Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6](=[O:23])[CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[C:17]2[C:18]([NH2:22])=[N:19][O:20][N:21]=2)=[CH:4][C:3]=1[N+:26]([O-])=O>C(O)C.O.Cl.[Fe]>[NH2:26][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:2]=1[Cl:1])[C:6](=[O:23])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:18]([NH2:22])=[N:19][O:20][N:21]=1
Reactant: Nc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(C(=O)Cn2c(-c3nonc3N)nc3ccccc32)ccc1Cl
Temperature: 80 °C

Procedure:
To a stirred solution of 4-[1-(4-chloro-3-nitrophenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine (0.07 g, 0.175 mmol) in ethanol (6 ml) and water (1 ml) is added two drops of concentrated hydrochloric acid and iron powder (0.1 g, 17.5 mmol). The reaction mixture is heated at 80° C. for 8 hours. Filtration and evaporation at reduced pressure gives the crude product. Purification by extraction with ethyl acetate and chromatography on silicagel yields the title compound as colorless solid, m.p. 228-230° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](O)=[N:6][CH:7]=1.CN(C=O)C.P(Br)(Br)([Br:19])=O.O>C1(C)C=CC=CC=1>[Br:19][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(Br)cnc1Br
Temperature: 90 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
To a suspension 5-bromo-3-nitro-pyridin-2-ol (20 g, 91.32 mmol) in toluene (100 ml) was added DMF (0.7 ml, 9.13 mmol) and the mixture was heated to 90° C. (the reaction mixture was protected from light). A solution of POBr3 (31.41 g, 109.51 mmol) in toluene (40 ml) was added dropwise at 90° C. and the reaction mixture was stirred at that temperature for 16 h. The mixture was allowed to cool to room temperature and toluene (50 ml) and water (50 ml) were added. The organic layer was separated, washed successively with aqueous 1N NaOH (60 ml), water (60 ml) and brine (30 ml), dried with Na2SO4 and evaporated obtain the title compound as yellow solid (25.2 g, 97%).
Reaction SMILES: C([C:5]1(C(C)(C)C)[C:14]2[N:13]=[C:12]([N:15](C([O-])=O)C([O-])=O)[C:11]3[N:22]=[C:23]([CH2:34][CH2:35][CH2:36][CH3:37])[N:24]([CH2:25][CH2:26][S:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:10]=3[C:9]=2[CH2:8][CH2:7][CH2:6]1)(C)(C)C.Cl.[Cl:43]CCl>O1CCOCC1>[ClH:43].[CH2:34]([C:23]1[N:24]([CH2:25][CH2:26][S:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:10]2[C:9]3[CH2:8][CH2:7][CH2:6][CH2:5][C:14]=3[N:13]=[C:12]([NH2:15])[C:11]=2[N:22]=1)[CH2:35][CH2:36][CH3:37]
Reactant: CCCCc1nc2c(N(C(=O)[O-])C(=O)[O-])nc3c(c2n1CCSc1ccccc1)CCCC3(C(C)(C)C)C(C)(C)C
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1nc2c(N)nc3c(c2n1CCSc1ccccc1)CCCC3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A round bottom flask was charged with a magnetic stir bar, di(tert-butyl)2-butyl-1-[2-(phenylthio)ethyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-ylimidodicarbonate (0.50 g, 0.86 mmol), a 4 M solution of hydrochloric acid in dioxane (5 mL), and dichloromethane (5 mL). The reaction was judged to be complete after stirring at ambient temperature for 2 hours. The volatiles were removed under reduced pressure to afford an off white solid. The material was recrystallized from acetonitrile to provide 2-butyl-1-[2-(phenylthio)ethyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine hydrochloride (0.17 g, 1.30 mmol) as fluffy white needles, m.p. 237-238° C. Analysis. Calculated for C22H28N4S.(H2O)1/4.(HCl)2: % C, 57.70; % H, 6.71; % N, 12.23. Found C, 57.62; % H, 6.57; % N, 12.41.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][Br:10])[N:4]=1.[CH:11]([O:14][CH2:15][CH2:16][OH:17])([CH3:13])[CH3:12]>>[Br:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][O:17][CH2:16][CH2:15][O:14][CH:11]([CH3:13])[CH3:12])[N:4]=1
Reactant: CC(C)OCCO
Reactant: BrCc1cccc(CBr)n1
Product: CC(C)OCCOCc1cccc(CBr)n1
Yield: 28 %

