Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:11]=[CH:10][C:8](N)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[ClH:12].N([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:22](#[N:25])[CH:23]=[CH2:24]>CC(C)=O.O>[Cl:12][CH:23]([CH2:24][C:8]1[CH:10]=[CH:11][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:6][CH:7]=1)[C:22]#[N:25]
Reactant: CCCCc1ccc(N)cc1
Reactant: C=CC#N
Reactant: Cl
Agent: CC(=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCc1ccc(CC(Cl)C#N)cc1
Temperature: 10 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
One and a half moles (237 mL) of 4-n-butylaniline was dissolved in acetone (1500 mL). The solution was cooled to 10° C. and water (150 mL) and concentrated aqueous HCl (300 mL) were added. Sodium nitrite (69.0 g, 1.73 moles) in water (200 mL) was added dropwise to the cooled solution. The solution was adjusted to pH 4 by addition of solid sodium acetate. Acrylonitrile (148 mL, 2.25 moles) was added, followed by CuCl2 ·2H2O (38.4 g) in 50 mL H2O. The reaction mixture was heated to 40° C. and was stirred at this temperature for 3 h. The aqueous layer was extracted with ether. The combined organics were washed with water and saturated aqueous NaHCO3, were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was fractionally distilled at reduced pressure. The product was collected at 115°-130° C. @2 mm Hg, as 166.3 g (50% yield) of an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[C:16]1[N:25]=[CH:24][C:23]2[CH2:22][CH2:21][C:20]3[N:26]=[C:27]([NH:29][C:30](=[O:32])[CH3:31])[S:28][C:19]=3[C:18]=2[N:17]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH:10]2[CH2:11][CH2:12][N:13]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:14][CH2:15]2)=[CH:4][C:3]=1[C:16]1[N:25]=[CH:24][C:23]2[CH2:22][CH2:21][C:20]3[N:26]=[C:27]([NH:29][C:30](=[O:32])[CH3:31])[S:28][C:19]=3[C:18]=2[N:17]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Nc1nc2c(s1)-c1nc(-c3cc(C#CC4CCNCC4)ccc3Cl)ncc1CC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc2c(s1)-c1nc(-c3cc(C#CC4CCN(S(C)(=O)=O)CC4)ccc3Cl)ncc1CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 50 mg (0.11 mmol) N-[8-(2-chloro-5-piperidin-4-ylethynyl-phenyl)-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl]-acetamide, 65 μL triethylamine and 15 μL methanesulphonic acid chloride in 1 mL dichloromethane is stirred for three hours at ambient temperature. The reaction mixture is washed with saturated aqueous sodium hydrogen carbonate solution and the organic phase is evaporated down. The residue remaining is purified by RP-HPLC. Yield: 23 mg yellow solid (MH+=542; RT=3.07; Method A)
Reaction SMILES: C(OO)(=[O:3])C.[NH2:6][C:7]1[N:12]=[C:11]([NH:13][C:14]([O:16][CH3:17])=[O:15])[CH:10]=[C:9]([O:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[N:8]=1.S([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C>C(O)C>[NH2:6][C:7]1[N+:12]([O-:3])=[C:11]([NH:13][C:14]([O:16][CH3:17])=[O:15])[CH:10]=[C:9]([O:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[N:8]=1
Reactant: CC(=O)OO
Reactant: COC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(N)n1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(N)[n+]1[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
6.75 ml of 40% peracetic acid are added dropwise at 0° to a suspension of 3.4 g (10 mmol) of methyl 2-amino-6-([p-toluenesulfonyl)oxy]-4-pyrimidinecarbamate in 120 ml of absolute ethanol. The mixture is stirred at room temperature for 48 hours and thereafter poured into an aqueous solution of sodium sulfite. Ethyl acetate is added thereto, the organic phase is separated, dried over sodium sulphate and evaporated under reduced pressure. The residue is recrystallized from methylene chloride/methanol, there being obtained methyl 2-amino-6-[(p-toluenesulfonyl)oxy]-4-pyrimidinecarbamate-3-oxide of melting point 144°-145°.
Reaction SMILES: [C:1]1([O-:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Na+].O[CH2:14][CH2:15][NH2:16].Cl[CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:24]=1.P(Cl)(Cl)Cl>C(#N)C>[C:1]1([O:11][CH2:14][CH2:15][NH:16][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:24]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Fc1ccc(-c2cncc(CCl)c2)cc1
Reactant: NCCO
Reactant: [O-]c1cccc2ccccc12
Agent: [Na+]
Solvent: ClP(Cl)Cl
Solvent: CC#N
Product: Fc1ccc(-c2cncc(CNCCOc3cccc4ccccc34)c2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Analogously to Example 7 a solution of 2.3 g sodium 1-naphtholate and 2.9 g N-2-chloroethyl-N-[5-(4-fluorophenyl-3-pyridylmethyl)-amine [obtainable by reaction of 2-hydroxyethylamine with 3-chloromethyl-5-(4-fluorophenyl)-pyridine and subsequent transformation of the product to the 2-chloroethyl-compound by reaction with PCl3 ] in 200 ml of acetonitrile is stirred for 5 hours at room temperature and worked up in a conventional manner to give N-[2(1-naphthyloxy)-ethyl]-N-[5-(4-fluorophenyl)-3-pyridylmethyl]-amine, m.p. 92°-94°.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.[CH:30](=O)[CH3:31]>>[Cl:14][C:11]1[C:12]([CH3:13])=[C:7]([CH:5]2[CH2:4][N:3]([CH2:30][CH3:31])[CH2:6]2)[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH3:27])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: CC=O
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Agent: Cl
Product: CCN1CC(c2c(C)c(Cl)cc(C(C)n3nc(C)c4c(N)ncnc43)c2OC)C1

