Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[C:15](=[O:26])[N:16]([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:17](=[O:20])[CH2:18][O:19][C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[N:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>O1CCOCC1>[CH2:1]([O:8][C:9]1[C:14]2[C:15](=[O:26])[N:16]([CH2:21][CH2:22][CH2:23][CH2:24][N:36]3[CH2:37][CH2:38][N:33]([C:28]4[N:27]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:34][CH2:35]3)[C:17](=[O:20])[CH2:18][O:19][C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C1COc2cccc(OCc3ccccc3)c2C(=O)N1CCCCBr
Solvent: C1COCCO1
Product: O=C1COc2cccc(OCc3ccccc3)c2C(=O)N1CCCCN1CCN(c2ncccn2)CC1
Yield: 79 %

Procedure:
A 202 mg amount of the compound of Example 13 was dissolved in 20 ml of dioxane, and 242 mg (3 equivalents) of 1-(2-pyrimidinyl)piperazine was added, followed by heating under reflux for 7 hours. The reaction treatment and purification were conducted as in Example 75, to give 195 mg of the desired compound (yield 79%). The maleic acid salt was obtained in a conventional manner.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:2]([OH:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: COC(=O)c1cc(O)ccc1O
Reactant: CCCCCCBr
Product: CCCCCCOc1ccc(O)c(C(=O)OC)c1
Yield: 58 %

Procedure:
Synthesis was carried out in the same manner as in Example 1, except for replacing methyl 2,4-dihydroxybenzoate with methyl 2,5-dihydroxybenzoate and replacing 2-ethylhexyl bromide with n-hexyl bromide, to obtain methyl 5-n-hexyloxy-2-hydroxybenzoate represented by the following chemical formula (hereinafter referred to as compound 12) as a colorless, clear and oily substance in a yield of 58%. The analytical results are shown below. ##STR33##
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1>C1COCC1.C(OCC)C>[CH:1]1([C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH3:6])=[CH:8][CH:9]=2)([OH:15])[CH3:14])[CH2:3][CH2:2]1
Reactant: CC(=O)c1ccc(C)cc1
Reactant: Br[Mg]C1CC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(C(C)(O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
27 ml (26.8 mmol) of 1N cyclopropylmagnesium bromide solution in THF were added to 3.00 g (22.4 mmol) of 1-(4-methylphenyl)ethanone in 60 ml of diethyl ether at RT, and the mixture was stirred at RT overnight. Then a further 11 ml (11.2 mmol) of 1N cyclopropylmagnesium bromide solution in THF were added, and the mixture was stirred at RT overnight. The reaction mixture was added to ice-water, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate gradient with addition of 0.1% triethylamine) to result in 491 mg (13% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C@H:16]([CH2:22][CH2:23][CH3:24])[CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:5]=[CH:6][C:7]=1[O:8]CC1C=CC=CC=1>[Pd].CCOC(C)=O>[OH:8][C:7]1[CH:6]=[CH:5][C:4]([C@H:16]([CH2:22][CH2:23][CH3:24])[CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:3][C:2]=1[CH3:1]
Reactant: CCC[C@H](CC(=O)OC)c1ccc(OCc2ccccc2)c(C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC[C@H](CC(=O)OC)c1ccc(O)c(C)c1
Reaction time: 8 h
Yield: 34 %

Procedure:
To a flask containing 27.3 (0.4140 g, 1.268 mmol) under an atmosphere of nitrogen was added 10% Pd/C (0.20 g, 1.88 mmol). The flask was sealed with a rubber septum. To this system was added EtOAc (10 mL) and then vacuum was applied followed by addition of H2 gas (this was repeated three times). A balloon was placed on the flask and the reaction was stirred under H2 overnight. The reaction was filtered, concentrated, and purified by silica gel chromatography (0 to 20% EtOAc/hexanes) to afford a 27.4 (0.102 g, 34% yield).
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:25]([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO>[CH2:1]([N:8]([CH3:25])[C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1NCc1ccccc1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CN(Cc1ccccc1)[C@@H]1CCCC[C@@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.7 %

