Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1([CH2:30][CH2:31][CH2:32][CH3:33])[C:17]2[CH:16]=[C:15]([C:18]#[C:19]C(C)(O)C)[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][C:8]([C:24]#[C:25]C(C)(O)C)=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4].[OH-].[K+]>C1(C)C=CC=CC=1.CC(O)C>[C:24]([C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[C:17](=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=3)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:30][CH2:31][CH2:32][CH3:33])[C:6]=2[CH:7]=1)#[CH:25]
Reactant: CCCCC1(CCCC)c2cc(C#CC(C)(C)O)ccc2-c2ccc(C#CC(C)(C)O)cc21
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: C#Cc1ccc2c(c1)C(CCCC)(CCCC)c1cc(C#C)ccc1-2
Yield: 70.4 %

Procedure:
To a solution of 4,4′-(9,9-dibutyl-9H-fluorene-2,7-diyl)bis(2-methyl-3-butyn-2-ol) (1.04 g, 2.35 mmol) in 20 mL of toluene/i-PrOH (3/1), was added solid KOH (0.39 g). The mixture was heated under reflux for 0.5 h. After cooling, KOH was filtered off and the solvents were evaporated and the residue was purified by column chromatography (heptane/CH2Cl2 70:30 then 20:80) to yield 0.54 g (71%) of 2,7-diethynyl-9,9-dibutyl-9H-fluorene: 1H NMR (200.13 MHz, CDCl3) δ 7.63 (d, J=8.6 Hz, 2H), 7.48 (d, J=8.6 Hz, 2H), 7.46 (s, 2H), 3.15 (s, 2H), 1.94 (m, 4H), 1.07 (m, 4H), 0.67 (t, J=7.2 Hz, 6H), 0.54 (m, 4H); 13C NMR (50.32 MHz, CDCl3) δ 151.0, 140.9, 131.2, 126.5, 120.8, 119.9, 84.5, 77.4, 55.1, 40.0, 25.8, 22.9, 13.7; HRMS (EI) calcd for C25H26 (M+·) m/z 326.2035. found 326.2036. Anal. Calcd for C25H26 (326.48): C, 91.97; H, 8.03. Found: C, 92.17; H, 8.07.
Reaction SMILES: CC([O:4][CH2:5][C:6]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][O:21][C:22]([CH3:24])=[O:23])=C2C=1C=CC=C2)=O.Cl>O>[OH:21][CH2:20][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]1[CH2:18][CH2:19][CH2:6][C:5]1=[O:4].[C:22]([O:21][CH2:20][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]1[CH2:18][CH2:19][CH2:6][C:5]1=[O:4])(=[O:23])[CH3:24]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: Cl
Solvent: O
Product: CC(=O)OCCCCCC1CCCC1=O
Product: O=C1CCCC1CCCCCO

Procedure:
A mixture of 4,500 g. (16.2 moles) of 2-(5-acetoxypentyl)-2-carbomethoxy/carboethoxy-cyclopentanone (Example 54), 2.2 l. of glacial acetic, 1 l. of concentrated hydrochloric acid, and 1 l. of water is refluxed for 18 hours, cooled, and partitioned between saturated brine and benzene. The organic phase is washed with saturated brine, dried (MgSO4), and evaporated in vacuo to yield 3155 g. of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[C:4](=[O:15])[C:3]=1[C:16]#[N:17].[Br:18]N1C(=O)CCC1=O>CN(C)C=O.O>[Br:18][C:7]1[C:2]([Cl:1])=[C:3]([C:16]#[N:17])[C:4](=[O:15])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1-n1ccc(Cl)c(C#N)c1=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1-n1cc(Br)c(Cl)c(C#N)c1=O
Temperature: 50 °C
Yield: 81.3 %

Procedure:
To a solution of 4-chloro-1-(2-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step D of Example 1 (4.00 g) in N,N-dimethylformamide (33 mL) was added N-bromosuccinimide (3.49 g) at 50° C. The reaction mixture was heated at 50° C. for 6 hr, cooled to room temperature, and diluted with water. The resulting solid was collected by filtration, and washed with acetonitrile. The solid was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.30 g).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[CH3:20][NH2:21]>O1CCCC1.O>[F:1][C:2]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH:21][CH3:20])=[O:10])[CH2:6]1
Reactant: O=C(Cl)N1CC(Oc2cc(C(F)(F)F)ccc2F)C1
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1CC(Oc2cc(C(F)(F)F)ccc2F)C1
Reaction time: 16 h
Yield: 79.8 %

Procedure:
A stirred solution of 4.5 g (0.015 mol) of 3-[2-fluoro-5-(trifluoromethyl)phenoxyl]-1-azetidinecarbonyl chloride in 20 mL of tetrahydrofuran was treated with 4.0 g (0.05 mol) of 40% aqueous monomethylamine. After stirring for 16 h the reaction mixture was diluted with 200 mL of water and the oil which separated slowly solidified. The solids were collected by filtration (3.9 g) and recrystallized from benzene/ligroin, yielding 3.5 g (79.8%) of white crystals, mp 93.5°-95° C.
