Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6](B(O)O)=[C:5]([CH3:10])[O:4][N:3]=1.[C:11]([C:13]1([NH:16][C:17]([C@H:19]2[CH2:23][C@H:22]([S:24]([C:27]3[CH:32]=[CH:31][C:30](Br)=[CH:29][C:28]=3[C:34]([F:37])([F:36])[F:35])(=[O:26])=[O:25])[CH2:21][C@@H:20]2[O:38][CH:39]([CH3:41])[CH3:40])=[O:18])[CH2:15][CH2:14]1)#[N:12].C(C1(NC([C@H]2C[C@H](S(C3C=CC(Br)=CC=3C(F)(F)F)(=O)=O)C[C@@H]2OC)=O)CC1)#N>>[C:11]([C:13]1([NH:16][C:17]([C@H:19]2[CH2:23][C@H:22]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:10])=[CH:29][C:28]=3[C:34]([F:37])([F:35])[F:36])(=[O:26])=[O:25])[CH2:21][C@@H:20]2[O:38][CH:39]([CH3:41])[CH3:40])=[O:18])[CH2:15][CH2:14]1)#[N:12]
Reactant: CC(C)O[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Reactant: Cc1noc(C)c1B(O)O
Agent: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Product: Cc1noc(C)c1-c1ccc(S(=O)(=O)[C@@H]2C[C@H](OC(C)C)[C@@H](C(=O)NC3(C#N)CC3)C2)c(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 62 using 3,5-dimethyl-isoxazole-4-boronic acid instead of 2.4-difluorophenylboronic acid and (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-isopropoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide instead of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide. White solid. MS (EI): 538.2 (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=O)[CH2:4][CH2:3]1.[F:21][C:22]1[C:23]([CH3:30])=[C:24]([NH2:29])[C:25]([NH2:28])=[CH:26][CH:27]=1>CN(C=O)C>[F:21][C:22]1[CH:27]=[CH:26][C:25]2[N:28]=[C:16]([C:15]3[CH:18]=[CH:19][CH:20]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][CH:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH:14]=3)[NH:29][C:24]=2[C:23]=1[CH3:30]
Reactant: Cc1c(F)ccc(N)c1N
Reactant: CN1CCC(OCCCOc2cccc(C=O)c2)CC1
Solvent: CN(C)C=O
Product: Cc1c(F)ccc2nc(-c3cccc(OCCCOC4CCN(C)CC4)c3)[nH]c12
Yield: 37.8 %

Procedure:
6-Fluoro-7-methyl-2-{3-[3-(1-methyl-piperidin-4-yloxy)-propoxy]-phenyl}-1H-benzoimidazole. To a stirred solution of 3-[3-(1-methyl-piperidin-4-yloxy)-propoxy]-benzonitrile (0187 g, 0.68 mmol, 1.0 equiv) in toluene (5.0 mL) at 0° C. was added 1.5 M diisobutylaluminum hydride in toluene (1.02 mL, 1.02 mmol, 1.5 equiv). After 3 h, methanol (9 mL) and 1 M H2SO4 (10 mL) were added. The mixture was stirred for 30 min, then 1.0 M NaOH (10 mL) was added, followed by satd. aq. sodium potassium tartrate (40 mL) and dichloromethane (100 mL). After stirring for 30 min, the mixture was extracted three times with chloroform (50 mL) and the combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was partially purified by Method 2 to afford 106 mg of a mixture of 3-[3-(1-methyl-piperidin-4-yloxy)-propoxy]-benzaldehyde and several other unidentified products. A solution of the crude 3-[3-(1-methyl-piperidin-4-yloxy)-propoxy]-benzaldehyde (53 mg), 4-fluoro-3-methyl-benzene-1,2-diamine (27 mg), and Na2S2O5 in DMF was stirred at 90° C. for 18 h. The reaction mixture was loaded directly on silica gel and purified according to Method 2, which afforded 28.7 mg of the title compound. MS (electrospray): mass calculated for C23H28FN3O2, 397.22. m/z found, 398.4 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.64-7.53 (m, 2H), 7.38-7.25 (m, 2H), 7.00-6.85 (m, 2H), 4.06 (t, J=6.1 Hz, 2H), 3.60-3.52 (m, 2H), 3.33-3.19 (br s, 1H), 2.58 (br s, 2H), 2.42 (s, 3H), 2.17-2.03 (m, 5H), 2.01-1.90 (m, 2H), 1.86-1.72 (m, 2H), 1.60-1.42 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:12]2[CH:13]=[C:14]([CH3:20])[NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:23]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[CH2:24][CH2:25][CH3:26].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([C:11]1[C:12]2[CH:13]=[C:14]([CH3:20])[N:15]([C:32](=[O:33])[C:31]3[CH:30]=[CH:29][C:28]([O:27][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:36][CH:35]=3)[C:16]=2[CH:17]=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Reactant: Cc1cc2c(C(=O)OCc3ccccc3)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOc1ccc(C(=O)n2c(C)cc3c(C(=O)OCc4ccccc4)cccc32)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 2-methyindole-4-carboxylic acid benzyl ester (690 mg; prepared in Reference Example 11) in N,N-dimethylformamide (8 ml) was added sodium hydride (114 mg; 60%) at 0° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added 4-butoxybenzoyl chloride (0.54 ml), and the mixture was stirred at room temperature overnight. To the reaction mixture was added water and ethyl acetate, and then separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, successively, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane-ethyl acetate) to give the title compound (1.02 g) having the following physical data.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12]C(Cl)=O.[C:16](=[N:19][OH:20])([NH2:18])[CH3:17]>N1C=CC=CC=1>[CH3:17][C:16]1[N:18]=[C:12]([N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[O:20][N:19]=1
Reactant: CC(N)=NO
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Solvent: c1ccncc1
Product: Cc1noc(N2C(=O)c3ccccc3C2=O)n1
Yield: 26.6 %

