Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1.[N:11]([O-])=[O:12].[Na+]>O>[N:11]([N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1)=[O:12]
Reactant: O=C(O)C1CCCNC1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=NN1CCCC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.2 %

Procedure:
Aqueous hydrochloric acid (2N, 20 mL) was added to piperidine-3-carboxylic acid (5.02 g, 38.87 mmol). The mixture was cooled with an ice bath and a solution of sodium nitrite (2.78 g, 40.29 mmol) in water (4 mL) was added. The reaction mixture was stirred at room temperature for 15 h. The mixture was extracted with dichloromethane (20 mL×3). The combined organics were washed with brine (2×), solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford 1-nitrosopiperidine-3-carboxylic acid (4.5 g). MS (EI+) (M+) 158.
Reaction SMILES: CS(O[CH2:6][CH:7]([CH3:11])[CH2:8][CH2:9][CH3:10])(=O)=O.C(O)C.[SH:15][C:16]1[S:17][C:18]([NH2:21])=[N:19][N:20]=1.[OH-].[Na+]>C(OCC)(=O)C>[CH3:11][CH:7]([CH2:8][CH2:9][CH3:10])[CH2:6][S:15][C:16]1[S:17][C:18]([NH2:21])=[N:19][N:20]=1
Reactant: Nc1nnc(S)s1
Reactant: CCCC(C)COS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCC(C)CSc1nnc(N)s1
Temperature: 25 °C

Procedure:
A three-necked 3-L round bottom flask was charged with 2-methylpentyl methanesulphonate (90 g, 0.5 mol), ethanol (1.5 L) and 2-mercapto-1,3,4-thiadiazole-5-amine (66.5 g, 0.5 mol). Sodium hydroxide (20 g, 0.5 mol) was added to the stirred suspension. The mixture was heated to reflux and held at reflux over night. As the mixture warmed the cream suspension gradually dissolved. Just before refluxing began a cloudy precipitate formed. The reaction mixture was cooled to room temperature, filtered, and the residue was washed well with ethanol. The resulting filtrate was concentrated to dryness to give an off-white solid that was dissolved in ethyl acetate (1.2 L) and washed with 1) water (800 mL) and 2) brine (1 L). The filtrate was dried (MgSO4) and concentrated to dryness. An off-white solid was obtained that was recrystallised from boiling acetonitrile (150 mL). The filtered material was washed well with acetonitrile and dried (Vac/40° C.). The required product was obtained as a white solid wt 83 g; 76.5%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15](=[O:17])[CH3:16])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]([N:32]3[C:44]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:38]4[C:33]3=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:29]=[CH:30][CH:31]=2)O1>C1(C)C=CC=CC=1.O.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].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[CH:34]1[C:33]2[N:32]([C:28]3[CH:27]=[C:26]([C:2]4[CH:3]=[CH:4][C:5]5[N:6]([C:15](=[O:17])[CH3:16])[C:7]6[C:12]([C:13]=5[CH:14]=4)=[CH:11][CH:10]=[CH:9][CH:8]=6)[CH:31]=[CH:30][CH:29]=3)[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38]=2[CH:37]=[CH:36][CH:35]=1
Reactant: CC1(C)OB(c2cccc(-n3c4ccccc4c4ccccc43)c2)OC1(C)C
Reactant: CC(=O)n1c2ccccc2c2cc(Br)ccc21
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)n1c2ccccc2c2cc(-c3cccc(-n4c5ccccc5c5ccccc54)c3)ccc21
Temperature: 25 °C
Yield: 92.8 %

