Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([OH:10])=O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.C(N(CC)C(C)C)(C)C.[CH3:38][C:39]([CH3:59])=[CH:40][CH2:41][CH2:42]/[C:43](/[CH3:58])=[CH:44]/[CH2:45][CH2:46]/[C:47](/[CH3:57])=[CH:48]/[CH2:49][S:50][CH2:51][C@H:52]([NH2:56])[C:53]([OH:55])=[O:54]>C(Cl)Cl.C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([NH:56][C@@H:52]([CH2:51][S:50][CH2:49]/[CH:48]=[C:47](\[CH3:57])/[CH2:46][CH2:45]/[CH:44]=[C:43](\[CH3:58])/[CH2:42][CH2:41][CH:40]=[C:39]([CH3:59])[CH3:38])[C:53]([OH:55])=[O:54])=[O:10]
Reactant: O=C(O)CCc1cccs1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)CCc1cccs1)C(=O)O
Reaction time: 0.08 h

Procedure:
To a solution of 3-(2-thienyl) propanoic acid (187 mg, 1.2 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM, 332 mg, 1.2 mmol) in CH2Cl2 (5 mL) was added N,N-diisopropyl-ethyl-amine (0.52 mL, 3 mmol). After stirring for 5 min, S-trans, trans-farnesyl-L-cysteine (325 mg, 1 mmol) was added slowly. The solution was stirred at room temperature for 4 h and then diluted with ethyl acetate (60 mL). The solution was washed sequentially with an NH4Cl saturated solution (15 mL×2), H2O (10 mL×1) and brine (15 mL×1). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (310 mg, 67%) to yield Compound N-31. 1H-NMR (500 MHz, CD3OD): δ 1.50 (s, 6H), 1.57 (s, 3H), 1.59 (s, 3H), 1.86-1.89 (m, 2H), 1.96-2.06 (m, 6 H), 2.54 (t, J=7.5 Hz, 2H), 2.56-2.61 (m, 1H), 2.87 (dd, J=4.5, 14.0 Hz, 1H), 3.00-3.06 (m, 3H), 3.11-3.15 (m, 1H), 4.49 (dd, J=5.0, 8.5 Hz, 1H), 5.00-5.01 (m, 2H), 5.12 (t, J=7.5 Hz, 1H). 13C-NMR (125 MHz, CD3OD): δ 16.16, 16.25, 17.81, 25.96, 26.74, 27.40, 27.79, 30.13, 33.42, 38.74, 40.79, 40.89, 53.32, 121.62, 124.36, 125.14, 125.47, 125.75, 127.81, 132.11, 136.27, 140.47, 144.46, 174.98, 174.64; ES-MS: mass calcd for Chemical Formula: C25H37NO3S2 463.70. Found (M+23) m/z 486.2.
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)[N:7]=1.Br>O>[NH2:10][CH2:9][CH2:8][C:6]1[N:7]=[C:3]([NH2:2])[S:4][CH:5]=1
Reactant: Nc1nc(CCN2C(=O)c3ccccc3C2=O)cs1
Agent: Br
Solvent: O
Product: NCCc1csc(N)n1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A suspension of 2-[2-(2-amino-thiazol-4-yl)-ethyl]isoindole-1,3-dione hydrobromide (25.7 g, 72.6 mmol, 1 eq.) in water (125 mL) was treated with 62% hydrobromic acid in water (125 mL). The resulting suspension was then refluxed (oil bath temperature=120° C.), under N2 for 18 hours. The resulting orange homogeneous reaction mixture was allowed to cool down to r.t. (fast precipitation of a beige solid occurred). The resulting suspension was filtered and the filter cake (phthalic acid) was washed with water. The obtained orange homogeneous filtrate was then concentrated in vacuo. The remaining water was finally removed by co-evaporation with toluene (repeated several times) and the obtained residue was further dried under hv to give the dihydrobromide salt of the title compound as an orange solid. The product was used without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10])(C)C.[H-].[Na+].[Cl:13][C:14]1[CH:19]=[C:18]([N+]([O-])=O)[CH:17]=[CH:16][N:15]=1>>[Cl:13][C:14]1[CH:19]=[C:18]([S:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH3:1])[CH:17]=[CH:16][N:15]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: CC(C)c1ccccc1S
Agent: [H-]
Agent: [Na+]
Product: Cc1ccccc1Sc1ccnc(Cl)c1
Yield: 101.7 %

Procedure:
