Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1C(O)=O.[O-:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:18]1([OH:24])C=CC=CC=1>O>[N:10]1[C:2]2[C:18](=[O:24])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[O:11][C:3]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: [O-]c1ccccc1
Reactant: Oc1ccccc1
Solvent: O
Product: O=c1c2ccccc2oc2cccnc12
Yield: 50 %

Procedure:
According to the invention, 2-chloronicotinic acid in alkaline metal salt form is reacted with alkaline metal phenoxide without an excess of phenol at 160°-200° C. The molten mass is partly cooled, water is added until complete solubilization, the aqueous solution is acidified and the solid obtained is dried. In the cyclization step the thus obtained 2-phenoxynicotinic acid is added portionwise to 5-10 times its weight of polyphosphoric acid which has been previously heated, the temperature is raised to 160°-200° C., the reaction mixture is cooled and diluted with water. Concentrated aqueous alkali hydroxide is added to adjust the pH to 2-3, the solid is filtered, washed, dried and recrystallized, obtaining very pure 1-azaxanthone in an overall yield of 50-70%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[NH2:23][C:24]1[C:25]([CH3:30])=[CH:26][CH:27]=[CH:28][CH:29]=1>O1CCCC1>[CH2:20]([O:19][C:17]([CH2:16][CH2:15][C:14]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30])=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH3:13])=[O:22])=[O:18])[CH3:21]
Reactant: Cc1ccccc1N
Reactant: CCOC(=O)CCC(=O)c1cnc2c(OC)cccc2c1Cl
Solvent: C1CCOC1
Product: CCOC(=O)CCC(=O)c1cnc2c(OC)cccc2c1Nc1ccccc1C
Temperature: 60 °C
Reaction time: 16 h
Yield: 83.3 %

Procedure:
In a flame-dried, three-necked round-bottomed reaction flask equipped with reflux condenser, magnetic stirring bar and addition funnel, there were placed 1.72 g (0.00535 mole) of 4-chloro-3-(3-ethoxycarbonylpropionyl)-8-methoxyquinoline (the product of Preparation C) dissolved in 15 mL of dry tetrahydrofuran. Stirring was commenced and the resulting organic solution was then treated dropwise with a solution consisting of 573 mg (0.00535 mole) of o-toluidine (available from the Aldrich Chemical Company, Inc. of Milwaukee, Wis.) dissolved in 15 mL of dry tetrahydrofuran. The resulting reaction mixture was then stirred and heated to 60° C. and thereafter kept at that temperature for a period of approximately 16 hours (i.e., overnight). Upon completion of this step, the final reaction mixture was slowly allowed to cool to ambient temperatures (ca. 20° C.) and the yellow precipitate which resulted was subsequently collected by means of suction filtration and air-dried on the filter funnel to constant weight. Recrystallization of the latter crude salt material from methylene chloride/ethyl acetate/petroleum ether then gave 1.75 g (76%) of pure 3-(3-ethoxycarbonylpropionyl)-8-methoxy-4-(2-methylphenylamino)quinoline as the hydrochloride salt, m.p. 210°-211° C. The pure product was further characterized by means of mass spectrum (MS) analysis and nuclear magnetic resonance (NMR) data, in addition to elemental analysis.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([OH:13])[CH:7]=[C:8]([O:10][CH2:11][CH3:12])[CH:9]=1)[CH3:2].Br[CH:15]([C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=1)[C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:19][O:18][C:16](=[O:17])[CH:15]([C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=1)[O:13][C:6]1[CH:7]=[C:8]([O:10][CH2:11][CH3:12])[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1
Reactant: CCOc1cc(O)cc(OCC)c1
Reactant: COC(=O)C(Br)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOc1cc(OCC)cc(OC(C(=O)OC)c2ccc(Br)cc2)c1

