Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[S:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>CCOCCO>[O:24]=[C:23]1[C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[S:20][N:1]1[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1SCl
Reactant: Nc1ccc(CC(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CCOCCO
Product: O=C(O)Cc1ccc(-n2sc3ccccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To a mixture of 7.55 g (0.05 mol) of 4-aminophenylacetic acid and 15.15 g (0.15 mol) of triethylamine in 25 mL of ethyl cellosolve was added 10.3 g (0.05 mol) of 2-chlorosulfenylbenzoyl chloride (Arzneimittel Forsch., 1964;14:1301). The mixture was stirred at room temperature for 3 hours, concentrated in vacuo, and water was added to the residue. The mixture was acidified with HCl and filtered to give 9.9 g of the title compound, mp 173-175° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[CH:2]1>C1COCC1.[Pd]>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:2]1
Reactant: COC(=O)/C=C/c1ccoc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)CCc1ccoc1
Yield: 93.2 %

Procedure:
A solution of 11a (2.0 g, 13.15 mmol) in 45 mL dry THF was treated with 10% Pd-C (30.0 mg, 1.5 wt %) at room temperature under a hydrogen atmosphere (balloon) (44 h). The reaction mixture was then filtered through a Celite plug, washed with EtOAc (150 mL), and concentrated in vacuo. SGC chromatotron (SiO2, 4 mm, 10-20% EtOAc/hexanes) afforded 12a (1.89 g, 2.03 g theoretical, 93%). For 12a: 1H NMR (CDCl3, 250 MHz) d 7.29 (br d, 1H, J=1.6 Hz, Fur C5-H), 7.19 (d, 1H, J=1.6 Hz, Fur C2-H), 6.22 (br s, 1H, Fur C4-H), 3.63 (s, 3H, OCH3), 2.71 (t, 2H, J=7.3 Hz, FurCH2), 2.52 (t, 2H, J=7.3 Hz, CH2 (C=O)); 13C NMR (CDCl3, 125 MHz) d 173.2, 142.8, 138.9, 123.4, 110.6, 51.5, 34.4, 20.1; IR (neat) nmax 2932, 2862, 1732, 1439, 1361, 1259, 1201, 1167, 1024, 874, 793, 731 cm-1. See FIG. 17h.
Reaction SMILES: [CH3:1][C:2]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)([CH3:15])[CH2:3][NH:4]C(=O)OCC1C=CC=CC=1>CO>[CH3:15][C:2]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)([CH3:1])[CH2:3][NH2:4]
Reactant: CC(C)(CNC(=O)OCc1ccccc1)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: CO
Product: CC(C)(CN)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1

Procedure:
The title compound was prepared as described in Example 66 using benzyl (2-methyl-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)carbamate (CB68) and methanol as solvent; isolated as a clear oil (0.427 g, 80%): 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.15 (d, J=8.4 Hz, 2H), 7.84-7.77 (m, 2H), 7.49-7.42 (m, 2H), 7.39 (dt, J=7.9, 1.0 Hz, 2H), 2.85 (s, 2H), 1.78 (s, 2H), 1.36 (s, 6H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 377 ([M+H]+).
Reaction SMILES: C1C2C(COC(=O)[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:40])[NH:32][C:33]5[CH:38]=[CH:37][C:36]([Br:39])=[CH:35][N:34]=5)=[CH:27][C:26]=4[NH:41][C:42]4[C:43]5[CH:51]=[CH:50][C:49]([CH:52]([CH3:54])[CH3:53])=[N:48][C:44]=5[N:45]=[CH:46][N:47]=4)=[CH:20][CH:19]=3)C3C(=CC=CC=3)C=2C=CC=1.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O.CCOC(C)=O.[Cl-].[Na+].O>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([Br:39])=[CH:35][N:34]=3)=[O:40])=[CH:27][C:26]=2[NH:41][C:42]2[C:43]3[CH:51]=[CH:50][C:49]([CH:52]([CH3:54])[CH3:53])=[N:48][C:44]=3[N:45]=[CH:46][N:47]=2)=[CH:20][CH:19]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cn4)ccc3Sc3ccc(NC(=O)OCC4c5ccccc5-c5ccccc54)cc3)ncnc2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cn4)ccc3Sc3ccc(N)cc3)ncnc2n1
Reaction time: 3 h
Yield: 96.3 %

