Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.[F-].[K+].CC[N:29](C(C)C)[CH:30]([CH3:32])[CH3:31].CC(N)C>CS(C)=O.O>[CH:30]([NH:29][C:2]1[N:7]=[C:6]2[CH:8]=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3ccncc3nc2Cl)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CC(C)N
Solvent: CS(C)=O
Product: CC(C)Nc1nc2cnccc2nc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 23 °C
Reaction time: 22 h
Yield: 59 %

Procedure:
To a flask charged with tert-butyl 4-(3-chloropyrido[3,4-b]pyrazin-2-yl)piperazine-1-carboxylate (3.35 g, 9.58 mmol) and potassium fluoride (0.723 g, 12.45 mmol) in DMSO (25 mL) was added DIPEA (3.34 mL, 19.15 mmol) and propan-2-amine (2.468 mL, 28.7 mmol) at 23° C. The reaction was stirred at 23° C. for 22 hr and diluted with water (100 mL) to furnish an orange, oily sludge. The mixture was cooled to 0° C. to furnish a yellow-orange suspension. The resulting solid was filtered, rinsed with water, and dried in vacuo. The crude material was dissolved in EtOAc, adsorbed on NH silica gel (11 g), and purified via medium pressure chromatography using a gradient of 10% to 100% EtOAc in heptane on an NH 60 μM size 400 column (Shoko Scientific Purif-Pack™) to give the title compound (2.105 g, 59.0%) as a light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.26 (d, J=6.8 Hz, 6H), 1.43 (s, 9H), 3.30-3.33 (m, 4H), 3.52-3.60 (m, 4H), 4.32-4.42 (m, 1H), 6.54 (d, J=7.8 Hz, 1H), 7.43-7.46 (m, 1H), 8.29 (d, J=5.4 Hz, 1H), 8.78 (s, 1H); ESI-MS m/z [M+F]+ 373.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][C:19]([F:23])=[CH:20][CH:21]=2)[N:16]([CH2:24][CH2:25][O:26][Si](C(C)(C)C)(C)C)[CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC.CCOC(C)=O>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][C:19]([F:23])=[CH:20][CH:21]=2)[N:16]([CH2:24][CH2:25][OH:26])[CH:15]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1Cc1cn(CCO[Si](C)(C)C(C)(C)C)c2cc(F)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCCC1Cc1cn(CCO)c2cc(F)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 114.2 %

Procedure:
A solution containing 22 (4.49 g, 9.42 mmol) in anhydrous THF (50 mL) was cooled to 0° C. Tetra-n-butylammonium fluoride (1 M in THF, 14 mL, 14 mmol) was added via syringe. After 1 h, reaction complete by TLC analysis [3:1 hexane/EtOAc, Rf(22)=0.7; Rf(23)=0.1] therefore diluted with EtOAc. The EtOAc solution was washed twice with 1 M HCl, water, brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 3.9 g of 23 (>100%; contaminated with some TBS-containing impurities) as a tan-colored oil which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ7.59 (br s, 1H), 7.01-6.85 (m, 3H), 4.19-4.10 (m, 3H), 3.90 (br s, 2H), 3.38-3.31 (m, 2H), 3.15 (dd, J=1.4, 4.6 Hz, 1H), 2.68 (m, 1H), 1.79-1.72 (m, 4H), 1.47 (d, J=10.9 Hz, 9H) ppm.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[CH:16]=[C:15]([CH3:17])[S:14][C:5]=2[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.CS(C)=O.[C:22]1([CH3:28])C=CC=CC=1.O>CN1CCNCC1>[CH3:17][C:15]1[S:14][C:5]2[NH:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[N:9]=[C:3]([N:2]3[CH2:28][CH2:22][N:6]([CH3:7])[CH2:5][CH2:4]3)[C:4]=2[CH:16]=1
Reactant: Cc1ccccc1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Agent: CN1CCNCC1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
4-Amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine, hydrochloride (100 g) was refluxed in a mixture of N-methylpiperazine (349 mL), dimethylsulphoxide (465 mL) and toluene (465 mL) under a nitrogen atmosphere for 20 hours. The mixture was cooled to 50° C., and water (465 mL) was added at 50-55° C. in 20 min. Then the reaction mass was cooled to 5° C. and stirred for 2 h. The product was filtered and washed with water (100 mL, 20° C.). Dried the product at 60-70° C. under reduced pressure to give crude 2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine or Olanzapine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.Br[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+].O>CN(C=O)C>[C:17]1([CH2:16][CH2:15][CH2:14][N:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[C:8]2=[O:12])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCCCc1ccccc1
Reactant: O=C1NCCc2cc(Br)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccc(Br)cc2CCN1CCCc1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 6-bromo-1-oxo-1,2,3,4-tetrahydroisoquinoline (2.82 g, 12.5 mmol) in DMF (80 ml) is added 1-bromo-3-phenylpropane (2.89 ml, 18.75 mmol), KI (200 mg, 1.25 mmol) and NaH (600 mg, 25 mmol). The reaction mixture is stirred for 3 hours and subsequently poured into H2O (300 ml). The resulting emulsion is extracted with EtOAc (2×150 mL) and the organic phase washed with 2N HCl (1×200 mL), H2O (1×200 mL), saturated NaHCO3 solution (1×200 mL), saturated NaCl solution (2×200 mL), dried over MgSO4 and concentrated in vacuo. The residue is chromatographed (silica gel, 9:1 hexane/EtOAc) to give 2-(3-phenylpropyl)-6-bromo-1-oxo-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])=[CH:4][CH:3]=1.[CH2:16]([CH:23]1[CH2:27][CH2:26][NH:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([CH:23]1[CH2:27][CH2:26][N:25]([C:2]2[N:7]=[N:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])=[CH:4][CH:3]=2)[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(CC2CCNC2)cc1
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Product: CC(C)CCNC(=O)c1ccc(N2CCC(Cc3ccccc3)C2)nn1