Procedure:
20.0 g (110 mmol) of 3,5-diethoxyphenol and 30.7 g (99.8 mmol) of methyl bromo(4-bromophenyl)acetate are dissolved in 39 ml of 2-butanone under argon at RT, and 31.0 g (225 mmol) of potassium carbonate are added. The reaction mixture is heated under RF for 4 h. After cooling, the precipitate is filtered off with suction and washed with 2-butanone, and the filtrate is concentrated. Chromatography on silica gel 60 (mobile phase: toluene) results in 33.1 g (81% of theory) of the product.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])=[CH:14][CH:13]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[O:2]1[C:6]2[CH2:7][N:8]([C:23](=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:15]3[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=3)[CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1
Reactant: c1cc2c(o1)CNCC2
Reactant: O=C(O)CCCCCc1ccc(F)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(CCCCCc1ccc(F)cc1)N1CCc2ccoc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.25 g (1.2 mmol) of 6-(4-fluorophenyl)hexanoic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to yield the desired product.
Reaction SMILES: O.Cl.[NH2:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].O1CCCC1.[C:15]([O-])(=[O:19])[CH:16]([CH3:18])[CH3:17].[Na+].Cl>O>[C:15]([NH:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6])(=[O:19])[CH:16]([CH3:18])[CH3:17]
Reactant: N[C@@H](CS)C(=O)O
Reactant: CC(C)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(=O)N[C@@H](CS)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 35.2 g (0.20 mol of L-cysteine hydrochloride monohydrate in 100 ml of a mixture of 80% of tetrahydrofuran (THF) and 20% of water was stirred under nitrogen at room temperature and treated with 44.0 g (0.40 mol of sodium isobutyrate. The reaction mixture (white slurry) was cooled to 0°-5° C. and, under nitrogen, 35 ml (0.21 mol) of isobutyryl anhydride was added dropwise. The resulting mobile suspension was stirred for 6 h at room temperature, allowed to stand overnight, and finally heated under reflux for 4 h. The reaction mixture was cooled on an ice bath and 18 ml of concentrated hydrogen chloride was added. The organic phase was evaporated to give a colourless oil. The oil was washed with hexane and thereafter treated with ether to give 12.9 g of the title compound as a white solid, mp 103°-104° C. (recrystallized from butyl acetate), [α]D25 =+23.4° C. (c 5.0 , H2O, pH=7.0), 1H-NMR (CDCl3): δ1.2 (6H, d, CH3), 1.4 (1H, t, SH), 2.5 (1H, sept, CH), 3.1 (2H, m, CH2), 4.9 (1H, dt, NCH), 6.7 (1H, d, NH), 10.6 (1H, s, OH). 13C-NMR (CDCl3): δ19, 19.5; 26.5; 36; 54, 172, 178. ms: 335 (M+ +2TMS, after silylation).
Reaction SMILES: [CH3:1][NH:2][CH3:3].O.C(O)C.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17]>C(OCC)(=O)C>[CH3:1][N:2]([CH3:3])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17]
Reactant: OCCCCCCCCBr
Reactant: CNC
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)CCCCCCCCO
Reaction time: 75 h
Yield: 91 %

