Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH:18]([CH3:20])[CH3:19].Cl>CN(C)C=O.O.C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:18]([CH3:20])[CH3:19])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: CC(C)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)Oc1ccc(C=O)cc1O
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 28.2 %

Procedure:
Commercially available 3,4-dihydroxybenzaldehyde (5 g, 36.2 mmol) and potassium carbonate (5.15 g, 37.3 mmol) were dissolved in N,N-dimethylformamide (20 mL), then 2-bromopropane (3.5 mL, 37.3 mmol) was added under nitrogen atmosphere at room temperature, and the mixture was heated and stirred at 40° C. for 2.5 hours. The reaction mixture was cooled to 0° C., and then 2 M hydrochloric acid, ethyl acetate, and water were added for partition. The aqueous layer was extracted with ethyl acetate, the combined organic layer was washed with water and a saturated saline solution, and the resultant was dried over anhydrous magnesium sulfate and then filtered. The solvent was evaporated, dichloromethane was added to the residue, the precipitate was separated by filtration, and the filtrate was concentrated under vacuum. The residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=19:1-13:7) and then the target fraction was concentrated under vacuum to obtain the title compound (1.84 g, 28%).
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:3][C:4](=[O:5])[NH:6][C:7]1=[N:8][C:18]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=1)=[O:19]
Reactant: CN1CC(=O)N=C1N
Reactant: COc1ccc(N=C=O)cc1
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)N=C2NC(=O)CN2C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirring suspension of creatinine (11.88 g, 0.105 mole) in 100 ml dry DMF, p-methoxyphenylisocyanate (14.91 g, 0.100 mole) is added dropwise over a period of about 15 minutes with cooling. After stirring for 8 hours, the mixture is poured into about 500 ml of ice water to yield white crystals of product which are filtered off, washed with water and purified by recrystallization (twice) from tetrahydrofuran-methanol. The crystalline product is reduced to finer size by adding a solution of the product in minimal DMF to vigorously stirred water (about 1.1 liters) and filtering off the resultant crystals which are then dried at room temperature in vacuo for 24 hours; m.p. 193°-5°C dec.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[CH:14][C:13]=2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[ClH:37].CCOCC>CO.C(OCC)(=O)C>[ClH:37].[N:18]1([C:15]2[CH:16]=[CH:17][C:12]([NH:11][S:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)(=[O:9])=[O:10])=[C:13]([NH:32][S:33]([CH3:36])(=[O:34])=[O:35])[CH:14]=2)[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(N3CCCN(C(=O)OC(C)(C)C)CC3)cc2NS(C)(=O)=O)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(N3CCCNCC3)cc2NS(C)(=O)=O)cc1
Reaction time: 2 h

Procedure:
tert-Butyl 4-{4-{[(4-methylphenyl)sulfonyl]amino}-3-[(methylsulfonyl)amino]phenyl}-1,4-diazepane-1-carboxylate (0.5 g) was dissolved in methanol (15 mL). A solution of HCl in ethyl acetate (1N, 25 mL) was added and the mixture stirred for 2 hours. Ether (200 mL) was added and the mixture stirred for 3 hours to allow full precipitation. The product was collected by filtration, washed with ether and dried. Yield 0.43 g (98%) 1H NMR (400 MHz, DMSO-d6) δ 2.03 (m, 2H), 2.36 (s, 3H), 2.9 (s, 3 H), 3.02-3.09 (br m, 2H), 3.11-3.19 (br m, 2H), 3.41 (br t, J=7.08 Hz, 2H), 3.63 (br m, 2H), 6.46 (d ab, J=2.8 Hz, 8.8 Hz, 1H), 6.62 (ab, J=8.8 Hz, 1H), 6.71 (d, J=2.8 Hz, 1H), 7.36 (ab, J=8.3 Hz, 2H), 7.58 (ab, J=8.3 Hz, 2H), 8.39 (s, 1H), 9.2 (br, 2H), 9.8 (s, 1H); MS (ESI+) for C19H27N4O4S2 m/z 439.148 (M+H)+ (Calculated 439.1474).
Reaction SMILES: CC([NH:4]P([O:9][C:10]1[CH:15]=CC(Cl)=CC=1Cl)(OC)=S)C.CC1(C)CC(C[N:27]=[C:28]=[O:29])(C)CC([N:30]=[C:31]=[O:32])C1.[OH-].[Na+].CCN(C(C1C=CC=C(C)C=1)=O)CC>O.CC(=O)OCC>[NH2:27][C:28]([O:9][CH2:10][CH3:15])=[O:29].[NH2:4][C:31]([NH2:30])=[O:32]
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Reactant: COP(=S)(NC(C)C)Oc1ccc(Cl)cc1Cl
Agent: CCN(CC)C(=O)c1cccc(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(N)=O
Product: NC(N)=O
Reaction time: 0.17 h

