Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([SH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]([O:14][CH2:15][CH:16]1[O:18][CH2:17]1)(=[O:13])[CH:11]=[CH2:12]>>[C:10]([O:14][CH2:15][CH:16]1[O:18][CH2:17]1)(=[O:13])[CH2:11][CH2:12][S:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCS
Reactant: C=CC(=O)OCC1CO1
Product: CCCCCCCCSCCC(=O)OCC1CO1

Procedure:
1-Octanethiol, 71 g (0.5 mole), was reacted with glycidyl acrylate, 62 g (0.5 mole), at 50°-70° C., to give glycidyl 4-thialaurate according to the following reaction: ##STR3##
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]([F:19])([F:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.S(=O)(=O)(O)O>C(O)(=O)C.IN1C(=O)CCC1=O>[I:1][C:13]1[CH:12]=[C:11]([C:10]([F:18])([F:19])[F:9])[CH:16]=[CH:15][C:14]=1[OH:17]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Oc1ccc(C(F)(F)F)cc1I
Temperature: 0 °C
Yield: 242.7 %

Procedure:
N-iodosuccinimide (69.5 g, 0.309 moles) was suspended in acetic acid (257 mL) and cooled to 0° C. 4-Trifluoromethylphenol (50.0 g, 0.310 moles) was added followed by sulphuric acid (5.44 mL) dropwise over 5 minutes. The orange-brown suspension was stirred whist warming slowly to room temperature over 18 hours. A further portion of N-iodosuccinimide (2.5 g, 0.011 moles) was added and the mixture was stirred at room temperature for 24 hours. The reaction was quenched by adding water (150 mL) and extracted with dichloromethane (2×100 mL). The combined organics were washed with a saturated aqueous solution of sodium metabisulphite (2×50 mL) and then with saturated aqueous sodium chloride solution (50 mL). The organics were dried over anhydrous magnesium sulphate, filtered and the solvents removed in vacuo to give the crude title product as a light yellow oil. This batch was combined with the products from two further identical reactions and purified by distillation in vacuo. The product was collected boiling at approximately 45° C. at 2mBar to give the title compound as a pink-orange semi-solid (216 g).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH2:40])[CH:31]=[CH:32][C:33]=1[C:34]1[O:38][C:37]([CH3:39])=[N:36][CH:35]=1.[CH2:41]([C:48]1[CH:53]=[C:52]([CH3:54])[N:51]=[C:50](Cl)[N:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.O>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:41]([C:48]1[CH:53]=[C:52]([CH3:54])[N:51]=[C:50]([NH:40][C:30]2[CH:31]=[CH:32][C:33]([C:34]3[O:38][C:37]([CH3:39])=[N:36][CH:35]=3)=[C:28]([O:27][CH3:26])[CH:29]=2)[N:49]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: COc1cc(N)ccc1-c1cnc(C)o1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(C)cc(Cc3ccccc3)n2)ccc1-c1cnc(C)o1
Yield: 26.7 %