Procedure:
A solution of 40% dimethylamine/water (30 mL, 26.9 g, 239 mmol) and ethanol (50 mL) was treated with a solution of 8-bromo-1-octanol (15.13 g, 72.3 mmol) and ethanol (20 mL), added dropwise over 10 minutes. The reaction mixture was stirred for 75 hours, diluted with ethyl acetate (80 mL) and washed with saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate solution (50 mL) and brine (2×40 mL), dried over sodium sulfate, and concentrated. The 11.4 g of 8-dimethylamino-1-octanol, isolated as a yellow oil, was used as is.
Reaction SMILES: B.CSC.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]=O)=[CH:8][C:7]=1[C:15]1([CH3:37])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=2)[N:17]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=2[O:34][CH3:35])[C:16]1=[O:36].Cl.CO>O1CCCC1>[Cl:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35])[C:16](=[O:36])[C:15]2([C:7]1[CH:8]=[C:9]([NH:12][CH3:13])[CH:10]=[CH:11][C:6]=1[Cl:5])[CH3:37]
Reactant: COc1ccc(CN2C(=O)C(C)(c3cc(NC=O)ccc3Cl)c3cc(Cl)ccc32)c(OC)c1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CSC
Product: CNc1ccc(Cl)c(C2(C)C(=O)N(Cc3ccc(OC)cc3OC)c3ccc(Cl)cc32)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.56 ml of a 2M solution of borane-dimethyl sulphide in tetrahydrofuran is added to a solution, cooled to 0° C., of 0.4 g of the compound of Example 67 in 1 ml of tetrahydrofuran. After 1 hour at 58° C. and then cooling to 0° C., 0.2 ml of 10N hydrochloric acid and 1 ml of methanol are added to the reaction mixture. The mixture is heated at 60° C. for 1 hour and cooled, and the solvents are evaporated under reduced pressure. The solid residue is treated with 1 ml of a saturated potassium carbonate solution and extraction is carried out several times with ethyl acetate. The organic phases are dried over anhydrous sodium sulphate and the solvents are evaporated under reduced pressure. Purification is carried out by chromatography on a column of silica gel, elution being carried out with an 85/15 (v/v) cyclohexane/ethyl acetate mixture. The expected product is isolated in the form of the hydrochloride by treating the residue obtained with diethyl ether comprising hydrogen chloride and then filtration is carried out; M.p.=121° C. (0.5H2O.1HCl).
Reaction SMILES: N.[H][H].[CH3:4][C:5]1[C:15]([CH3:16])=[C:14]([CH2:17][CH2:18][O:19][CH2:20][CH3:21])[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]=[N:10]O>[Ni].CO>[CH3:4][C:5]1[C:15]([CH3:16])=[C:14]([CH2:17][CH2:18][O:19][CH2:20][CH3:21])[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH2:9][NH2:10]
Reactant: CCOCCc1ccc(OCC=NO)c(C)c1C
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCOCCc1ccc(OCCN)c(C)c1C
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
Into a 20-liter autoclave charged were Raney nickel prepared (50 g as 50% alloy), 10 liters of methanol and 1.5 kg of liquid ammonia. After the hydrogen pressure was adjusted to 20 atm., the mixture was heated to 100° C. with stirring and stirred for one hour Into the mixture of activated Raney nickel thus obtained was charged 820 g of 2-[2,3-dimethyl-4-(2-ethoxyethyl)-phenoxy]-acetaldehyde oxime. Hydrogen was introduced until 20 atm., and the mixture was heated and stirred at 100° C. Absorption of hydrogen began at around 80° C. When the pressure was lowered, hydrogen was introduced to maintain the pressure at 20 atm. After about 0.5 to 2.5 hours, theoretical amount of hydrogen was absorbed, and then after cooling and releasing pressure, the catalyst was removed by filtration through a Nutze having Celite The filtrate was concentrated under reduced pressure to obtain a crude product. Yield 85-93%. The crude product was purified by distillation to obtain 2-[2,3-dimethyl-4-(2-ethoxyethyl)phenoxy]ethylamine (boiling point 170°-175° C./1 mmHg).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([S:8]([NH:11][C:12]2[S:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:2]=1.[C:17]1(=[O:23])O[C:20](=[O:21])[CH:19]=[CH:18]1>>[S:16]1[CH:15]=[CH:14][N:13]=[C:12]1[NH:11][S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:1][CH:2]=1)(=[O:10])=[O:9].[NH:7]1[C:20](=[O:21])[CH:19]=[CH:18][C:17]1=[O:23]
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Reactant: O=C1C=CC(=O)O1
Product: O=C1C=CC(=O)N1
Product: O=S(=O)(Nc1nccs1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30.4 %