Procedure:
95.4 g of Rucoflex XS-5570-55, 205.8 g of Rucoflex S-1011-55 and 6.7 g of DMPA are reacted with 44.4 g of IPDI and 16.8 g of HDI at 80° C. for 3 hours to prepare a prepolymer. The prepolymer is then dispersed in a solution of 2.8 g of NaOH and 1.83 g of EA in 515.0 g of water. After 10 minutes, a solution of 1.8 g of EDA and 2.04 g of DETA is added to form an aqueous poly(urethane/urea) dispersion. A finely divided dispersion having a solids content of 39.896 and a pH of 7.2 is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([CH3:13])[CH3:12])[N:6]=[C:5]2[CH:14]1[CH2:17][CH2:16][CH2:15]1.C(OC([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][C@@H:26]1[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=O)(C)(C)C>>[CH2:31]([C@@H:26]1[NH:25][CH2:30][CH2:29][N:28]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]([CH3:13])[CH3:12])[N:6]=[C:5]3[CH:14]2[CH2:17][CH2:16][CH2:15]2)[CH2:27]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)n1nc(C2CCC2)c2cc(Br)ccc21
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1Cc1ccccc1
Product: CC(C)n1nc(C2CCC2)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc21
Yield: 55 %

Procedure:
The title compound was prepared by the method outlined for Example 1 using 5-Bromo-3-cyclobutyl-1-isopropyl-1H-indazole as the aryl halide and (S)-2-benzyl-piperazine-1-carboxylic acid tert-butyl ester as the amine component to afford the title compound as a brown oil (780 mg, 55%). 1H NMR (MeOH-d4) 7.44-7.20 (m, 5H), 7.16-6.87 (m, 3H), 4.78 (td, J=13.4, 6.7 Hz, 1H), 3.95-3.83 (m, 1H), 3.46-3.33 (m, 2H), 3.20-3.05 (m, 2H), 3.03-2.91 (m, 1H), 2.82-2.75 (m, 3H), 2.57-2.36 (m, 6H), 2.24-2.09 (m, 1H), 1.50 (d, J=6.7 Hz, 6H). LC/MS (Method B) 2.79 min, [M+1]+ 389.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:10]#[N:11].Cl[CH2:20][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1.CS(C)=O.[OH-].[Na+]>O>[C:10]([C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[CH2:20][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)#[N:11]
Reactant: ClCn1cncn1
Reactant: COc1ccccc1C(C#N)Cc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1C(C#N)(Cc1ccccn1)Cn1cncn1
Reaction time: 2 h

Procedure:
To a flask was added 5.0 g. (0.021 mole) of 2-(2-methoxyphenyl)-3-(2-pyridyl)propionitrile, 5.0 g. (0.031 mole) of 1-(chloromethyl)-1,2,4-triazole, and 150 ml. of DMSO, followed by 10 g. (0.125 mole) of 50% aqueous sodium hydroxide over 30 minutes. The reaction exothermed to 40° C. and was stirred for an additional two hours. After cooling, water was added and the organic material extracted with ether. The combined ether extracts were then washed with water, dried using magnesium sulfate, filtered, and the ether removed by rotary evaporation to obtain 3.0 g. of organic residue which was recrystallized from ether yielding 1.3 g. of the product as a grey solid, melting point 155°-158° C.
Reaction SMILES: [Na].[C:2]1([CH3:9])[C:3](C)=[CH:4][CH:5]=[CH:6][CH:7]=1.[P:10]([O-:17])([O:14]CC)[O:11]CC.C1(C(Cl)(Cl)Cl)C=CC=CC=1>O1CCCC1>[C:2]1([C:9]([P:10]([OH:17])(=[O:11])[OH:14])([P:10]([OH:17])(=[O:14])[OH:11])[P:10]([OH:17])(=[O:14])[OH:11])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1C
Reactant: CCOP([O-])OCC
Agent: [Na]
Solvent: ClC(Cl)(Cl)c1ccccc1
Solvent: C1CCOC1
Product: O=P(O)(O)C(c1ccccc1)(P(=O)(O)O)P(=O)(O)O
Temperature: 100 °C