Procedure:
(±)-cis-N1-Benzyl-N2-tert-butoxycarbonyl-1,2-cyclohexanediamine (3.24 g) was dissolved in methanol (30 ml), and to the solution an aqueous solution (35%, 0.909 ml) of formaldehyde was added, and the mixture was stirred at room temperature for 10 minutes. Sodium cyanoborohydride (666 mg) was added to this mixture, and the resultant mixture was stirred at room temperature for 6 hours. Thereafter, a saturated aqueous solution of sodium hydrogencarbonate was added, and the solvent was concentrated under reduced pressure. Dichloromethane was added to the residue to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain the title compound (1.98 g) as a yellow oil.
Reaction SMILES: [CH2:1]([S:5](Cl)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[I:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1>N1C=CC=CC=1>[I:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:7])=[O:6])=[CH:12][CH:11]=1
Reactant: CCCCS(=O)(=O)Cl
Reactant: Nc1ccc(I)cc1
Solvent: c1ccncc1
Product: CCCCS(=O)(=O)Nc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
Butanesulphonyl chloride (7.8 g) was added dropwise to a stirred solution of 4-iodobenzeneamine (10 g) in pyridine (50 ml) at 0°, the mixture was stirred at room temperature for 1 h, concentrated, and partitioned between 2 N hydrochloric acid (100 ml) and EA (100 ml). The organic layer was washed with 2 N hydrochloric acid, water and brine, dried and concentrated to a solid which was recrystallised from cyclohexane to give the title compound (10.5 g) m.p. 80°-81°.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([C:8]2([OH:18])[CH2:17][CH2:16][C:11]3(OCCO3)[CH2:10][CH2:9]2)=[CH:6][N:7]=1.[NH:19]1[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[O:25])[CH2:20]1>>[OH:18][C:8]1([C:5]2[S:4][C:3]([S:2][CH3:1])=[N:7][CH:6]=2)[CH2:9][CH2:10][CH:11]([N:19]2[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=3)=[O:25])[CH2:20]2)[CH2:16][CH2:17]1
Reactant: CSc1ncc(C2(O)CCC3(CC2)OCCO3)s1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: CSc1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
The title compounds were prepared as white solids from reductive amination of 8-(2-methylsulfanyl-thiazol-5-yl)-1,4-dioxa-spiro[4.5]decan-8-ol, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:23]=[CH:22][C:8]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][O:18]C(=O)C)=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.[OH-].[Na+]>C(O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][OH:18])=[N:15][CH:16]=2)=[CH:22][CH:23]=1)(=[O:4])=[O:3]
Reactant: CC(=O)OCc1ccc(OCc2ccc(S(C)(=O)=O)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(COc2ccc(CO)nc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.4 %

Procedure:
Acetic acid 5-(4-methanesulfonyl-benzyloxy)-pyridin-2-ylmethyl ester (10.4 g, 31 mmol) was suspended in a water (20 mL) and ethanol (80 mL). To this was added NaOH (2.2 g, 55 mmol) and the reaction was heated to reflux for 2 h. The reaction mixture was cooled to rt and stirred for 24 h and then concentrated under reduced pressure. The resulting residue was partitioned between water and ethyl acetate. The organic layer was dried over Na2SO4, filtered and volatiles were removed under reduced pressure to yield [5-(4-methanesulfonyl-benzyloxy)-pyridin-2-yl]-methanol (4.04 g, 44%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[CH:13]1([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:18][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1ccc(C(=O)Cl)nc1Cl
Reactant: OC1CCCC1
Product: COc1ccc(C(=O)OC2CCCC2)nc1Cl