Reaction SMILES: O.C(O[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([CH:15]=[O:16])=[O:14])CCC.[CH3:17][C:18]([NH2:30])([CH3:29])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]2[O:26][CH2:27][O:28][C:22]=2[CH:21]=1>CS(C)=O>[CH3:29][C:18]([N:30]=[C:15]([O:16][CH2:12][CH2:7][CH2:8][CH3:9])[C:13]([C:8]1[CH:7]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:14])([CH3:17])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]2[O:26][CH2:27][O:28][C:22]=2[CH:21]=1
Reactant: CC(C)(N)Cc1ccc2c(c1)OCO2
Reactant: CCCCOc1ccccc1C(=O)C=O
Solvent: CS(C)=O
Solvent: O
Product: CCCCOC(=NC(C)(C)Cc1ccc2c(c1)OCO2)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 700 mg of 2-n-butoxyphenylglyoxal hydrate, 500 mg of α,α-dimethyl-3,4-methylenedioxyphenethylamine and 1.5 ml of dimethylsulfoxide is stirred at room temperature for 45 minutes, whereby a solution of α-(α,α-dimethyl-3,4-methylenedioxyphenethylimino)-2-n-butoxyacetophenone in dimethylsulfoxide is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1I)[C:15]#[N:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][OH:29].[C]=O.CN(C)[CH:34]=[O:35]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15]#[N:16])[CH:17]=[CH:18][C:19]=1[C:28]([O:35][CH3:34])=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(C#N)ccc1I
Reactant: CO
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#N)cc1OCCNC(=O)OC(C)(C)C

Procedure:
5 g (12.88 mmol) of 3-(2-(t-butoxycarbonylamino)ethoxy)-4-iodobenzonitrile was dissolved in 60 ml of N,N-dimethylformamide (dehydrated). 3.6 ml (25.8 mmol) of triethylamine, 10 ml (25.8 mmol) of methanol and 145 mg (0.644 mmol) of palladium acetate were added to the obtained solution, and they were stirred in the presence of carbon monoxide at 90° C. for 6 hours. The solvent was evaporated. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: C(O)(C)C.[BH4-].[Na+].[CH:7]([CH:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][CH2:11][C:12](OC)=[O:13])=[O:8].Cl>O.CC(C)=O>[CH2:16]([CH:9]([CH2:10][CH2:11][CH2:12][OH:13])[CH2:7][OH:8])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCC(C=O)CCC(=O)OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCC(CO)CCCO
Temperature: 5 °C
Reaction time: 29 h
Yield: 71.2 %

Procedure:
390.0 g of isopropanol and 22.4 g (0.59 mol) of sodium borohydride are placed in a one-liter round-bottomed flask with a magnetic stirrer, a thermometer and an addition funnel. 148.4 g (0.59 mol) of 91% methyl 4-formylundecanoate (6) are added dropwise over one hour. The temperature in the bulk rises to 35° C. during the addition. The addition is continued for 29 hours, while allowing the temperature in the bulk to return to room temperature (about 20° C.). After cooling the reaction medium to 5° C., 8.6 g of acetone are added, without exceeding 10° C. in the bulk. The reaction medium is again cooled to 5° C. and 240.0 g of hydrochloric acid are added over one hour, without exceeding 10° C. in the bulk. 250.0 g of water are added to facilitate the separation of the phases. The aqueous phase is extracted twice with 200 ml of toluene. The organic phases are combined and are washed once with 100.0 ml of water and once with 100 ml of brine. The resulting organic phase is dried over magnesium sulfate and filtered. The solvent is evaporated off under reduced pressure (3990 Pa) without exceeding 50° C. in the bulk. 118.0 g (0.42 mol) of 72% 2-heptylpentane-1,5-diol (10) are obtained, and are used directly in the cyclization step.