Procedure:
To 4.4 g of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride in 20 ml of pyridine are added 1.48 g of acetamidoxime, and the mixture is refluxed for 1 hour. The reaction medium is concentrated and taken up in ethyl acetate and water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 7/3 (v/v) toluene/ethyl acetate mixture to give 1.2 g of expected product.
Reaction SMILES: [CH3:1]OC(OC)N(C)C.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]#[C:23][C:24]3[CH:25]=[CH:26][C:27]([O:31][CH2:32][CH2:33][N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[C:28]([NH2:30])[CH:29]=3)=[N:20][CH:21]=2)=[CH:12][CH:11]=1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]#[C:23][C:24]3[CH:25]=[CH:26][C:27]([O:31][CH2:32][CH2:33][N:34]4[CH2:35][CH2:36][CH2:37][CH2:38]4)=[C:28]([NH:30][CH3:1])[CH:29]=3)=[N:20][CH:21]=2)=[CH:12][CH:11]=1
Reactant: COC(OC)N(C)C
Reactant: Nc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
Under a nitrogen atmosphere 178 μL (1.35 mmol) N,N-dimethylformamide dimethylacetal are added to a solution of 100 mg (0.24 mmol) 5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-phenylamine in 2 mL DMF, the reaction mixture is stirred for 5 h at 60° C. and cooled to RT overnight. Then 32 mg (0.85 mmol) NaBH4 are added and the mixture is again heated to 60° C. for 1 h. To complete the reaction a further 32 mg NaBH4 are added and the mixture is heated to 60° C. for a further 4 h. After cooling it is combined with saturated NaHCO3 solution, exhaustively extracted with EtOAc and the organic phase is dried over MgSO4. After the desiccant and solvent have been eliminated the residue is purified by HPLC.
Reaction SMILES: [C:1]([C:3]1([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)#[CH:2].N1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CO>[CH2:1]([C:3]1([C:20]#[C:21][C:22]#[C:23][C:24]2([CH2:11][CH2:10][CH2:9][CH2:14][CH3:13])[CH2:30][CH2:29][CH:28]([CH:6]3[CH2:7][CH2:8][CH:3]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:4][CH2:5]3)[CH2:27][CH2:26]2)[CH2:4][CH2:5][CH:6]([CH:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]2)[CH2:7][CH2:8]1)[CH2:2][CH2:16][CH2:15][CH3:12]
Reactant: c1ccncc1
Reactant: C#CC1(CCCCC)CCC(C2CCC(CCCCC)CC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: O
Product: CCCCCC1CCC(C2CCC(C#CC#CC3(CCCCC)CCC(C4CCC(CCCCC)CC4)CC3)(CCCCC)CC2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 5.00 g of 4-ethynyl-4,4′-dipentylbicyclohexyl, 12.5 ml of pyridine, 12.5 ml of methanol and 3.635 g of copper(II) acetate monohydrate is stirred at RT for 1.5 hours and subsequently heated at the boil. The mixture is stirred for 10 hours and subjected to conventional work-up, giving 4-[4-(4,4′-dipentylbicyclohexyl-4-yl)buta-1,3-diynyl]-4,4′-dipentylbicyclohexyl (C 77 SmB 198 I, Δn=0.013, Δε=−0.27).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].Cl.[CH:14]([N:17]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:19][CH2:20]Cl)([CH3:16])[CH3:15]>>[CH:14]([N:17]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:19][CH2:20][N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=2)[C:5](=[O:12])[C:6]1=[O:11])([CH3:16])[CH3:15]
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: CC(C)N(CCCCl)C(C)C
Agent: Cl
Product: Cc1ccc2c(c1)C(=O)C(=O)N2CCCN(C(C)C)C(C)C