Procedure:
Prepared from 2,6-bis(bromomethyl)pyridine and 2-(isopropyloxy)ethanol by the alkylation method described for the final step of Example 32 to give the title compound (28%); NMR δH (400 MHz, CDCl3) 7.69 (1H, t, J 7.5 Hz), 7.43 (1H, d, J 7.5 Hz), 7.33 (1H, d, J 7.5 Hz), 4.69 (2H, s), 4.53 (2H, s), 3.73-3.69 (2H, m), 3.68-3.58 (3H, m), 1.18 (6H, d, J 6.0 Hz); (M+H)+ 288, 290.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C:8](=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH:19]=[CH:18][N:17]=[N:16]2)[CH:10]=1)(C)([CH3:3])[CH3:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(O)(C(F)(F)F)=O.CC(C)=O>[CH3:2][C:1]1([CH3:3])[O:5][C:6](=[O:21])[CH:7]=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[CH:10]=2)[O:20]1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OC(=O)C=C(c2cccc(-n3ccnn3)c2)O1

Procedure:
The title compound was prepared from 3-oxo-3-(3-[1,2,3]triazol-1-yl -phenyl)-propionic acid tert.-butyl ester (Example K23) by stirring in TFA/acetone with TFAA according to general procedure L (method b). Obtained as a beige solid (7.80 g).
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][CH2:23][CH:24]=[O:25])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=[O:27].[K+].Cl.S(=O)(O)[O-].[Na+]>CC(C)=O.O>[C:1]([O:20][CH2:21][CH2:22][CH2:23][C:24]([OH:27])=[O:25])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=CCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=S([O-])O
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)CCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 78.1 %

Procedure:
To a stirred mixture of 56.2 g of 4-trityloxy-butanal in 430 ml of acetone and 170 ml of water were added portionwise over 1.5 h 27.0 g of potassium permanganate, the temperature of the mixture being maintained at 20° to 25° C. Stirring was continued for 3 h, and then, the pH of the mixture was set to 5 by addition of 22 ml of 3N hydrochloric acid. Over 30 min, 300 ml of 38% sodium bisulfite solution were added dropwise at a reaction temperature of 20° to 30° C. The pH was lowered to 2 by addition of 80 ml of 3N hydrochloric acid, and subsequently the mixture was extracted with 1 l of ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and the solvent was evaporated in vacuo. The residue was crystallized from ethyl acetate/hexane to yield 46.0 g of 4-trityloxy-butyric acid as a white solid of m.p. 137°-140° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21][CH3:22])[CH:15]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][Cl:33]>CC(CC(C)C)=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:31][CH2:32][Cl:33])=[C:16]([O:21][CH3:22])[CH:15]=2)[CH2:4][CH2:3]1
Reactant: ClCCBr
Reactant: COc1cc(CCCCC(=O)N[C@H]2CC[C@H](C)CC2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: COc1cc(CCCCC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl

Procedure:
Using 2.3 g of N-(trans-4-methylcyclohexyl)-5-(4-hydroxy-3-methoxyphenyl)valeramide (Example 118), 100 ml of methylisobutylketone, 5 g of potassium carbonate, and 4 ml of 1-bromo-2-chloroethane, a reaction similar to that conducted in Example 106 was carried out. As a result, 2.1 g of N-(trans-4-methylcyclohexyl)-5-[4-(2-chloroethoxy)-3-methoxyphenyl]valeramide (a compound of the present invention) was obtained as a pale yellow oil, which had the following physiochemical properties:
Reaction SMILES: C(N(CC)CC)C.C([NH:11][CH:12]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:13]([OH:15])=[O:14])(=O)C>C(OCC)(=O)C>[NH2:11][CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([OH:15])=[O:14]
Reactant: CC(=O)NC(C(=O)O)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: NC(C(=O)O)c1ccccc1

Procedure:
Triethylamine (8.39 ml) was added to a suspension of DL-N-acetyl-2-cyclohexylglycine (10.00 g) obtained from α-aminophenylacetic acid according to a known method [Collect. Czeck. Chem. Commun., 31: 4563 (1996)] in ethyl acetate (50 ml). Ethyl chlorocarbonate (5.28 ml) was dropwise added to the mixture under ice-cooling. The mixture was stirred under ice-cooling for one hour, added with ethyl acetate (150 ml), and washed successively with water and saturated brine. The ethyl acetate solution was concentrated under reduced pressure to give 9.86 g of the title compound as an oil.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:3]1.Br[CH2:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>>[C:25]([C:24]1[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=1[CH2:22][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:3]1)#[N:26]
Reactant: N#Cc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2)C(OCc2ccccc2C#N)C1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-phenyl-piperidine-1-carboxylate [Example 2(a)] with 2-bromomethylbenzonitrile there was obtained tert-butyl (3RS,4RS)-3-(2-cyano-benzyloxy)-4-phenyl-piperidine-1-carboxylate as a colourless oil; MS: 393 (M+H)+.
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]O>>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:14][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][Cl:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCCCCCl
Reactant: OC(c1ccccc1)c1ccccc1
Product: ClCCCCCCOC(c1ccccc1)c1ccccc1
Yield: 88 %