Reaction SMILES: S(O)(O)(=O)=O.C[NH:7][C:8](=[NH:11])[NH:9][CH3:10].[Na].C[O:14][C:15](=O)[CH2:16][C:17]([CH2:19][S:20][CH2:21][CH3:22])=O.[CH2:24](O)C>>[CH3:10][N:9]([CH3:24])[C:8]1[N:11]=[C:17]([CH2:19][S:20][CH2:21][CH3:22])[CH:16]=[C:15]([OH:14])[N:7]=1
Reactant: CCO
Reactant: CNC(=N)NC
Reactant: CCSCC(=O)CC(=O)OC
Agent: O=S(=O)(O)O
Agent: [Na]
Product: CCSCc1cc(O)nc(N(C)C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
47.9 g of dimethylguanidine sulfate was added in portions, at room temperature, to a solution of 8.1 g of sodium in 300 ml of abs. ethanol. The mixture obtained was stirred for one hour at room temperature, and was subsequently refluxed for a further 30 minutes. After cooling, there was added dropwise 62.0 g of γ-ethylmercaptoacetoacetic acid methyl ester, and the resulting reaction mixture was refluxed for 24 hours. The reaction mixture obtained was cooled and subsequently poured into ice/water, and the pH was adjusted to 7. After extraction of the reaction mixture with methylene chloride, the organic phase was dried over Na2SO4 ; the solvent was then distilled off, and the resulting crude product was recrystallised from water to thus yield 2-dimethylamino-4-ethylmercaptomethyl-6-hydroxy-pyrimidine in the form of colourless crystals having a melting point of 119°-121° C.
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[C:15]([O:19][C:20]([NH:22][C@H:23]1[CH2:28][O:27][CH:26]([CH2:29][C@@H:30]2[O:45][C:33]3[CH:34]=[N:35][C:36]4[CH:37]=[CH:38][C:39]([O:43][CH3:44])=[C:40]([F:42])[C:41]=4[C:32]=3[CH:31]2OC(=O)C)[CH2:25][CH2:24]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:15]([O:19][C:20](=[O:21])[NH:22][C@@H:23]1[CH2:24][CH2:25][C@@H:26]([CH2:29][CH:30]2[O:45][C:33]3[CH:34]=[N:35][C:36]4[CH:37]=[CH:38][C:39]([O:43][CH3:44])=[C:40]([F:42])[C:41]=4[C:32]=3[CH2:31]2)[O:27][CH2:28]1)([CH3:16])([CH3:18])[CH3:17]
Reactant: COc1ccc2ncc3c(c2c1F)C(OC(C)=O)[C@H](CC1CC[C@@H](NC(=O)OC(C)(C)C)CO1)O3
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc2ncc3c(c2c1F)CC(C[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)CO1)O3
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.8 %

Procedure:
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (833 mg, 3.67 mmol, 5.0 eq) is added at room temperature to a stirred solution of acetic acid 2-(2S,5R)-(5-tert-butoxycarbonylamino-tetrahydro-pyran-2-ylmethyl)-9-fluoro-8-methoxy-1,2-dihydro-furo[2,3-c]quinolin-1-yl ester (360 mg, 0.73 mmol, 1.0 eq) in toluene (60 mL). After 2 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×100 mL) and a saturated sodium carbonate aqueous solution (100 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: n-hexane:ethyl acetate, 10:1 to 1:1, v/v) to afford (3R,6S)-[6-(9-fluoro-8-methoxy-1,2-dihydro-furo[2,3-c]quinolin-2-ylmethyl)-tetrahydro-pyran-3-yl]-carbamic acid tert-butyl ester as a light yellow solid (75 mg, 24% yield).