Procedure:
By using 5-methylisatin and 3-diisopropylaminopropyl chloride hydrochloride, a method analogous to that described in Reference Example 1 was carried out to obtain 1-(3-diisopropylaminopropyl)-5-methylisatin having a melting point of 87°-89° C. (yeld: 53.3%).
Reaction SMILES: C([N:4]([C:15](=[O:17])[CH3:16])[C:5]1[NH:6][C:7](=[O:14])[C:8]2[NH:9][CH:10]=[N:11][C:12]=2[N:13]=1)(=O)C.[C:18]([O:21][CH:22]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[CH2:23][O:24][CH2:25]OC(=O)C)(=[O:20])[CH3:19].C(S(O)(=O)=O)C>>[C:15]([NH:4][C:5]1[NH:6][C:7](=[O:14])[C:8]2[N:9]=[CH:10][N:11]([CH2:25][O:24][CH2:23][CH:22]([O:21][C:18](=[O:20])[CH3:19])[CH2:30][O:31][C:32](=[O:34])[CH3:33])[C:12]=2[N:13]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)N(C(C)=O)c1nc2nc[nH]c2c(=O)[nH]1
Reactant: CC(=O)OCOCC(COC(C)=O)OC(C)=O
Agent: CCS(=O)(=O)O
Product: CC(=O)Nc1nc2c(ncn2COCC(COC(C)=O)OC(C)=O)c(=O)[nH]1
Reaction time: 0.75 h

Procedure:
A mixture of 2.61 g (11.1 mmole) of diacetylguanine (VII), 5.50 g (22.2 mmole) of acetoxymethyl 2,3-diacetoxy-1-propyl ether from Step A above and 55 mg of ethanesulfonic acid was heated in a flask fitted with a distillation adapter under low vacuum in an oil bath at 155°-160°. The mixture gradually thinned enough to permit magnetic stirring, and some distillate was collected. The mixture became homogenous after about 45 minutes and was cooled after 75 minutes. The viscous oil as taken up in about 100 ml of ethyl acetate and induced to crystallize with a yield of 1.23 g (29%) of nearly white crystals, mp 162.5°-165°. Thin layer chromatography (TLC) (9:1 CHCl3 --CH3OH) showed a single spot.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:13][C:14]([OH:16])=O)[CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1>O>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([C:14](=[O:16])[CH2:13][CH:8]2[CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CC(CC(=O)O)c1cccc(F)c1
Solvent: O
Product: O=C(O)CC1CC(=O)c2ccc(F)cc21
Temperature: 120 °C
Yield: 87.2 %

Procedure:
Polyphosphoric acid (39.6 g, Aldrich) and 3-(3-fluorophenyl)glutaric acid (6.6 g, 0.0292 mol) were combined and the mixture heated with an oil bath at 120° C. for 10 min. The now red solution was cooled to approximately 60° C. and water (approximately 100 ml) was added dropwise, with efficient stirring. The resulting precipitate was collected and washed with water. Recrystallization from dichloromethane and hexanes gave 5.3 g (87%) of 2-(6-fluoro-3-oxo-1-indanyl)acetic acid: m.p., 150°-151° C.;
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][C:10]([NH2:29])([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]1(=[O:36])[O:35][C:33](=[O:34])[CH2:32][CH2:31]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([CH2:8][CH2:9][C:10]([NH:29][C:30]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:36])([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CCC(N)(CCC(=O)OC(C)(C)C)CCC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCC(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)NC(=O)CCC(=O)O
Reaction time: 0.25 h
Yield: 64.2 %