Procedure:
A solution of 1-(3-bromo-9H-carbazol-9-yl)ethanone (2.000 g, 6.94 mmol), 9-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-9H-carbazole (2.56 g, 6.94 mmol), Pd2(dba)3 (0.064 g, 0.069 mmol), SPhos (0.057 g, 0.139 mmol) and potassium phosphate tribasic hydrate (4.80 g, 20.82 mmol) in toluene (100 mL) and water (10 mL) was stirred at 70° C. under nitrogen overnight. After cooling to room temperature, the organic phase was isolated. Upon evaporation of the solvent, the residue was purified by column chromatography on silica gel with hexane:DCM (1:4, v/v) as eluent to yield 1-(3-(3-(9H-carbazol-9-yl)phenyl)-9H-carbazol-9-yl)ethanone (2.9 g, 94%) as a white solid.
Reaction SMILES: [C:1](=[O:4])([O-:3])O.[Na+].[C:6](=O)([O:14]C1C=CC=CC=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:6]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:14])[C:1]([O:3][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: O=C([O-])O
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: [Na+]
Product: O=C(Oc1ccccc1)C(=O)Oc1ccccc1

Procedure:
400 parts of an aqueous solution of sodium hydrogencarbonate having a pH of 10 were added to 200 parts of diphenyl carbonate, obtained through the decarbonylation reaction of diphenyl oxalate using tetraphenyl phosphonium bromide and hydrogen chloride as catalysts, and the mixture was heated to 90° C. and stirred for 1 hour to obtain diphenyl carbonate containing 9.1 ppm of hydrolyzable halogen. An ester interchange reaction between this diphenyl carbonate and bisphenol A was carried out in the same manner as in Example 1 except that a disodium salt of bisphenol A was used in place of sodium hydroxide as an ester interchange catalyst in an amount of 2.0×10−6 mole, in terms of sodium, based on bisphenol A, to synthesize polycarbonate. A pellet of this polycarbonate was used for the measurement of its physical properties. The conditions and results are shown in Tables II-A and II-B below.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[CH:4][CH:3]=1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[O:21]=[C:13]1[N:12]2[CH2:22][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:30]([NH:29][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:31])=[CH:3][CH:4]=3)[CH2:9][N:10]=[C:11]2[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:14]1
Reactant: Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 70.7 %

Procedure:
To a mixture of 3-(4-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (25.1 mg, 0.086 mmol) in 1.1 mL THF was added phenyl isocyanate (0.0103 mL, 0.095 mmol) and the reaction stirred at rt. After 45 min, the reaction was briefly warmed to approximately 50° C. and then allowed to cool to rt. At 2.5 hours the reaction was quenched with MeOH, evaporated, then triturated with MeOH, EtOAc, and then 50% EtOAc/hexane to give the title compound as a light tan solid (25.0 mg, 71%). 1H NMR (DMSO-d6) δ: 10.69 (br. s, 1H), 8.64 (br. s, 2H), 7.98 (d, J=7.0 Hz, 1H), 7.40-7.47 (m, 5H), 7.21-7.31 (m, 4H), 6.92-7.10 (m, 3H), 4.18-4.26 (m, 1H), 3.67-3.77 (m, 1H), 3.49-3.61 (m, 2H), 2.89-3.03 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=1.B(F)(F)F.CCOCC>O1CCCC1>[C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=[N:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Reactant: Nc1ccc(CCC(=O)O)cc1
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)C1=CC(=Nc2ccc(CCC(=O)O)cc2)C=C(C(C)(C)C)C1=O
Yield: 55.5 %

Procedure:
A mixture of 5.51 g (0. 025 mole ) of 2,6-di-tertiary-butyl-p-benzoquinone, 4.54 g (0.027 mole) of 3-(4-aminophenyl)propionic acid, 50 ml of tetrahydrofuran and 0.25 ml of boron trifluoride etherate was heated on a steam cone under a slow stream of nitrogen for two hours. The resulting solid was triturated with hexane, collected, rinsed with hexane and recrystallized from a mixture of ethyl acetate and hexane to give 5.1 g yellow 3-[4-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)phenyl]propionic acid, m.p. 165°-167° C. Analysis: Calculated for C23H29NO3 : % C, 75.2; % H, 8.0; % N, 3.8; Found % C, 74.8; % H, 7.9; % N, 3.7.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:13].[N+:24]([O-])([OH:26])=[O:25]>CC(O)=O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:24]([O-:26])=[O:25])=[CH:4][C:3]=1[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)=[O:13]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(COC(=O)c2ccc3ccccc3c2O)cc1
Solvent: CC(=O)O
Product: COc1ccc(COC(=O)c2cc([N+](=O)[O-])c3ccccc3c2O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61782.3 %