Procedure:
There were mixed together 23.0 grams (1.0 mole) of sodium metal along with 90 cc. of xylene and 80 cc. of tetrahydrofurane and the mixture placed under a nitrogen atmosphere. There were then added over a 35 minute period 138.10 grams (1.0 mole) of diethyl phosphite using external cooling to control the reaction exotherm and maintain the temperature at 60° to 65° C. After addition was complete the mixture was heated to 100° C. and maintained there for about 1 hour until there was no more sodium. The mixture was cooled to 60° C. and there was started the addition of 64.5 grams (0.33 mole) of benzotrichloride (α,α,α-trichlorotoluene). The exothermic reaction was cooled to maintain the temperature at 60° to 65° C. during the 25 minute addition period. The mixture was heated at 70° to 75° C. for 7 hours and the sodium chloride filtered off. The product in the pot was then subjected to distillation, terminal conditions being a pot temperature of 205° C., distillate temperature 125° C. and pressure 4 mm. The solid residue in the pot was hexaethyl phenyl methane triphosphonate. This product was hydrolyzed and the hydrolysis product purified as in Example 1 to obtain phenyl methane triphosphonic acid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:54]=[CH:53][C:16]([CH2:17][C:18]4[N:19]([C:31]5[CH:36]=[CH:35][C:34]([N:37]6[S:41](=[O:43])(=[O:42])[N:40]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[C:39](=[O:52])[CH2:38]6)=[CH:33][CH:32]=5)[CH:20]=[C:21]([C:23]5[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=5[Cl:30])[N:22]=4)=[CH:15][CH:14]=3)=[N:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>C(O)(=O)C.O.CCOC(C)=O.[Fe]>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:54]=[CH:53][C:16]([CH2:17][C:18]4[N:19]([C:31]5[CH:36]=[CH:35][C:34]([N:37]6[S:41](=[O:43])(=[O:42])[N:40]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:49])([CH3:50])[CH3:51])[C:39](=[O:52])[CH2:38]6)=[CH:33][CH:32]=5)[CH:20]=[C:21]([C:23]5[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=5[Cl:30])[N:22]=4)=[CH:15][CH:14]=3)=[N:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(C5=CCCCC5)cn4)cc3)cc2)S1(=O)=O
Agent: [Fe]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(C5CCCCC5)cn4)cc3)cc2)S1(=O)=O
Temperature: 100 °C