Procedure:
This compound was prepared using procedures analogous to those for Example 1, with racemic 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride from Example 2, Step 1 and acetaldehyde instead of acetone. The crude purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The product was isolated as a racemic mixture. LCMS calculated for C21H28ClN6O (M+H)+: m/z=415.2; Found: 415.1
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8](I)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]([Cu])#[N:14]>CC(N(C)C)=O>[Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]([C:13]#[N:14])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(I)ccnc1Cl
Reactant: N#C[Cu]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1c(C#N)ccnc1Cl
Yield: 34.5 %

Procedure:
A solution of methyl 2-chloro-4-iodonicotinate (3.20 g, 10.76 mmol) and cyanocopper (0.963 g, 10.76 mmol) in DMA (40 mL) was stirred at 140° C. overnight. Following reaction, the mixture was filtered through Celite and the filtrate was diluted with H2O and EtOAc. The aqueous phase was extracted with EtOAc. The organic phases were combined, washed with H2O and brine, dried over MgSO4, and evaporated. The residue was purified by chromatography on SiO2 (Hexane/EtOAc=10/1) to give the title compound as a white solid (730 mg, 34.5%). 1H NMR (500 MHz, CDCl3) δ ppm 4.07 (s, 3H), 7.57 (d, J=5.37 Hz, 1H), 8.66 (d, J=4.88 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:42])[O:10][CH2:11][CH:12]([O:36][C:37]1[CH:41]=[CH:40][O:39][N:38]=1)[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[O:17][N:16]=1.[C:43](OC(=O)C)(=[O:45])[CH3:44]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[C:43]([N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:9](=[O:42])[O:10][CH2:11][CH:12]([O:36][C:37]1[CH:41]=[CH:40][O:39][N:38]=1)[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[O:17][N:16]=1)(=[O:45])[CH3:44]
Reactant: CCCCCCCCCCCCCCCCc1cc(OCC(COC(=O)NCc2ccccn2)Oc2ccon2)no1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCc1cc(OCC(COC(=O)N(Cc2ccccn2)C(C)=O)Oc2ccon2)no1
Reaction time: 48 h

