Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.Br[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:34])=[C:23]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=1.C(OCC)(=O)C>CN(C=O)C>[Cl:34][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:8]([C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)[N:6]2[CH:5]=[N:4][N:3]=[CH:7]2)=[CH:24][C:23]=1[O:25][C:26](=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Reactant: O=C(Oc1cc(CBr)ccc1Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(Cc2ccc(Cl)c(OC(=O)c3ccccc3)c2)n2cnnc2)cc1
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 200 mg, 5.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMF (20 mL) at r.t. The mixture was stirred for 1 hour at this temperature and benzoic acid 5-bromomethyl-2-chloro-phenyl ester (CAB02138, 1.63 g, 5.0 mmol) was added. The reaction mixture was stirred overnight and ethyl acetate (75 mL) was added. The mixture was transferred into a separation funnel and washed with water (2×50 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc, Rf:0.31) to give a white solid. Yield: 1.773 g (82%). 1H-NMR (400 MHz, CDCl3) δ=4.93 (s, 2H), 6.66 (d, 9.0 Hz, 2H), 7.06 (dd, J=8.2, 2.0 Hz, 1H), 7.27 (d, J=2.0 Hz, 1H), 7.45 (d, J=8.2 Hz, 1H), 7.47-7.58 (m, 4H), 7.60-7.69 (m, 1H), 8.16-8.21 (m, 2H), 8.24 (s, 2H). LRMS (FAB+): 430.1 (100, [M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:26](SC)=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([CH:18]3[CH2:20][CH2:19]3)=[CH:16][C:15]([C:21]([F:24])([F:23])[F:22])=[N:14]2)=[CH:9][CH:8]=1)=[O:5].O[O:32][S:33]([O-:35])=O.[K+].[CH3:37]C(C)=O>O>[Cl:1][C:2]1[CH:28]=[CH:27][C:26]([S:33]([CH3:37])(=[O:35])=[O:32])=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17]([CH:18]3[CH2:20][CH2:19]3)=[CH:16][C:15]([C:21]([F:23])([F:22])[F:24])=[N:14]2)=[CH:11][CH:12]=1)=[O:5]
Reactant: O=S([O-])OO
Reactant: CSc1ccc(Cl)c(C(=O)Nc2ccc(-n3nc(C(F)(F)F)cc3C3CC3)cc2)c1
Reactant: CC(C)=O
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccc(Cl)c(C(=O)Nc2ccc(-n3nc(C(F)(F)F)cc3C3CC3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-chloro-N-{4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-5-(methylthio)benzamide (40 mg, 0.08 mmols) was dissolved in a 5 mL mixture of H2O and acetone (1:1) at 0° C. and added Oxone (108 mg, 0.16 mmols). The mixture was stirred at ambient temperature for one hour. The reaction mixture was filtered to remove oxone and filtrate was worked up (AcOEt: H2O). Title compound (38 mg) was obtained as a white solid. M.P. 132-135° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 10.97 (s, 1H), 8.19 (d, J 2.2, 1H), 8.04 (dd, J 8.4, 2.2, 1H), 7.89 (d, J 8.6, 3H), 7.65 (d, J 8.8, 2H), 6.62 (s, 1H), 3.30 (s, 3H), 1.97-1.81 (m, 1H), 0.99-0.94 (m, 2H), 0.86-0.79 (m, 2H). MS (m/z): 481.85 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[O:15][CH2:16][O:17][CH3:18].C([Li])CCC.[CH3:24][S:25]SC.C(OCC)C>C1(C)C=CC=CC=1.CN(C)P(=O)(N(C)C)N(C)C.CN(C)CCN(C)C>[CH3:14][O:13][C:6]1[CH:5]=[C:4]([O:15][CH2:16][O:17][CH3:18])[C:3]([O:2][CH3:1])=[C:8]([S:25][CH3:24])[C:7]=1[O:9][CH2:10][O:11][CH3:12]
Reactant: COCOc1cc(OC)c(OCOC)cc1OC
Reactant: CSSC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COCOc1cc(OC)c(OCOC)c(SC)c1OC
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