Procedure:
To a solution of amine 72 (513 mg, 1.23 mmol) in CH2Cl2 (6.2 mL) was added succinic anhydride (135 mg, 1.35 mmol) and DMAP (8 mg, 0.062 mmol). The mixture was stirred for 6 h 15 min and concentrated to dryness. The crude product was purified by flash chromatography on a Biotage™ flash chromatography system, using a gradient of 50-100% EtOAc in CH2Cl2 as eluent to yield acid 73 (407 mg, 64%) as a white foam: 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 27H), 1.97-2.01 (m, 6H), 2.23-2.26 (m, 6H), 2.47-2.51 (m, 2H), 2.65-2.68 (m, 2H), 6.83 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=2)[O:17][CH2:18][C:19]([OH:21])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=CC(S(NCCC2C=C(C=CC=2)OCCCC(O)=O)(=O)=O)=CC=1.C(C1NC=CN=1)(C1NC=CN=1)=O.C1C([N+]([O-])=O)=CC=C(O)C=1.[CH2:73]([NH2:80])[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1>>[CH2:73]([NH:80][C:19](=[O:21])[CH2:18][O:17][C:16]1[CH:22]=[CH:23][CH:24]=[C:14]([CH2:13][CH2:12][NH:11][S:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])[CH:15]=1)[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1
Reactant: Cc1ccc(S(=O)(=O)NCCc2cccc(OCC(=O)O)c2)cc1
Reactant: NCc1ccccc1
Agent: O=C(O)CCCOc1cccc(CCNS(=O)(=O)c2ccc(Cl)cc2)c1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: O=[N+]([O-])c1ccc(O)cc1
Product: Cc1ccc(S(=O)(=O)NCCc2cccc(OCC(=O)NCc3ccccc3)c2)cc1
Temperature: 40 °C

Procedure:
To a 40° C. warm mixture of 10.0 g (28.6 mmol) 3-[2-(4-methylphenylsulphonylamino)-ethyl]-phenoxyacetic acid and 100 ml abs. THF one adds 4.64 g (28.6 mmol) carbonyl-bisimidazole and allows to react for 10 min. 0.4 g (28.6 mmol) p-nitrophenol are then added thereto. After 10 min. one adds thereto 3.1 g (28.6 mmol) benzylamine and stirs fortwo hrs. at 60° C. Subsequently, THF is distilled off, the residue mixed with ice and dil. HCl and shaken out with methylene chloride. One extracts the organic phase twice with NaHCO3 solution and once with water. After drying with MgSO4, it is evaporated and recrystallised (ethanol). Yield 10.2 g (81% of theory); m.p. 118°-120° C.
Reaction SMILES: [C:1]([CH2:3]C(O)=O)#[N:2].[N+:7]([C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1)([O-:9])=[O:8].C([O-])(=O)C.[NH4+].C1(C)C=CC=CC=1>N1C=CC=CC=1>[N+:7]([C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH:3][C:1]#[N:2])=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: N#CCC(=O)O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: N#CC=Cc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of cyanoacetic acid (12.76 g, 150.0 mmol), 4-nitrobenzaldehyde (24.60 g, 162.8 mmol), ammonium acetate (500 mg), toluene (140 mL), and pyridine (75 mL) is refluxed for 64 hours in a flask fitted with a Dean-Stark trap and condenser. After evaporation of the solvents, a solution of the residue in CHCl3 is filtered and washed with H2 O. The dried (Na2SO4) organic layer is evaporated, and the bright yellow-orange solid is recrystallized from benzene. The yellow solid 3-(4-nitrophenyl)-acrylonitrile, obtained as a mixture of cis-trans isomers, is suitable for use as an intermediate without further purification.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(NC1C=CC(S([N:27]=[N+:28]=[N-])(=O)=O)=CC=1)=O.C1CCN2C(=NCCC2)CC1>CC#N>[N+:27](=[C:9](/[CH:8]=[CH:7]/[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:10]([O:12][CH3:13])=[O:11])=[N-:28]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: COC(=O)C/C=C/c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)C(/C=C/c1ccccc1)=[N+]=[N-]
Temperature: 25 °C
Yield: 80.1 %

