Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OOS([O-])=O.[K+].C1(S[C:14]2([O:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][C:19]=3[C@H:29]3[CH2:33][O:32][C@:31]4([CH2:39][CH2:38][C@@H:37]5[NH:40][C@@:34]4([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[CH2:35][C@H:36]5S(C4C=CC=CC=4)(=O)=O)[CH2:30]3)[CH2:16][CH2:15]2)C=CC=CC=1.[O-2].[Al+3].[O-2].[O-2].[Al+3].P([O-])([O-])(O)=O.[Na+].[Na+]>[Na].[Hg].CO.C(Cl)(Cl)Cl>[CH:14]1([O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][C:19]=2[C@H:29]2[CH2:33][O:32][C@:31]3([CH2:39][CH2:38][C@H:37]4[NH:40][C@@:34]3([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH2:35][CH2:36]4)[CH2:30]2)[CH2:16][CH2:15]1
Reactant: O=S(=O)(c1ccccc1)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@@]21C[C@@H](c2cc(OC(F)(F)F)ccc2OC2(Sc3ccccc3)CC2)CO1
Agent: O=P([O-])([O-])O
Agent: O=S([O-])OO
Agent: [Al+3]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: FC(F)(F)Oc1ccc(OC2CC2)c([C@H]2CO[C@]3(CC[C@@H]4CC[C@]3(c3ccccc3)N4)C2)c1
Reaction time: 5 h
Yield: 61.7 %

Procedure:
Oxone (400 mg, 0.65 mmol) was added to a stirred mixture of (1R*,2R*,4′S*,5S*,6R*)-2′,3′,4′,5′-tetrahydro-4′-[2-(1-phenylthiocyclopropyloxy)-5-trifluoromethoxyphenyl]-1-phenyl-6-phenylsulphonylspiro[8-azabicyclo[3.2.1]octane-2,2′-furan] (Description 17; 88 mg, 0.12 mmol), wet aluminium oxide (5 g of Al2O3 in 1 ml of water, 370 mg) and chloroform (5 ml) at room temperature. The reaction mixture was stirred for 5 hours then filtered and concentrated to give crude disulphone (95 mg). Sodium amalgam (10%, 700 mg) was added in small portions to the stirred mixture of the disulphone (95 mg), disodium hydrogen orthophosphate (700 mg), and methanol (5 ml) at +5° C. After reaction went to completion, the mixture was quenched with saturated aqueous NaHCO3, decanted and extracted into dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (dichloromethane:methanol) to give the title compound (34 mg, 60%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]([CH:15]([CH3:17])[CH3:16])[CH2:7][CH2:8][N:9]2[CH:12]([CH3:14])[CH3:13])=[CH:4][C:3]=1[CH3:18].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH3:18])=[C:2]([C:22]3[CH:23]=[C:24]([CH:25]=[CH:26][C:21]=3[O:20][CH3:19])[CH:27]=[O:28])[CH:11]=2)[N:6]([CH:15]([CH3:17])[CH3:16])[CH2:7][CH2:8]1)([CH3:14])[CH3:13]
Reactant: Cc1cc2c(cc1Br)N(C(C)C)CCN2C(C)C
Reactant: COc1ccc(C=O)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(C=O)cc1-c1cc2c(cc1C)N(C(C)C)CCN2C(C)C
Temperature: 25 °C

Procedure:
A mixture of 7-bromo-1,4-diisopropyl-6-methyl-1,2,3,4-tetrahydroquinoxaline (469 mg, 1.51 mmol), 2-methoxy-5-formylphenylboronic acid (407 mg, 2.26 mmol), potassium carbonate (834 mg, 6.03 mmol) and water (2.5 mL) in anhydrous 1,2-dimethoxyethane (30 mL) was degassed with argon for 15 minutes prior to the addition of tetrakis(triphenylphosphine)palladium (0) (349 mg, 0.30 mmol). The reaction mixture was heated under reflux for 8.5 hours, allowed to cool to room temperature and extracted with ethyl acetate (2×100 mL). The organic extracts were successively washed with water (100 mL), saturated aqueous NH4Cl (100 mL), saturated aqueous NaCl (100 mL), dried over MgSO4 and filtered. Removal of the solvent under reduced pressure gave an oil which was purified by column chromatography, using a Biotage 40S cartridge, eluting with 10% ethyl acetate/90% hexane. The title compound was isolated as bright yellow solid (315 mg, 57%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:29])=[CH:26][CH:25]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)OC2CCN(Cc3ccccc3)CC2)cc1
Yield: 34.9 %