Using the method of Example 3, Step A, 2-isopropylbenzenethiol (0.749 g, 4.92 mmol), 60% sodium hydride in mineral oil (197 mg, 4.92 mmol), and 2-chloro-4-nitropyridine (0.780 g, 12.6 mmol) to provide 2-chloro-4-(o-tolylthio)pyridine (1.18 g, 91% yield) as an oil. 1H NMR (CDCl3) δ 8.08 (d, 1H), 7.46-7.55 (m, 3H), 7.28 (t, 1H), 6.82 (s, 1H), 6.77 (d, 1H), 3.42 (heptet, 1H), 1.19 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].C(N(CC)CC)C.CO>ClCCl>[C:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH2:15][CH2:16]2)=[O:10])=[CH:4][CH:3]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2ncnc(N3CCN(C(=O)Nc4ccc(N)cc4)CC3)c2cc1OC
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2ncnc(N3CCN(C(=O)Nc4ccc(NC(C)=O)cc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a solution of 514.0 mg (1.26 mmol) of N-(4-aminophenyl)-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamide obtained in Example 221 in 10 ml of dichloromethane were added 0.18 ml (1.89 mmol) of acetic anhydride and 0.53 ml (3.78 mmol) of triethylamine under ice-cooling. After the resulting mixture was stirred overnight at room temperature, 0.18 ml (1.89 mmol) of acetic anhydride and 0.53 ml (3.78 mmol) of triethylamine were added thereto, followed by overnight stirring. To the reaction mixture was added methanol and the solvent was evaporated. Then, the residue was purified by silica gel chromatography to give the desired compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13](Cl)=[O:14])[N:10]=[C:9]2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:4][CH:3]=1.[NH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([NH:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:14])[N:10]=[C:9]2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: NN1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NN1CCCCC1)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
Part D: Crude 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carbonyl chloride (919 mg, ˜2.39 mmol), 1-aminopiperidine (0.469 g, 4.69 mmol) and triethylamine (0.363 g, 3.59 mmol) are dissolved in dichloromethane and stirred for one hour at room temperature. The mixture is washed with a saturated aqueous NaHCO3 solution (3×20 mL), dried over Na2SO4 and concentrated in vacuo and further purified by column chromatography (ethyl acetate, silicagel) to give 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide (356 mg, 26% yield (based on ethyl 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate). Mass Spectrometry (MS): 449.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[CH:5]2.[CH2:12]([O:14][C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:13].C1(C2C=CC=CC=2)C(O)=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>C1COCC1.[Cu](I)I>[CH2:12]([O:14][C:15](=[O:22])[CH:16]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[CH:5]2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:13]
Reactant: Ic1ccc2ncncc2c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1ccccc1-c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1ccc2ncncc2c1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
A solution of 6-iodo-quinazoline (0.500 g, 1.95 mmol), malonic acid diethyl ester (0.93 g, 5.81 mmol), copper iodide (0.019 g, 0.097 mmol), biphenyl-2-ol (0.033 g, 0.195 mmol) and cesium carbonate (0.953 g, 2.93 mmol) in THF (5 mL) was heated to 70° C. in a sealed tube for 24 hours. The solution was then cooled to room temperature, saturated ammonium chloride was added and the crude product was extracted from ethyl acetate. The product was purified via silica gel column chromatography in hexane:ethyl acetate (1:1) to give 0.39 g (80%) of 2-quinazolin-6-yl-malonic acid diethyl ester. 1H NMR (400 MHz, CDCl3) δ 9.37 (bs, 2H), 7.96 (m, 3H), 4.78 (s, 1H), 4.18 (m, 4H), 1.19 (m, 6H).