Procedure:
Prepared using general procedure 44. A mixture of sulfathiazole (5 gm, 19.5 mmol) and maleic anhydride (1.92 g, 19.5 mmol) was heated under refluxed for 16 hrs. The reaction was cooled to RT and then to 0° C. for 4 hrs. The formed precipitate was filtered off and washed with cold water. The crude solid was dissolved in CH2Cl2 and absorbed onto Celite. Purification via silica gel chromatography using 10% MeOH in CH2Cl2 gave (1H-pyrrole-2,5-dione)-N-(thiazol-2-yl)benzene sulfonamide (2 g, 30%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=336.2; tR=2.12 min.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([N:20]([C:24]([C:26]2[CH:27]=[N:28][C:29](Br)=[CH:30][CH:31]=2)=[O:25])[CH:21]2[CH2:23][CH2:22]2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH3:33][S:34]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)(=[O:36])=[O:35]>CN(C)C=O>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([N:20]([CH:21]2[CH2:23][CH2:22]2)[C:24]([C:26]2[CH:27]=[N:28][C:29]([C:40]3[CH:41]=[CH:42][C:37]([S:34]([CH3:33])(=[O:36])=[O:35])=[CH:38][CH:39]=3)=[CH:30][CH:31]=2)=[O:25])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2ccc(Br)nc2)C2CC2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)C2CC2)CC1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
2 M aqueous Na2CO3 solution (8.26 mL) is added to a mixture of 4-[(6-bromo-pyridine-3-carbonyl)-cyclopropyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (500 mg) and 4-(methanesulfonyl)phenylboronic acid (259 mg) in N,N-dimethylformamide (5 mL). The mixture is sparged with argon for 10 min and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium dichloromethane complex (96 mg) is added. The resulting mixture is stirred for 6 h at 90° C. After cooling to room temperature, water (50 mL) is added and the aqueous phase is extracted with ethyl acetate. The organic phase is dried over MgSO4, the solvent is evaporated, and the residue is chromatographed on silica gel (ethyl acetate/cyclohexane 3:1→1:0) to afford the title compound. LC (method 6): tR=1.17 min; Mass spectrum (ESI+): m/z=500 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:10]([OH:12])=O.[N+:22]([C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27])([O-:24])=[O:23].C(N(CC)CC)C>C(Cl)Cl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:10]([NH:27][C:26]1[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=1[N+:22]([O-:24])=[O:23])=[O:12]
Reactant: COc1cc(C(=O)O)ccc1-c1ccccn1
Reactant: Nc1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COc1cc(C(=O)Nc2ccccc2[N+](=O)[O-])ccc1-c1ccccn1
Temperature: 25 °C

Procedure:
To thionyl chloride (20 mL) was added 3-methoxy-4-(pyridin-2-yl)benzoic acid (500 mg, 2.2 mmol). The mixture was heated at reflux for 3 h, cooled to rt, and concentrated. The resultant acid chloride was taken up in 20 mL of CH2Cl2 and the mixture cooled to 0° C. before addition of 2-nitroaniline (301 mg, 2.2 mmol) and triethylamine (0.3 mL, 2.2 mmol), and the solution warmed to rt overnight. The reaction mixture was diluted with CH2Cl2, washed successively with water, saturated Na2CO3, and brine, and the organic layer dried (MgSO4) and concentrated. The crude product was purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (1:1 to 1:1) to afford the desired 3-methoxy-4-(pyridin-2-yl)-2′-nitrobenzanilide as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:22]2([C:26]([O:28]CC)=[O:27])[CH2:25][CH2:24][CH2:23]2)[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:22]2([C:26]([OH:28])=[O:27])[CH2:25][CH2:24][CH2:23]2)[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(CC)cc3)c2)CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCc1ccc(-c2cc(C3(C(=O)O)CCC3)cc(Cl)c2OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
A mixture of ethyl 1-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylate (350 mg, 0.84 mmol) and lithium hydroxide monohydrate (222 mg, 9.2 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10/ml) was stirred for 3 h at room temperature. After completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water, dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Flash Column Chromatography to give 1-(5-chloro-4′-ethyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylic acid (260 mg) as white solid. 1HNMR (CDCl3, 500 MHz): 7.42 (d, 2H), 7.38 (s, 1H), 7.22 (d, 2H) 7.20 (s, 1H), 3.85 (q, 2H); 2.82 (m, 2H), 2.71 (q, 2H), 2.52 (m, 2H), 2.15 (m, 1H), 1.91 (m, 1H); 1.27 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24](O)=[C:23]([CH3:28])[CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][O:17][C:24]2[CH:25]=[CH:26][C:21]([C:20]([O:19][CH3:18])=[O:29])=[CH:22][C:23]=2[CH3:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(O)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCCC2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Temperature: 0 °C
Yield: 53 %