Procedure:
6—Chloro-5-methoxypyridine-2-carbonyl chloride (5.8 g) is added to dry cyclopentanol (50 mL) and the mixture refluxed for 4 hours. The mixture is concentrated, the residue dissolved in ethyl acetate (400 mL) and the ethyl acetate solution is washed with water (3×250 mL). After drying (MgSO4) the solution is evaporated to dryness to give cyclopentyl 6-chloro-5-methoxypyridine-2-carboxylate (6.3 g) as a buff solid, m.p. 90–92° C. [Elemental analysis:—C, 55.9; H, 5.47; Cl, 13.9; N, 5.48%. calculated:—C, 56.36; H, 5.52; Cl, 13.8; N, 5.48%.].
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:3].[B-](F)(F)(F)F.CNC.[N+:26]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][C:34]=1[O:35][CH:36]1[CH2:41][CH2:40][CH:39]([C:42]([OH:44])=O)[CH2:38][CH2:37]1)([O-:28])=[O:27].CCN(C(C)C)C(C)C>C1COCC1>[CH3:1][N:2]([CH3:3])[C:42]([CH:39]1[CH2:38][CH2:37][CH:36]([O:35][C:34]2[CH:33]=[CH:32][N:31]=[CH:30][C:29]=2[N+:26]([O-:28])=[O:27])[CH2:41][CH2:40]1)=[O:44]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)C1CCC(Oc2ccncc2[N+](=O)[O-])CC1
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)C1CCC(Oc2ccncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TBTU (630.0 mg, 1.962 mmol) and dimethylamine (1.784 mL of 2 M, 3.568 mmol) were added to a solution of 4-[(3-nitro-4-pyridyl)oxy]cyclohexanecarboxylic acid (475 mg, 1.784 mmol) and DIPEA (253.6 mg, 341.8 μL, 1.962 mmol) in THF (9.500 mL) and the resulting solution was stirred at RT overnight. The reaction mixture was partitioned between EtOAc and water, and the combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 0-100% EtOAc/petroleum ether using the ISCO column companion system (12 g column) Clean fractions were combined and concentrated in vacuo to yield N,N-dimethyl-4-[(3-nitro-4-pyridyl)oxy]cyclohexanecarboxamide as a pale yellow oil. (180 mg, 34%). MS (ES+) 294.3.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:20])([C:13]#[C:14][C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[C:9]([F:12])([F:11])[F:10])=[CH:6][C:5]([Cl:21])=[CH:4][CH:3]=1.N1C=CC=CC=1.Br[CH2:29][CH2:30][C:31](Br)=[O:32]>CCOCC>[Cl:21][C:5]1[CH:4]=[CH:3][C:2]2[NH:1][C:31](=[O:32])[C@H:30]([CH3:29])[O:20][C@:8]([C:13]#[C:14][C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)([C:9]([F:10])([F:11])[F:12])[C:7]=2[CH:6]=1
Reactant: Nc1ccc(Cl)cc1C(O)(C#Cc1ccco1)C(F)(F)F
Reactant: O=C(Br)CCBr
Solvent: c1ccncc1
Solvent: CCOCC
Product: C[C@@H]1O[C@](C#Cc2ccco2)(C(F)(F)F)c2cc(Cl)ccc2NC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred ice-cooled solution of 265 mg of 6-amino-3-chloro-α-(furan-2-yl)ethynyl-α-(trifluoromethyl)benzyl alcohol in 10 mL of dry ether was added 0.150 mL of dry pyridine and 0.100 mL of bromopropionyl bromide. After 30 min, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 10 mL of dry DMF at 0°, 25 mg of 100% sodium hydride was added, and the resulting mixture was stirred for 15 min at 0° and at room temperature for 30 min. The reaction mixture was then poured onto water and extracted twice with ether. The combined extracts were washed with water and brine, dried and evaporated to a residue which was purified by column chromatography on silica gel (elution with 17-33% ethyl acetate in hexanes) affording after crystallization from ethyl acetate/hexanes 5 mg of the title compound: HRMS: Calcd. for C17H12NO3C1F3 (M+H)+: 369.037956. Found: 369.036835.
Reaction SMILES: [Na].[CH:2]1([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[C:15]([F:17])[CH:16]=[C:11]3[C:10]([C:18]#[N:19])=[N:9]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:20]([OH:23])(=[O:22])[CH3:21].[Cl-].[NH4+:25]>CO>[C:20]([OH:23])(=[O:22])[CH3:21].[CH:2]1([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[C:15]([F:17])[CH:16]=[C:11]3[C:10]([C:18](=[NH:25])[NH2:19])=[N:9]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#Cc1nn(CC2CCCC2)c2ncc(F)cc12
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: N=C(N)c1nn(CC2CCCC2)c2ncc(F)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of argon, 296 mg (12.861 mmol) of sodium were, a little at a time, stirred into methanol. After the sodium had been consumed, 3.670 g (purity 86%, about 12.861 mmol) of 1-(cyclopentylmethyl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile were added a little at a time, and the mixture was stirred at RT for 2 h. 3.004 g (50.021 mmol) of acetic acid and 825 mg (15.433 mmol) of ammonium chloride were then added, and the mixture was boiled under reflux overnight. The reaction mixture was concentrated, the residue was triturated with 1N sodium hydroxide solution and the precipitate was filtered off with suction and dried under high vacuum. This gave 2.840 g (purity 98%, 83% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5](O)=[O:6].S(Cl)([Cl:12])=O>>[CH3:1][C:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5]([Cl:12])=[O:6]
Reactant: CC(C)(C)CCC(=O)O
Reactant: O=S(Cl)Cl
Product: CC(C)(C)CCC(=O)Cl
Yield: 83.2 %