259 Milligrams of 1,4-dimethoxy-2,5-bis(methoxymethoxy)benzene was dissolved in a mixed solvent of 12 ml of toluene with 3 ml of hexamethylphosphoric triamide, and further 0.303 ml of N,N,N',N'-tetramethylethylenediamine was added thereto, and the mixture was cooled to -78° C. on a dry ice-acetone mixture bath. 1.34 Milliliters of n-butyllithium (1.6 M, n-hexane solution) was added dropwise to the reaction mixture and stirred for 20 minutes. Then 0.14 ml of dimethyl disulfide was added dropwise thereto, and reacted for additional 2 hours with stirring. The reaction mixture was warmed until room temperature, then 30 ml of diethyl ether was added thereto, and the organic layer was washed three times with 20 ml of water, then washed three times with 20 ml of a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. The diethyl ether extract was concentrated under a reduce pressure, the residue obtained was purified by means of a thin layer chromatography (thickness: 2 mm, adsorbent: silica gel, developing solvent: 40%-ethyl acetate-n-hexane). There was obtained 152 mg of 1,4-dimethoxy-2,5-bis(methoxymethoxy)-3-methylthiobenzene. Colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]([CH2:11][CH2:12][CH2:13][OH:14])[C:8](=[O:15])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([OH:26])(=[O:14])=[O:25].[Cl:1][C:2]1[C:10]2[N:9]([CH2:11][CH2:12][CH2:13][OH:14])[C:8](=[O:15])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Agent: O=c1[nH]c2cccc(Cl)c2n1CCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O
Reaction time: 1 h

Procedure:
To a stirred mixture of 9 parts of 4-chloro-1,3-dihydro-3-(3-hydroxypropyl)-2H-benzimidazol-2-one, 7 parts of N,N-diethylethanamine and 130 parts of dichloromethane are added dropwise 12 parts of methanesulfonyl chloride (exothermic reaction: temperature rises to reflux). Upon completion, stirring is continued for 1 hour at reflux temperature. The reaction mixture is cooled and poured onto water. The organic phase is separated, washed with acidified water, dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 9 parts (75%) of 4-chloro-1,3-dihydro-3-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:21]=[CH:22][N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][Si:34]([CH3:41])([CH3:40])[CH2:35][CH2:36][O:37][CH2:38]Cl.[C:42](#N)C>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[CH:22][N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:24]=1[CH3:33])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1.[Si:1]([O:18][CH2:19][C:20]1[N:21]([CH2:38][O:37][CH2:36][CH2:35][Si:34]([CH3:41])([CH3:40])[CH3:33])[CH:22]=[N:23][C:24]=1[CH3:42])([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)(C)[Si](OCc1cn(COCC[Si](C)(C)C)cn1)(c1ccccc1)c1ccccc1
Product: Cc1c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ncn1COCC[Si](C)(C)C