Procedure:
4-(3-Hydroxy-propyl)-piperidine-1-carboxylic acid tert-butyl ester from Example E68.1 (400 mg, 1.64 mmol) and 4-hydroxy-3-methyl-benzoic acid methyl ester from Example E29 (274 mg, 1.64 mmol) were dissolved in THF (30 ml) and cooled down to 0° C. Polymer-supported triphenyl-phosphine (1.7 g, 2.46 mmol) then DEAD (0.387 ml, 2.46 mmol) were added and the mixture was heated at re-flux for 20 h. The resin was filtered off, washed with EtOAc and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; 20% EtOAC:80% cyclohexane) to yield the title compound (340 mg, 53%).
Reaction SMILES: O[CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1)=[O:4].OC1C=C(C(=O)C)C=CC=1.O.C(O)C>O.[Zn]>[OH:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(c1cccc(O)c1)C(O)c1cccc(O)c1
Agent: CC(=O)c1cccc(O)c1
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: O=C(Cc1cccc(O)c1)c1cccc(O)c1
Reaction time: 11 h

Procedure:
2-Hydroxy-1,2-bis(3-hydroxyphenyl)ethanone was reduced by the procedure of M. Pisova and M. Soncek [Coll. Czech, Chem. Comm., 38, 3876 (1973)]. A mixture of 2-hydroxy-1,2-bis(3-hydroxyphenylethanone (18 g.) chromic sulfate hydrate (20.9% Cr; 60 g.), zinc dust (49 g.) and water-ethanol (1:1, 1 liter) was stirred under an atmosphere of nitrogen for 11 hours. The mixture was diluted with water and extracted with three portions of ethyl acetate. The organic solution was washed with saturated brine solution and dried over magnesium sulfate. The solution was concentrated and the product crystallized from ethyl acetate-benzene (seeding); yield: 8.51 g., m.p. 155°-156°.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:19][CH2:18][C@@H:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C@H:10]1[OH:31].[C:32](OC(=O)C)(=[O:34])[CH3:33].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:32]([O:31][C@@H:10]1[C:11]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C@H:17]([O:20][Si:21]([CH:25]([CH3:27])[CH3:26])([CH:28]([CH3:30])[CH3:29])[CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:19][C@H:9]1[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])(=[O:34])[CH3:33]
Reactant: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)[C@H](O)c2cccnc21)(C(C)C)C(C)C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H]1c2cccnc2[C@H](O[Si](C(C)C)(C(C)C)C(C)C)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Yield: 100 %

Procedure:
In a 250 mL round-bottom flask was dissolved (5S,6S,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-ol (1.004 g, 2.243 mmol) in methylene chloride (20 mL) to give a colorless solution. Acetic anhydride (0.423 mL, 4.49 mmol) and triethylamine (0.938 mL, 6.73 mmol) were added, followed by DMAP (0.055 g, 0.449 mmol). The mixture was stirred at room temperature under nitrogen. 2 h: LCMS showed complete conversion. It was quenched with Sodium bicarbonate solution and diluted with ethyl acetate. The layers were separated. The organic layer was washed with brine, dried and concentrated to give a colorless oil (100%), which was directly carried onto next reaction without further purification and characterization. MS(ESI)[M+H+]=490.26.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[CH3:16][S:17]([C:20]1[CH:21]=[C:22]([CH2:26][NH2:27])[CH:23]=[CH:24][CH:25]=1)(=[O:19])=[O:18].C(N(CC)CC)C>CO.C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:27]([CH2:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([S:17]([CH3:16])(=[O:19])=[O:18])[CH:21]=2)[CH:10]=1
Reactant: CS(=O)(=O)c1cccc(CN)c1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCO
Product: CS(=O)(=O)c1cccc(Cn2cc(Cl)cc(C(N)=O)c2=N)c1
Reaction time: 24 h
Yield: 19.5 %

Procedure:
To a solution of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.5 g) in methanol (5 ml) was added a solution (3 ml) of 1-[3-(methylsulfonyl)phenyl]methanamine hydrochloride (1.4 g) and triethylamine (0.9 ml) in ethanol at room temperature, and the mixture was stirred for 24 hr. The reaction solvent was evaporated under reduced pressure, DMSO (5 ml) was added, and the mixture was stirred at 80° C. for 4 hr. The solvent was evaporated under reduced pressure and partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=4/1-1/0). 2N Hydrochloric acid-methanol solution (1 ml) was added to the obtained yellow oil at room temperature, and the precipitated crystals were filtered and recrystallized to give the title compound (78 mg).