Procedure:
5-{4-[2-[4-(5-Cyclohex-1-enyl-pyridin-2-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (40 mg, 0.05 mmol) was dissolved in 1 mL dry acetic acid, iron powder (−325 mesh, 56 mg, 1 mmol) was added and the mixture was then heated at 100° C. under nitrogen for 2 days. At completion, the reaction mixture was then diluted with water/EtOAc and the leftover iron powder was filtered and washed with EtOAc. The combined organic layer was washed with water, saturated NaHCO3 and brine. The organic layer was then dried over Na2SO4, filtered, and the filtrate was concentrated and purified by silica gel chromatography to afford 5-{4-[2-[4-(5-cyclohexyl-pyridin-2-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([O:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N:12]2)=[C:7](Br)[N:6]=1)=[O:4].[S:27]([C:31]1C=CC(C)=CC=1)([O-])(=[O:29])=[O:28].[N:38]1C=CC=C[C:39]=1C1C=CC=CN=1>[Cu-]=O.CN(C=O)C>[CH3:39][N:38]([S:27]([CH3:31])(=[O:29])=[O:28])[C:7]1[N:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:14]([O:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: COC(=O)c1nc(Br)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Reactant: c1ccc(-c2ccccn2)nc1
Agent: O=[Cu-]
Solvent: CN(C)C=O
Product: COC(=O)c1nc(N(C)S(C)(=O)=O)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
In a dried sealable pressure tube flushed with nitrogen was placed methyl 5-bromo-8-{[(4-methylphenyl)sulfonyl]oxy}-1,6-naphthyridine-7-carboxylate (500 mg, 1.14 mmol, prepared as described in Example 2, Step 2), N-methylmethanesulfonamide (168 mg, 1.54 mmol, prepared as in J. Chem. Soc., Perkins Trans. 1986, 2 (8): 1211-16), 2,2′-bipyridyl (241 mg, 1.54 mmol), dry DMF (3 mL) and copper(I) oxide (221 mg, 1.54 mmol). The tube was capped and heated to 85° C. overnight. In the morning, the reaction was cooled and filtered through a glass fiber filter, washing with chloroform. The filtrate was diluted with chloroform (about 100 mL total volume) and stirred with an EDTA solution (5 g EDTA in 100 mL water) for two hours or until the aqueous layer became aqua in color and the organic layer became yellow. The layers were separated and the aqueous layer was extracted twice more with chloroform. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (ISCO column, 110 g silica) eluting with a 0-5% MeOH/CHCl3 gradient over 35 minutes. The concentrated fractions were triturated with methanol to give the product as a white solid.
Reaction SMILES: O=C1CCC(=O)C1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[NH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[OH:25]>CO>[OH:25][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH:19]1[NH:18][C:8](=[O:9])[O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NC1CCCCC1O
Reactant: O=C1CCC(=O)C1C(=O)OCc1ccccc1
Solvent: CO
Product: O=C(NC1CCCCC1O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
At 0° C. to a solution of benzyl 2,5-dioxocyclopentanecarboxylate (2.58 g, 10.35 mmol) in MeOH (20 mL) was added 2-aminocyclohexanol (1.25 g, 10.87 mmol). The reaction mixture was stirred at room temperature for 18 h and quenched with 0.25 N HCl (8 mL). MeOH was removed under vacuum and the aqueous layer was extracted with CH2Cl2 (4×10 mL). The combined organic layers were washed with sat. NaCl (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by ISCO chromatography (40 g column) using hexanes/EtOAc (0-5% over 15 min, 5-10% over 7 min) to give benzyl 2-hydroxycyclohexylcarbamate as a light yellow solid at a retention time of 11-13 min (2.15 g, 83% yield). HPLC: RT=2.83 min, Purity 95% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm) NMR: 400 MHz 1H (CDCl3) 7.33 ppm, 5H, m; 5.16 ppm, 1H, m; 5.09 ppm, 2H, s; 3.95 ppm, 1H, s; 3.68 ppm, 1H, m; 1.54 ppm, 8H, m.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[CH:15]2[N:12]([C:13](=[O:17])[C:14]2=O)[CH:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:30][C:31](=[O:33])[CH3:32])C=CC=CC=1>C1C=CC=CC=1>[C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[C@H:15]2[N:12]([C:13](=[O:17])/[C:14]/2=[CH:30]\[C:31]([CH3:32])=[O:33])[C@@H:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21].[C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[C@H:15]2[N:12]([C:13](=[O:17])/[C:14]/2=[CH:30]/[C:31]([CH3:32])=[O:33])[C@@H:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21]
Reactant: C=S1C2C(=O)C(=O)N2C(C(=O)O)C1(C)C
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)C(=O)O
Solvent: c1ccccc1
Product: C=S1[C@@H]2/C(=C/C(C)=O)C(=O)N2[C@@H](C(=O)O)C1(C)C
Product: C=S1[C@@H]2/C(=C\C(C)=O)C(=O)N2[C@@H](C(=O)O)C1(C)C
Reaction time: 0.17 h