Reaction SMILES: CC1C=CC(C)=CC=1.[C:9]([O:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([O:22][C:23](=[O:25])[CH3:24])[CH:21]=1)[C:16](Cl)=O)(=[O:11])[CH3:10].[Cl:26][CH2:27][C:28]([O:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=C)=[CH:33][CH:32]=1)=[O:29].CN1CCOCC1>[Pd].[Cl-].C(C1C=CC=C(C(C)C)C=1[NH+]1CCN(C2C(C(C)C)=CC=CC=2C(C)C)C1)(C)C.CCOC(C)=O>[C:9]([O:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:35][C:34]2[CH:33]=[CH:32][C:31]([O:30][C:28](=[O:29])[CH2:27][Cl:26])=[CH:38][CH:37]=2)[CH:19]=[C:20]([O:22][C:23](=[O:25])[CH3:24])[CH:21]=1)(=[O:11])[CH3:10]
Reactant: C=Cc1ccc(OC(=O)CCl)cc1
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)Cl)c1
Agent: [Pd]
Agent: CC(C)c1cccc(C(C)C)c1N1CC[NH+](c2c(C(C)C)cccc2C(C)C)C1
Agent: [Cl-]
Solvent: Cc1ccc(C)cc1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(=O)Oc1cc(C=Cc2ccc(OC(=O)CCl)cc2)cc(OC(C)=O)c1
Temperature: 120 °C
Reaction time: 3.5 h
Yield: 69.4 %

Procedure:
A 10 mL round bottom flask was charged with p-xylene (4 mL), Pd II catalyst (4.5 mg, 0.02 mmol), 1,3-bis-(2,6-diisopropylphenyl) imidazolinium chloride (8.6 mg, 0.02 mmol), 3,5-diacetoxybenzoyl chloride (0.7695 g, 3 mmol), 4-chloroacetoxystyrene (0.393 g, 2 mmol), and N-methyl morpholine (0.276 g, 2.4 mmol). The mixture was stirred at 120° C. for 3.5 h under nitrogen atmosphere. Then it was cooled to room temperature and EtOAc was added and filtered. The filtrate was washed with brine and dried over Na2SO4. Then it was filtered and purified via flash chromatography and gave the product (0.54 g, 69.4%) as white solid. Data are: 1H NMR (CDCl3, 300 MHz) δ 7.47 (d, 2H, J=8.7 Hz), 7.14-7.10 (m, 4H), 6.99 (q, 2H, J=16.2 Hz), 6.83 (t, 1H, J=2.1 Hz), 4.29 (s, 2H), 2.29 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 169.1, 165.9, 151.4, 150.1, 139.5, 135.1, 129.5, 127.9, 127.7, 121.6, 117.1, 114.7, 41.0, 21.2; HRMS (EI+) found 388.0710 M+, calcd 388.0714 for C20H17ClO6.
Reaction SMILES: ClC1N=CN=C2C=1N=CN2[C@H]1[C@@H]2[O:16]C(C)(C)O[C@@H]2[C@@H](CO)C1.C(NS(=O)=O)(OC(C)(C)C)=O.[C:34]1([P:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CCOC(C)=O>[C:47]1([P:40](=[O:16])([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](n3cnc4c(Cl)ncnc43)[C@@H]2O1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)OC(=O)N[SH](=O)=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CCOC(C)=O
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ((3aR,4R,6R,6aS)-[6-(6-chloro-purin-9-yl)-2,2-dimethyltetrahydro-cyclopenta[1,3]dioxol-4-yl]-methanol (Yang, M.; Wei, Y.; Schneller, S. W. J. Org. Chem. 2004, 69, 3993-3996) (250.0 mg, 0.77 mmol), N-Boc-sulfonamide (226.6 mg, 1.16 mmol) and triphenylphosphine (242.3 mg, 0.92 mol) in EtOAc (8 mL) was added diisopropyl azodicarboxylate (227.3 μL, 1.16 mmol) dropwise as a solution in EtOAc (1 mL). The reaction was stirred at r.t. overnight, quenched with water and extracted with EtOAc. The organics were concentrated and the residue purified by flash chromatography (0 to 100% EtOAc/DCM) to obtain the product as an inseparable mixture with triphenylphosphine oxide. The material was carried on as such.