Product: Cc1ncn(COCC[Si](C)(C)C)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The mixture obtained in (1) (35.4 g) was dissolved in acetonitrile (500 mL), TEA (37.8 mL) and then 2-trimethylsilylethoxymethyl chloride (21.4 mL) were added under ice cooling and stirring, and stirring was conducted at 70° C. for 12 hours. The reaction mixture was allowed to cool to room temperature, and the solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by flash chromatography (ethyl acetate/hexane=15%→50%) using a silica gel column (trade name: Cartridge 65i, manufactured by Biotage Ltd.) to give 4-(tert-butyldiphenylsilyloxymethyl)-5-methyl-1-(2-trimethylsilylethoxymethyl)-1H-imidazole (17.9 g) as a low polarity component and 5-(tert-butyldiphenylsilyloxymethyl)-4-methyl-1-(2-trimethylsilylethoxymethyl)-1H-imidazole (9.42 g) as a high polarity component.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O.C(O)(=O)C.[OH-].[Na+]>O.[Fe]>[N:9]1([CH2:8][C:7]2[CH:15]=[CH:16][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Yield: 85.5 %

Procedure:
A stirred suspension of 4-(4-nitrobenzyl)morpholine (500 mg) (prepared according to a modified procedure described by Leffler and Volwiler, JACS, 1938, 60, 896) in water (4.15 mL) was treated with glacial acetic acid (0.5 mL). The reaction mixture was heated to gentle reflux and then treated with iron powder (500 mg) over 10 minutes. After stirring at reflux for a further 10 minutes the reaction mixture was allowed to cool to room temperature. The reaction mixture was treated with water (10 mL) and then basified to pH 12 with a 4 M aqueous solution of sodium hydroxide. The aqueous was extracted three times with diethyl ether (1×40 mL, 2×10 mL). The combined organic extracts were dried over magnesium sulfate and then evaporated to give the title compound (370 mg) as a white solid, m.p. 96–97° C. MS: 193 [MH]+.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH:3]=[CH:4][CH:5]=[O:6].[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1.C(O)(C(F)(F)F)=O.C([C@@H]1N[C@H](C(C)(C)C)N(C)C1=O)C1C=CC=CC=1>C(Cl)Cl.C(O)(C)C>[CH3:1][CH:2]([CH3:7])[C@@H:3]([C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]([CH3:8])[CH:10]=1)[CH2:4][CH:5]=[O:6]
Reactant: CC(C)C=CC=O
Reactant: Cn1ccc2ccccc21
Agent: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](CC=O)c1cn(C)c2ccccc12
Yield: 74.1 %

Procedure:
Prepared according to the general procedure from 4-methyl-2-pentenal (175 μL, 1.50 mmol), 1-methyl-1H-indole (64 μL, 0.50 mmol), TFA (7.7 μL, 0.10 mmol) and (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-imidazolidin-4-one (24.6 mg, 0.100 mmol) in CH2Cl2 (0.90 mL) and isopropanol (0.10 mL) at −50° C. for 32 h to provide, after silica gel chromatography (10:90 EtOAc/hexanes), the title compound as a colorless oil (85 mg, 74% yield, 93% ee). IR (film) 3052, 2958, 2870, 2834, 2716, 1723, 1609, 1546, 1482, 1469, 1423, 1373, 1328, 1246, 1160, 1138, 1015, 743 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.61 (dd, J=2.4, 2.4 Hz, 1H, CHO), 7.63 (dt, J=0.9, 8.1 Hz, 1H, ArH), 7.33-7.22 (m, 2H, ArH), 7.13 (ddd, J=1.5, 6.9, 8.1 Hz, 1H, ArH), 6.82 (s, 1H, NCH), 3.75 (s, 3H, NCH3), 3.40 (dt, J=6.6, 7.8 Hz, 1H, ArCH), 2.81 (d, J=2.4 Hz, 1H, CH2CO); 2.79 (d, J=2.4 Hz, 1H, CH2CO); 2.10 (ddd, J=6.6, 13.2, 19.8 Hz, 1H, CH(CH3)2, 0.96 (d, J=2.1, 3H, CH(CH3)2, 0.94 (d, J=2.1 Hz, 3H, CH(CH3)2; 13C NMR (75 MHz, CDCl3) δ 203.4, 137.0, 127.6, 126.7, 121.6, 119.4, 118.8, 115.6, 109.3, 46.1, 38.0, 32.9, 32.9, 20.6, 20.4; HRMS (CI) exact mass calcd for (C15H19NO) requires m/z 229.1467, found m/z 229.1465. [α]D=+15.8 (c=1.0, CHCl3). The enantiomeric ratio was determined by HPLC analysis of the alcohol, obtained by NaBH4 reduction of the aldehyde, using a Chiracel AS and AS guard column (4% ethanol/hexanes, 1 mL/min); R isomer tr=13.4 min and S isomer tr=16.7 min.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].C(N(C(C)C)CC)(C)C.[CH2:15]([N:27]=C=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].CN(C=[O:34])C>O.O1CCCC1>[C:15]([NH:27][NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:34])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CN(C)C=O