Procedure:
A solution of 3.5 g of methylene-6,7-dioxo-3,3-dimethyl-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate in 150 ml of benzene is treated at room temperature with 6.3 g of 1-triphenylphosphoranylidene-2-propanone. After 10 minutes, the reaction mixture is evaporated. The residue is chromatographed on silica gel while eluting with cyclohexane/ethyl acetate (6:4). There are obtained methylene-(2S,5R)-6-[(E)-acetonylidene]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate [Rf: 0.47; cyclohexane/ethyl acetate (6:4); NMR (CDCl3), δ (ppm): 1.24 (9H); 1.52 (3H); 1.62 (3H); 2.62 (3H, Ac); 4.65 (1H3); 5.82 (1H5); 5.9 (m, 2H); 6.11 (1H)] and methylene-(2S,5R)-6-[(Z)-acetonylidene]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate [Rf: 0.53; cyclohexane/ethyl acetate (6:4); NMR (CDCl3), δ (ppm): 1.25 (9H); 1.53 (3H); 1.61 (3H); 2.38 (3H, Ac); 4.64 (1H3); 5.91 (m, 2H); 6.08 (1H5): 6.63 (1H)].
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12]OS(C)(=O)=O)[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.[CH2:39]([NH:42][CH3:43])[CH:40]=[CH2:41]>>[CH2:39]([N:42]([CH3:43])[CH2:12][CH2:11][CH2:10][CH2:9][C@H:6]1[CH2:5][CH2:4][C@H:3]([N:2]([CH3:1])[S:33]([C:30]2[CH:31]=[CH:32][C:27]([C:26]([F:38])([F:37])[F:25])=[CH:28][CH:29]=2)(=[O:35])=[O:34])[CH2:8][CH2:7]1)[CH:40]=[CH2:41]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: C=CCNC
Reactant: CN[C@H]1CC[C@H](CCCCOS(C)(=O)=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: C=CCN(C)CCCC[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
In analogy to examples 31.5 and 31.6, trans-Methanesulfonic acid 4-(4-methylamino-cyclohexyl)-butyl ester.trifluoro-acetic acid and and 4-trifluoromethyl-phenyl-sulfonylchloride were reacted, followed by treatment with N-allyl-N-methylamine to give trans-N-{4-[4-(Allyl-methyl-amino)-butyl]-cyclohexyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide, MS: 447 (MH+).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11]CC2C=CC=CC=2)[C@H:9]([O:19]CC2C=CC=CC=2)[C@@H:8]([CH2:27][OH:28])[O:7][C@H:6]1[O:29][C@H:30]1[C@@H:63]([O:64]CC2C=CC=CC=2)[C@@H:62]([CH2:72][OH:73])[O:61][C@@H:32]([O:33][CH2:34][CH:35]([CH2:37][CH2:38][CH2:39][C@H:40]([C@@H:42]2[C@:59]3([CH3:60])[C@H:45]([C@H:46]4[C@H:56]([CH2:57][CH2:58]3)[C@:54]3([CH3:55])[CH:49]([CH2:50][CH2:51][CH2:52][CH2:53]3)[CH2:48][CH2:47]4)[CH2:44][CH2:43]2)[CH3:41])[CH3:36])[C@@H:31]1[O:74]CC1C=CC=CC=1)(=[O:3])[CH3:2].[H][H]>CO.O.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[C:1]([NH:4][C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:19])[C@@H:8]([CH2:27][OH:28])[O:7][C@H:6]1[O:29][C@H:30]1[C@@H:63]([OH:64])[C@@H:62]([CH2:72][OH:73])[O:61][C@@H:32]([O:33][CH2:34][CH:35]([CH2:37][CH2:38][CH2:39][C@H:40]([C@@H:42]2[C@:59]3([CH3:60])[C@H:45]([C@H:46]4[C@H:56]([CH2:57][CH2:58]3)[C@:54]3([CH3:55])[CH:49]([CH2:50][CH2:51][CH2:52][CH2:53]3)[CH2:48][CH2:47]4)[CH2:44][CH2:43]2)[CH3:41])[CH3:36])[C@@H:31]1[OH:74])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@H]1[C@H](O[C@H]2[C@@H](OCc3ccccc3)[C@@H](CO)O[C@@H](OCC(C)CCC[C@@H](C)[C@H]3CC[C@H]4[C@@H]5CCC6CCCC[C@]6(C)[C@H]5CC[C@]34C)[C@@H]2OCc2ccccc2)O[C@H](CO)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)N[C@H]1[C@H](O[C@H]2[C@@H](O)[C@@H](CO)O[C@@H](OCC(C)CCC[C@@H](C)[C@H]3CC[C@H]4[C@@H]5CCC6CCCC[C@]6(C)[C@H]5CC[C@]34C)[C@@H]2O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reaction time: 20 h
Yield: 80 %