Procedure:
Using benzhydrol and 6-chloro-1-hexanol, the procedure of Reference Example 15 was otherwise repeated to provided the title compound. Yield 88%. Oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:39])[N:20]([CH2:22][CH2:23][CH2:24][S:25]([CH2:28][CH2:29][CH2:30][O:31][Si](C(C)(C)C)(C)C)(=[O:27])=[O:26])[N:21]=[C:8]2[N:7]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=2)[C:6]=1[CH3:50])=[O:4].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=2)[N:9]2[C:19](=[O:39])[N:20]([CH2:22][CH2:23][CH2:24][S:25]([CH2:28][CH2:29][CH2:30][OH:31])(=[O:26])=[O:27])[N:21]=[C:8]2[N:7]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:48])([F:47])[F:49])[CH:41]=2)[C:6]=1[CH3:50])=[O:4]
Reactant: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CCCS(=O)(=O)CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C1c1ccc(C#N)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CCCS(=O)(=O)CCCO)c(=O)n2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.8 %

Procedure:
Intermediate 21 (282 mg, 0.38 mmol) was dissolved in THF (3 mL), and then a solution of 1 M TBAF in THF (760 μl, 0.76 mmol) was added. The reaction mixture was stirred at RT for 4 hours and then partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer further extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-2% methanol in EtOAc to afford the title compound (89 mg).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14](Br)=[C:13]([Br:16])[N:12]=[C:11]1[CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.CN([CH:33]=[O:34])C>C1COCC1>[CH2:1]([O:8][CH2:9][N:10]1[C:14]([CH:33]=[O:34])=[C:13]([Br:16])[N:12]=[C:11]1[CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CCc1nc(Br)c(Br)n1COCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1nc(Br)c(C=O)n1COCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
A solution of 1-[(Benzyloxy)methyl]-4,5-dibromo-2-ethylimidazole (28.0 g, 75.0 mmol, Part A of example 544) in THF (300 mL) was cooled to −78° C. under nitrogen atmosphere and then added dropwise 1.6 M n-BuLi in hexane (51.75 mL, 82.5 mmol, Aldrich) over 30 mins. The mixture was stirred at −78° C. for 30 mins and then added DMF (16.5 g, 225 mmol, Aldrich) dropwise over 15 mins. The mixture was stirred at −78° C. for 30 mins. A small portion of the reaction mixture was quenched with satd. NH4Cl at −78° C. TLC (30:70 EtOAc/hexane) revealed both starting material and product showed almost identical Rf values (0.71 & 0.70) along with another minor spot at Rf=0.15. However, mass spectrum (CI—NH3) revealed absence of starting material and formation of product (m/z=325, M+2H). The reaction mixture was quenched with satd. ammonium chloride (20 mL) at −78° C. and brought to room temp. The reaction mixture was extracted with ethyl acetate (3×100 mL), washed with brine and dried with anhydrous MgSO4. The solvent was evaporated under reduced pressure to afford crude yellow oil. The crude was purified by flah column chromatography on a silica gel using dichloromethane as eluent to afford 22.6 g (93%) of colorless oil. HRMS calcd. for C14H16N2O2Br: 323.0395. Found: 323.0394 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.Br[CH2:22][C:23](=[O:39])[CH2:24][C@H:25]1[C@H:30]([O:31][CH3:32])[CH2:29][CH2:28][CH2:27][N:26]1[C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34]>C[O-].[Na+].CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[N:7]([CH2:22][C:23](=[O:39])[CH2:24][C@H:25]3[C@H:30]([O:31][CH3:32])[CH2:29][CH2:28][CH2:27][N:26]3[C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34])[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1
Reactant: O=c1[nH]cnc2cc(Cl)c(Oc3ccc(Cl)cc3)cc12
Reactant: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2cc(Cl)c(Oc3ccc(Cl)cc3)cc2c1=O
Reaction time: 0.25 h