Reactant: CCCCCCCCCCCCN=C=O
Reactant: NCC(=O)O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCCCCCCCCCC(=O)NNCC(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Glycine (0.40 g, 5.25 mmol) and 0.91 mL of diisopropylethylamine (5.25 mmol) were dissolved in 4 mL DMF and 6 mL water. Dodecylisocyanate (0.72 mL, 3.0 mmol) in 7 mL tetrahydrofuran was added and the mixture was stirred for 1 h at room temperature. Water (40 mL) was added and the resulting mixture was washed with ethyl acetate twice. The aqueous layer was acidified with 6N HCl, the resulting precipitate was filtered, and then dried to provide 575 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18](Br)=[CH:17][N:16]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([C:27]5[CH:28]=[CH:29][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:25][CH:26]=5)=[CH:17][N:16]=4)[CH2:10][CH2:9]3)=[N:6][CH:7]=2)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Brc1ccc(N2CCCN(c3ccc(Br)cn3)CC2)nc1
Product: FC(F)(F)c1ccc(-c2ccc(N3CCCN(c4ccc(-c5ccc(C(F)(F)F)cc5)cn4)CC3)nc2)cc1
Yield: 40.6 %

Procedure:
Following the procedure of Example 1, crude crystals were obtained from the 1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (206.0 mg, 0.500 mmol) synthesized in Reference Example 1 and 4-trifluoromethylphenylboronic acid (227.0 mg, 1.20 mmol). The crude crystals were recrystallized from chloroform-hexane to yield the title compound as colorless needles (melting point: 236.0-238.0° C.) (110.0 mg, yield: 40%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C@@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.[CH2:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[C:20]1(/[CH:19]=[CH:18]/[C:2]2[CH:3]=[C:4]3[CH2:10][C@@:9]4([CH:15]5[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]5)[CH2:11]4)[O:8][C:5]3=[N:6][CH:7]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C=Cc1ccccc1
Reactant: Brc1cnc2c(c1)C[C@]1(CN3CCC1CC3)O2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C(=C/c1cnc2c(c1)C[C@]1(CN3CCC1CC3)O2)\c1ccccc1
Temperature: 100 °C
Yield: 54.9 %

Procedure:
A solution of (S)-(+)-5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (150 mg, 0.51 mmol), styrene (0.07 mL, 0.61 mmol), palladium(II)acetate (1.2 mg, 0.0053 mmol), tri-o-tolylphosphine (6.4 mg, 0.021 mmol), and triethylamine (0.5 mL, 3.6 mmol) in anhydrous acetonitrile (0.5 mL), in a heavy-walled threaded glass tube containing a magnetic stir bar, was purged with argon and sealed with a Teflon plug and FETFE O-ring. The mixture was stirred and heated at 100° C. for 2 hours, cooled to room temperature, dissolved in chloroform (10 mL), washed with saturated aqueous sodium carbonate (1 mL), dried (MgSO4), and evaporated under reduced pressure. Recrystallization from ethyl acetate afforded the title compound (90 mg, 0.28 mmol, 55%) as a light tan solid: electrospray MS (m/z, relative intensity) 319 ([MH]+, 100).