Procedure:
A 3 liter, 3-neck round bottom flask under N2 equipped with an addition funnel and overhead stirrer was charged with the product from Example 17E (32.35 g, 40.0 mmol) and anhydrous tetrahydrofuran (0.5 L). To the yellow solution was added tetrabutylammonium fluoride (1.0 M in THF, 32.0 mL, 32 mmol) at a fast drip rate. After the addition was completed the red, transparent solution was stirred for 3 hours, diluted with 1.0 L of water and 400 mL of EtOAc and stirred vigorously for 5 minutes. The layers were allowed to separate and the aqueous layer was removed and discarded. The organic layer was washed with a second liter of water and again the water was removed. The mix was diluted again with 1 L of water and 400 mL of EtOAc and stirred vigorously for 5 minutes to give an emulsion. The emulsion was broken by adding 50-100 mL of saturated brine and stirring gently. The organic layer was washed 4×1 L with water using brine as necessary to break the emulsions. After the final aqueous wash 400 mL of EtOAc was added and the suspension was stirred for 1 hour and the solid was collected by filtration, rinsed with 400 mL of EtOAc, rinsed with 500 mL of water and dried to constant mass in a vacuum oven (60° C., house vacuum, 24 hours) to give the title compound (22.6 g, 96%) as a cream colored powder.
Reaction SMILES: I[CH3:2].[OH-].[K+].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:29])[O:14][CH2:15][C@@:16]([OH:28])([CH3:27])[CH2:17][N:18]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[N:20]=[C:19]2Cl)=[CH:8][CH:7]=1.Cl>CS(C)=O>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH3:2])[C:13](=[O:29])[O:14][CH2:15][C@:16]2([CH3:27])[O:28][C:19]3=[N:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][N:18]3[CH2:17]2)=[CH:8][CH:7]=1
Reactant: C[C@](O)(COC(=O)Nc1ccc(Cl)cc1)Cn1cc([N+](=O)[O-])nc1Cl
Reactant: CI
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CN(C(=O)OC[C@@]1(C)Cn2cc([N+](=O)[O-])nc2O1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.1 %

