Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:19]([O:21]CC)=[CH2:20])CCC.Cl>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:9]1([CH3:13])[C:10]2[CH:11]=[C:2]([C:19](=[O:21])[CH3:20])[CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1
Reactant: CC1(C)CCCc2ccc(Br)cc21
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)C(C)(C)CCC2
Temperature: 80 °C
Reaction time: 18 h
Yield: 55.7 %

Procedure:
A solution of 7-bromo-1,1-dimethyl-1,2,3,4-tetrahydro-naphthalene (Compound 15, 1.20 g, 5.94 mmol) in 20 ml of THF was first degassed by bubbling with argon for 30 min. Tributyl(1-ethoxyvinyl)tin (4.29 g, 11.88 mmol) and PdCl2(PPh3)2 (422 mg, 0.60 mmol) were added. After stirring at 80° C. for 18 h, the mixture was cooled to room temperature and 3 mL of 10 % HCl was added. The mixture was then stirred for another 30 min, then extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with brine (1×10 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chromatography (80:20 hexane/ethyl acetate) afforded the title compound (669 mg, 56% yield) as a colorless oil:
Reaction SMILES: [NH2:1][C:2]([N:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)[CH2:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=[O:14])=[CH:9][CH:8]=1)=[S:3].[F:33][C:34]1[CH:35]=[C:36]([CH:41]=[CH:42][C:43]=1[F:44])[C:37](=O)[CH2:38]Br>>[F:33][C:34]1[CH:35]=[C:36]([C:37]2[N:1]=[C:2]([N:4]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=3)[CH2:5][CH2:6][C:7]3[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:18])([CH3:19])[C:13]([OH:15])=[O:14])=[CH:9][CH:8]=3)[S:3][CH:38]=2)[CH:41]=[CH:42][C:43]=1[F:44]
Reactant: O=C(CBr)c1ccc(F)c(F)c1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)C(N)=S)cc1
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2nc(-c3ccc(F)c(F)c3)cs2)cc1)C(=O)O

Procedure:
Similarly prepared from ethyl 2-[4-(2-{(aminocarbonothioyl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and 3,4-difluorophenacyl bromide.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:6][O:5][C:4]([C:7]2[O:11][N:10]=[C:9]([O:12][CH2:13][CH3:14])[C:8]=2[CH3:15])=[N:3]1.C1C(=O)N([Br:24])C(=O)C1>ClC(Cl)(Cl)Cl>[Br:24][CH2:15][C:8]1[C:9]([O:12][CH2:13][CH3:14])=[N:10][O:11][C:7]=1[C:4]1[O:5][CH2:6][C:2]([CH3:1])([CH3:16])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1noc(C2=NC(C)(C)CO2)c1C
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1noc(C2=NC(C)(C)CO2)c1CBr
Yield: 74.1 %

Procedure:
5-(4,5-Dihydro-4,4-dimethyl-1,3-oxazol-2-yl)-3-ethoxy-4-methylisoxazole (2.0 g, 8.9 mmol), NBS (1.75 g, 9.8 mmol) and tetrachloromethane (150 mL) was boiled under reflux for 5 h. The mixture was cooled, filtered and concentrated in vacuo. Flash chromatography (silica gel, eluent: toluene/EtOAc/triethylamine=100:10:1) gave the title compound as a yellow oil (2.0 g, 74%).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH3:14][CH:13]([S:10]([NH:9][CH2:8][CH:7]([O:6][C:5]1[CH:17]=[CH:18][C:2]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:3][CH:4]=1)[CH3:16])(=[O:12])=[O:11])[CH3:15]
Reactant: Cc1ccccc1B(O)O
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccccc1-c1ccc(OC(C)CNS(=O)(=O)C(C)C)cc1
Yield: 33.9 %

Procedure:
The title compound (120 mg, 34%, yellow foam) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (343 mg, 1.02 mmol, prepared in example 1), 2-methylbenzeneboronic acid (165 mg, 1.21 mmol), dichlorobis(triphenylphosphine)palladium(II) (30 mg, 0.043 mmol), 2 M sodium carbonate (370 mg in 1.75 mL water), and 1,2-dimethoxyethane (6.8 mL) in a manner analogous to the procedure described in Example 8.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:13].[H-].[Na+].[CH:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.Cl>CN(C)C=O>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]2[C:3]=1[CH2:4][C:5](=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:6]2=[O:13]
Reactant: COc1ccc(C=O)cc1
Reactant: Cc1cc(C)c2c(c1O)C(=O)CC2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C=C2Cc3c(C)cc(C)c(O)c3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10 Grams of 2,3-dihydro-4,6dimethyl-7-hydroxy-1H-inden-1-one was dissolved in 200 ml of dimethylformamide, then 5.45 g of 60%-sodium hydride was added gradually thereto and the reaction mixture was stirred at room temperature for 30 minutes. Next, 6.91 ml of p-anisaldehyde was added to the reaction mixture and further stirred at room temperature for 1 hour. The reaction mixture was poured into 500 ml of ice-water, then acidified by adding hydrochloric acid, and the crystals formed were collected by filtration. The crystals were washed with water and with n-hexane and dried. Recrystallized from ethanol to obtain 16.09 g of 2,3-dihydro-4,6-dimethyl-7-hydroxy-2-(4-methoxybenzylidene)-1H-inden-1-one. Yellow needle-like crystals. Melting point: 192°-193° C.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=1)=O.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:13][C:5]1[CH:4]=[C:3]([CH2:1][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: C1CCNCC1
Reactant: COC(=O)c1ccc(C=O)cc1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(CN2CCCCC2)cc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.5 %