Procedure:
1.41 g (0.00733 mol) of 1-benzyl-4-hydroxypiperidine and 1.8 ml (0.0129 mol) of triethylamine were dissolved in 50 ml of toluene and treated with 0.79 ml (0.00586 mol) of 4-methoxy-benzoyl chloride. The mixture was boiled at reflux for 2 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:3→1:2). 0.666 g (35%) of 1-benzyl-piperidin-4-yl 4-methoxy-benzoate was obtained as yellowish crystals; m.p. 55°-56°.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].[OH-].[Na+:18]>>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([CH3:16])[C:13]([O-:15])=[O:14])=[CH:10][CH:11]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].[Na+:18]
Reactant: CC(C)=CCc1ccc(C(C)C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)=CCc1ccc(C(C)C(=O)[O-])cc1

Procedure:
4.8 g of 2-(p-prenylphenyl)propionic acid as prepared in Example 1 was dissolved in 5% aqueous sodium hydroxide solution to adjust to pH 9.0. After evaporation of the water, the resulting solid was recystallized from ethyl acetate to give 4.5 g of sodium 2-(p-prenylphenyl)propionate, colorless prisms, m.p. 65°-66° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([F:9])[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:15](=[O:17])=[O:16].[Cl-].[NH4+]>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([OH:17])=[O:16])=[C:6]([F:9])[C:7]=1[CH3:8]
Reactant: Cc1c(F)cccc1Cl
Reactant: O=C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c(Cl)ccc(C(=O)O)c1F
Temperature: -70 °C
Reaction time: 2 h
Yield: 24 %

Procedure:
29.0 g (0.200 mol) of 6-chloro-2-fluorotoluene are dissolved, with stirring, in 200 ml of dry THF. After cooling to -70° C., 151.0 ml (0.24 mol) of n-butyllithium in solution in hexane are added dropwise. After 2 hours, the reaction mixture maintained at -70° C. is poured onto solid carbon dioxide. After returning to room temperature, an aqueous ammonium chloride solution is added. The aqueous phase is extracted with ether, acidified with 6N hydrochloric acid and extracted with ether. The organic phases are dried over magnesium sulphate and concentrated to dryness. The residue is washed with heptane to give 9.0 g (0.048 mol) of 4-chloro-2-fluoro-3-methylbenzoic acid in the form of a white powder (yield: 24%; melting point: 198° C.).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[CH3:29][C:30]1[S:31][C:32]([CH:36]=O)=[C:33]([CH3:35])[N:34]=1.C(O)(=O)C.[OH-].[Na+]>ClCCCl>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH2:36][C:32]2[S:31][C:30]([CH3:29])=[N:34][C:33]=2[CH3:35])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1nc(C)c(C=O)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1nc(C)c(CNC2CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
Sodium triacetoxyborohydride (4.5 g, 21.23 mmol) is added to a stirred solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.63 g, 13.13 mmol), 2,4-dimethyl-thiazole-5-carboxaldehyde (1.95 g, 13.81 mmol, Maybridge), acetic acid (0.80 ml, 13.98 mmol) and 1,2-dichloroethane (125 ml). The reaction is stirred overnight at room temperature under nitrogen. The reaction is poured into 2N NaOH (300 ml) and extracted with ethyl acetate (200 ml×3). The ethyl acetate is dried over sodium sulfate, filtered, and the filtrate concentrated. The crude product is purified by flash chromatography on silica gel eluting with 0.5% concentrated ammonium hydroxide/5% ethanol/chloroform to yield (2.93 g, 69%) of 4-{[(2,4-dimethyl-thiazol-5-yl)methyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=326.2 (M+1); 1H NMR (CDCl3): δ=4.10 (2H, br m), 3.91 (2H, s), 2.88-2.79 (2H, brm), 2.73-2.66 (1H, m), 2.66 (3H, s), 2.34 (3H, s), 1.86 (2H, brd), 1.48 (9H, s), 1.36-1.24 (3H, m).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH:7]=[O:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Mg]Br)=[CH:12][CH:11]=1>C1COCC1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:7]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[OH:8])=[CH:12][CH:11]=1
Reactant: O=CC1CCCCO1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)C1CCCCO1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tetrahydro-pyran-2-carbaldehyde (114.00 mg, 1.00 mmol) in THF (10 mL) was added 4-chlorophenylmagnesium bromide (1.0 M in diethyl ether, 1.5 mL, 1.50 mmol) at −78° C. The mixture was stirred at −78° C. for 2 hrs. The solvent was then removed under reduced pressure and the resulting residue was purified by a flash chromatography (eluting with 20% AcOEt in Hexane).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.Br[CH2:13][C:14]([C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1)=[O:15]>C1(C)C=CC=CC=1>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([C:14](=[O:15])[CH2:13][N:1]2[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]2)=[CH:17][CH:18]=1)#[N:21]
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: CCOC(=O)[C@H]1CCCNC1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@H]1CCCN(CC(=O)c2ccc(C#N)cc2)C1
Reaction time: 48 h
Yield: 125.6 %