Procedure:
The title compound was prepared in the same manner as described for Example 16 from 6-chloro-N-(3-methylbutyl)pyridazine-3-carboxamide and 3-benzylpyrrolidine. MS (+ESI) m/z 353 (MH+).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25]I>CN(C=O)C.Cl>[CH2:1]([O:8][N:9]([CH3:25])[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CCCCCCCCCCNC(=O)NOCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCNC(=O)N(C)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
To a solution of decyl isocyanate (19.6 g, 0.11 mol) in 1,2-dichloroethane (100 ml) was added a solution of benzyloxyamine (0.114 mol) in methylene chloride (100 ml). The solution was refluxed for 20 minutes, evaporated, and the residue triturated with pentane to give N-benzyloxy-N'-decylurea as a white solid (22.36 g, 67% yield). This urea (2.95 g, 10 mmol) was dissolved in DMF (30 ml) at 40° C. Sodium hydride (425 mg of a 60% dispersion in oil) was added. Within 15 minutes, a precipitate formed. After 30 minutes, methyl iodide (0.64 ml) was added, and the mixture was stirred for one hour at room temperature. The resulting solution was poured in 1% HCl, and the resulting solid was washed with water, collected by filtration, and air-dried. Recrystallization from pentane provided N-benzyloxy-N-methyl-N'-decylurea as a white solid (2.25 g, 73% yield). Hydrogenolysis as in Example 2 above, and recrystallization from ethanol-water, provided the title compound as a white solid (1.43 g, 91% yield), mp 74°-76° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:19]1[N:23]=[C:22]([CH2:24][C:25]2[CH:44]=[CH:43][C:28]([O:29][CH2:30][CH2:31][NH:32]C(=O)OCC3C=CC=CC=3)=[CH:27][CH:26]=2)[O:21][N:20]=1)(=[O:12])=[O:11].Br>C(O)(=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:19]1[N:23]=[C:22]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:29][CH2:30][CH2:31][NH2:32])=[CH:43][CH:44]=2)[O:21][N:20]=1)(=[O:12])=[O:11]
Reactant: O=C(NCCOc1ccc(Cc2nc(C3CCCCN3S(=O)(=O)c3nc4ccccc4[nH]3)no2)cc1)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: NCCOc1ccc(Cc2nc(C3CCCCN3S(=O)(=O)c3nc4ccccc4[nH]3)no2)cc1