Procedure:
0.370 g of (2RS)-3-(5-hexadecyl-3-isoxazolyloxy)-2-(3-isoxazolyloxy)propyl N-(2-pyridylmethyl)carbamate (prepared as described in Example 30), 0.60 ml of acetic anhydride and 0.733 g of 4-(N,N-dimethylamino)pyridine were dissolved in 10 ml of toluene, and the mixture was stirred on an oil bath kept at 90° C. for 48 hours. The solvent was distilled off, and the residue was purified by column chromatography through 15 g of silica gel and by medium pressure liquid chromatography using a Lobar B column, 0.308 g of the title compound was obtained, as an oil, from the fractions eluted with methylene chloride.
Reaction SMILES: N[C:2]1([O:8]O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:10](=[O:14])[CH2:11][CH2:12][CH3:13].C(O)(=O)C.N>CO>[C:2]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:10](=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: NC1(OO)CCCCC1
Agent: N
Solvent: CCCC=O
Solvent: CC(=O)O
Solvent: CO
Product: O=C1CCCCC1
Reaction time: 8 h

Procedure:
1-Aminocyclohexyl hydroperoxide (13.1 g.), butyraldehyde (7.2 g.), methanol (25 cc.) and ammonia acetate (1.0 g.) were mixed and stored at 0°C overnight. Working up as in Example 39 gave cyclohexanone and butyraldehyde, and a product (8.4 g.), b.p. 89°/0.3 mm. (peroxide equivalent, 204; pechloric acid equivalent, 206; which was identified as ##SPC37##
Reaction SMILES: C1C=CC(P(C2C=CC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)=CC=2)C2C=CC=CC=2)=CC=1.[OH:47][CH2:48][C@@H:49]1[NH:53][C:52](=[O:54])[CH2:51][CH2:50]1.[Br:55][C:56]1[CH:57]=[N:58][CH:59]=[C:60](O)[CH:61]=1>C1COCC1>[Br:55][C:56]1[CH:61]=[C:60]([O:47][CH2:48][C@@H:49]2[NH:53][C:52](=[O:54])[CH2:51][CH2:50]2)[CH:59]=[N:58][CH:57]=1
Reactant: O=C1CC[C@H](CO)N1
Reactant: Oc1cncc(Br)c1
Agent: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCc1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CC[C@H](COc2cncc(Br)c2)N1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.7 %