Procedure:
To a mixture of (S)-ethyl piperidine-3-carboxylate (5 g, 31.8 mmol) in toluene (50 mL) was added 4-(2-bromoacetyl)benzonitrile (7.84 g, 35.0 mmol). The reaction mixture was stirred for 48 hours. The reaction mixture was concentrated in vacuo to yield 12 g of a yellow solid which was purified by triturating in EtOAc. The solid material was collected and washed with EtOAc then dried in vacuo to give 6 g of (S)-ethyl 1-(2-(4-cyanophenyl)-2-oxoethyl)piperidine-3-carboxylate, hydrobromide. MS (m+1)=301. HPLC Peak RT=1.57 minutes (Analytical Method B).
Reaction SMILES: [N:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.NN.C(O)COCCO.C(O)C(O)C(O)C(O)C(O)C=O.[O-]S([O-])(=O)=O.[Mg+2]>CCCCCC>[N:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2-c2cccnc21
Agent: NN
Agent: O=CC(O)C(O)C(O)C(O)CO
Agent: O=S(=O)([O-])[O-]
Solvent: CCCCCC
Solvent: OCCOCCO
Product: c1ccc2c(c1)Cc1ncccc1-2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 66.6 %

Procedure:
4.6 g (25.4 mmole) of 1-azafluoren-9-one was added to a solution of 9 ml (0.28 mole) of hydrazine and 50 ml of diethyleneglycol. Heating was started and the temperature was kept at 100° for 15 minutes, then raised to 195° and kept there for 1 hr. TLC showed the reaction was complete. The reaction solution was cooled to below 100° and poured into 300 ml of ice water. The aqueous phase was saturated with salt and extracted with 8×100 ml ether. The ether was dried with sodium sulfate and evaporated to yield 3.73 g of crude product. This was dissolved in hexane and treated with Magnesol, filtered and evaporated and finally recrystallized from hexane to yield 2.83 g of pure 1-azafluorene.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:17])=[CH:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)=[O:5])[CH3:2].C(N(CC)CC)C.F[B-](F)(F)F.C(C(=NOC(N(C)C)=[N+](C)C)C(OCC)=O)#N.[CH2:47]([NH2:51])[CH2:48][CH2:49][CH3:50]>CN(C)C=O>[CH2:47]([NH:51][C:10]([C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[CH:7]=[C:6]([CH3:17])[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:12])[CH2:48][CH2:49][CH3:50]
Reactant: CCCCN
Reactant: CCOC(=O)C(C)=Cc1ccccc1C(=O)O
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCNC(=O)c1ccccc1C=C(C)C(=O)OCC
Yield: 78.1 %

Procedure:
Ethyl 3-(2-butylcarbamoylphenyl)-2-methylacrylate is prepared as described in Example 30, starting with 1.17 g (5.0 mmol) of 2-(2-ethoxycarbonylpropen-1-yl)benzoic acid in 10 cm3 of dimethylformamide, a solution of 0.69 cm3 (5.0 mmol) of triethylamine, 1.64 g (5.0 mmol) of O-[(cyano(ethoxycarbonyl)methylene)amino]-1,1,3,3-tetramethyluronium tetrafluoroborate (“TOTU”) in 6 cm3 of dimethylformamide and a second solution consisting of 366 mg (5.0 mmol) of n-butylamine and 0.69 cm3 (5.0 mmol) of triethylamine in 10 cm3 of dimethylformamide. 1.13 g of ethyl 3-(2-butylcarbamoylphenyl)-2-methylacrylate are thus obtained in the form of a yellowish oil, which can be reacted in the following step without further purification.
Reaction SMILES: C1(C)C=CC=CC=1.[CH:8]([NH:11][C:12]1[N:17]=[C:16]([NH:18][CH:19]([CH3:21])[CH3:20])[N:15]=[C:14](P(OCC)(=O)OCC)[N:13]=1)([CH3:10])[CH3:9].[Cl:30]C(Cl)(Cl)C>O1CCOCC1>[Cl:30][C:14]1[N:13]=[C:12]([NH:11][CH:8]([CH3:10])[CH3:9])[N:17]=[C:16]([NH:18][CH:19]([CH3:21])[CH3:20])[N:15]=1
Reactant: CC(Cl)(Cl)Cl
Reactant: CCOP(=O)(OCC)c1nc(NC(C)C)nc(NC(C)C)n1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC(C)Nc1nc(Cl)nc(NC(C)C)n1
Yield: 12 %

