Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[C:10]([Cl:17])=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:12]=2)=[C:4]([Cl:26])[CH:3]=1.[CH3:27][S:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29].C([O-])([O-])=O.[K+].[K+].O>COCCOC>[Cl:17][C:10]1[N:9]([C:18]2[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([S:28]([CH3:27])(=[O:30])=[O:29])[CH:36]=3)=[CH:3][C:4]=2[Cl:26])=[N:12][C:11]=1[C:13]([OH:16])([CH3:15])[CH3:14]
Reactant: CC(C)(O)c1nc(-c2ccc(Br)cc2Cl)n(-c2c(Cl)cccc2Cl)c1Cl
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(O)c1nc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2Cl)n(-c2c(Cl)cccc2Cl)c1Cl
Temperature: 60 °C
Reaction time: 1.17 h
Yield: 78.2 %

Procedure:
A mixture of 2-[2-(4-bromo-2-chlorophenyl)-5-chloro-1-(2,6-dichlorophenyl)-1H-imidazol-4-yl]-propan-2-ol (184 mg, 0.37 mmol), 3-methanesulfonyl-phenylboronic acid (90 mg, 0.45 mmol), K2CO3 (0.15 g, 1.1 mmol), Cl2 Pd(dppf)-DCM (15 mg, 5 mol %) and H2O (0.2 mL) in DME (2 mL) was sparged with Argon for 5 min and then heated at 60° C. as a sealed flask. After 70 min the reaction mixture was allowed to cool to ambient temperature, filtered (Celite™) and the filter agent rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 20:80 to 60:40) to give the title compound (165 mg, 78%) as a white solid. 1H-NMR (DCM-d2): δ 8.08 (m, 1H), 7.93 (m, 1H), 7.84 (m, 1H), 7.73 (d, 1H), 7.67 (m, 1H), 7.33-7.47 (m, 5H), 3.42 (br s, 1H), 3.06 (s, 3H), 1.68 (s, 6H); MS (ES): 591, 593, 595 [M+Na]+.
Reaction SMILES: [CH2:1]([OH:10])[C:2]#[C:3][CH2:4]/[CH:5]=[CH:6]/[CH2:7][CH2:8][CH3:9].S([O-])([O-])(=O)=O.[NH4+].[NH4+].[Na].[Cl-].[NH4+]>O>[CH2:1]([OH:10])/[CH:2]=[CH:3]/[CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH3:9]
Reactant: CCC/C=C/CC#CCO
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CCCC=CC/C=C/CO
Temperature: -78 °C
Reaction time: 6 h
Yield: 71.8 %

Procedure:
trans-5-nonen-2-yne-1-ol (21 g) was dissolved in liquid ammonia-ether solution (1:1) (200 ml) at -78° C. To the solution was added ammonium sulfate (105 g) and sodium metal (11 g) little by little. The mixture was stirred for 6 hours at -78° C. To the reaction mixture was added ammonium chloride to destroy excess sodium metal. The resultant mixture was stirred at ambient temperature to give a residue, which was dissolved in water. The aqueous solution was extracted with ether, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a yellowish oily residue, which was distilled under reduced pressure to give colorless oily trans, trans-2,5-nonadien-1-ol (15.3 g).
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[S:10][CH:11]=[C:12]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[O:15])[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:44]2[C@H:45]([CH3:68])[C@H:46]3[C@@H:63]([C@H:64]([OH:66])[CH3:65])[C:62](=[O:67])[N:47]3[C:48]=2[C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=2)=[O:50])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[CH3:22][N:19]1[CH2:20][CH2:21][N:16]([C:14]([C:12]2[N:13]=[C:9]([N:7]3[CH2:8][CH:5]([S:4][C:44]4[C@H:45]([CH3:68])[C@@H:46]5[C@@H:63]([C@H:64]([OH:66])[CH3:65])[C:62](=[O:67])[N:47]5[C:48]=4[C:49]([O:51][CH2:52][C:53]4[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=4)=[O:50])[CH2:6]3)[S:10][CH:11]=2)=[O:15])[CH2:17][CH2:18]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Reactant: CC(=O)SC1CN(c2nc(C(=O)N3CCN(C)CC3)cs2)C1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)N5CCN(C)CC5)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.4 %