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:5][N:4]([C:6]2[CH:7]=[CH:8][C:9]([C:17]([OH:19])=O)=[N:10][C:11]=2[O:12][CH2:13][CH2:14][O:15][CH3:16])[CH2:3]1.[NH2:21][C@@H:22]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23]([NH2:25])=[O:24]>>[C:23]([C@@H:22]([NH:21][C:17]([C:9]1[CH:8]=[CH:7][C:6]([N:4]2[CH2:3][C:2]([F:1])([F:20])[CH2:5]2)=[C:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])[N:10]=1)=[O:19])[CH2:26][CH:27]([CH3:29])[CH3:28])(=[O:24])[NH2:25]
Reactant: COCCOc1nc(C(=O)O)ccc1N1CC(F)(F)C1
Reactant: CC(C)C[C@H](N)C(N)=O
Product: COCCOc1nc(C(=O)N[C@@H](CC(C)C)C(N)=O)ccc1N1CC(F)(F)C1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(3,3-difluoro-azetidin-1-yl)-6-(2-methoxy-ethoxy)-pyridine-2-carboxylic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=401.1 [M+H]+.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[CH3:17])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[C@@H:19]12[CH2:25][C@@H:22]([CH:23]=[CH:24]1)[CH2:21][C@H:20]2[CH2:26][C:27](O)=[O:28]>>[C@@H:19]12[CH2:25][C@@H:22]([CH:23]=[CH:24]1)[CH2:21][C@H:20]2[CH2:26][C:27]([NH:1][N:2]1[N:11]=[C:10]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[CH3:17])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18])=[O:28]
Reactant: Cc1ccsc1-c1nn(N)c(=O)c2ccccc12
Reactant: O=C(O)C[C@@H]1C[C@@H]2C=C[C@H]1C2
Product: Cc1ccsc1-c1nn(NC(=O)C[C@@H]2C[C@@H]3C=C[C@H]2C3)c(=O)c2ccccc12

Procedure:
The product from Example 14B and 2-((1S,2S,4S)-bicyclo[2.2.1]hept-5-en-2-yl)acetic acid was processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.31 (s, 1H), 8.38-8.40 (m, 1H), 7.89-8.05 (m, 2H), 7.72 (d, J=5.1 Hz, 1H), 7.62-7.65 (m, 1H), 7.12 (d, J=5.1 Hz, 1H), 6.22 (dd, J=5.7, 3.0 Hz, 1H), 6.06 (dd, J=5.7, 2.8 Hz, 1H), 2.88-2.90 (m, 1H), 2.77-2.79 (m, 1H), 2.42-2.52 (m, 1H), 2.10 (s, 3H), 2.08 (m, 2H), 1.90 (ddd, J=11.5, 9.1, 3.7 Hz, 1H), 1.33-1.36 (m, 1H), 1.26 (d, J=8.0 Hz, 1H), 0.60 (ddd, J=11.5, 4.3, 2.5 Hz, 1H); MS (APCI) M/Z 392 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[F:10][C:11]([F:23])([F:22])[O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>COCCOC.O>[F:10][C:11]([F:22])([F:23])[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: N#Cc1ccnc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
A solution of 19 (2.5 g, 18 mmol) in DME (90 mL) was added 4-trifluoromethoxy phenyl boronic acid (1.1 mol eq, 4.46 g) and NaHCO3 (3 mol eq, 4.66 g) suspended in water (50 mL). The mixture was degassed under vacuum, then Tetrakispalladium was added (catalytic amount) and the reaction stirred at 100° C. under inert atmosphere for 12 h. The solvent was removed under reduced pressure and water was added to the residue (100 mL). The aqueous phase was extracted with EtOAc (3×50 mL) and the combined organic layer was washed with brine (100 mL) and dried over Na2SO4. The solvent was evaporated under vacuum to obtain 20B as a pale yellow crystals (96% Yield, 4.6 g, 17.4 mmol). 