Procedure:
Under a nitrogen atmosphere in a flame-dried flask at room temperature and with magnetic stirring, 0.921 g (0.003 mol) of 7-chloro-6-(4-chlorophenoxy)quinazolin-4(3H)-one was slurried in 3.0 ml of 1.1N sodium methoxide. After 15 minutes, 1.00 g (0.003 mol) of allyl trans-2-(3-bromo-2-oxopropyl)-3-methoxy-1-piperidinecarboxylate in 10 ml of methanol was added dropwise. After 2 hours, the reaction mixture was evaporated under reduced pressure, and the residue treated with water. The aqueous solution was extracted three times with 75 ml of dichloromethane. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and evaporated to afford the title compound: yield 1.28 g (76%); m.p. 138°-141° C. H-NMR(CDCl3) 1.3 to 1.9 (m, 4H), 2.6-3.4 (m, 6H), 3.3 (s, 3H), 4.9 (s, 2H), 4.5-6.2 (m, 5H), 7.1 (q, 4H), 7.6 (s, 1H), 7.8 (d, 2H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O)=[O:5].S(Cl)(Cl)=O.[CH3:24][NH:25][CH2:26][C:27]([O:29][CH3:30])=[O:28].CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C)C=O>[CH3:1][C:2]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([N:25]([CH3:24])[CH2:26][C:27]([O:29][CH3:30])=[O:28])=[O:10])=[O:5]
Reactant: Cc1ccc(C(=O)c2ccccc2C(=O)O)c(C)c1
Reactant: CNCC(=O)OC
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)CN(C)C(=O)c1ccccc1C(=O)c1ccc(C)cc1C
Temperature: 70 °C

Procedure:
A mixture of 2-(2,4-dimethylbenzoyl)benzoic acid (50 g, 197 mmol) and thionyl chloride (215 mL, 2949 mmol) was heated at 70° C. for 1.5 hours. The mixture was concentrated, dissolved in tetrahydrofuran (THF) (200 mL) and N,N-dimethylformamide (DMF) (40 mL) and treated with methyl N-methylglycinate (27.4 g, 197 mmol). The mixture was cooled to 0° C. and treated with Hunig's base (103 mL, 590 mmol). The mixture was heated to 70° C. for 1 hour, cooled to ambient temperature and then diluted with ethyl acetate. The organic phase was washed with 1N HCl, water, then brine, dried over sodium sulfate, filtered and concentrated to a brown thick oil (60 g, 90%) which was used without further purification. LC/MS (m/z) ES+=340 (M+1).
Reaction SMILES: [Br:1][C:2]([Br:6])([Br:5])[CH:3]=[O:4].[CH2:7]=[C:8]([CH3:10])[CH3:9].[Cl-].[Al+3].[Cl-].[Cl-]>O>[Br:1][C:2]([Br:6])([Br:5])[CH:3]([OH:4])[CH2:9][C:8]([CH3:10])=[CH2:7]
Reactant: C=C(C)C
Reactant: O=CC(Br)(Br)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: C=C(C)CC(O)C(Br)(Br)Br
Reaction time: 5 h
Yield: 85 %

Procedure:
A mixture of 281 parts of tribromoacetaldehyde, 168 parts of isobutene and 150 parts of petroleum ether was cooled to - 20° to - 5° C., and 13 parts of anhydrous aluminum chloride was added to the mixture dividedly in several times. The mixture was agitated at the above temperature for 5 hours. As the reaction advanced, crystals were precipitated from the reaction mixture. At the point of termination of the reaction, diethyl ether was added to the reaction mixture to form a homogeneous solution. The solution was then agitated at room temperature for 30 minutes, and 200 parts of water was added to the reaction mixture. The organic layer was recovered, low-boiling-point substances were removed by distillation, and the residue was subjected to distillation under reduced pressure to obtain 287 parts of 1,1,1-tribromo-4-methyl-4-penten-2-ol. The yield was 85%.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[C:4]([CH3:10])[C:3]=1[OH:11].[Br:12]Br>C(O)(=O)C>[Br:12][C:6]1[C:5]([CH3:9])=[C:4]([CH3:10])[C:3]([OH:11])=[C:2]([CH3:1])[C:7]=1[CH3:8]
Reactant: BrBr
Reactant: Cc1cc(C)c(C)c(O)c1C
Solvent: CC(=O)O
Product: Cc1c(C)c(Br)c(C)c(C)c1O
Reaction time: 5 h
Yield: 65.5 %

