
Amine preparation: A mixture of 1-BOC-piperazine (3.26 g), 3-chloropropanesulfonyl chloride (2.63 g) and triethylamine (2.68 mL) was stirred at room temperature in DCM (25 mL). After 2 h the reaction mixture was diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 4-(3-chloro-propane-1-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (4.65 g). A mixture of 4-(3-chloro-propane-1-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (4.65 g), potassium iodide (1.1 g), potassium carbonate and morpholine (1.6 mL) was heated to reflux in MeCN (100 ml). After 16 h, the reaction mixture was cooled, diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 4-(3-morpholin-4-yl-propane-1-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (4.8 g). Treatment of this compound with HCl in DCM/MeOH yielded the desired compound, which was isolated as the hydrochloride salt.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3](=[O:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:12]([Mg]Br)=[CH2:13]>C1COCC1>[CH2:7]([O:6][C:4](=[O:5])[C:3]([OH:9])([C:2]([F:10])([F:11])[F:1])[CH:12]=[CH2:13])[CH3:8]
Reactant: CCOC(=O)C(=O)C(F)(F)F
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)(C(=O)OCC)C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of ethyl 3,3,3-trifluoropyruvate (14.2 g) in THF (200 mL) at −78° C. was added vinyl magnesium bromide (84 mL of 1M in THF) dropwise via addition funnel. The resulting mixture was then warmed to ambient temperature over 2 h. The reaction was quenched by pouring the mixture over ice. To the resulting mixture was then added 2 N HCl, the mixture was extracted with EtOAc, and dried over Na2SO4. After concentration, the resulting crude material was filtered through a plug of silica gel and rinsed with 50% Et2O/hexanes. The resulting mixture was concentrated to yield the title compound as a golden oil.