Procedure:
4,4-Dimethylpentanoic acid (40 g; Chem Lett, (1980), 571) was treated at 20° for 16 h with thionyl chloride (40 g) and the mixture distilled under reduced pressure to yield 4,4-dimethylpentanoyl chloride (38 g) b.p. 52°-58° at 10 mm Hg; δ (CDCl3) 0.94 (9H, s, C(CH3)3 ; 1.66 (2H, t, J=9 Hz, CH2) and 2.88 (2H, t, J=9 Hz, CH2CO).
Reaction SMILES: CN1CCOCC1.[F:8][C:9]([F:29])([F:28])[C:10]1[N:18]2[C:13]([C:14]3([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=32)=[CH:12][CH:11]=1.[C:30]([S:34]([C:36]1[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=1)=[O:35])([CH3:33])([CH3:32])[CH3:31].CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[C:30]([S:34]([C:36]1[CH:37]=[CH:38][C:39]([C:40]([N:25]2[CH2:24][CH2:23][C:14]3([C:13]4=[CH:12][CH:11]=[C:10]([C:9]([F:8])([F:28])[F:29])[N:18]4[C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[O:15]3)[CH2:27][CH2:26]2)=[O:41])=[CH:43][CH:44]=1)=[O:35])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)S(=O)c1ccc(C(=O)O)cc1
Reactant: FC(F)(F)c1ccc2n1-c1ccccc1OC21CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)S(=O)c1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2c(C(F)(F)F)ccc23)cc1
Temperature: 50 °C
Yield: 45.2 %