Procedure:
Similar reactions, in which 1,1,1-trichloroethane (reflux 75° C.) and 1,4-dioxan (reflux 105° C.) were used as solvents instead of toluene, both gave diethyl 2,4-bis(isopropylamino)-1,3,5-triazine-6-phosphonate in 81% yield, together with 2-chloro-4,6-bis(isopropylamino)-1,3,5-triazine (yield 12-17%).
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[C:5]([OH:8])=[C:4]([CH3:9])[O:3]1.[CH:10]([O:12][CH2:13][CH3:14])=[CH2:11].C(=O)(O)[O-].[Na+]>Cl>[CH3:9][CH:4]1[C:5](=[O:8])[C:6]([O:7][CH:10]([O:12][CH2:13][CH3:14])[CH3:11])=[C:2]([CH3:1])[O:3]1
Reactant: CC1=C(O)C(=O)C(C)O1
Reactant: C=COCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(C)OC1=C(C)OC(C)C1=O
Reaction time: 1.5 h
Yield: 80.8 %

Procedure:
To a heterogenous solution of 2,5-dimethyl-4-hydroxy-3-(2H)-furanone (133.0 g, 1.0 mole) and ethyl vinyl ether (144.0 g, 2.0 moles) at 10° C., under N2, is added dropwise, concentrated hydrochloric acid (1.0 g). The temperature rises to 11° C. and the solution becomes homogeneous. It is stirred for 1.5 hours, and then the coolant is removed. Stirring is continued at room temperature for an additional six hours, after which the reaction is quenched by the addition of solid sodium bicarbonate (10 g, 0.12 mole). The reaction mixture is washed with 100 ml water and a second time with 100 ml of 5% NaHCO3. The product is dried over Na2SO4 and distilled to give a 78.9% yield (161.8 g) of 2,5-dimethyl-4-[(1'-ethoxy)ethoxy]-3(2H)-furanone, b.p. 91° C. (0.05 torr), IR (neat, film) 1200, 1625, 1700, 2030, 2978 cm-1 ; 1H NMR (CDCl3) δ1.20 (t, J=8 Hz, 3), 1.32 (d, J=5 Hz, 3), 1.42 (d, J=7 Hz, 3), 2.2 (S, 3), 3.72 (m, 2), 4.48 (q, J=7 Hz, 1), 5.32 (q, J=5 Hz, 1).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH:18]1[CH2:26][CH:27]=O>O1CCCC1>[CH2:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17][CH:18]1[CH2:26]/[CH:27]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=CCC1Cc2ccccc2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/CC1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
3.90 g of 63% sodium hydride was suspended in 60 ml of tetrahydrofuran, and 22.8 g of ethyl diethylphosphonoacetate dissolved in 100 ml of tetrahydrofuran was added dropwise to the suspension under water cooling. The mixture was stirred at the same temperature for 30 minutes. 13.58 g of 2-indanacetaldehyde dissolved in 100 ml of tetrahydrofuran was added dropwise to said mixture. The resulting mixture was stirred at the same temperature for 1 hour and further stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. After the ethyl acetate layer was washed and dried, the solvent was removed. The residue was purified by silica gel column chromatography (hexane-ethyl acetate (20:1)) to obtain 19.22 g of ethyl 2-indanecrotonate.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[C:13]1[C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=1.[OH:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>O>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:19][C:18]1[C:13]([C:39]2[CH:40]=[CH:41][C:36]([OH:35])=[CH:37][CH:38]=2)=[N:14][C:15]([CH3:34])=[CH:16][CH:17]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccc(O)cc3)c2cc1OC
Temperature: 70 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
N,N-Dimethylformamide (1 ml) and a 2 M aqueous potassium carbonate solution (0.5 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 4-hydroxyphenylboronic acid (81 mg) under an argon atmosphere, and the mixture was stirred at 70° C. overnight. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (34 mg, yield 75%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:12]=3[CH3:20])=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1>[Pd].C(O)C>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:12]=3[CH3:20])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: Cc1[nH]c2ccccc2c1C1=CCC2(CC1)OCCO2
Agent: [Pd]
Solvent: CCO
Product: Cc1[nH]c2ccccc2c1C1CCC2(CC1)OCCO2
Reaction time: 3 h
Yield: 96.9 %