Procedure:
A warm vigorously stirred solution of 2 (25.4 g, 0.082 mmol) in AcOH (260 mL) was cooled to 25° C. and treated in one portion with a solution of HNO3 (70% w/w, 18.6 g, 0.20 mmol) in AcOH (25 mL). The temperature rose to 35° C. (controlled with external cooling) and a solid separated. After stirring for a further 10 min at 30° C., the mixture was cooled to 0° C. The precipitate was collected, washed with cold AcOH and iPr2O, and recrystallised from CH2Cl2 /petroleum ether to give 4-methoxybenzyl 1-hydroxy-4-nitronaphthalene-2-carboxylate (3) (17.9 g, 61%) mp 163-164° C. 1H NMR [(CD3)2SO] δ 12.46 (br s, 1H, OH), 8.60 (s, 1H, H-3), 8.60 (d, J=8.6 Hz, 1H, H-5), 8.47 (d, J=8.3 Hz, 1H, H-8), 7.97 (br t, J=7.8 Hz, 1H, H-6), 7.79 (br t, J=7.7 Hz, 1H, H-7), 7.50 (d, J=8.6 Hz, 2H, H-2',6'), 7.00 (d, J=8.7 Hz, 2H, H-3',5'), 5.32 (s, 2H, CH2), 3.78 (s, 3H, OCH3). Anal. Calculated for C19H15NO6 : C, 64.6; H, 4.3; N, 4.0. Found: C, 64.7; H, 4.0; N, 4.2%.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][OH:11])=[CH:7][CH:8]=2)[CH2:3][O:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl.CCOCC>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH2:3][O:2]1
Reactant: OCc1ccc2c(c1)COC2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1ccc2c(c1)COC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(1,3-Dihydro-isobenzofuran-5-yl)-methanol (440 mg, 2.9 mmol) was dissolved in 20 ml of DCM. 1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin reagent) (1.3 g, 3.2 mmol) was added and the reaction was stirred at r.t. for 4 h. The reaction mixture was diluted with ether and extracted 2× with NaOH 1N, 2× with H2O and dried over MgSO4. The crude product was sufficiently pure and used without any further purification.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([O:6][CH3:7])=[O:5])[CH3:3].Cl.[CH2:9]([C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:9]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([NH:1][C@@H:2]([CH3:3])[C:4]([O:6][CH3:7])=[O:5])=[O:22])=[CH:24][CH:25]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCc1ccc(C(=O)O)cc1
Reactant: COC(=O)[C@@H](C)N
Agent: Cl
Product: CCCCCCCCc1ccc(C(=O)N[C@@H](C)C(=O)OC)cc1

Procedure:
General procedure F was used to couple 0.31 mmols of H-D-Ala-OMe.HCl to 0.31 mmols of 2. The product was isolated by flash chromatography to yield 0.075 g (0.23 mmols). 1H NMR (300 MHz, CDCl3) δ 7.75 (d, J=8.1, 2H), 7.27 (d, J=8.1, 2H), 6.77 (s, 1H), 4.84 (s, 1H), 3.82 (s, 3H), 2.79-2.60 (m, 2H), 1.64 (s, 2H), 1.55 (d, J=7.1, 3H), 1.29 (s, 14H), 0.90 (t, J=6.9, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C@@H:8]([C@H:10]1[CH2:14][N:13]([C@@H:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH3:16])[C:12](=[O:25])[CH2:11]1)[CH3:9].Cl[C:27]1[C:28]2[N:29]([N:45]=[CH:46][C:47]=2[CH3:48])[CH:30]=[C:31]([C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:35][CH:34]=2)[N:32]=1>C1COCC1>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([C@H:15]([N:13]2[CH2:14][C@H:10]([C@H:8]([O:7][C:27]3[C:28]4[N:29]([N:45]=[CH:46][C:47]=4[CH3:48])[CH:30]=[C:31]([C:33]4[CH:38]=[CH:37][C:36]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[CH:35][CH:34]=4)[N:32]=3)[CH3:9])[CH2:11][C:12]2=[O:25])[CH3:16])=[CH:22][CH:21]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)O)CC2=O)cc1
Reactant: Cc1cnn2cc(-c3ccc(N4CCOCC4)cc3)nc(Cl)c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(-c4ccc(N5CCOCC5)cc4)cn4ncc(C)c34)CC2=O)cc1
Reaction time: 0.25 h