Procedure:
Compound 30 (230 mg, 0.209 mmol) was dissolved in a mixture of methanol, water and ethyl acetate (4:1:1, 25 mL), and palladium hydroxide/carbon (230 mg) was added thereto. Inside of the reaction system was replaced with hydrogen gas, and catalytic reduction was performed at room temperature for 20 hours. The reaction mixture was filtered through Celite, and the filtrate was evaporated. The residue was purified with a column of Sephadex LH-20 (CHCl3:MeOH=1:1) to obtain Compound 33 (126.1 mg, 81.5%).
Reaction SMILES: [C:1]([O:4][N:5]=[C:6]([C:23](=O)[CH2:24]Br)[C:7]([O:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:3])[CH3:2].[NH2:27][C:28]([NH2:30])=[S:29]>CN(C)C(=O)C>[C:1]([O:4][N:5]=[C:6]([C:23]1[NH:30][C:28](=[NH:27])[S:29][CH:24]=1)[C:7]([O:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)ON=C(C(=O)CBr)C(=O)OC(c1ccccc1)c1ccccc1
Reactant: NC(N)=S
Solvent: CC(=O)N(C)C
Product: CC(=O)ON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1csc(=N)[nH]1
Yield: 43 %

Procedure:
In 20 ml of N,N-dimethylacetamide there were dissolved 26.5 g of benzhydryl 2-acetoxyimino-4-bromo-3-oxobutyrate and, under ice-cooling and stirring, 4.81 g of thiourea was added. The mixture were stirred at room temperature for 3 hours and 15 minutes, after which it was washed well with 80 ml of ether. The ether was discarded after being removed by decantation. The above procedure was carried out once again and the mixture was poured into 100 ml of water, whereupon crystals separated out. After loosening, the crystals were recovered by filtration and washed with ether, a small amount of ethyl acetate and ether in the order mentioned. By the above procedure there were obtained 10.738 g of crystals of the captioned compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]1.[Br:22][C:23]1[S:24][CH:25]=[C:26]([C:28](O)=[O:29])[N:27]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[Br:22][C:23]1[S:24][CH:25]=[C:26]([C:28]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:9]2)=[O:29])[N:27]=1
Reactant: O=C(O)c1csc(Br)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N)C1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2NC(=O)c2csc(Br)n2)C1
Reaction time: 60 h

Procedure:
A solution containing 1 eq each of (S)-tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate, 2-bromothiazole-4-carboxylic acid, HOAT and EDC in DMF, at a concentration of 0.5 M, was stirred for 60 hours. The solution was diluted with EtOAc and was washed with H2O (4×), NaCl(sat.), was dried over MgSO4, was filtered and the volatiles were removed in vacuo yielding (S)-tert-butyl 1-(3-(2-bromothiazole-4-carboxamido)pyridin-4-yl)piperidin-3-ylcarbamate, LCMS (m/z): 416.1 (MH+); LC Rt=1.95 min.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[OH:13].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:14]([O:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:13])=[C:2]([CH3:1])[CH:11]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cc(O)c2ccccc2c1O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Cc1cc(OC(=O)c2ccccc2)c2ccccc2c1O
Reaction time: 1 h
Yield: 69.3 %

Procedure:
9.7 g (0.056 mol) of 2-methyl-1,4-dihydroxynaphthalene was dissolved in 60 ml of pyridine, and, while stirring under ice-cooling, 8.4 g (0.06 mol) of benzoyl chloride was added dropwise. Following completion of the addition, stirring was continued under ice-cooling for 30 minutes, and for further one hour at room temperature. The reaction mixture was concentrated under reduced pressure, the residual oil extracted with ethyl acetate, washed with 1N HCl and then water, and the organic layer concentrated under reduced pressure. Methanol was added to the residue, the precipitated crystals collected by filtration and recrystallized from methanol to give 10.8 g of white crystals, m.p. 172-174° C.