Procedure:
4-methyl morpholine (1.96 mL, 17.8 mmol) was added to a mixture of 1′-(trifluoromethyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (1.45 g, 3.56 mmol), 4-tert-butylsulfinylbenzoic acid (807 mg, 3.56 mmol), EDCI (1.03 g, 5.35 mmol), 1-hydroxybenzotriazole (723 mg, 5.35 mmol) and DMF (14.5 mL) at room temperature. The mixture was heated at 50° C. overnight before it was cooled to room temperature and partitioned between ethyl acetate and 1N HCl. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (0-30% ethyl acetate/CH2Cl2, then 0-100% ethyl acetate/hexanes) to provide (4-tert-butylsulfinylphenyl)-[1′-(trifluoromethyl)spiro-[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl]methanone (831 mg, 44%) as a white solid. 1H NMR (400 MHz, DMSO) δ 7.68-7.62 (m, 4H), 7.57 (d, J=8.1 Hz, 1H), 7.33-7.26 (m, 2H), 7.24-7.17 (m, 1H), 7.02 (d, J=4.0 Hz, 1H), 6.41 (d, J=4.0 Hz, 1H), 4.52-4.37 (m, 1H), 3.49 (s, 2H), 3.26-3.13 (m, 1H), 2.16-1.96 (m, 3H), 1.96-1.80 (m, 1H), 1.09 (s, 9H). ESI-MS m/z calc. 516.2, found 517.2 (M+1)+; Retention time: 1.94 minutes (3 min run).
Reaction SMILES: [CH:1]1([CH3:11])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([SH:10])[CH2:2]1.CI.[O-][CH2:15]C.[Na+]>C(O)C>[CH3:15][S:10][CH:3]1[CH:4]([CH:7]([CH3:8])[CH3:9])[CH2:5][CH2:6][CH:1]([CH3:11])[CH2:2]1
Reactant: CC[O-]
Reactant: CC1CCC(C(C)C)C(S)C1
Agent: [Na+]
Solvent: CCO
Solvent: CI
Product: CSC1CC(C)CCC1C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
p-Menthane-3-thiol (3.5 g., 20 mmole), methyl iodide (3.5 g., 25 mmole) and sodium ethoxide in ethanol (25 ml. of 0.8 M solution) were mixed together and stirred at room temperature for 21/2 hours. The ethanol was then removed and water was added to the residue, which was extracted with ether. The ether extracts were dried (MgSO4) and the solvent was removed. The residue was eluted with 40/60 petroleum ether down a silica column and the product was distilled to give p-menth-3-yl methyl sulphide b.p. 83°-5°/0.05 mm.
Reaction SMILES: [Li]C(C)(C)C.I[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]([CH3:15])[CH3:14].[CH2:16]=[O:17].[NH4+].[Cl-]>C1COCC1>[CH:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:16][OH:17])([CH3:15])[CH3:14]
Reactant: C=O
Reactant: CC(C)c1ccccc1I
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)c1ccccc1CO
Reaction time: 0.17 h

Procedure:
Add 1.7M tert-BuLi (26 ml, 44 mmol) dropwise, at −78° C. under inert atmosphere, to a solution of 1-Iodo-2-iso-propylbenzene (5 g, 20.3 mmol) in 70 ml of dry THF and stir. After 10 min, add Paraformaldehyde (2 g, 66.7 mmol) in a single portion. Stir the reaction at this temperature for 15 min and then at room temperature for 2 h. Add a saturated aqueous solution of NH4Cl and extract with CH2Cl2 three times. Dry the combined organic extracts over Na2SO4, filter and concentrate under reduced pressure to give a residue. Purify the residue by column chromatography on silica gel eluting with CH2Cl2 to afford pure (2-Isopropyl-phenyl)-methanol as pale purple oil. Add aqueous concentrated HBr (15 ml) to a solution of (2-Isopropyl-phenyl)-methanol (1,93 g, 12.85 mmol) in CH2Cl2(15 ml) and stir at room temperature. After 2 h. separate phases and wash the organic one with H2O; dry over Na2SO4 and evaporate at vacuum to obtain a residue. Purify the residue by column chromatography on silica gel eluting with CH2Cl2 to obtain 1-Bromomethyl-2-isopropyl-benzene as very pale pink light oil. 1H-NMR (CDCl3, 200 MHz): δ 7.33-7.25 (m, 3H), 7.19-7.11 (m, 1H), 4.58 (s, 1H), 3.31 (sep, J=6.8 Hz, 1H), 1.30 (d, J=6.8 Hz, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[C:27]1(B(O)O)[CH2:31][CH2:30][CH2:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CCO.O1CCOCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2[C:27]2[CH2:31][CH2:30][CH2:29][CH:28]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: OB(O)C1=CCCC1
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccc(F)cc2C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2C2=CCCC2)Cc2ccc(F)cc2C1
Yield: 69.3 %

Procedure:
To a solution of 5-fluoro-2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (400 mg, 0.85 mmol) and cyclopenten-1-ylboronic acid (383 mg, 3.42 mmol) in EtOH (10 mL) and dioxane (5 mL) is added palladium anchored homogeneous catalyst, FibreCatPd(0) (4.84% Pd, 186 mg, 8.5% mmol) and 2M aqueous solution of K2SO4 (1.71 mL, 3.42 mmol). The resulting reaction mixture is covered with argon and run in a microwave reaction: 110° C., 8 h. After concentration in vacuo, the residue is purified HPLC to give a pure product (151) as white solid (240 mg, 69%).
Reaction SMILES: [CH:1]([C:3]1[CH:24]=[CH:23][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=2)=[CH:5][CH:4]=1)=O.[CH2:25]([SH:29])[CH2:26][CH2:27][SH:28].Cl>C(Cl)(Cl)Cl>[S:28]1[CH2:27][CH2:26][CH2:25][S:29][CH:1]1[C:3]1[CH:24]=[CH:23][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[S:29][CH2:25][CH2:26][CH2:27][S:28]3)=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(OCCCCCCOc2ccc(C=O)cc2)cc1
Reactant: SCCCS
Agent: Cl
Solvent: ClC(Cl)Cl
Product: c1cc(C2SCCCS2)ccc1OCCCCCCOc1ccc(C2SCCCS2)cc1
Temperature: -10 °C