Procedure:
Palladium(II) acetate (5.4 mg, 0.024 mmol) and 2-(dicyclohexylphosphino)biphenyl (17 mg, 0.048 mmol) were stirred in dioxane (3 mL) for 20 minutes under an atmosphere of nitrogen. Sodium tert.-butylate (44 mg, 0.45 mmol), 3-methoxy-4-(2-methyl-oxazol-5-yl)-phenylamine (61 mg, 0.30 mmol, CAS 568556-28-5; E. J. Iwanowicz et. al. Bioorganic & Medicinal Chemistry Letters, 13(12), 2059-2063; 2003) and 4-benzyl-2-chloro-6-methyl-pyrimidine (72 mg, 0.33 mmol) were added. The reaction was heated for 30 minutes to 130° C. in a microwave oven. Water was added and the reaction was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane and then methylenechloride/methanol (19:1 v/v) as eluent to yield the title compound as a yellow solid (31 mg, 27%). MS ISP (m/e): 387.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.86 (s, 1H), 7.61 (d, 2H), 7.26-7.33 (m, 5H), 7.15 (br s, 1H), 6.98 (d, 1H), 6.48 (s, 1H), 3.97 (s, 2H), 3.90 (s, 3H), 2.51 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[Br:21][C:22]1[CH:23]=[C:24]([CH2:28][CH:29]=O)[CH:25]=[CH:26][CH:27]=1>>[Br:21][C:22]1[CH:23]=[C:24]([C:28]2[CH:29]=[N:1][C:2]3[C:3]([C:12]=2[C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)=[CH:4][CH:5]=[CH:6][C:7]=3[C:8]([F:11])([F:10])[F:9])[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Reactant: O=CCc1cccc(Br)c1
Product: Oc1cccc(-c2c(-c3cccc(Br)c3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and (3-Bromo-phenyl)-acetaldehyde following the procedure of Example 457: MS (ES) m/z 441.8; HRMS: calcd for C22H13BrF3NO+H+, 444.02053; found (ESI, [M+H]+), 444.0206.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([OH:18])=[O:17].[C:19](O)(=O)C>CO.C1(C)C=CC=CC=1>[CH3:19][O:17][C:16](=[O:18])[CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[Br:8]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: CC(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccccc1Br
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
Trimethylsilyldiazomethane (2 M solution in diethyl ether, 0.349 mL, 0.698 mmol) was added to a solution of (2-bromo-phenyl)acetic acid (50 mg, 0.233 mmol) in methanol (0.4 mL) and toluene (2 mL), and the mixture was stirred at room temperature for five minutes. Acetic acid was added to the reaction mixture to terminate the reaction, and then the mixture was concentrated under reduced pressure to give the target compound as a colorless oil (53 mg, 99%).
Reaction SMILES: C(N)CN.C(C1OC=NC=1CCl)C1C=CC=CC=1.[CH2:19]([C:26]1[O:30][CH:29]=[N:28][C:27]=1[CH2:31][NH:32][CH2:33][CH2:34][NH2:35])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:36][N:37]=[C:38]=[S:39]>>[CH3:36][NH:37][C:38]([NH:35][CH2:34][CH2:33][NH:32][CH2:31][C:27]1[N:28]=[CH:29][O:30][C:26]=1[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[S:39]
Reactant: NCCNCc1ncoc1Cc1ccccc1
Reactant: CN=C=S
Agent: ClCc1ncoc1Cc1ccccc1
Solvent: NCCN
Product: CNC(=S)NCCNCc1ncoc1Cc1ccccc1

Procedure:
Reacting ethylenediamine with 5-benzyl-4-chloromethyloxazole by the procedure of Example 34, then reacting the resulting N-(5-benzyl-4-oxazolylmethyl)ethylenediamine with methyl isothiocyanate by the procedure of Example 3(b) and chromatographing gives N-methyl-N'-[2-((5-benzyl-4-oxazolyl)methylamino)ethyl]-thiourea. Reacting this thiourea with lead cyanamide by the procedure of Example 3(b) gives N-[2-((5-benzyl-4-oxazolyl)methylamino)ethyl]-N'-cyano-N"-methylguanidine.
Reaction SMILES: C(O[C:4](=S)[S:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([Br:16])[CH:7]=1)C.[OH-].[K+].[CH2:20](Br)C.C([O-])([O-])=O.[K+].[K+]>O.CCO>[Br:16][C:8]1[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=[C:6]([S:5][CH2:4][CH3:20])[CH:7]=1
Reactant: CCBr
Reactant: CCOC(=S)Sc1cc(Br)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCSc1cc(Br)cc(C(F)(F)F)c1
Yield: 45.3 %