Procedure:
The title compound was prepared by a similar method to Example 27 from benzyl N-(2-[4-(3-[1-(1H-benzo[d]imidazol-2-ylsulfonyl)2-piperidyl]-1,2,4-oxadiazol-5-yl methyl)phenoxy]ethyl)carbamate [see Preparation 56] and 45% w/w hydrogen bromide in glacial acetic acid to afford 2-[4-(3-[1-(1H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1,2,4-oxadiazol-5-ylmethyl)phenoxy]ethylamine as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[Br:14]N1C(=O)CCC1=O>C1COCC1>[Br:14][C:5]1[S:1][C:2]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)Nc1nccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ncc(Br)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tert-butyl 1,3-thiazol-2-ylcarbamate (90 g, 449.8 mmol, 1 eq.) is taken in THF (1.4 L) to which is added N-bromosuccinimide (88.06 g, 494.8 mmol, 1.1 eq.) portion wise. The reaction mixture is then stirred at RT overnight. The reaction mass is concentrated to remove THF. The crude is purified by column chromatography to get the titled produce. 1H NMR (DMSO-d6, 400 MHz): δ 11.73 (bs, 1H), 7.42 (s, 1H), 1.46 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([N:12]2[CH2:21][CH2:20][C:15]3(OCC[O:16]3)[CH2:14][CH2:13]2)=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.Cl.C(=O)([O-])O.[Na+]>C1COCC1>[NH2:1][C:2]1[S:3][C:4]([N:12]2[CH2:21][CH2:20][C:15](=[O:16])[CH2:14][CH2:13]2)=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: Nc1nc(-c2ccco2)c(N2CCC3(CC2)OCCO3)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc(-c2ccco2)c(N2CCC(=O)CC2)s1
Yield: 17.6 %

Procedure:
2-Amino-5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-4-(2-furyl)thiazole (1.00 g, 3.25 mmol) obtained in Step 1 was dissolved in THF (10 mL), 2 mol/L hydrochloric acid (5 mL) was added thereto, followed by stirring under heating and reflux for 4 hours. The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:1) to afford 2-amino-4-(2-furyl)-5-(4-oxopiperidino)thiazole (151 mg, 18%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[OH-].[Na+]>CC(C)=O>[CH3:13][C@:12]12[CH2:14][CH2:15][C@H:16]3[C@@H:7]([CH2:6][CH2:5][C@@H:4]4[C@:17]3([CH3:20])[CH2:18][CH2:19][C:2](=[O:1])[CH2:3]4)[C@@H:8]1[CH2:9][CH2:10][C:11]2=[O:21]
Reactant: C[C@]12CC[C@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)=O
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 95.1 %

Procedure:
To the mixture of 6 (5 g, 17.2 mmol) and 75 ml acetone at room temperature 1.5 ml of Jones reagent (CrO3, H2SO4, H2O) was added by drops. After the reaction was completed, NaOH was added, liquid phase was separated and then 90 ml water was added. The resulting precipitate was filtered off to afford product 7 (4.72 g, 94%). M.p. 134-137° C.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:7])[CH:4]([CH3:6])[CH3:5].[H-].[Na+].[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][C:20](OC)=O)=[O:16])([CH3:13])([CH3:12])[CH3:11].O>CN(C)C=O>[CH:4]([C:3]1[N:7]=[C:20]([CH2:19][CH2:18][NH:17][C:15](=[O:16])[O:14][C:10]([CH3:13])([CH3:12])[CH3:11])[O:1][N:2]=1)([CH3:6])[CH3:5]
Reactant: CC(C)C(=N)NO
Reactant: COC(=O)CCNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1noc(CCNC(=O)OC(C)(C)C)n1
Temperature: 50 °C
Reaction time: 0.1 h

Procedure:
2.20 g (21.54 mmol) N-hydroxy-isobutyramidine are placed in 10 ml dimethylformamide and molecular sieve. 0.948 g (23.69 mmol) sodium hydride (60% in mineral oil) are added. The mixture is stirred for 0.1 hours at 50° C., then 6.20 g (30.51 mmol) methyl 3-tert-butoxycarbonylamino-propionate in 20 ml dimethylformamide are added. The reaction mixture is stirred for 3 hours at 50° C. After cooling 15 ml of water are added and the mixture is suction filtered through Celite. The 2 phases of the filtrate are separated, the aqueous phase is extracted with ethyl acetate, the combined organic phases are evaporated down. The residue is purified by chromatography.
Reaction SMILES: C(N(CC)CC)C.C(Cl)Cl.[CH:11]1([CH2:14][N:15]2[C:23]([N:24]3[CH2:29][CH2:28][NH:27][C@H:26]([CH3:30])[CH2:25]3)=[N:22][C:21]3[C:16]2=[N:17][C:18]([C:37]2[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=2)=[N:19][C:20]=3[N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH2:13][CH2:12]1.[C:44](OC(=O)C)(=[O:46])[CH3:45]>C(Cl)Cl.CO>[C:44]([N:27]1[CH2:28][CH2:29][N:24]([C:23]2[N:15]([CH2:14][CH:11]3[CH2:13][CH2:12]3)[C:16]3[C:21]([N:22]=2)=[C:20]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:19]=[C:18]([C:37]2[CH:42]=[N:41][C:40]([NH2:43])=[N:39][CH:38]=2)[N:17]=3)[CH2:25][C@H:26]1[CH3:30])(=[O:46])[CH3:45]
Reactant: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)CCN1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)C[C@H]1C
Temperature: 25 °C
Reaction time: 1.58 h
Yield: 100.9 %