1HNMR (DMSO, 200 MHz) δ 7.5 (dd, 2H, J=2), 7.84 (dd, 1H, J=1.8), 8.31 (d, 2H, J=9.8), 8.54 (d, 1H, J=2), 8.93 (dd, 1H, J=1.9).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][S:6](=[O:9])(=[O:8])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.[CH2:13](Br)[CH2:14][CH2:15][CH3:16]>CCOCC>[CH2:13]([N:3]1[C:2]([CH3:12])([CH3:1])[CH2:7][S:6](=[O:9])(=[O:8])[CH2:5][C:4]1([CH3:11])[CH3:10])[CH2:14][CH2:15][CH3:16]
Reactant: CC1(C)CS(=O)(=O)CC(C)(C)N1
Reactant: CCCCBr
Solvent: CCOCC
Product: CCCCN1C(C)(C)CS(=O)(=O)CC1(C)C

Procedure:
38.2 g (0.2 mole) of 2,2,6,6-tetramethyl-1-aza-4-thiacyclohexane-4,4-dioxide is heated with 13.7 g of n-butylbromide for 120 hours at 95°-100°C. After cooling, the contents of the flask are taken up in 300 ml of ether. The difficulty soluble hydrobromide of 2,2,6,6-tetramethyl-1-aza-4-thiacyclohexane-4,4-dioxide is separated by filtration, and the ether solution extracted twice with 100 ml of water each time, in order to remove the last traces of starting product or its hydrobromide. The ether solution is dried over sodium sulphate and then fully concentrated by evaporation. The residue is crystallised from ligroin to obtain 1-butyl-2,2,6,6-tetramethyl-1-aza-4-thiacyclohexane-4,4-dioxide, M.P. 180°C (3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:17]([O:21][C:22](=[O:30])[NH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].P.CC([O-])(C)C.[Na+].Cl>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O.O.C1(C)C=CC=CC=1>[S:16]1[C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:27]3[CH2:26][CH2:25][CH:24]([NH:23][C:22](=[O:30])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:29][CH2:28]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[N:13][CH:14]=[N:15]1
Reactant: O=S(=O)(Nc1ncns1)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(S(=O)(=O)Nc3ncns3)cc2)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 7 %

Procedure:
Prepared using general procedure 27. A mixture of 4-bromo-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (3.7 g, 11.6 mmol), tert-butyl-piperidin-4-ylcarbamate (2.32 g, 11.6 mmol), Pd2(dba)3 (319 mg, 0.35 mmol), phosphine (415 mg, 1.39 mmol), NaOtBu (3.55 g, 34.8 mmol) and toluene (30 mL) was stirred at 70° C. for 3 h. After allowing the mixture to cool to RT, H2O (50 mL) and EtOAc (50 mL) were added. After acidifying with a 1 M HCl solution to pH 4, the layers were separated, and the aqueous phase was extracted 3 times with CH2Cl2 (50 mL). The combined organic extracts were dried over MgSO4 and absorbed onto Celite. Purification via silica gel chromatography using 10% MeOH in CH2Cl2 gave tert-Butyl 1-(4-(N-1,2,4-thiadiazol-5-ylsulfamoyl)phenyl)-piperidin-4-ylcarbamate as an off-white foam (357 mg, 70%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=440.5; tR=2.76 min.