Reaction SMILES: [C:1]([C:5]1[C:6]([O:34][CH3:35])=[C:7]([CH:23]=[C:24]([N:26]2[CH:31]=[CH:30][C:29](=[O:32])[NH:28][C:27]2=[O:33])[CH:25]=1)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][C:11]=1[CH2:21]O)([CH3:4])([CH3:3])[CH3:2].I([C:39]1[CH:47]=CC=[CH:44][C:40]=1[C:41](O)=O)(=O)=O.CC([N:51](C)C)=O>>[C:1]([C:5]1[C:6]([O:34][CH3:35])=[C:7]([CH:23]=[C:24]([N:26]2[CH:31]=[CH:30][C:29](=[O:32])[NH:28][C:27]2=[O:33])[CH:25]=1)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][C:11]=1[CH2:21][NH:51][CH2:47][CH2:39][CH:40]([CH3:44])[CH3:41])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(=O)N(C)C
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2CO)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Reactant: O=C(O)c1ccccc1I(=O)=O
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2CNCCC(C)C)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of the product from Example 28 (0.60 g, 1.20 mmol) in anhydrous DMA (15 ml) was added 2-iodoxybenzoic acid (336 mg, 1.20 mmol). The mixture was stirred at room temperature for 1 h, and then partitioned between EtOAc (20 ml) and H2O (2×20 ml). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 2% MeOH in CH2Cl2 as the eluent to give the title compound as a colorless solid (395 mg, 66%). 1H NMR (300 MHz, DMSO-d6) δ ppm 11.43 (d, J=2.21 Hz, 1 H) 10.45 (s, 1 H) 10.15 (s, 1 H) 8.06 (d, J=16.18 Hz, 1 H) 7.97 (d, J=8.82 Hz, 1 H) 7.73-7.78 (m, 2 H) 7.69 (d, J=2.57 Hz, 1 H) 7.51 (dd, J=8.64, 2.39 Hz, 1 H) 7.30 (d, J=16.18 Hz, 1 H) 7.26 (d, J=2.57 Hz, 1 H) 5.66 (dd, J=7.72, 2.21 Hz, 1 H) 3.81 (s, 3 H) 3.07 (s, 3 H) 1.39 (s, 9 H).
Reaction SMILES: [O:1]=[C:2]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]3[NH:28][N:27]=[N:26][N:25]=3)[CH:22]=2)[O:17][C:4]2([CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]2)[CH2:3]1.[ClH:29]>CO>[ClH:29].[NH:28]1[C:24]([C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[O:17][C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3][C:2]3=[O:1])=[N:25][N:26]=[N:27]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(-c3nnn[nH]3)ccc1O2
Agent: Cl
Solvent: CO
Product: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21

Procedure:
A mixture of 5-bromo-2-hydroxyacetophenone (104.35 g, 485.26 mmol), N-Boc-piperidin-4-one (98.62 g, 494.96 mmol), 20 mL of pyrrolidine (17.26 g, 242.63 mmol) and 261 mL of MeOH was heated under reflux until the reaction was complete. The mixture was cooled, then 87 mL of H2O were added, and the mixture was filtered and dried to give tert-butyl 6-bromo-4-oxospiro-[chroman-2,4′-piperidine]-1′-carboxylate. Alternatively, 10 mL of pyrrolidine (121.31 mmol) may be used in this procedure. To a solution of tert-butyl 6-bromo-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (6593 g, 16.6 mol) and DMF (33 L) was added Zn(CN)2 (1947 g, 16.6 mol) and Pd(PPh3)4 (192 g, 0.17 mol). The slurry was heated to 90° C. for 3 hours, then cooled to room temperature and filtered. Water (16 L) was added to the filtrate. The resulting slurry was cooled to 5° C., stirred for 1 hour and filtered. The solid was washed with DMF/water (2:1) and dried under vacuum to give tert-butyl 6-cyano-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate. A solution of 23 g of tert-butyl 6-cyano-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (67.17 mmol), 13.10 g sodium azide (201.52 mmol), 27.74 g of triethylamine hydrochloride (201.52 mmol), and 460 mL of dry DMF was stirred under a nitrogen atmosphere at 100° C. for 12 hours. After cooling to room temperature, 506 mL of EtOAc were added, followed by 322 mL of 1M HCl (322 mmol). Alternatively, 0.5M HCl maybe added until pH=3. The resulting layers were separated, the organic layer was washed with water/methanol (115 mL/46 mL), and then concentrated to give tert-butyl 4-oxo-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-1′-carboxylate. A solution of 5.08 g of tert-butyl 4-oxo-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-1′-carboxylate (13.18 mmol), 8.8 mL of 12 M HCl (105.44 mmol) and 8 mL of methanol was heated to 50° C. until the reaction was complete. The resulting slurry was filtered, washed with 25 mL of methanol at room temperature, and dried to give 6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-4-one hydrochloride salt.