Reaction SMILES: O[C@H:2]([C:22]([CH3:25])([CH3:24])[CH3:23])[C@@H:3]([NH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:9])[C:4]([OH:6])=[O:5].O[C@@H](C(C)(C)C)[C@@H](NC(OCCCCCC1C=CC=CC=1)=O)C(O)=O.CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:8](=[O:9])[NH:7][C@H:3]2[C:4](=[O:6])[O:5][C@@H:2]2[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[C@@H](O)[C@@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Agent: CC(C)(C)[C@H](O)[C@@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[C@H]1OC(=O)[C@@H]1NC(=O)OCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 54 %

Procedure:
Under nitrogen atmosphere, to a stirred mixture of (2R*,3R*)-3-hydroxy-4,4-dimethyl-2-(5-phenylpentoxy-carbonylamino)-pentanoic acid and (2R*,3S*)-3-hydroxy-4,4-dimethyl-2-(5-phenylpentoxy-carbonylamino)-pentanoic acid (0.325 g, 0.92 mmol) in dry CH2Cl2, (40 mL). at 0° C., Et3N (0.38 mL, 2.77 mmol) (0.2 mL, 1.44 mmol) and subsequently TBTU (0.356 g, 1.11 mmol) were added. The mixture was left stirring at 0° C. for 1 h and at rt for 15 h. The organics were then removed under reduced pressure, and the resulting crude product purified by column chromatography, using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (from 90:10 to 70:30) to afford the title compound (0.165 g, 54%), as pure anti diastereoisomer, as white solid. MS (ESI) m/z: 351 [M−NH4]+; (ESI) m/z: 332 [M−H]−. 1H NMR (DMSO-d6) δ 0.94 (s, 9H), 1.29-1.39 (m, 2H), 1.52-1.65 (m, 4H), 2.58 (t, J=7.65 Hz, 2H), 4.01 (t, J=6.59 Hz, 2H), 4.33 (d, J=4.66 Hz, 1H), 4.76 (dd, J=4.65, 8.16 Hz, 1H), 7.11-7.36 (m, 5H), 8.05 (d, J=8.15 Hz, 1H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[C:21]([CH2:22][CH:23]([CH3:25])[CH3:24])=[C:20]2[C:11]([C:12]([NH2:26])=[N:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=32)=[N:10]1.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>ClCCl>[CH2:22]([C:21]1[N:9]([CH3:8])[N:10]=[C:11]2[C:20]=1[C:19]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:13]=[C:12]2[NH:26][C:28](=[O:29])[O:30][CH2:31][CH3:32])[CH:23]([CH3:24])[CH3:25]
Reactant: CC(C)Cc1c2c(nn1C)c(N)nc1ccccc12
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Nc1nc2ccccc2c2c(CC(C)C)n(C)nc12
Temperature: 4 °C
Yield: 46.7 %

Procedure:
Triethylamine (0.49 mL, 3.53 mmol) was added to a suspension of 2-methyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 3) (0.75 g, 2.95 mmol) in dichloromethane (30 mL) and cooled to 4° C. Ethyl chloroformate (0.352 g, 3.24 mmol) was added in dichloromethane (5 mL) dropwise over 5 minutes to the reaction mixture and maintained at ambient temperature for 16 hours. The reaction mixture was diluted with dichloromethane (25 mL) and washed sequentially with water (25 mL), 4% sodium bicarbonate (2×25 mL), water (25 mL), and brine (25 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified via column chromatography on silica gel (80 g, eluting with 0-10% CMA/chloroform), concentrated under reduced pressure, and recrystallized from diethyl ether to afford 0.45 g of ethyl 1-isobutyl-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-ylcarbamate as white crystals, mp 120-121° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:18]=[C:17]([C:28]([N:30]([O:32][CH3:33])[CH3:31])=[O:29])[CH:16]=2)=[CH:11][CH:10]=1.CCN(CC)CC>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:18]=[C:17]([C:28]([N:30]([O:32][CH3:33])[CH3:31])=[O:29])[CH:16]=2)=[CH:13][CH:14]=1)(=[O:4])=[O:3]
Reactant: COc1ccc(-n2nc(C(=O)N(C)OC)cc2-c2ccc(CCO)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(=O)N(C)OC)cc2-c2ccc(CCOS(C)(=O)=O)cc2)cc1
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A solution of methanesulfonyl chloride (328 mg) in CH2Cl2 (2 ml) was added to a solution of 5-[4-(2-hydroxyethyl)-phenyl]-N-methoxy-1-(4-methoxyphenyl)-N-methyl-1H-pyrazole-3-carboxamide (840 mg) and Et3N (334 mg) in CH2Cl2 (10 ml) under ice bath cooling. The mixture was stirred at same temperature for 1 hour. The mixture was diluted with CHCl3 and washed with 1M HCl, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt/n-hexane=80%, 90%. The pure fractions were collected and concentrated in vacuo to give 2-{4-[3-{[methoxy(methyl)amino]carbonyl}-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenyl}ethyl methanesulfonate (1.01 g) as an oil.