Procedure:
Iodomethane (0.71 ml, 11.4 mmol) and potassium hydroxide (0.64 g, 11.4 mmol) were added to a solution of (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-chlorophenylcarbamate prepared in Example 64 (1.5 g, 3.8 mmol) in DMSO (40 ml) followed by stirring at room temperature for 4 hours. The mixture was cooled on ice-bath and added 10% hydrochloric acid. The resulting mixture was extracted with ethyl acetate, and the extract was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1) and recrystallized from isopropanol to afford (R)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl N-(4-chlorophenyl)-N-methylcarbamate (0.67 g, 60%) as a white solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH2:47][CH3:48])[CH:42]=[N:43][CH:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH2:47][CH3:48])[CH:42]=[N:43][CH:44]=5)=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cncn4CCCC)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCCC)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-butylimidazol-4-yl)methylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1.15 g) was dissolved in dichloromethane (40 ml), and the mixture was cooled to −78° C. A solution of 3-chloroperbenzoic acid (0.62 g) in dichloromethane (10 ml) was added dropwise to the solution. The mixture was stirred for 1 hour at −78° C., and then, an aqueous solution of sodium thiosulfate was added to the mixture. The mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-butylimidazol-4-yl)methylsulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 401) (0.72 g) as yellow amorphous.
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:9][C:10]1([CH2:13][O:14][Si](C(C)(C)C)(C)C)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.F[Si-2](F)(F)(F)(F)F.[H+].[H+]>O>[CH2:1]([N:8]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:9][C:10]1([CH2:13][OH:14])[CH2:11][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CN(Cc1ccccc1)CC1(CO[Si](C)(C)C(C)(C)C)CC1
Agent: [H+]
Solvent: CC#N
Solvent: O
Product: COC(=O)CN(Cc1ccccc1)CC1(CO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
To a stirred solution of methyl (benzyl{[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-cyclopropyl]methyl}amino)acetate (4.0 g, 0.010 mol) in ACN (100 mL, 2 mol) was added at RT, fluorosilicic acid in water (2.00 M, 10.6 mL). The resulting mixture was stirred at RT overnight. The reaction was quenched by the addition of saturated aqueous NaHCO3 until the reaction mixture was alkaline and then extracted with EtOAc (2×). The organic extracts were combined and washed with brine, then dried (MgSO4), filtered and concentrated in vacuo to afford the desired product (1.1 g), which was identified by 1H NMR spectroscopy and used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26](O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:26]([O:11][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:18][CH:19]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-2-(t-Butoxycarbonylamino)-3-(biphenyl-4-yl)propionic acid (5 g, 14.6 mmol) is dissolved in methylene chloride (25 mL) under nitrogen and the solution is cooled to 0°. Benzyl alcohol (2 mL, 19 mmol) and 4-dimethylaminopyridine (0.1 g) are added, followed by a solution of dicyclohexyl-carbodiimide (3.3 g, 16.1 mmol) in methylene chloride (15 mL). After stirring for 1 hours at 0° and 1 hours at room temperature, the reaction mixture is filtered and the filtrate concentrated in vacuo. The residue is redissolved in ether (100 mL), washed successively with water, 0.5M sodium dihydrogenophosphate, water, saturated sodium bicarbonate and water. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. (S)-2-(t-butoxycarbonylamino)-3-(biphenyl-4-yl)-propionic acid benzyl ester is obtained as a white solid, [α]D =-3.33 (c 0.91, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:26][CH2:27][CH:28]=[C:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]=2[CH2:33][O:32][C:31]2[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([OH:14])[CH2:9][CH2:10][N:11]([CH2:26][CH2:27][CH:28]=[C:29]2[C:35]3[CH:36]=[CH:37][CH:38]=[N:39][C:34]=3[CH2:33][O:32][C:31]3[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]2=3)[CH2:12][CH2:13]1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: OC1(c2ccccc2Cl)CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(O)(c3ccccc3Cl)CC1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 14 h
Yield: 51.4 %

Procedure:
To a solution of the 4-(2-chloro-phenyl)-piperidin-4-ol (0.210 g, 1.0 mmol) in isopropanol was added 2,6-lutidine (0.31 mL, 2.7 mmol) and catalytic potassium iodide. This mixture was heated to 80° C., and treated with 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.287 g, 0.77 mmol), added in portions over 1 h. The solution was then stirred at 80° C. for an additional 14 h. The reaction was concentrated in vacuo, then purified by Isco flash chromatography (15% methanol/85% methylene chloride) to yield the title compound (0.200 g, 52%).
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=1.F[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24].[NH4+].[Cl-]>C1COCC1>[F:22][C:20]1[CH:19]=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[C:16]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=2)[CH:21]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Nc1cncc(F)c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1Nc1cncc(F)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 58 %