Reaction SMILES: CN(C)[C:3](=[CH:9][CH:10]=[C:11]([S:26][CH3:27])[C:12](=[O:25])[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.C([OH:32])C>>[OH:32][C:3](=[CH:9][CH:10]=[C:11]([S:26][CH3:27])[C:12](=[O:25])[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCO
Reactant: CCOC(=O)C(=CC=C(SC)C(=O)c1ccc(N2CCCCC2)cc1)N(C)C
Agent: Cl
Product: CCOC(=O)C(O)=CC=C(SC)C(=O)c1ccc(N2CCCCC2)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
The procedure is as in Example 4, starting with ethyl 2-dimethylamino-5-methylthio-6-oxo-6-(4-piperidinophenyl)-2,4-hexadienoate (23.5 g) and 1N hydrochloric acid (139 cc) in ethanol (139 cc). The mixture is stirred for 16 hours at a temperature in the region of 20° C. After purification by chromatrography on a silica column with dichloromethane as eluent and a second chromatography on a second silica column with a mixture of cyclohexane and ethyl acetate (50:50 by volume) as eluents; the corresponding eluate is concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue is recrystallized in boiling isopropyl ether (100 cc). Ethyl 2-hydroxy-5-methylthio-6-oxo-6-(4-piperidinophenyl)-2,4-hexadienoate (3 g), m.p. 65° C., is thereby obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=1.[Cl-].[Cl-].[NH3+:19][C@@H:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[CH:24][NH+:23]=1)[CH3:21].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14]([NH:19][C@@H:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:31])[F:32])=[CH:24][N:23]=2)[CH3:21])=[O:16])=[CH:11][CH:12]=1
Reactant: C[C@@H]([NH3+])c1ccc(OCC(F)(F)F)c[nH+]1
Reactant: O=C(O)Cc1ccc(-c2cnccn2)cc1
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)Cc1ccc(-c2cnccn2)cc1)c1ccc(OCC(F)(F)F)cn1
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 0.10 g (0.48 mmol) (4-pyrazin-2-ylphenyl)acetic acid in 2.00 ml of CH2Cl2 was added 0.17 g (0.58 mmol) of 2-[(1R)-1-ammonioethyl]-5-(2,2,2-trifluoroethoxy)pyridinium dichloride, 0.085 g (0.63 mmol) of HOAt, 0.12 g (0.63 mmol) of EDC, and 0.25 mL (1.44 mmol) of DIEA. After 1 h at room temperature, the reaction mixture was diluted with CH2Cl2, washed three times with water, and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, linear gradient 50-100% EtOAc in hexanes) afforded 0.14 g (70%) of 2-(4-pyrazin-2-ylphenyl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide. 1H NMR (CD3OD, 400 MHz) 9.09 (d, J=1.46 Hz, 1H); 8.65 (t, J=1.74 Hz, 1H); 8.51 (d, J=2.57 Hz, 1H); 8.26 (d, J=3.02 Hz, 1H); 8.03 (d, J=8.15 Hz, 2H); 7.46 (d, J=8.15 Hz, 2H); 7.43 (dd, J=3.02, 8.70 Hz, 1H); 7.30 (d, J=8.70 Hz, 1H); 5.03 (quintet, J=6.96 Hz, 1H); 4.62 (q, J=8.34 Hz, 2H); 3.64 (s, 2H); 1.46 (d, 3H, J=6.96 Hz). HRMS (ES) [M+1]+calcd for C21H20F3N4O2: 417.1538, Found: 417.1523. FLIPR alpha1I IP=30 nM.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][CH:5]=1.CN(CCN(C)C)C.C([Li])(CC)C.C1CCCCC1.C1C[O:42][CH2:41]C1>CN(C)C=O>[CH:41]([C:6]1[CH:5]=[C:4]([O:3][C:2]([F:18])([F:19])[F:1])[CH:9]=[CH:8][C:7]=1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:42]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CN(C)C=O
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A magnetically stirred solution of tert-butyl 4-(trifluoromethoxy)phenylcarbamate (19.95 g, 72 mmol) and TMEDA (16.7 g, 144 mmol) in THF (300 mL) at −78° C. was treated with the dropwise addition of a 1.4M solution of sec-butyllithium in cyclohexane (170 mL, 237 mmol), at a rate which maintained the internal temperature below −60° C. The mixture was stirred for 1 h at −78° C., then allowed to warm to −50° C. and stirred an additional 30 min. The solution was returned to −78° C., treated with the dropwise addition of N,N-dimethylformamide, at a rate which maintained the internal temperature below −60° C. The reaction was stirred at −78° C. for 30 min, allowed to warm to −20° C., then quenched with the addition of saturated ammonium chloride solution (200 mL). The mixture was transferred to a 1 L seperatory funnel, diluted with diethyl ether (400 mL), and the layers were separated. The organic phase was washed successively with saturated ammonium chloride solution (100 mL), water (100 mL), and brine (100 mL), dried over sodium sulfate, and concentrated in-vacuo to a yellow solid. The solid was purified over silica gel, eluting with 5% ethyl acetate/hexanes, to yield 18.36 g of a colorless solid as product. 1H NMR (400 MHz, CDCl3) δ ppm 1.55 (m, 9 H) 7.26 (s, 4 H) 7.43 (dd, J=9.23, 2.64 Hz, 6 H) 7.48 (s, 1 H) 8.54 (d, J=9.23 Hz, 1 H) 9.88 (s, 1 H) 10.33 (s, 1 H).