Procedure:
Dithiocarbonic acid S-(3-bromo-5-trifluoromethyl-phenyl) ester O-ethyl ester (3.3 g, 10.3 mmoles) was dissolved into 30 mL of EtOH, 10 mL of H2O, and was sealed under nitrogen. To this stirring mixture was added KOH (2.8 g, 50 mmoles) and this mix was stirred at reflux (under nitrogen) for 12 hours. After this period the reaction mixture was evaporated in vacuo and combined with 50 mL of water. The pH was adjusted to <2 using 6N HCl and the resulting mixture was extracted with diethyl ether (3×50 mL). The combined ethereal layer was washed with brine and dried over anhydrous MgSO4. Following evaporation in vacuo the crude thiol was dissolved into 50 mL of acetone. Ethyl bromide (1.5 mL, 20.1 mmoles) and K2CO3 (5 g, 36.2 mmoles) were added, and the mixture was stirring at ambient temperature (under nitrogen) for 6 hours. After this period the mixture was gravity filtered, and evaporated in vacuo to yield crude product. The crude product was purified using flash silica chromatography (0-1% EtOAc/Hexane) to yield 1-bromo-3-ethylsulfanyl-5-trifluoromethyl-benzene (1.33 g, 45% yield) as a yellowish liquid. 1H-NMR (CDCl3): δ 7.56 (s, 1H), 7.52 (s, 1H), 7.43 (s, 1H), 3.0 (q, J=7.3 Hz, 2H), 1.36 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5](I)=[CH:4][N:3]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:36][Si:37]([C:40]#[CH:41])([CH3:39])[CH3:38]>C1COCC1.[Pd](Cl)Cl.[Cu](I)I>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:41]#[C:40][Si:37]([CH3:39])([CH3:38])[CH3:36])=[CH:4][N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Clc1ncc(I)c(Cl)n1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnc(Cl)nc1Cl

Procedure:
66.55 g of 2,4-dichloro-5-iodo-pyrimidine is stirred for three hous in 1.2 litres of absolute THF with 70 ml of triethylamine, 4.9 g of palladium chloride, 13.3 g of triphenylphosphine, 4 g of copper iodide and 39.3 ml of trimethylsilylacetylene at 40° C. After the reaction has ended the solvent is eliminated in vacuo and the dark red oil remaining is subjected to fractional distillation. The product is distilled over at 0.01 Torr and 100° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)=[CH:21][CH:20]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: Fc1ccc(CBr)cc1
Product: Cc1onc(-c2ccccc2)c1-c1cn(Cc2ccc(F)cc2)cn1
Yield: 70 %

Procedure:
As described for Example 34, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (100 mg, 0.44 mmol) using 4-fluorobenzyl bromide instead of benzyl bromide was converted to the title compound (104 mg, 70%) as a colourless gum. MS: m/e=334.1 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]([NH:15][C:16]([C@H:18]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:21][CH2:20][S:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[CH2:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:38]([NH:45][CH2:6][CH2:7][CH:8]([NH:15][C:16]([CH:18]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)(=[O:24])=[O:25])[CH2:21][CH2:20][S:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CS(=O)(=O)OCC[C@H](NC(=O)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Reactant: NCc1ccccc1
Product: O=C(NC(CCNCc1ccccc1)c1ccccc1)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general method B as outlined in Example 16, starting from 3-({[3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and benzylamine, the title compound was obtained in 99% purity by HPLC.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:23][NH2:24].[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(Cl)Cl.O>[Cl:22][C:17]1[CH:16]=[C:15]([CH:10]([C:11]([F:14])([F:12])[F:13])/[CH:9]=[CH:8]/[C:6]2[CH:7]=[CH:2][C:3]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])=[CH:4][CH:5]=2)[CH:20]=[C:19]([Cl:21])[CH:18]=1
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(=O)NCc1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 62.2 %

Procedure:
To a stirred solution of (E)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.3 g, 0.8 mmol) in CH2Cl2 (10 mL) was added acetic anhydride (0.12 mL, 1.14 mmol), and TEA (0.217 mL, 1.52 mmol), and the resultant reaction mixture was stirred at ambient temperature for 6 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined CH2Cl2 layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a off-white solid (0.2 g, 60%) mp 107-109° C.; 1H NMR (400 MHz, CDCl3) δ 7.37 (m, 3H), 7.28 (m, 4H), 6.60 (d, J=16.0 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 5.75 (br s, 1H), 4.46 (d, J=6 Hz, 2H), 4.01 (m, 1H), 2.11 (s, 3H); ESIMS m/z 402.00 ([M+H]+).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:17][CH:16]=2)[C:13](=[O:27])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:28])[N:6]=1)[CH2:3][CH3:4].Cl[C:30]1[C:31]2[CH:38]=[CH:37][NH:36][C:32]=2[N:33]=[CH:34][N:35]=1.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:33]1[C:32]2[NH:36][CH:37]=[CH:38][C:31]=2[C:30]([NH:1][C@H:2]([C:5]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([F:26])([F:24])[F:25])=[CH:17][CH:16]=3)[C:13](=[O:27])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[F:28])[N:6]=2)[CH2:3][CH3:4])=[N:35][CH:34]=1
Reactant: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CC[C@H](Nc1ncnc2[nH]ccc12)c1nc2cccc(F)c2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 13.4 %