Procedure:
Methyl (E)-2-diazo-4-phenyl-3-butenoate (9) was prepared according to the procedure described in Davies, et al., J. Org. Chem., 56:3817 (1997) (“Davies II”), which is hereby incorporated by reference). The scheme is set forth in FIG. 7B. Briefly, to a stirred solution of methyl trans-4-phenylbut-3-enoate (1.0 g, 5.68 mmol) and p-ABSA (1.64 g, 6.82 mmol) in CH3CN (150 mL) cooled to 0° C., was added DBU (0.95 g, 6.25 mmol) in one portion. The reaction mixture was allowed to warm to room temperature over 7 h then quenched with saturated ammonium chloride (NH4Cl). The aqueous layer was extracted with diethyl ether, and the combined organic layers were washed with brine and dried (Na2SO4). The solvent was removed under reduced pressure, and the residue was triturated with a solution of pentane/diethyl:ether (1:1). The solid was filtered off, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (SiO2, pentane/diethyl:ether (15:1)) to give methyl (E)-2-diazo-4-phenyl-3-butenoate (9) (0.92 g, 80% yield) as an orange oil, which was stored neat at −10° C. until ready for use. The spectroscopic data are consistent with previously reported data ((Davies II, which is hereby incorporated by reference).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1)=[O:3].N1C=CC=CC=1.[C:19](O)(=[O:21])[CH3:20]>C1COCC1>[C:19]([O:10][C:9]1[CH:11]=[CH:12][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=1[O:7][CH3:8])(=[O:21])[CH3:20]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: CC(=O)O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cc(C(C)=O)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
As shown in the above-described reaction formula, acetovanillone (500 mg, 3 mM) dissolved in 20 ml of THF was mixed with 0.5 ml of pyridine and 0.6 ml of anhydrous acetic acid. The mixture was stirred for 3 hours at room temperature. The resulting product was recovered with the extraction with diethylether and dried with anhydrous magnesium sulfate to remove remaining solvent. The remaining residue was performed to Silica gel column chromatography with a mobile phase (n-hexane:ethylacetate=4:1) to obtain white solid type of 4-acetyl-2-methoxyphenyl acetate (1; 625 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][NH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[CH:24]([NH:27][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([NH:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: Cc1onc(-c2ccccc2)c1CNc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1CNc1ccc(C(=O)NC(C)C)cn1
Yield: 82 %

Procedure:
As described for example 162b, 6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-nicotinic acid (200 mg, 0.65 mmol) was converted using isopropylamine instead of ethanolamine to the title compound (SiO2, heptane:ethyl acetate=50:50 to 0:100, 185 mg, 82%) which was obtained as a white solid. MS: m/e=351.3 [M+H]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12].Cl.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1>>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([C:19]1[CH:20]=[CH:21][C:16]([F:15])=[CH:17][C:18]=1[F:22])=[O:12]
Reactant: O=C(Cl)CCCCCBr
Reactant: Fc1cccc(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCCCBr)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Aluminum chloride (1.31 g) was added to a solution of 6-bromohexanoyl chloride (2 g) in 1,3-difluorobenzene (20 ml) under ice-cooling and the mixture was stirred at room temperature for 2 hr. Ice water and conc. hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 1.16 g of 6-bromo-1-(2,4-difluorophenyl)-1-hexanone.
Reaction SMILES: Cl[CH2:2][C:3]([C:5](=[N:11][O:12][CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:4].[SH:14][CH2:15][CH2:16]O.Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1.C(N(CC)CC)C>[O:4]1[C:3]([C:5](=[N:11][O:12][CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:2][S:14][CH2:15][CH2:16]1
Reactant: OCCS
Reactant: CCOC(=O)C(=NOC)C(=O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=NOC)C1=CSCCO1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 29 %

Procedure:
A solution of ethyl 2-chloroacetyl-2-methoxyiminoacetate (65 g.) in dry chloroform (130 ml.) was added to a stirred mixture of 2-mercaptoethanol (25 g.), triethylamine (35 g.) and dry chloroform (70 ml.) at 20° C. over 30 minutes, and stirred at the same temperature for 2.5 hours. After the solution was adjusted to pH 1.0 with 10% hydrochloric acid under ice cooling, the chloroform layer was separated, washed with water twice and dried over magnesium sulfate. The solution was concentrated in vacuo at 40° C. to give yellow oil. The oil was dissolved in toluene (600 ml.), and then p-toluenesulfonic acid (5.5 g.) was added to the toluene solution. The solution was heated under reflux for 2 hours while removing the produced water. The resultant solution was allowed to cool at room temperature and filtered. The filtrate was washed with water (100 ml.) three times, a saturated aqueous solution of sodium bicarbonate (100 ml.) twice and water (100 ml.) twice in turn, and then dried over magnesium sulfate. The solution was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel "Kieselgel 60" [Trademark: manufactured by E. Merck] (1 kg.) and eluted with benzene. After the eluate was concentrated under reduced pressure, the residue was washed with diisopropyl ether and dried to give ethyl 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetate (syn isomer, 21 g.), pale yellow crystals, mp. 64° to 66° C.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[NH:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)[N:19]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>CO>[ClH:1].[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]2[N:19]=[C:15]([CH:12]3[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]3)[NH:16][CH:17]=2)=[CH:21][C:22]=1[C:27]([F:28])([F:29])[F:30]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Agent: Cl
Solvent: CO
Product: Fc1ccc(-c2c[nH]c(C3CCNCC3)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Add hydrogen chloride (2 mL, 12 M aqueous) to a solution of 4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (275 mg; 665.19 μmoles) in methanol (10 mL). Stir the mixture at room temperature overnight, and then concentrate and dry to offer 210 mg (90% yield) of the title compound.