Procedure:
Alternative procedure: Potassium tert-butoxide (28.1 g, 0.25 mol) was added, in 2 portions, to a stirred solution of 3-amino-5-fluoropyridine (14.0 g, 0.125 mol) in anhydrous THF (400 mL) under a nitrogen atmosphere at 0° C. After 45 min stirring at 0° C., the resulting dark purple solution was transferred by cannula to a stirred solution of 2,4-difluoro-1-nitrobenzene (13.8 mL, 0.125 mol) in anhydrous THF (100 mL), at 0° C., over a period of 20 min. The resulting mixture was stirred for a further 45 min then poured onto a RT solution of NH4Cl (1:1 saturated solution:H2O, 1 L). The resulting yellow precipitate was filtered, washed with water and dried under vacuum at 50° C. to afford the title compound as an orange solid (18.2 g). The filtrate was partially evaporated, to remove some of the reaction solvent, the resulting precipitate was filtered then triturated with EtOAc to give a further 3.5 g of the title compound (overall 21.7 g, 69%) LCMS (Method C): RT 3.18 min [M+H]+ 252.13
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:27])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2].C(N(CC)CC)C.FC(F)(F)C(O)=O.[CH3:42][O:43][P:44]([CH2:48][N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)([O:46][CH3:47])=[O:45].C(OC1C=CC(S(N2CCN(P(OC)(OC)=O)CC2C)(=O)=O)=CC=1C1NC(=O)C2=C(C)N=C(CCC)N2N=1)C>ClCCl.CO>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:52]2[CH2:51][CH2:50][N:49]([CH2:48][P:44]([O:43][CH3:42])([O:46][CH3:47])=[O:45])[CH2:54][CH2:53]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:27])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2]
Reactant: COP(=O)(CN1CCNCC1)OC
Reactant: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12
Agent: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(P(=O)(OC)OC)CC4C)ccc3OCC)nn12
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(CP(=O)(OC)OC)CC4)ccc3OCC)nn12

Procedure:
By the same method, starting with 0.4 g (0.97 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride, 390 mg of triethylamine and 0.86 g (2.99 mmol) of 4-dimethoxyphosphorylmethyl-piperazine trifluoroacetate, 321 mg (53%) of 2-[2-ethoxy-5-(4-dimethoxyphosphoryl-methyl-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one are obtained. Rf=0.4 (dichloromethane/methanol=20:1)
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[Cl:14][C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][C:21]([OH:23])=O)=[CH:17][CH:16]=1.CCOCC>C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]([N:2]([CH3:1])[C@@H:3]2[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]2[N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:23])=[CH:24][CH:25]=1
Reactant: CN[C@@H]1CCCC[C@H]1N1CCCC1
Reactant: O=C(O)COc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CN(C(=O)COc1ccc(Cl)cc1)[C@@H]1CCCC[C@H]1N1CCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Trans-N-Methyl-2-(1-pyrrolidinyl]cyclohexanamine (0.182 g) was dissolved in methylene chloride (10 ml) and stirred at room temperature. The acid chloride of 4-chlorophenoxyacetic acid (0.205 g) dissolved in methylene chloride (10 ml) was added and let stand for 12 hours. Ether was added to rapidly stirred solution until no more precipitate appeared. After further rapid stirring for one hour, the precipitate was filtered and dried in a vacuum oven at 90° C. for one hour, and stored in a predried bottle. The product was in the form of white needles (360 mg) mp 184°-186° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][OH:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:24]([Si:28]([CH3:31])([CH3:30])Cl)([CH3:27])([CH3:26])[CH3:25].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][O:18][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:31])[CH3:30])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCc1cccc(OCc2ccccc2)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCc1cccc(OCc2ccccc2)c1
Reaction time: 2 h
Yield: 116.3 %

Procedure:
To a solution of 3-[3-(benzyloxy)phenyl]-1-propanol (1.73 g) in DMF (20 mL) were added imidazole (1.07 g) and tert-butyldimethylchlorosilane (1.83 g) at ambient temperature and the mixture was stirred at the same temperature for 2 hours. Water (20 mL) was added to the mixture at ambient temperature and the mixture was extracted with EtOAc (20 mL) two times. The organic layer was washed successively with 12% NaCl aqueous solution and brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo to afford {3-[3-(benzyloxy)phenyl]propoxy}(tert-butyl)dimethylsilane (2.96 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[N:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C([O-])(=O)C.C(=O)([O-])O.[Na+]>COCCOC.C(O)C.O>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:30]4[CH:31]=[N:26][CH:27]=[N:28][CH:29]=4)[CH:3]=3)[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)=[CH:19][CH:20]=1
Reactant: OB(O)c1cncnc1
Reactant: COc1ccc(C2(c3cccc(Br)c3)N=C(N)c3ncccc32)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: COc1ccc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3ncccc32)cc1
Temperature: 130 °C
Yield: 26 %