Procedure:
A solution of 1M potassium tertbutoxide in THF (0.10 mL, 0.10 mmol) was added to a solution of (R)-4-((R)-1-hydroxyethyl)-1-4R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.04 (27 mg, 0.1 mmol) in THF (0.5 mL) at room temperature. After 15 minutes, a solution of 4-(4-(4-chloro-3-methylpyrazolo[1,5-a]pyrazin-6-yl)phenyl)morpholine 5.11 (20 mg, 0.06 mmol) in THF (1.2 mL) was added under argon. After 90 minutes, an additional 14 mg of (R)-4-((R)-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.04 and 0.05 mL of 1M potassium tertbutoxide in THF were added. After 5 hours, mixture was quenched by addition of sat. NH4Cl (aq) and extracted with ethyl acetate. Combined organics were washed with 1:1 water/brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to yield (R)-1-((R)-1-(4-methoxyphenyl)ethyl)-4-((R)-1-(3-methyl-6-(4-morpholinophenyl)pyrazolo[1,5-a]pyrazin-4-yloxy)ethyl)pyrrolidin-2-one 5.12, which was used without further purification.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:7]=[C:6]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: CCCCC(=O)c1cccc(Br)n1
Reactant: OB(O)c1ccc(C(F)(F)F)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: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCCCC(=O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 94.8 %

Procedure:
A solution of 1-(6-bromo-2-pyridinyl)-1-pentanone (2.51 g, 10.37 mmol) in DME (13 mL) was treated with 4-(triflouromethyl)benzeneboronic acid (2.36 g, 12.43 mmol), Pd(PPh3)4 (1.19 g, 1.03 mmol) and then a slurry of Na2CO3 (3.29 g, 31.04 mmol) in water (13 mL). The resulting mixture was then heated to reflux over 30 minutes and then stirred at this temperature for 17 hours. The mixture was then allowed to cool to rt and was reduced and the residue partitioned between EtOAc (200 mL) and water (200 mL). The aqueous was re-extracted with EtOAc (100 mL) and the combined organic layer washed with saturated aqueous NaHCO3 (250 mL), brine (250 mL), dried (MgSO4), filtered and reduced to give a brown orange solid residue. Purification by Biotage™ chromatography (silica) eluting with cyclohexane:EtOAc (gradient 1:0 to 10:1) afforded the title compound as a white solid (3.02 g).
Reaction SMILES: [NH:1]([C:5]1[S:6][C:7]([C:11]([OH:13])=O)=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3].Cl.[NH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:22])[CH2:16]1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(OCC)(=O)C.CN(C=O)C>[NH:1]([C:5]1[S:6][C:7]([C:11]([N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:22])[CH2:16]2)=[O:13])=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CCOC(=O)CCNC(=O)C1CCCNC1
Reactant: Cc1nc(NC(=N)N)sc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)C1CCCN(C(=O)c2sc(NC(=N)N)nc2C)C1
Yield: 65.7 %