Procedure:
Under nitrogen, to (S)-2-(1-aminopropyl)-5-fluoro-3-(4-(2,2,2-trifluoroethoxy)phenyl)quinazolin-4(3H)-one (35 mg, 0.089 mmol, 1.0 equiv) in t-BuOH (0.09 mL) at 23° C. was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (16 mg, 0.11 mmol, 1.2 equiv) and diisopropylethylamine (31 μL, 0.18 mmol, 2.0 equiv). After stirring for 16 hr at 120° C. in a sealed tube, the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC eluting with CH2Cl2/MeOH to afford 6.1 mg of the title compound (13% yield).
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[OH:67][CH:68]1[CH2:73][CH2:72][N:71]([C:74]2[CH:81]=[CH:80][C:77]([CH:78]=O)=[CH:76][CH:75]=2)[CH2:70][CH2:69]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:78]([C:77]3[CH:76]=[CH:75][C:74]([N:71]4[CH2:72][CH2:73][CH:68]([OH:67])[CH2:69][CH2:70]4)=[CH:81][CH:80]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(N2CCC(O)CC2)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: OC1CCN(c2ccc(-c3nc4c(N5CCN(Cc6cccnc6)CC5)c(Br)cnc4[nH]3)cc2)CC1
Reaction time: 6 h
Yield: 26.4 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (30 mg, 0.076 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.23 mmol, 0.23 mL) and 4-(4-hydroxypiperidin-1-yl)benzaldehyde (1.2 eq, 0.091 mmol, 19 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 85:15) gave the product (11 mg, 26%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.41-1.49 (m, 2H, 2× piperidine CHAHB), 1.81-1.84 (m, 2H, 2× piperidine CHAHB), 2.62 (s, br, 4H, piperazine N(CH2)2), 2.97-3.02 (m, 2H, 2× piperidine CHAHB), 3.62 (s, 2H, NCH2), 3.64 (t, J=4.7 Hz, 4H, piperazine N(CH2)2), 3.66-3.70 (m, 2H, 2× piperidine CHAHB), 4.68 (d, J=4.2 Hz, 1H, CHOH), 7.04 (d, J=9.0 Hz, 2H, phenyl H-2 & H-6), 7.39 (dd, J=7.6, 4.7 Hz, 1H, pyridine H-5), 7.78 (d, br, J=7.8 Hz, 1H, pyridine H-4), 7.99 (d, J=9.0 Hz, 2H, phenyl H-3 & H-5), 8.16 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.49 (d, br, J=4.5 Hz, 1H, pyridine H-6), 8.56 (s, br, 1H, pyridine H-2), 13.17 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [CH2:1]([N:4]1[C@H:13]2[C@@H:8]([CH2:9][C:10](=O)[CH2:11][CH2:12]2)[CH2:7][CH2:6][C:5]1=O)[CH2:2][CH3:3].[C:16]([NH2:20])(=[O:19])[CH:17]=[CH2:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.COC1C=CC(O)=CC=1>[O:19]=[C:16]1[NH:20][C:10]2[CH2:9][C@H:8]3[C@H:13]([CH2:12][C:11]=2[CH2:18][CH2:17]1)[N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7]3
Reactant: C=CC(N)=O
Reactant: CCCN1C(=O)CC[C@@H]2CC(=O)CC[C@H]21
Agent: COc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCN1CCC[C@H]2CC3=C(CCC(=O)N3)C[C@@H]21
Yield: 36.6 %

Procedure:
A mixture of (±)-trans-1-propyl-6-oxodecahydroquinolone (30.0 g, 154 mMol), acrylamide (32.8 g, 462 mMol), p-toluenesulfonic acid monohydrate (35.2 g, 185 mMol), and p-methoxyphenol (500 mg) in toluene (1000 mL) was heated to reflux, water being collected in a Dean-Stark trap. After 17 hr of reflux, the reaction was poured into dilute NaOH solution and extracted with methylene chloride. The extract was dried (Na2SO4) and concentrated to give the crude product as a brown foam. Recrystallization (ethyl acetate/hexanes) provided the desired product as a tan solid (14.0 g, 37% yield). Purification of the mother liquors by flash chromatography (2:1 THF: hexanes, 0.5% NH4OH) provided additional product (Rf=0.40, 2.6 g, 7% yield). Recrystallization of this material (ethyl acetate) provided analytically pure material. m.p.=183.0-184.0°.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: BrCCC1CCCCO1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCC1CCCCO1