Procedure:
To a suspension of 2,3,5,6-tetramethylphenol (5.10 g, 34.0 mmol) in acetic acid (90 ml) was added dropwise a solution of bromine (1.98 mL, 38.6 mmol) in acetic acid (30 mL) at room temperature, and the mixture was stirred for 5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, and washed successively with aqueous sodium thiosulfate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals were washed with petroleum ether to give the title compound (5.10 g, yield 66%) as pale-yellow crystals. The mother solution was concentrated under reduced pressure, and washed with petroleum ether to give second crop (1.38 g, yield 18%).
Reaction SMILES: [C:1]([CH:5]1[CH2:17][CH2:16][C:8]2([O:12][CH2:11][C:10]([CH2:14][NH2:15])([OH:13])[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:18]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[C:1]([CH:5]1[CH2:17][CH2:16][C:8]2([O:12][CH2:11][C:10]([CH2:14][NH:15][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)([OH:13])[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCCCC1
Reactant: CC(C)(C)C1CCC2(CC1)CC(O)(CN)CO2
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)C1CCC2(CC1)CC(O)(CNC1CCCCC1)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a solution of 8-t-butyl-3-aminomethyl-3-hydroxy-1-oxaspiro-(4,5)decane (1.8 g, 7.5 mmol), cyclohexanone (1.36 g, 8 mmol) and zinc chloride (0.61 g, 4.5 mmol) in methanol (20 ml) was added sodium cyanoborohydride (0.56 g, 9 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was then evaporated in vacuo and to the resulting residue was added saturated sodium carbonate solution and toluene (50 ml each). The organic layer was separated, dried (MgSO4) and evaporated in vacuo to yield a semisolid residue (2.0 g) which was treated with light petroleum. A colourless powder was isolated by filtration (1.0 g) which melted at 113°-115° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[C:30](=O)([O:36]N1C(=O)CCC1=O)[O:31][CH2:32][CH:33]1[CH2:35][CH2:34]1>ClCCl.[NH4+].[Cl-]>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:30]([O:31][CH2:32][CH:33]3[CH2:35][CH2:34]3)=[O:36])[CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCNCC2)nc1
Reactant: O=C(OCC1CC1)ON1C(=O)CCC1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCC3CC3)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 5-(methylsulfonyl)-2-(2-((1S,2R)-2-(piperidin-4-yl)cyclopropyl)ethoxy)pyridine (Step A, Example 11; 0.30 g, 0.93 mmol) in dichloromethane (4.6 mL) under a nitrogen atmosphere was added triethylamine (0.36 mL, 2.6 mmol) and cyclopropylmethyl 2,5-dioxopyrrolidin-1-yl carbonate (0.35 g, 1.67 mmol). The resulting solution was stirred for 18 h at ambient temperature. The solution was diluted with saturated NH4Cl(aq.) (10 mL). The resulting layers were separated and the aqueous phase extracted with dichloromethane (2×30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification of the obtained residue by CombiFlash chromatography (12 g silica gel, 0 to 25% EtOAc in heptane) provided the title compound as an off white semi-solid: 1H NMR (500 MHz, CDCl3) δ 8.72 (d, J=2.0 Hz, 1 h), 8.03 (m, 1H), 6.84 (d, J=8.5 Hz, 1H), 4.49 (m, 2H), 4.15 (m, 2H), 3.90 (d, J=7.0 Hz, 2H), 3.07 (s, 3H), 2.80-2.68 (m, 2H), 2.10 (m, 1H), 1.75 (m, 2H) 1.52 (m, 1H), 1.37-1.29 (m, 2H), 1.13 (m, 1H), 1.01-0.87 (m, 2H), 0.70-0.53 (m, 4H), 0.27 (m, 2H), −0.11 (q, J=5.0 Hz, 1H); MS (ESI) m/z 423 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](=[O:12])[CH3:11])=[CH:7][C:6]=2[CH:13]=1.[CH2:14]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[CH2:14]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:1][C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([C:10](=[O:12])[CH3:11])=[CH:7][C:6]=3[CH:13]=2)=[CH:19][CH:18]=1)[CH3:15]
Reactant: CCOc1ccc(CCl)cc1
Reactant: CC(=O)c1cc2cc(O)ccc2o1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(COc2ccc3oc(C(C)=O)cc3c2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 163.5 %

Procedure:
To a solution of 1-(5-hydroxy-1-benzofuran-2-yl)ethanone (2.40 g, 13.7 mmol) in anhydrous DMF (1 mL) were added 4-ethoxybenzyl chloride (2.81 g, 16.5 mmol) and potassium carbonate (3.78 g, 27.4 mmol) and the mixture was stirred at 50° C. overnight. Saturated brine was added thereto, and the mixture was extracted three times with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 1-{5-[(4-ethoxybenzyl)oxy]-1-benzofuran-2-yl}ethanone (6.95 g). This was directly used for the next reaction.