Procedure:
A 5 mL, one neck round bottom flask was charged with diphenyl-[4-(1 h,1 h,2h,2h-perfluorodecyl)phenyl]phosphine (Fluorous Technologies, Pittsburgh, Pa., 0.35 g, 0.49 mmol), a stirbar, and 1 mL dry THF. The flask was fitted with an inert atmosphere inlet, and swept with Ar for several minutes. The solution was cooled using a ice-water bath, and treated with fDEAD (Fluorous Technologies, 0.41 g, 0.49 mmol) dissolved in 1 mL dry THF. After 5 minutes, (R)-(−)-5-(hydroxymethyl)-2-pyrrolidinone (0.056 g, 0.49 mmol) and 3-bromo-5-hydroxypyridine (0.0565 g, 0.32 mmol) were added in succession. The reaction warmed to room temperature over 1 h, and was stirred a total of 96 h. The THF was removed using a stream of nitrogen, and the residue was dissolved in 0.5 mL dry DMF. The solution was loaded onto a FluoroFlash® Fluorous SPE cartridge (5 g, 15 mL tube, PN 801-0058S) that had been pre-conditioned with 50 mL MeOH, followed by 50 mL 20% MeOH in water. Two additional 0.5 mL aliquots of DMF were used to quantitate the transfer. The cartridge was eluted with 50 mL of 70% aqueous methanol, 50 mL of 80% aqueous methanol. The combined eluents were concentrated in vacuo. The residue was taken up in 2 mL dry THF, and passed through 250 mg of SiO2 wet-packed with THF. The silica was washed with 5 mL dry THF, and concentrated in vacuo. The residue was dissolved in 3 mL dry THF, and treated with 0.68 mmol g−1 Si carbonate (0.48 g, 0.32 mmol). The slurry was stirred at room temperature for 30 minutes, and filtered. The silica was eluted with 5 mL dry THF, and the combined eluents were concentrated in vacuo to afford (R)-5-((5-bromopyridin-3-yloxy)methyl)pyrrolidin-2-one (0.0813 g, 92% yield). HPLC-MS: retention time=1.09 min (94.1%@215 nm; 93.2% @254 nm; m/z=271.0, calculated for C10H1179BrN2O2+H+=271.0; m/z=272.9, calculated for C10H1181BrN2O2+H+=273.0).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[SH:41][C@@H:42]1[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]2[CH2:54][CH2:53][C@H:52]([CH2:55][NH:56][C:57]([O:59][CH2:60][C:61]3[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=3)=[O:58])[CH2:51]2)=[O:49])[CH2:43]1.C(OCC)(=O)C>C(#N)C.C(N(CC)C(C)C)(C)C>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8]([S:41][C@@H:42]3[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]4[CH2:54][CH2:53][C@H:52]([CH2:55][NH:56][C:57]([O:59][CH2:60][C:61]5[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=5)=[O:58])[CH2:51]4)=[O:49])[CH2:43]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CN1C[C@@H](S)C[C@H]1C(=O)N1CC[C@H](CNC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](CNC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C)C3)[C@H](C)[C@H]12
Yield: 75.5 %

Procedure:
To a solution of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (0.72 g) in anhydrous acetonitrile (7 ml), N,N-diisopropylethylamine (0.21 ml) and a solution of (2S,4S)-4-mercapto-1-methyl-2-[(3R)-3-(4-nitrobenzyloxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]pyrrolidine (0.54 g) in anhydrous acetonitrile (10 ml) were added while stirring in an ice bath. The resulting mixture was stirred overnight at 0° C. To the reaction mixture, ethyl acetate was added. The resulting mixture was washed with water and saturated saline solution, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column (ethyl acetate/methanol=7/3), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-1-methyl-2-[(3R)-3-(4-nitrobenzyloxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (0.74 g) was obtained.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[C:20](Cl)(=[O:24])[C:21]([CH3:23])=[CH2:22]>C(Cl)Cl>[CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:20](=[O:24])[C:21]([CH3:23])=[CH2:22])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)c1ccc(O)cc1
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Oc1ccc(S(=O)(=O)NC)cc1
Reaction time: 3 h
Yield: 79.3 %

Procedure:
To a solution of 15.00 g (0.08 mole) of N-methyl-4-hydroxybenzenesulfonamide, 8.11 g (0.08 mole) of triethylamine and 200 ml of methylene chloride cooled to 0° C. was added a solution of 8.37 g (0.08 mole) of methacryloyl chloride in 100 ml of methylene chloride over a period of approximately 30 minutes. The solution was then stirred for another 3 hours with cooling; washed once with 100 ml of 2 percent HCl solution, and twice with water; dried over magnesium sulfate and concentrated in vacuo in a warm water bath. The resultant solid was recrystallized from 150 ml of ethyl alcohol:water (1:1) with filtering through diatomaceous earth. Collection of the white solid and drying at room temperature in vacuo gave 16.20 g (79.9 percent of theory) of N-methyl-4-methacryloyloxybenzenesulfonamide; m.p.=106° to 107° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[N+:10]([O-])([OH:12])=[O:11]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([F:8])=[CH:4][C:3]=1[OH:9]
Reactant: O=[N+]([O-])O
Reactant: Oc1cc(F)ccc1Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Cl)c(O)cc1F