Procedure:
Prepared similarly to Intermediate 216 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(2-bromoethyl)tetrahydro-2H-pyran.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1>O1CCCC1>[C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:34]([NH:33][C:29]4[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:25])([F:36])[F:37])[CH:28]=4)=[O:35])[CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(C(F)(F)F)c1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.7 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 3-trifluoromethylphenyl isocyanate (0.170 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 55.4 mg (15.7%) of the desired product as a solid.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]([C:20]2[C:21]([CH2:32][CH:33]=O)=[N:22][O:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=O)[N:9]=[N:8]1.C([O-])(=O)C.[NH4+:48]>C(O)(=O)C>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:40])([F:39])[F:41])[CH:37]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([C:18]2[C:20]3=[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:31])[O:23][N:22]=[C:21]3[CH:32]=[CH:33][N:48]=2)[N:9]=[N:8]1
Reactant: O=CCc1noc(-c2ccccc2Cl)c1C(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(Cn2nnc(-c3nccc4noc(-c5ccccc5Cl)c34)c2-c2ccccc2)cc(C(F)(F)F)c1
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
Combine [4-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carbonyl]-5-(2-chloro-phenyl)-isoxazol-3-yl]-acetaldehyde (0.401 g, 0.65 mmol) and acetic acid (4.5 mL), add ammonium acetate (0.25 g, 3.2 mmol) and stir at 65° C. for 90 minutes. Concentrate, neutralize with saturated aqeous NaHCO3, extract with ether, dry over MgSO4, filter and concentrate under vacuum. Purify on chromatotron, using EtOAc/Hexane (10%-85%) to give the title compound: Exact mass 599.1, MS (IS) 600.1 (M+1), 1H NMR (CDCl3): δ 8.15 (d, J=6.6 Hz, 1H), 7.85 (s, 1H), 7.60 (m, 1H), 7.52-7.38 (m, 8H), 7.17 (m, 2H), 5.54 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1.Cl.[NH2:27][OH:28].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9]/[C:10](=[N:27]\[OH:28])/[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccccc1[C@H](CC(=O)Cc1ccccn1)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1[C@H](C/C(Cc1ccccn1)=N\O)c1ccc(Br)cc1

Procedure:
In analogy to example 74, step 7, from (R)-4-(4-bromophenyl)-1-(pyridin-2-yl)-4-o-tolylbutan-2-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a colorless oil, MS (ESI+): m/z=409.0904 ([M+H]+, 1Br).
Reaction SMILES: [OH-].[K+].[CH3:3][C@H:4]1[CH2:9][N:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:7][CH2:6][N:5]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>O.CO>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:8]2[CH2:7][CH2:6][N:5]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:4]([CH3:3])[CH2:9]2)=[CH:12][CH:13]=1
Reactant: C[C@H]1CN(Cc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H]1CN(Cc2ccc(N)cc2)CCN1C(=O)OC(C)(C)C
Reaction time: 0.29 h
Yield: 93.3 %

Procedure:
To a solution of potassium hydroxide (16.5 g, 0.29 mol) in water (35 mL) was added dry 10% Pd/C catalyst (10 g). MeOH (150 mL) was added and the mixture was hydrogenated at room temperature and atmospheric pressure for 15-20 minutes. 1,1-Dimethylethyl (2S)-2-methyl-4-[(4-nitrophenyl)methyl]-1-piperazinecarboxylate (D21) (10 g, 29.8 mmol) in MeOH (165 mL) was added and the reaction was hydrogenated for a total of 5 hrs. The catalyst was removed by filtration, washed with MeOH and water, and the filtrate/washings were concentrated in vacuo. The residue was partitioned between DCM and water and aqueous layer was further extracted with DCM. The combined organics were washed with brine, dried and concentrated to give the title compound as a colourless gum (8.49 g) which was used in the next step without further purification.