Procedure:
To a solution of 3-acetylthio-1-[4-(4-methylpiperazine-1-carbonyl)-1,3-thiazol-2-yl]azetidine (1.35 g, 3.97 mmol) (obtained as described in Reference Example 30) in dimethylformamide (40 ml) was added hydrazine acetate (438 mg, 4.76 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (2.36 g, 3.97 mmol) in acetonitrile (40 ml) was added dropwise to the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (2.77 ml, 15.9 mmol). The mixture was stirred overnight while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate and ethyl acetate: methanol (1:5) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-(4-methylpiperazine-1-carbonyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (828 mg, yield 60%) as a pale yellow solid.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].OS([O-])(=O)=O.[K+]>C1COCC1>[F:15][C:14]([F:16])([F:17])[C:13]([C:10]1[CH:11]=[CH:12][C:7]([OH:6])=[CH:8][CH:9]=1)([O:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[C:18]([F:19])([F:21])[F:20]
Reactant: COc1ccc(COC(c2ccc(O[Si](C)(C)C(C)(C)C)cc2)(C(F)(F)F)C(F)(F)F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(COC(c2ccc(O)cc2)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8.39 g (17.0 mmol) of tert-butyl-dimethyl-{4-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenoxy}-silane was dissolved in 70 mL of THF and 25.4 ml (25.4 mmol) of 1M TBAF solution in THF was added at 0° C. The mixture was stirred at room temperature overnight, a 1M KHSO4 solution was added and the product was extracted with ethyl acetate (2×). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated. Column chromatography on silica gel with n-heptane/ethyl acetate 5:1 as eluent yielded 4-[2,2,2-trifluoro- 1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenol as a yellow liquid, MS: 379 (M−H)−.
Reaction SMILES: [O:1]([C:8]1[CH:20]=[CH:19][C:11]([O:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23](=[O:27])[CH2:24][CH2:25]Br.C(N(CC)CC)C>C(Cl)Cl>[CH3:21][O:22][C:23](=[O:27])[CH2:24][CH2:25][N:16]1[CH2:15][CH2:14][CH:13]([O:12][C:11]2[CH:19]=[CH:20][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)[CH2:18][CH2:17]1
Reactant: COC(=O)CCBr
Reactant: c1ccc(Oc2ccc(OC3CCNCC3)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCN1CCC(Oc2ccc(Oc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.2 %

Procedure:
To a solution of 4-(4-Phenoxy-phenoxy)-piperidine (152 mg, 0.5 mmol) in anhydrous CH2Cl2 (0.5 mL) was added methyl-3-bromopropionate (91 mg, 0.55 mmol) in CH2Cl2 (0.5 mL) and triethylamine (101 mg, 1.0 mmol). The resulting mixture was purged with nitrogen and stirred at rt for 48 h. CH2Cl2 was removed in vacuo and crude mixture was partioned between EtOAc and water. EtOAc layer was removed, washed with saturated NaHCO3, dried over anhydrous MgSO4 and concentrated. The crude mixture was purified by silica gel flash chromatography (50% EtOAc/Hexane) to obtain the product (146 mg, 82%): MS; m/z 356.5 (M+H); 1H NMR (400 MHz, DMSO-d6); δ 1.56-1.60 (m, 2H), 1.89-1.92 (m, 2H), 2.19-2.49 (m, 2H), 2.46-2.49 (m, 2H), 2.58 (t, 2H, J=6.8Hz), 2.60-2.69 (m, 2H), 3.59 (s, 3H), 4.28-4.30 (m, 1H), 6.91-6.96 (m, 6H), 7.04-7.08 (m, 1H), 7.32-7.36 (m, 2H); HPLC (UV); 94.7%.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([SH:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[C:29](=[O:42])[CH:30]=[C:31]([CH2:34][O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[O:32][CH:33]=1>CN(C=O)C.O>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]3[C:29](=[O:42])[CH:30]=[C:31]([CH2:34][O:35][CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[O:32][CH:33]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=c1cc(COC2CCCCO2)occ1OCCCCCCCCBr
Reactant: FC(F)(F)c1ccc2c(S)ccnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(COC2CCCCO2)occ1OCCCCCCCCSc1ccnc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-Trifluoromethyl-4-quinoline-thiol (300 mg, 1.3 mmol) was charged in a 50 mL round-bottomed flask equipped with a magnetic stirrer and under inert atmosphere. Anhydrous DMF (10 mL) and NaH 60% dispersion in oil (53 mg, 1.3 mmol) were successively added at 4° C. After 30 min a solution of 5-(8-bromo-octyloxy)-2-(tetrahydro-pyran-2-yloxymethyl)-4H-pyran-4-one 5 (500 mg, 1.2 mmol) in DMF (5 mL) was added at room temperature. The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was poured in 150 mL of H2O, extracted with EtOAc (3×80 mL). The organic layer was washed with brine (2×20 mL), dried over MgSO4, filtered and evaporated to dryness. The crude compound was purified by column chromatography (SiO2; CH2Cl2:MeOH=95:5 to 98:2) to give 5-(8-(7-(trifluoromethyl)quinolin-4-ylthio)octyloxy)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-4-one EHT 1006 (320 mg, 47% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH2:15][CH:16]([CH3:27])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:37]=[CH:38][C:39]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH2:15][CH:16]([CH3:27])[CH2:17][C:18]4[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=4)=[CH:6][CH:7]=3)=[CH:40][CH:41]=2)[CH2:34][CH2:35]1)=[O:32])[CH3:29]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NCC(C)Cc1ccc(C(C)C)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NCC(C)Cc4ccc(C(C)C)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(4-isopropyl-phenyl)-2-methyl-propyl]-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C(OC(=O)[N:7]([CH2:15][CH2:16]O)[C@H:8]1[CH2:13][CH2:12][C@H:11]([CH3:14])[CH2:10][CH2:9]1)(C)(C)C.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:50]1([SH:56])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C1COCC1>[CH3:14][CH:11]1[CH2:10][CH2:9][CH:8]([NH:7][CH2:15][CH2:16][S:56][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N(CCO)[C@H]1CC[C@H](C)CC1
Reactant: Sc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1CCC(NCCSc2ccccc2)CC1
Reaction time: 18 h