Procedure:
A suspension of 52.55 g (0.16 mol) 1,6-bis(4-formylphenoxy)hexane, 200 ml chloroform and 34.85 g (0.32 mol) 1,3-propanedithiol was stirred in a 500-ml three-necked flask with gas-entry tube, reflux cooler, internal thermometer and magnetic stirrer and cooled to −10° C. Dry HCl gas was introduced for approx. 15 min, whereupon the suspension thickened markedly. After the introduction of the HCl was complete, the reaction mixture was stirred for another 30 min accompanied by ice-cooling, the ice bath was removed and the red-brown suspension was stirred for a further 2 h at room temperature. The solvent was then distilled off with a membrane pump (400 to 10 mbar) into a cold trap, 300 ml ethyl acetate and 100 ml methanol added to the residue and the reaction mixture stirred. The suspension was filtered, the solid residue washed with 100 ml methanol and 100 ml acetone and dried to constant weight in the vacuum drying cupboard. 78.2 g (96% of the theoretical value) 1,6-bis[4-(1,3-dithian-2-yl)phenoxy]hexane was obtained as a reddish, poorly soluble solid (m.p.: 189-192° C.).
Reaction SMILES: [BH4-].[Na+].[C:3]1([S:9]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([CH:21]=[CH:22][N+:23]([O-:25])=[O:24])=[CH:18][CH:19]=3)[C:14]3[CH:26]=[C:27]([Cl:30])[CH:28]=[N:29][C:13]2=3)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(Cl)(Cl)Cl>C(O)(C)C>[C:3]1([S:9]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([CH2:21][CH2:22][N+:23]([O-:25])=[O:24])=[CH:18][CH:19]=3)[C:14]3[CH:26]=[C:27]([Cl:30])[CH:28]=[N:29][C:13]2=3)(=[O:10])=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])C=Cc1ccc2c(c1)c1cc(Cl)cnc1n2S(=O)(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])CCc1ccc2c(c1)c1cc(Cl)cnc1n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
NaBH4 (46 mg, 2.5 equiv.) was added in small portions to a suspension of 14 (200 mg, 0.48 mmol) and 240 mg of silica (40-60 mesh) in a solution of chloroform and isopropanol (11.6 mL, 8.6:3). The solution was stirred for 1 h 30 at room temperature and then filtered through celite. Solvents were removed under reduced pressure and the crude product was purified by flash chromatography (CH2Cl2/PE 7:3) to afford 15 in 73% yield as a white solid, 1H-NMR (300 MHz, CDCl3): δ 8.49 (d, 1H, J=1.2 Hz), 8.41 (d, 1H, J=8.6 Hz), 8.14-8.10 (m, 3H), 7.74 (bs, 1H), 7.55 (t, 1H, J=7.5 Hz), 7.45-7.40 (m, 3H), 4.70 (t, 2H, J=7.1 Hz), 3.46 (t, 1H, J=7.1 Hz), 13C-NMR (75 MHz, CDCl3): δ 162.4 (C), 149.0 (C), 145.8 (CH), 138.4 (C), 137.7 (C), 134.3 (CH), 131.9 (C), 129.9 (CH), 129.2 (2 CH), 128.2 (CH), 127.7 (2C), 122.3 (C), 121.0 (CH), 119.4 (C), 115.7 (CH), 76.4 (CH2), 33.2 (CH2), MS (ESI) m/z 416 [M+H+]