Procedure:
A mixture of 5-(3-bromophenyl)-5-(4-methoxyphenyl)-5H-pyrrolo[3,4-b]pyridin-7-amine (Example 3, 85 mg, 0.215 mmol), pyrimidin-5-ylboronic acid (35 mg, 0.280 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (18 mg, 0.022 mmol) and cesium carbonate (210 mg, 0.645 mmol) in a mixture of 1,2-dimethoxyethane, water and ethanol (6:3:1, 5 mL) was heated by microwave irradiation at 130° C., under an argon atmosphere for 15 min. After cooling to ambient temperature the mixture was filtered, concentrated in vacuo and purified by preparative HPLC to give 22 mg (26% yield) after liberating the free base by treatment of the acetate with sodium hydrogen carbonate. 1H NMR (CDCl3) δ 9.17 (s, 1H), 8.86 (s, 2H), 8.63 (dd, 1H), 7.92 (dd, 1H), 7.55 (m, 1H), 7.48-7.40 (m, 3H), 7.36 (dd, 1H), 7.26 (m, 2H), 6.82 (m, 2H), 3.78 (s, 3H); MS (ESI) m/z 394 [M+1]+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([NH2:15])=[C:5]([C:7]([CH2:9][C@H:10]([NH2:14])[C:11]([OH:13])=[O:12])=[O:8])[CH:6]=1.[N+:16]([C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1F)([O-:18])=[O:17].C([O-])(O)=O.[Na+]>C(O)C>[NH2:15][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[C:7]([CH2:9][CH:10]([NH:14][C:20]1[CH:21]=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:19]=1[N+:16]([O-:18])=[O:17])[C:11]([OH:13])=[O:12])=[O:8]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1C(=O)C[C@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1ccccc1C(=O)CC(Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)O
Reaction time: 0.08 h
Yield: 71 %

Procedure:
L-Kynurenine (125 mg) is dissolved in 5 cc of absolute ethanol in a 50 cc flask. A solution of 2,4-dinitrofluorobenzene, 71 mg in EtOH 5 cc is then added (a clear yellow solution is formed). After five minutes, 2 cc of a 10% NaHCO3 solution are introduced drop-wise in the flask. The reaction is left at room temperature overnight. The following morning the formed light yellow precipitate is filtered, washed with water and ethanol and dried in UHV obtaining 80 mg of product (approx. yield 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:15]([O:12][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=1[C:7]([OH:9])=[O:8])[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: COC(=O)c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(Cl)cc1C(=O)O

Procedure:
The reaction of methyl 5-chloro-2-hydroxyl-benzoate and allyl bromide in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 2-Allyloxy-5-chloro-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.96 (s, —CO2H); 7.61 (m, 1 arom. H); 7.52 (m, 1 arom. H); 7.12 (m, 1 arom. H); 5.99 (m, —CH═CH2); 5.47, 5.23 (2 d-like, CH═CH2); 4.62 (d-like, CH2—CH═CH2). 13C-NMR (100 MHz, d6-DMSO): 166.08 (C═O); 155.70; 133.02; 132.25; 129.84; 123.85; 123.36; 117.15; 115.70; 68.91.
Reaction SMILES: [CH3:1][C:2]1([OH:12])[CH2:11][CH2:10][C:5]2(OCC[O:6]2)[CH2:4][CH2:3]1.CC(C)=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O>[OH:12][C:2]1([CH3:1])[CH2:11][CH2:10][C:5](=[O:6])[CH2:4][CH2:3]1
Reactant: CC1(O)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: CC1(O)CCC(=O)CC1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a solution of 8-methyl-1,4-dioxaspiro[4.5]decan-8-ol (1 equiv) in a 2:1 mixture of acetone and water (0.38 M) was added pyridinium p-toluenesulfonate (0.2 equiv).The resulting mixture was refluxed for 8 h. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (0-30% ethyl acetate in petroleum ether) to afford the title compound (86% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d1) δ ppm 3.96-3.93 (m, 2H), 2.27-2.25 (m, 1H), 2.25-2.22 (m, 1H), 2.01-1.94 (m, 2H), 1.90-1.82 (m, 2H), 1.38 (s, 3H).