Procedure:
Triethylamine (77.3 μl, 0.55 mmol) was added to a methylene chloride solution (3.0 ml) of 5-{9-(cyclopropylmethyl)-8-[(3R)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (104.1 mg, 0.23 mmol) at room temperature followed by the addition of acetic anhydride (26.2 μl, 0.28 mmol) with ice cooling. The resulting mixture was stirred at room temperature for 95 minutes and the reaction mixture was poured into methylene chloride-methanol (10:1), washed with water, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by medium pressure silica gel column chromatography (methylene chloride:methanol=32:1 to 16:1) to give the title compound (114.3 mg, 100%) as a pale yellow solid.
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15](N)=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])[CH3:3].[C:19]([BH3-])#[N:20].[Na+].C(=O)(O)[O-].[Na+]>CO>[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:20][CH2:19][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])[CH3:3]
Reactant: CC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Reactant: [BH3-]C#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCCCNc1ccc(OC2CCN(C(C)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 149.4 %

Procedure:
1-Acetyl-4-(4-aminophenyloxy)piperidine hydrochloride (2.5 g) obatined in Example 1, (2) was dissolved in methanol (20 ml) and to the solution were added sodium cyano borohydride (1.2 g) and pentylaldehyde (0.8 g) at room temperature. The mixture was stirred at room temperature for 1 hour. To the mixture was added aqueous saturated solution of sodium bicarbonate (50 ml) and the mixture was extracted with methylene chloride (50 ml×3). The combined extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (delveoping solvent: ethyl acetate/hexane=3/1 (v/v)) to obtain 1-acetyl-4-(4-pentylaminophenyloxy)piperidine (2.1 g) as white crystals, m.p. 69°-71° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:11]([C:17]([OH:19])=[O:18])[CH:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1.Cl.[CH2:21](O)[CH3:22]>>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:11]([C:17]([O:19][CH2:21][CH3:22])=[O:18])[CH:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: NS(=O)(=O)c1c(C(=O)O)cnn1-c1cccc(Cl)n1
Agent: Cl
Product: CCOC(=O)c1cnn(-c2cccc(Cl)n2)c1S(N)(=O)=O

Procedure:
Next, the above sulfonamide was introduced in ethanol saturated with hydrogen chloride, and, while stirring, heated under reflux for 7 hours. After solvent was evaporated, water was added, followed by extraction with chloroform. Extract liquid was evaporated to dryness to obtain 0.62 g of the title compound. m.p.: 125° to 128° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.C(N(CC)CC)C.[CH2:18]([S:20](Cl)(=[O:22])=[O:21])[CH3:19]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:20]([CH2:18][CH3:19])(=[O:22])=[O:21])[CH2:6][CH2:5]2
Reactant: CCS(=O)(=O)Cl
Reactant: Brc1ccc2c(c1)CCN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCc2cc(Br)ccc21
Reaction time: 2 h
Yield: 72.4 %

Procedure:
5-Bromoindoline (1.98 g, 10 mmol) was dissolved in methylene chloride (100 mL) and triethylamine (4.3 mL, 30 mmol) was added. The mixture was treated with ethanesulfonyl chloride (1.41 mL, 15 mmol) and stirred for 2 hours. The mixture was diluted with methylene chloride, washed with water, 2N HCl, brine, dried over anhydrous magnesium sulfate, and concentrated. Purification via Isco chromatography (the Redisep® column, silica, 1% ethyl acetate in methylene chloride) afforded 5-bromo-1-(ethylsulfonyl)indoline (2.1 g) as a white solid. MS (EI) m/z 286.9; HPLC purity 100.0% at 210-370 nm, 10.2 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium formate buffer pH=3.5μ acetonitrile+MeOH) for 10 minutes, hold 4 minutes.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH2:20][S:19][CH2:18][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH2:10][CH:11]([CH2:16][CH3:17])[CH2:12][CH2:13][CH2:14][CH3:15])=[O:8].C1C=C(Cl)C=C(C(OO)=O)C=1>C(OCC)(=O)C>[F:1][C:2]1[C:3]2[C:4](=[CH:18][S:19][CH:20]=2)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH:11]([CH2:16][CH3:17])[CH2:12][CH2:13][CH2:14][CH3:15])=[O:8]
Reactant: CCCCC(CC)COC(=O)c1sc2c(c1F)CSC2
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: CCCCC(CC)COC(=O)c1sc2cscc2c1F
Temperature: -78 °C
Yield: 76.5 %