Procedure:
To a solution of (2-Hydroxy-ethyl)-(trans-4-methyl-cyclohexyl)-carbamic acid tert-butyl ester (0.50 g, 1.94 mmol) in THF (20 mL) was added DEAD (372 mg, 2.14 mmol) and resin bound triphenyl phosphine (polystyrene 2% cross linking, loading=3 mmol/g, 0.97 g). The mixture was stirred for 15 m before thiophenol (0.21 g, 1.94 mmol) was added. The mixture was stirred for 18 h before another portion of resin bound triphenyl phosphine (0.97 g) and DEAD (372 mg, 2.14 mmol) was added. The mixture was stirred for 1 h before a new portion of thiophenol (0.21 g, 1.94 mmol) was added. The mixture was stirred for 18 h before it was filtered. The resin was washed with THF (2×20 mL) and the combined filtrates were concentrated in vacuo. The residue was divided between DCM (100 mL) and H2O (100 mL). The aqueous layer was extracted once more with DCM (100 mL). The organic fractions were combined, dried (MgSO4), filtered and concentrated in vacuo to give the crude intermediate (4-methyl-cyclohexyl)-(2-phenylsulfanyl-ethyl)-amine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][N:9]=[C:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]([F:19])([F:18])[F:17].[F:20][C:21]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25](F)[C:22]=1[CH2:23]Br>CN(C=O)C>[F:20][C:21]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:22]=1[CH2:23][N:8]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[C:15]2[C:10]([C:11]([C:16]([F:19])([F:17])[F:18])=[CH:12][CH:13]=[CH:14]2)=[N:9]1
Reactant: FC(F)(F)c1cccc2c(-c3ccccn3)[nH]nc12
Reactant: Fc1cc(F)c(CBr)c(F)c1
Solvent: CN(C)C=O
Product: Fc1ccc(Cn2nc3c(C(F)(F)F)cccc3c2-c2ccccn2)c(F)c1
Reaction time: 120 h
Yield: 12.1 %