Reaction SMILES: C([O:4][C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[CH2:13][CH2:12]2)[N:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)C=C.N#N>C(O)CC.[Rh](Cl)(Cl)Cl>[CH2:25]([O:24][C:6]1[C:5](=[O:4])[NH:10][C:9]([N:11]2[CH2:12][CH2:13][CH:14]([CH2:17][OH:18])[CH2:15][CH2:16]2)=[N:8][C:7]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C=CCOc1nc(N2CCC(CO)CC2)nc(C(=O)OCC)c1OCc1ccccc1
Agent: Cl[Rh](Cl)Cl
Agent: N#N
Solvent: CCCO
Product: CCOC(=O)c1nc(N2CCC(CO)CC2)[nH]c(=O)c1OCc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
A solution of ethyl 6-(allyloxy)-5-(benzyloxy)-2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidine-4-carboxylate (1.206 g, 2.82 mmol) in n-propanol (10 mL) was sparged with N2. Rhodium(III) chloride (0.030 g, 0.141 mmol) was added and the resulting mixture was stirred overnight at 100° C. The mixture was cooled to room temperature and partitioned between water and CH2Cl2. The organic phase was dried (Na2SO4), filtered and concentrated to give a yellow solid that was triturated with Et2O. The product was collected by filtration to give the title compound as a white solid (0.8252 g, 76% yield). 1H NMR (300 MHz, CDCl3) δ: 7.43 (2H, d, J=7.3 Hz), 7.37-7.29 (3H, m), 5.05 (2H, s), 4.46 (2H, d, J=13.1 Hz), 4.31 (2H, q, J=7.1 Hz), 3.44 (2H, d, J=5.8 Hz), 2.94-2.88 (2H, m), 1.74 (2H, d, J=13.1 Hz), 1.73-1.66 (1H, m), 1.29 (3H, t, J=7.2 Hz), 1.28-1.22 (2H, m). LCMS (M+H) calcd for C20H26N3O5: 388.18; found: 388.23.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:18][CH2:17][N:16](CC3C=CC=CC=3)[CH2:15][CH2:14]2)[CH2:9][CH2:8]1)=[O:6])[CH3:3]>[OH-].[OH-].[Pd+2]>[CH3:3][C:2]([CH3:26])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)[CH2:9][CH2:8]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCN(Cc3ccccc3)CC2)CC1
Agent: [Pd+2]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCN(C2CCNCC2)CC1
Yield: 79.7 %

Procedure:
Prepared analogously to Example A3f) from 1-(1,1-dimethylethoxycarbonyl)-4-[1-(phenylmethyl)-4-piperidinyl]piperazine by hydrogenolysis, but using Pearlman's catalyst instead of palladium/charcoal, in a yield of 79.7% of theory.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[CH3:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18]1>ClCCl>[CH3:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]1[C:13]([C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:14]
Reactant: CC1Cc2ccccc2N1
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(-c2oncc2C(=O)N2c3ccccc3CC2C)cc1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (10 mg, 0.045 mmol) in dichloromethane (1 mL) was added 2-methylindoline (6.6 mg, 0.050 mmol, 1.1 eq.), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C20H18N2O2: 318.1368, found 318.1379.