Procedure:
475 mg of 2-ethylhexyl 3-fluoro-4,6-dihydrothieno[3,4-b]thiophene-2-carboxylate (1.50 mmol) was dissolved in 10 ml of ethyl acetate, the solution was cooled to −78° C. 337 mg of 77% m-CPBA (1.50 mmol) in 3 ml ethyl acetate was added and the reaction mixture was allowed to warm up to room temperature overnight. The solvent was removed by rotary evaporation and the residue was re-dissolved in 10 ml acetic anhydride, and heated to reflux for about 30 min. The solvent was removed by rotary evaporation and the product was purified by column (silica gel, hexane:dichloromethane=4:1) to produce 361 mg of product. The yield was about 76.5% for the two steps.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C@H:8]([NH:13][C@H:14]([C:19]([NH:21][C:22]2([C:25]#[N:26])[CH2:24][CH2:23]2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[C:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])[CH3:28].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)CC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:27]([C:30]1[CH:35]=[CH:34][C:33]([C:2]2[N:7]=[CH:6][C:5]([C@H:8]([NH:13][C@H:14]([C:19]([NH:21][C:22]3([C:25]#[N:26])[CH2:24][CH2:23]3)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=2)=[CH:32][CH:31]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)C[C@H](N[C@@H](c1ccc(Cl)nc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCO
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(-c2ccc([C@H](N[C@@H](CC(C)C)C(=O)NC3(C#N)CC3)C(F)(F)F)cn2)cc1
Temperature: 150 °C

Procedure:
To a solution of N2-[(1S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl]-N1-(1-cyanocyclopropyl)-L-leucinamide (100 mg, 0.26 mmol) in toluene (1.5 mL) and n-propanol (0.4 mL) was added under a stream of nitrogen, 4-(acetyl)phenylboronic acid (55 mg, 0.33 mmol), Pd(PPh3)4 (15 mg, 0.013 mmol) and Na2CO3 (2 M, 0.5 mL). The mixture was degassed with a rapid stream of nitrogen bubbling through the mixture and the mixture was heated to 150° C. in a Smith Creator microwave reactor (Personal Chemistry AB, Uppsala, Sweden) for 800 sec. The mixture was cooled, diluted with EtOAc and washed with water. Chromatography (50% EtOAc/Hexane) gave the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)[CH2:7][CH2:6]1.[H-].[Na+].[CH3:41]N(C)C=O.CI>C(OCC)(=O)C>[CH3:41][O:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)[CH2:7][CH2:6]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(OCCO)CC2)c2ncnn12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(OCCOC)CC2)c2ncnn12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 38 %

Procedure:
A mixture of 4′-({4-[4-(2-hydroxyethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.2 g), sodium hydride (0.019 g) and N,N-dimethylformamide (10 mL) was stirred at 0° C. for 10 min, methyl iodide (0.029 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.078 g, 38%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(=O)([O-])O.[Na+]>C(OCC)C>[CH3:20][S:21]([O:1][CH2:2][C@H:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1)(=[O:23])=[O:22]
Reactant: OC[C@@H]1COc2ccccc2O1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1COc2ccccc2O1
Reaction time: 0.5 h

Procedure:
To a solution of 0.410 g (2.467 mM) of (R)-2-hydroxymethyl-1,4-benzodioxane and 0.52 ml (3.70 mM) of triethylamine in 30 ml of diethyl ether was added 0.21 ml (2.71 mM) of methanesulfonyl chloride dropwise with ice-cooling and the mixture was stirred for 0.5 hour. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 2 portions of ethyl acetate. The organic layers were combined and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was passed through a short silica gel column (hexane-ethyl acetate=3/1 to 2/1) to provide crude (S)-2-methanesulfonyloxymethyl-1,4-benzodioxane.