Procedure:
Then a solution of 3-pyridin-2-yl-7-(trifluoromethyl)-2H-indazole (0.183 g, 0.7 mmol) and 2,4,6-trifluorobenzyl bromide (0.203 g, 0.9 mmol) in DMF (5 mL) was heated at 120° C. After 5 days, the reaction mixture was partitioned with EtOAc and water. Organics were washed with water (3×), then brine and dried over MgSO4, then stripped and the resulting crude product was flashed by reverse phase HPLC to afford the title compound (0.033 g, 5%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][N:14](C=O)[CH3:15].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>O>[CH3:13][N:14]([CH3:15])[C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
To a solution of 4-nitro-benzoic acid (20 g, 0.1196 mol) in DMF (300 mL) N, N-dimethylamine hydrochloride (11.7 g, 0.1436 mol), HOBt (20.9 g, 0.1554 mol), EDC.HCl (34.3 g, 0.1794 mol) and DIPEA (30.91 g, 0.2392 mol) were added. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3×500 mL). The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to afford the title compound [23.0 g, 99%]; LC-MS (ESI): Calculated mass: 194.1; Observed mass: 195.1 [M+H]+ (RT: 1.70 min).
Reaction SMILES: CC(N[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:28]=[CH:27][CH:26]=[CH:25][C:12]=1[C:13]([NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[CH:19][NH:20]2)=[O:14])(C)C.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH2:41][CH2:42][N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[NH:20]1[C:21]2[C:17](=[C:16]([NH:15][C:13](=[O:14])[C:12]3[CH:25]=[CH:26][CH:27]=[CH:28][C:11]=3[O:10][CH2:9][CH2:8][CH2:7][CH2:6][N:46]3[CH2:47][CH2:48][N:43]([CH2:42][CH2:41][C:33]4[CH:32]=[C:31]([O:30][CH3:29])[C:36]([O:37][CH3:38])=[C:35]([O:39][CH3:40])[CH:34]=4)[CH2:44][CH2:45]3)[CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:19]1
Reactant: COc1cc(CCN2CCNCC2)cc(OC)c1OC
Reactant: CC(C)(C)NCCCCOc1ccccc1C(=O)Nc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(CCN2CCN(CCCCOc3ccccc3C(=O)Nc3cccc4[nH]ccc34)CC2)cc(OC)c1OC
Yield: 90.8 %

Procedure:
2.5 g of 2-(4-bromobutoxy)-N-(1H-indol-4-yl)benzamide of Example 33, 2.71 g of 1-[2-(3,4,5-trimethoxyphenyl)ethyl]piperazine [German Patent No. 3,347,173] and 0.683 g of sodium carbonate in 25 ml of ethanol were heated to 60° C. for 10 hours and the mixture is cooled and poured into ater and extracted with ethyl acetate. The extract was washed with water and dried and the solvents were evaporated under reduced pressure. The residue was chromatographed over silica (eluant:chloroform/acetone/triethylamine 6:3:1) to obtain 3.51 g of N-(1H-indol-4-yl)-2-[4-[4-[2-(3,4,5-trimethoxyphenyl)ethyl]-1-piperazinyl]butoxy]benzamide.
Reaction SMILES: COC[O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][S:35][CH2:36][CH2:37][O:38][CH2:39][C:40]([F:43])([F:42])[F:41])[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22]COC)=[CH:18][CH:17]=3)([CH3:15])[CH2:11][S:12]2)=[CH:7][CH:6]=1>Cl.CO>[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][S:35][CH2:36][CH2:37][O:38][CH2:39][C:40]([F:43])([F:42])[F:41])[C:10]([C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)([CH3:15])[CH2:11][S:12]2)=[CH:7][CH:6]=1
Reactant: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2CCCCCCCCCSCCOCC(F)(F)F)cc1
Agent: Cl
Solvent: CO
Product: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCCSCCOCC(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.1 %

Procedure:
(3RS,4RS)-7-Methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methyl-4-{9-[2-(2,2,2-trifluoroethoxy)ethylthio]nonyl}thiochroman (136 mg, 0.211 mmol) was dissolved in 10% HCl/MeOH (20 ml) and the mixture was stirred at room temperature for 1 day. After the reaction was completed, the mixture was concentrated, and silica gel column chromatography (n-hexane/ethyl acetate=5/1) gave (3RS,4RS)-7-Hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-{9-[2-(2,2,2-trifluoroethoxy)ethylthio}nonyl}thiochroman (100 mg, 85%)
Reaction SMILES: [F:1][CH2:2][C:3]12[CH2:10][N:9](C(OCC)=O)[CH2:8][CH:7]1[N:6]([CH3:16])[CH2:5][CH2:4]2>Cl>[F:1][CH2:2][C:3]12[CH2:10][NH:9][CH2:8][CH:7]1[N:6]([CH3:16])[CH2:5][CH2:4]2
Reactant: CCOC(=O)N1CC2N(C)CCC2(CF)C1
Agent: Cl
Product: CN1CCC2(CF)CNCC12