Reaction SMILES: C1C=CC=CC=1.[C:7]1([CH3:35])[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[C:8]=1[NH:15][CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[C:27]1[N:32]=[C:31]([CH:33]=O)[CH:30]=[CH:29][CH:28]=1.[CH:36]([C:39]1[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]([CH3:48])[CH3:47])[C:40]=1[NH2:41])([CH3:38])[CH3:37].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[CH:46]([C:42]1[CH:43]=[CH:44][CH:45]=[C:39]([CH:36]([CH3:38])[CH3:37])[C:40]=1[N:41]=[CH:33][C:31]1[N:32]=[C:27]([C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:25]=[CH:26][C:17]=2[CH2:16][NH:15][C:8]2[C:7]([CH3:35])=[CH:12][C:11]([CH3:13])=[CH:10][C:9]=2[CH3:14])[CH:28]=[CH:29][CH:30]=1)([CH3:48])[CH3:47]
Reactant: Cc1cc(C)c(NCc2ccc3ccccc3c2-c2cccc(C=O)n2)c(C)c1
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O
Product: Cc1cc(C)c(NCc2ccc3ccccc3c2-c2cccc(C=Nc3c(C(C)C)cccc3C(C)C)n2)c(C)c1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
Benzene (200 mL) was added to compound 5b (6.69 g, 17.6 mmol), and 2,6-diisopropylaniline (3.12 g, 17.6 mmol), and p-toluenesulfonic acid monohydrate (5 mg) in a 500 mL round-bottomed flask fitted with a Dean-Stark trap. The mixture was heated to reflux under nitrogen. After 2 hours, 1H NMR spectroscopy of an aliquot indicated that the reaction had proceeded to around 90% completion. All but about 50 mL of the benzene was removed by distillation and toluene (200 mL) was added. The mixture was heated to reflux and most of the toluene was removed by distillation. Drying of the residue under reduced pressure afforded a dirty yellow solid. Dissolution of the solid in warm Et2O, followed by filtration and cooling to −20° C. afforded 6b as nice yellow crystals. Yield from two crops: 6.5 g, 69%. 1H NMR (500 MHz, CD2Cl2): 8.36 (d, 1H), 8.33 (s, 1H), 7.97 (t, 1H), 7.93 (d, 2H), 7.59 (d, 1H), 7.39-7.51 (m, 4H), 7.17 (d, 2H), 7.10 (m, 1H), 6.72 (s, 2H), 4.01 (br d, 1H), 3.92 (d, 1H), 3.39 (br, 1H), 3.03 (sept, 2H), 2.18 (s, 3H), 2.03 (s, 6H), 1.18 (d, 12H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:35][CH2:34][CH2:33]4)[C:15]=3[NH:14][CH:13]=2)=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:35][CH2:34][CH2:33]4)[C:15]=3[NH:14][CH:13]=2)=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CCC5)ccc5c4OCO5)ncnc23)CC1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CCC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from trans-4-(5-cyclobutylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide hydrochloride (example A173) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl-:1].[NH2:2][N+:3]1[CH:7]=[CH:6][N:5]([N:8]=[C:9]([CH3:19])[C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[C:4]=1[CH2:20][CH3:21].[CH3:22][N:23]([CH3:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C(O)(=O)C>[Cl-:1].[CH3:22][N:23]([CH3:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[N:2][N:3]2[CH:7]=[CH:6][N+:5]([N:8]=[C:9]([CH3:19])[C:10]3[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=3)=[C:4]2[CH2:20][CH3:21])=[CH:26][CH:25]=1
Reactant: CCc1n(N=C(C)c2ccc([N+](=O)[O-])cc2)cc[n+]1N
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Cl-]
Solvent: CC(=O)O
Product: CCc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=C(C)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 1.15 g (3.7 mmol) of 1-amino-2-ethyl-3-[(α-methyl-p-nitrobenzylidene)amino]-imidazolium chloride and 0.55 g (3.7 mmol) of p-dimethylaminobenzaldehyde in 25 ml of glacial acetic acid is stirred for 18 hours. The product is crystallized out by the addition of ether. The product is recrystallized from ethanol/ether. There is obtained 3-[[p-(dimethylamino)-benzylidene]amino]-2-ethyl-1-[(α-methyl-p-nitrobenzylidene)amino]-imidazolium chloride of melting point 233°.