Procedure:
A solution of 2-chloro-5-fluorophenol (1.5 g) in dichloromethane (50 ml) at 0° C. was treated with nitric acid (70%, 0.7 ml). The cooling bath was removed and after 15 min at room temperature the solution washed with water then dried over MgSO4, filtered and evaporated. The product was crystallised from diethyl ether to yield the title compound, 500 mg.
Reaction SMILES: [CH:1]1([C:6]2[N:7]=[C:8]([CH3:25])[N:9]3[C:14](=[O:15])[NH:13][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:22][CH2:23][CH3:24])=[N:11][C:10]=23)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:26][S:27](O)(=[O:29])=[O:28]>ClCCl>[CH2:23]([O:22][C:17]1[CH:18]=[CH:19][C:20]([S:27]([Cl:26])(=[O:29])=[O:28])=[CH:21][C:16]=1[C:12]1[NH:13][C:14](=[O:15])[N:9]2[C:8]([CH3:25])=[N:7][C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[C:10]2[N:11]=1)[CH3:24]
Reactant: O=S(=O)(O)Cl
Reactant: CCOc1ccccc1-c1nc2c(C3CCCC3)nc(C)n2c(=O)[nH]1
Solvent: ClCCl
Product: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nc2c(C3CCCC3)nc(C)n2c(=O)[nH]1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
372.3 mg (1.1 mmol) of 8-cyclopentyl-2-(2-ethoxy-phenyl)-6-methyl-3H-imidazo[1,5-a][1,3,5]triazin-4-one (example IX) are added in portions to 0.66 ml (9.9 mmol) of ice-cooled chlorosulfonic acid. The mixture is subsequently stirred overnight at room temperature before being diluted with dichloromethane and poured onto ice water. The organic phase is separated off. The aqueous phase is extracted once again with dichloromethane and the organic phases are combined, dried and evaporated.
Reaction SMILES: [NH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)[NH2:2].O.[F:20][C:21]([F:25])([F:24])[CH:22]=O>CCO>[F:20][C:21]([F:25])([F:24])[CH:22]=[N:2][NH:1][CH:3]1[CH2:4][CH2:5][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:7][CH2:8]1
Reactant: O=CC(F)(F)F
Reactant: NNC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: O
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCC(NN=CC(F)(F)F)CC1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 109 (4 g, 8.38 mmol) in EtOH (42 ml) was added trifluoroacetaldehyde hydrate (0.648 ml, 8.38 mmol) and the resulting solution was allowed to stir for 3 h at 70° C. The solvent was evaporated and AcOEt was added to the residue and the organic layer was washed with 1N HCl then with brine, dried over MgSO4, filtrated and concentrated. Crude 110 was obtained as yellow oil and was used as is for the next step. LRMS (ESI): calc. 329.3; found 330.2 (MH)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[C@H:10]([CH2:19][C:20]([OH:22])=O)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([O:31][C:32](=[O:36])[CH2:33][CH2:34][NH2:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:8][C:9](=[O:23])[C@H:10]([CH2:19][C:20](=[O:22])[NH:35][CH2:34][CH2:33][C:32]([O:31][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:36])[NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OCc1ccccc1
Reactant: NCCC(=O)OCc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)NCCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1

Procedure:
N-(t-butoxycarbonyl)-L-aspartic acid 1-benzyl ester was coupled with β-alanine benzyl ester to give 3-[[2-[(benzyloxy)carbonyl]ethyl]carbamoyl]-N-(t-butoxycarbonyl)-L-alanine benzyl ester, m.p. 77°-78° C.
Reaction SMILES: [NH2:1][C:2](=[O:44])[CH2:3][C:4]1[CH:43]=[CH:42][CH:41]=[CH:40][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:39]=[CH:38][C:22]([C:23]([N:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[O:24])=[CH:21][CH:20]=2)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C1CCCCC1>[N:25]1([C:23]([C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:10]3[N:9]=[C:8]([CH2:7][CH2:6][C:5]4[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=4[CH2:3][C:2]([NH2:1])=[O:44])[C:13]([C:14]([F:16])([F:15])[F:17])=[CH:12][N:11]=3)=[CH:39][CH:38]=2)=[O:24])[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C(=O)N3CCNCC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.7 %