Procedure:
220 mg of 2-guanidino-4-methyl-thiazole-5-carboxylic acid, 265 mg of ethyl (RS)-3-[(piperidine-3-carbonyl)-amino]-propionate hydrochloride, 3 ml of DMF, 0.34 ml of N-methylmorpholine (N-MM) and 569 mg of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) are stirred at RT for 22 hours. The reaction mixture is diluted with ethyl acetate and washed firstly with a dilute aqueous solution of sodium carbonate and sodium chloride, then with dilute sodium chloride solution and finally with saturated sodium chloride solution. The organic phase is dried over sodium sulphate and evaporated in a vacuum. Chromatography on silica gel with ethyl acetate: ethanol 5:1 gives 270 mg of ethyl (RS)-3-[[1-(2-guanidino-4-methyl-thiazole-5-carbonyl)-piperidine-3-carbonyl]-amino]-propionate as a pale yellow foam. MS: 411 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:9][C@H:10]2[CH2:15][CH2:14][C@@H:13]([OH:16])[CH2:12][CH2:11]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:17](Br)[CH2:18][CH3:19]>COCCOC>[CH:3]1([NH:9][C@H:10]2[CH2:15][CH2:14][C@@H:13]([O:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:11]2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O[C@H]1CC[C@@H](NC2CCCCC2)CC1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCO[C@H]1CC[C@@H](NC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of NaH (60% susp., 1.4 mmol) and ethylene glycol dimethylether (3 mL) was added cyclohexyl-cis-(4-hydroxycyclohexyl)-amine (0.36 mmol) and the mixture was stirred under N2 at rt for 5 min followed by addition of propylbromide (5.5 mmol). The mixture was refluxed for 18 h under N2. The reaction mixture was cooled to rt and quenched with anhydrous EtOH (0.5 mL). The mixture was filtered and the residue was extracted with ethylene glycol di-methylether (2 mL). The organic phase was evaporated to dryness under reduced pressure and co-evaporated with toluene (10 LI). The residue was added HCl in MeOH (1.25 M, 5 mL) and evaporated under reduced pressure affording a white solid. The solid was washed with TBME (2 mL) and dissolved in a mixture of DCM (5 mL) and 1 M aqueous NaOH (5 mL). The organic phase was washed with H2O (5 mL), dried (Na2SO4), and evaporated under reduced pressure to give the desired cyclohexyl-cis-(4-propoxycyclohexyl)amine as an oil which was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]2[C:9]([CH:44]=1)=[CH:10][C:11]1[C:12]([O:35][CH2:36][CH:37]([CH2:42][CH3:43])[CH2:38][CH2:39][CH2:40][CH3:41])=[C:13]3[S:29][C:28]([C:30]([O:32]CC)=[O:31])=[CH:27][C:14]3=[CH:15][C:16]=1[C:17]=2[O:18][CH2:19][CH:20]([CH2:25][CH3:26])[CH2:21][CH2:22][CH2:23][CH3:24])=[O:5])C.O.[OH-].[Li+]>C1COCC1.CO>[CH2:25]([CH:20]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:19][O:18][C:17]1[C:16]2[CH:15]=[C:14]3[CH:27]=[C:28]([C:30]([OH:32])=[O:31])[S:29][C:13]3=[C:12]([O:35][CH2:36][CH:37]([CH2:42][CH3:43])[CH2:38][CH2:39][CH2:40][CH3:41])[C:11]=2[CH:10]=[C:9]2[CH:44]=[C:6]([C:4]([OH:5])=[O:3])[S:7][C:8]=12)[CH3:26]
Reactant: CCCCC(CC)COc1c2cc3cc(C(=O)OCC)sc3c(OCC(CC)CCCC)c2cc2cc(C(=O)OCC)sc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCCC(CC)COc1c2cc3cc(C(=O)O)sc3c(OCC(CC)CCCC)c2cc2cc(C(=O)O)sc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 760 %