Procedure:
7.1 g (26 mmol) of ethyl 5-fluoromethyl-2-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate in 100 ml of concentrated hydrochloric acid are refluxed overnight. The mixture is concentrated, the concentrate is taken up in 20 ml of water, this mixture is rendered alkaline using potassium carbonate and extracted ten times using 50 ml portions of chloroform, and the extracts are dried over potassium carbonate, concentrated and distilled.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.FC(F)(F)C([O-])=O.[F:30][C:31]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=1[C@H:38]1[CH2:44][NH:43][C:42](=[N:45][CH2:46][CH:47](O)[CH:48]([CH3:50])[CH3:49])[C@H:41]([NH:52][C:53]([N:55]2[CH2:60][CH2:59][CH:58]([N:61]3[C:69]4[C:64](=[N:65][CH:66]=[CH:67][CH:68]=4)[NH:63][C:62]3=[O:70])[CH2:57][CH2:56]2)=[O:54])[CH2:40][CH2:39]1.C(O)(=O)C.S([O-])([O-])=O.[Na+].[Na+]>ClCCl.C(O)C>[F:30][C:31]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=1[C@H:38]1[CH2:44][N:43]2[C:47]([CH:48]([CH3:50])[CH3:49])=[CH:46][N:45]=[C:42]2[C@H:41]([NH:52][C:53]([N:55]2[CH2:60][CH2:59][CH:58]([N:61]3[C:69]4[C:64](=[N:65][CH:66]=[CH:67][CH:68]=4)[NH:63][C:62]3=[O:70])[CH2:57][CH2:56]2)=[O:54])[CH2:40][CH2:39]1
Reactant: CC(C)C(O)CN=C1NC[C@H](c2cccc(F)c2F)CC[C@H]1NC(=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])C(F)(F)F
Agent: O=S([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
Dess-Martin reagent [1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1)-one] (174 mg, 0.411 mmol) was added to a solution of the trifluoroacetate salt of N-{(3R,6S)-6-(2,3-difluorophenyl)-2-[(2-hydroxy-3-methylbutyl)imino]azepan-3-yl}-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide (164 mg, 0.206 mmol) and acetic acid (24 μL, 0.411 mmol) in dichloromethane (10 mL). After 1 h, sodium sulfite (100 mg, 0.793 mmol) and ethanol (10 mL) were added and the mixture was heated to 80° C. After 1 h, the reaction was allowed to cool to ambient temperature and concentrated. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography [100% dichloromethane→93% dichloromethane/methanol)] gave the title compound (76 mg). MS 550.2748 (M+1).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([CH:8]=[O:9])[N:5]=[CH:4]1.[C:10]([O:16][CH2:17]Cl)(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]>O1CCCC1.CN(C=O)C>[C:10]([O:16][CH2:17][N:3]1[CH:7]=[C:6]([CH:8]=[O:9])[N:5]=[CH:4]1)(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: O=Cc1c[nH]cn1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCn1cnc(C=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a suspension of sodium hydride (60% in oil, 1.0 g, 26 mmol) in tetrahydrofuran (10 ml) was added dropwise a solution of 1H-imidazole-4-carbaldehyde (1.92 g, 20 mmol) in DMF (5 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. Chloromethyl pivalate (3.92 g, 26 mmol) was further added dropwise at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with 6% aqueous sodium hydrogen carbonate solution and saturated brine, dried (over anhydrous MgSO4), and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (100 g), and eluted with hexane-ethyl acetate (4:1-1:2, v/v) to give the title compound (4.11 g, 98%) as a pale-yellow oil.
Reaction SMILES: [OH-].[K+].ClC[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]1=O>C(O)CCC>[O:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:7][CH2:6][CH2:5][CH2:8]1
Reactant: O=c1oc2ccccc2n1CCCCl
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: c1ccc2c(c1)NCCCO2
Yield: 54.4 %

Procedure:
Powdered KOH (37.60 g, 0.67 mol) was added to a slurry of 3-(3-chloropropyl)-1,3-benzoxazol-2(3H)-one (35.75 g, 0.169 mol) in n-butanol (450 mL) under N2 gas and refluxed for 52 hours. The mixture was filtered and reduced to dryness under reduced pressure. The residue was taken up in H2O (500 mL) and extracted with ether (3×200 mL). The organic was washed with 10% HCl (2×200 mL), dried over MgSO4, and stripped of solvent under reduced pressure. Purification by flash chromatography (50% EtOAc in hexanes) yielded 13.72 g (54%) of 2,3,4,5-tetrahydro-1,5-benzoxazepine as a powder, m.p. 50-51° C. (M+H)+ 149.