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.[NH2:19][OH:20].C(=O)([O-])O.[Na+].[OH-].[Na+]>O.[Ag]>[N:2]1([CH2:8][CH2:9][C:10](=[N:19][OH:20])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NO
Reactant: O=C(CCN1CCCCC1)c1ccccc1
Agent: [Ag]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Product: ON=C(CCN1CCCCC1)c1ccccc1
Reaction time: 8 h
Yield: 74.8 %

Procedure:
In 470 ml of water were dissolved 60.2 g of β-piperidinopropiophenone hydrochloride and 18.1 g of hydroxylamine hydrochloride. To this solution was added portionwise 21.9 g of sodium hydrogencarbonate. After the whole amount was added, the mixture was stirred overnight. To the stirred mixture was then added an aqueous solution of 14.2 g of sodium hydroxide in 47 ml of water. Thus obtained mixture was well stirred and allowed to stand for 2 hours to produce a white precipitate. The precipitate was collected by filtration and washed successively with two portions of 200 ml of water and ethanol. The washed precipitate was dried to obtain a white solid. The solid was then recrystallized from methanol to obtain 41.2 g (yield: 74.8%) of the subject compound as a silver-white scaly product.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]=[CH:6][N:5]([CH3:13])[C:4]=2[CH:3]=1.[BH4-].[Na+]>C(O)(C)C>[Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[NH:7][CH2:6][N:5]([CH3:13])[C:4]=2[CH:3]=1
Reactant: CN1C=NS(=O)(=O)c2sc(Cl)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CN1CNS(=O)(=O)c2sc(Cl)cc21
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
200 mg of the compound of Step A above are dissolved in 5 ml of isopropanol. The solution is heated at about 60° C., and 400 mg of NaBH4 are added. After 20 minutes, the solvent is removed under reduced pressure and the residue is taken up in water. The pH is adjusted to about 5-6 and the product is extracted with 3×10 ml of chloroform. The organic phase is then dried over magnesium sulphate, filtered and then concentrated under reduced pressure. The residue is taken up in a minimum of chloroform and then the product is precipitated by addition of hexane. The product is then collected by filtration and washed with hexane and dried.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]=[CH:8][C:7]2[CH:10]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)[NH:12][C:6]=2[CH:5]=1.Br[CH2:20][CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C=O)C.O.CCOC(C)=O>[Br:3][C:4]1[N:9]=[CH:8][C:7]2[CH:10]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)[N:12]([CH2:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:6]=2[CH:5]=1
Reactant: BrCC1CCCC1
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc3cnc(Br)cc3n2CC2CCCC2)cn1
Temperature: 60 °C
Reaction time: 24 h
Yield: 69.6 %

Procedure:
Sodium hydride (60% in mineral oil, 10.8 mg, 0.271 mmol) was added to a solution of 6-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22, 50 mg, 0.180 mmol) in DMF (780 mL). The reaction mixture was then stirred for 15 minutes at room temperature before the addition of (bromomethyl)cyclopentane (44 mg, 0.271 mmol). The reaction mixture was then stirred overnight at room temperature and for 24 hours at 60° C. Sodium hydride (60% in mineral oil, 5 mg, 0.125 mmol) was added and the reaction was stirred for another 7 hours at 60° C. The reaction mixture was then diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude was purified via Biotage silica gel column chromatography eluting with (DCM/EtOAc 99/1 to 80/20) to afford the title product as a colourless oil (45 mg, 69%). 1H NMR (500 MHz, CDCl3) d 1.10-1.19 (m, 2H), 1.46-1.64 (m, 6H), 2.24-2.33 (m, 1H), 4.03 (s, 3H), 4.09 (d, J=7.6 Hz, 2H), 6.53 (d, J=0.9 Hz, 1H), 7.45 (t, J=0.9 Hz, 1H), 7.59 (s, 1H), 7.68 (s, 1H), 8.60 (d, J=0.9 Hz, 1H). LC (Method B)-MS (ESI, m/z) tR 3.03 min, 359 [(M+H+), 100%].
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[S:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[O:20]=[CH:21][C:22]1[CH:30]=[CH:29][C:27]([OH:28])=[C:24]([O:25][CH3:26])[CH:23]=1.CN(C)C=O>O>[CH3:26][O:25][C:24]1[CH:23]=[C:22]([CH:30]=[CH:29][C:27]=1[O:28][CH2:2][C:3]1[N:4]=[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[S:6][CH:7]=1)[CH:21]=[O:20]
Reactant: ClCc1csc(N2CCOCC2)n1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCc1csc(N2CCOCC2)n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A mixture of 4-(4-chloromethyl-1,3-thiazol-2-yl)morpholine (1.00 g), potassium carbonate (0.64 g), vanillin (0.70 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give 3-methoxy-4-[(2-morpholin-4-yl-1,3-thiazol-4-yl)methoxy]benzaldehyde as colorless crystals (1.33 g, 86%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 122-123° C.