Procedure:
A mixture of 3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-2-methyl-1H-indole (2.39 g, 8.9 mmol) and 10% palladium on carbon (0.35 g) in ethanol (80 ml) was hydrogenated for 3 hours. The catalyst was filtered off and then a solution of methylene-methanol (80 ml) was used to dissolve any solids within the celite. The solvent removed under vacuum to afford 2.34 g (97%) of product as an off-white solid, which was triturated with ethyl ether (40 ml) to afford a white solid: mp 166-168° C. The mother liquor was concentrated to afford another 1.2 g of product as a yellow solid.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>C(#N)C>[N:13]1([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1ccc(F)cc1
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1ccc(N2CCCCC2)cc1

Procedure:
Reaction of ethyl 4-fluorobenzoate with piperidine (3 equivalents) in acetonitrile may be carried out at reflux for 4 days. Dilution of the cooled reaction mixture with several volumes of water provides a precipitate, which may be filtered to provide ethyl 4-(piperidin-1-yl)benzoate. Reduction of the ester with lithium aluminum hydride (2 equivalents) in tetrahydrofuran provides the corresponding alcohol.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:39])[CH:6]([OH:38])[C@@H:7]([NH:15][C:16](=[O:37])[C@H:17]([CH2:31][C:32]1[N:36]=[CH:35][NH:34][CH:33]=1)[NH:18]C(OCC1C=CC(OC)=CC=1)=O)[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:3])[CH3:2].[ClH:40]>CO.[Pd]>[ClH:40].[ClH:40].[CH:1]([O:4][C:5](=[O:39])[CH:6]([OH:38])[C@@H:7]([NH:15][C:16](=[O:37])[C@H:17]([CH2:31][C:32]1[N:36]=[CH:35][NH:34][CH:33]=1)[NH2:18])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:3])[CH3:2]
Reactant: COc1ccc(COC(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N[C@@H](CC2CCCCC2)C(O)C(=O)OC(C)C)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)OC(=O)C(O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1

Procedure:
In 15 ml of N,N-dimethylformamide was suspended 1.37 g of the hydrazide compound, and to the suspension were successively added a solution of a 5.95N-dry hydrogen chloride in 2.29 ml of N,N-dimethylformamide and 0.66 ml of isoamyl nitrate with stirring at -20° C. After disappearance of the hydrazide compound, the reaction mixture was cooled to -30° C., and then neutralized by an addition of 1.89 ml of triethylamine to prepare a cold solution of N-(4-methoxybenzyloxycarbonyl)-L-histidine azide. The cold azide solution was added to a solution of 1.00 g of (2RS, 3S)-3-amino-4-cyclohexyl-2-hydroxybutyric acid isopropyl ester in 40 ml of N,N-dimethylformamide with stirring under ice-cooling. The mixture was still stirred for 16 hours, and then the reaction mixture was evaporated under reduced pressure. To the residue was added a 5% aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: chloroform/methanol=15/1) to obtain 1.70 g of (2RS, 3S)-3-[N-(4-methoxybenzyloxycarbonyl)-L-histidyl]amino-4-cyclohexyl-2-hydroxybutyric acid isopropyl ester as a white powder. In 50 ml of methanol was 1.70 g of the butyric acid isopropyl ester compound, and to the solution were added 10 ml of a 2N hydrochloric acid and 200 mg of a 10% palladium charcoal. The mixture was hydrogenated under an atmospheric pressure. After filtration of the catalyst, the filtrate was evaporated under reduced pressure to obtain 1.36 g of (2RS, 3S)-3-(L-histidyl)amino-4-cyclohexyl-2-hydroxybutyric acid isopropyl ester dihydrochloride as a white powder.