Procedure:
0.06 g of 5,10-bis(2-ethylhexyloxy)-1,6-dithia-dicyclopenta[b,g]naphthalene-2,7-dicarboxylic acid diethyl ester (0.009 mmol) was dissolved in 0.5 mL of THF:Methanol (1:1), and 0.2 mL of water and 0.01 g of lithium hydroxide (0.04 mmol) were added thereto and stirred at room temperature for 8 hours. Again, the mixture was further stirred at 50° C. for 8 hours, the solvent was removed, and a temperature was lowered to 0° C., and the resultant was acidified by 2N HCl solution, thereby obtaining 0.04 g of the title compound (74.0%).
Reaction SMILES: I[C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:18][N:19]1[C:23](B(O)O)=[CH:22][C:21]([C:27]([F:30])([F:29])[F:28])=[N:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH3:18][N:19]1[C:23]([C:2]2[CH:17]=[CH:16][C:5]([O:6][C:7]3[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=3)=[CH:4][CH:3]=2)=[CH:22][C:21]([C:27]([F:30])([F:29])[F:28])=[N:20]1
Reactant: Cn1nc(C(F)(F)F)cc1B(O)O
Reactant: O=C(O)c1ccc(Oc2ccc(I)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nc(C(F)(F)F)cc1-c1ccc(Oc2ccc(C(=O)O)cc2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A suspension of 4-(4-iodophenoxy)benzoic acid (Preparation 143, 470 mg, 1.38 mmol), 1-methyl-3-trifluoromethylpyrazole-5-boronic acid (322 mg, 1.66 mmol), palladium tetrakis triphenyl phosphine (239 mg, 0.207 mmol) and cesium carbonate (1.35 g, 4.15 mmol) in dioxane/water (10 mL/5 mL) was heated to 80° C. for 6 hours then left to stir at room temperature overnight. The reaction was quenched by the addition of 1N HCl and extracted into ethyl acetate. The organic layer was collected, dried over magnesium sulfate and concentrated in vacuo to furnish the crude title compound that was taken on directly to the next step.
Reaction SMILES: C1[O:18][CH2:17][CH2:16]OCCOCCOCCOCCOC1.FC(F)(F)COP(CC(OC)=O)(=O)OCC(F)(F)F.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:48][C:49]1[N:53]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[N:52]=[CH:51][C:50]=1[CH:60]=O>C1(C)C=CC=CC=1.C1COCC1>[C:54]1([N:53]2[C:49]3[NH:48][C:17](=[O:18])[CH:16]=[CH:60][C:50]=3[CH:51]=[N:52]2)[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: Nc1c(C=O)cnn1-c1ccccc1
Agent: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=c1ccc2cnn(-c3ccccc3)c2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.2 %

Procedure:
To a semi-solid mixture of 18-crown-6 (4.31 g, 16 mmol) and THF (30 ml) at −40° C. under nitrogen was added bis(2,2,2-trifluoroethyl)-(methoxycarbonylmethyl)phosphonate (0.69 ml, 3.26 mmol) followed by a solution of potassium bis(trimethylsilyl)amide in toluene (6.52 ml of a 0.5M solution, 3.26 mmol). A solution of 5-amino-1-phenyl-1H-pyrazole-4-carboxaldehyde (0.61 g, 3.26 mmol) in THF (10 ml+5 ml washings) was then added via cannula and the resulting mixture was stirred for 20 h, allowing to warm to room temperature. The reaction mixture was partitioned between saturated aqueous ammonium chloride solution and diethyl ether. The aqueous phase was extracted a second time with diethyl ether, and the combined organic extracts were washed with brine, dried (MgSO4) and concentrated. The crude material was dissolved in THF (20 ml), under nitrogen, and the resulting solution cooled to 0° C. A solution of potassium bis(trimethylsilyl)amide in toluene (13.0 ml of a 0.5M solution, 6.5 mmol) was added dropwise and the reaction mixture was stirred for 17 h during which time it was allowed to warm to room temperature. The reaction mixture was partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The aqueous phase was extracted a second time with ethyl acetate, and the combined organic extracts were washed sequentially with 0.5M aqueous hydrochloric acid and brine before being dried (MgSO4) and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with 30% ethyl acetate-hexane to give 1,7-dihydro-1-phenylpyrazolo[3,4-b]pyridin-6-one (0.49 g, 71%). δH (400 MHz; CDCl3) 6.50 (1H, d, J=9), 7.29-7.33 (1H, m), 7.42-7.45 (2H, m), 7.71-7.73 (2H, m), 7.85 (1H, d, J=9), 7.91 (1H, s).