Procedure:
To a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoyl)piperazine-1-carboxylate (A26) (0.182 g, 0.297 mmol) in DCM (4 mL) was added TFA (1 mL) and the resulting mixture was stirred at room temperature for 16 hours. The volatiles were removed in vacuo and the residue partitioned between EtOAc (10 mL) and 2 M aqueous NaOH (10 mL). The aqueous layer was extracted with EtOAc (2×10 mL) then the combined organic fractions were washed with water (10 mL), brine (10 mL) and dried over MgSO4. The volatiles were removed in vacuo to give a yellow solid, which was suspended in cyclohexane and then filtered to give the title compound 6 as a white solid (0.132 g, 87%); 1H NMR (400 MHz, d4-MeOH) δ 8.62 (s, 1H), 7.83 (d, J=8.7 Hz, 2H), 7.42 (d, J=8.8 Hz, 2H), 7.27 (d, J=6.3 Hz, 1H), 7.23-7.15 (m, 3H), 3.68 (s, 2H), 3.82-3.46 (m, 4H), 3.23-3.15 (m, 2H), 3.12 (dd, J=9.8, 5.4 Hz, 2H), 3.02-2.71 (m, 4H). LCMS-A: rt 4.676 min; m/z 513.3 [M+H]+.
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[CH:12]([C:31]2[CH:36]=[CH:35][C:34](Cl)=[C:33]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH3:47])=[CH:41][CH:40]=3)[CH:32]=2)[N:11]([CH3:48])[CH:10]1[CH2:49][O:50]CC1C=CC=CC=1)C1C=CC=CC=1>CO.C(O)(=O)C.[Pd]>[CH2:46]([O:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][C:33]2[CH:32]=[C:31]([C@H:12]3[C@H:13]([OH:23])[C@@H:14]([OH:15])[C@H:9]([OH:8])[C@@H:10]([CH2:49][OH:50])[N:11]3[CH3:48])[CH:36]=[CH:35][CH:34]=2)=[CH:40][CH:41]=1)[CH3:47]
Reactant: CCOc1ccc(Cc2cc(C3[C@H](OCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)C(COCc4ccccc4)N3C)ccc2Cl)cc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCOc1ccc(Cc2cccc([C@H]3[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)N3C)c2)cc1
Yield: 24.2 %

Procedure:
Compound from step E (50 mg) in methanol and acetic acid (25 uL) was treated 5% wet Pd—C (10 mg) under H2 atmosphere for 4 h. The reaction mixture was filtered through a pad of celite and concentrated. Chromatography on silica gel (10 to 100% acetonitrile containing 0.1% ammonium acetate/water gradient) provided (2S,3S,4R,5R,6R)-2-[3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-1-methyl-piperidine-3,4,5-triol (6 mg, 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][C:4]=1[CH3:16].[OH-].[Na+].[CH2:19](O)[CH3:20]>OS(O)(=O)=O.O>[CH2:19]([O:13][C:12](=[O:14])[CH2:11][CH2:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:16])[CH:5]=1)=[O:15])[CH3:20]
Reactant: CCO
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)CCC(=O)c1ccc(OC)c(C)c1
Temperature: 25 °C
Yield: 84 %

Procedure:
To a solution of 4-(4-methoxy-3-methylphenyl)-4-oxobutyric acid (Compound 2, 21.75 g, 98.0 mmol) in absolute ethanol (200 mL) was added 10 drops of concentrated H2SO4. The resulting solution was refluxed for 3 days, then cooled to room temperature, treated with 30 mL of NaOH 2 N, diluted with 50 mL of water, and extracted 3 times with EtOAc. The combined organic layers were washed with brine, and dried over MgSO4, and filtered. The solvent was removed to afford 20.6 g (84%) of the title compound as a yellow solid.