Procedure:
To a solution of methyl 4-formyl-2-methylbenzoate (300 mg, 1.7 mmol) and piperidine (92 mg, 1.1 mmol) in methanol (50 mL) was added acetic acid (1 drop) followed by sodium cyanoborohydride (221 mg, 3.5 mmol). The mixture was stirred at room temperature for 24 hours. The mixture was filtered, acidified with concentrated hydrochloride acid (1 mL) and concentrated in vacuo. To the residue, water (50 mL) was added. The mixture was extracted with dichloromethane (50 mL). The combined organic phase was separated, dried by sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=4:1, 1% NH3) to give methyl 2-methyl-4-(piperidin-1-ylmethyl)benzoate as a yellow oil (200 mg, 60%). LRMS (M+H+) m/z: calcd 247.16. found 247. 1H NMR (300 MHz, CDCl3): δ 7.73 (d, J=8.7 Hz, 1H), 7.52-7.50 (m, 2H), 3.91 (s, 3H), 3.62 (s, 2H), 2.52 (s, 3H), 2.32-2.24 (m, 4H), 1.47-1.44 (m, 6H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[O:13].P(Cl)(Cl)(Cl)(Cl)[Cl:17]>>[Cl-:17].[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[O:13]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C1Nc2ccc(C(F)(F)F)cc2C1=O
Product: [Cl-]

Procedure:
By reacting 5-trifluoromethylisatin with phosphorus penta-chloride, there is obtained 5-trifluoromethylisatin chloride which, on reaction with 3(2H)-thianaphthenone, yields 5'-trifluoromethyl-2'-indole-2-thianaphthenone indigo, which also is useful as a dyestuff.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[C:6](O)(=[O:14])[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH2:9].Cl>ClCCl>[CH2:2]([C:1]1[O:4][C:6](=[O:14])[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH3:3]
Reactant: CCC(=O)Cl
Reactant: Nc1ccccc1C(=O)O
Agent: Cl
Solvent: ClCCl
Product: CCc1nc2ccccc2c(=O)o1
Yield: 78.2 %

Procedure:
Propanoyl chloride (6.2 g, 67 mmol) was added to a solution of anthranilic acid (1 g, 7.3 mmol) in dichloromethane (20 mL). The reaction medium was kept under reflux and agitation, with the end of the reaction being monitored by CG/MS. After the end of the reaction, a hydrochloric acid solution was added (20 mL, 1M), and the resulting mixture was extracted with ethyl acetate (100 mL), the extract was dried with magnesium sulfate and the solvent was evaporated. Acetic anhydride (15 mL) was added to the residue and the reaction medium was taken to reflux and accompanied through CG/MS in order to monitor cyclization. After the end of the reaction, the reaction medium spin dried at a temperature of 65° C. using portions of toluene to facilitate the elimination of the anhydride. 1.0 g of the raw product 2-ethyl-4H-3,1-benzoxazin-4-one was obtained, which was used directly in the stage subsequent to reaction.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:22])[C:6]([CH3:21])([CH3:20])[C:7]1[CH2:8][CH2:9][N:10](CC2C=CC=CC=2)[CH2:11][CH:12]=1)[CH3:3].[H][H].[OH-].[Na+]>C(O)C.O.[Pd]>[CH2:2]([O:4][C:5](=[O:22])[C:6]([CH3:21])([CH3:20])[CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)[CH3:3]
Reactant: [H][H]
Reactant: CCOC(=O)C(C)(C)C1=CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)(C)C1CCNCC1
Yield: 82 %

Procedure:
A solution of 246 g (76.6×10-2 mole) of the hydrochloride of 1-phenylmethyl-α,α-dimethyl-1,2,3,6-tetrahydro-4-pyridine-acetic acid ethyl ester in 1.5 liters of ethanol was hydrogenated in a Parr's apparatus at 50° C. at a hydrogen pressure of 3.106Pa in the presence of 20 g of 5% palladium/charcoal. After filtering, the filtrate obtained was evaporated off under reduced pressure. The residue obtained was taken up in water and rendered alkaline with 500 ml of 5N sodium hydroxide. It was extracted with ethyl acetate. The organic phase was dried over magnesium sulphate and filtered and the solvents were evaporated off under reduced pressure. 125.3 g (yield: 82%) of the desired product was obtained as an oil. n21 =1.47
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH2:22][CH2:23][S:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9](=[O:21])NC2SC(SCC(O)=O)=CN=2)[CH2:4][CH2:3]1.C([O:33][C:34](=[O:45])[C:35]([S:38][C:39]1[S:43][C:42]([NH2:44])=[N:41][CH:40]=1)([CH3:37])[CH3:36])C>>[CH3:37][C:35]([S:38][C:39]1[S:43][C:42]([NH:44][C:9]([N:8]([C@H:5]2[CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:7][CH2:6]2)[CH2:22][CH2:23][S:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:21])=[N:41][CH:40]=1)([CH3:36])[C:34]([OH:33])=[O:45]
Reactant: C[C@H]1CC[C@H](N(CCSc2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCSc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[3-(trans-4-methyl-cyclohexyl)-3-(2-phenylsulfanyl-ethyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [Na].N.Cl[CH:4]([CH2:14]Cl)[CH2:5][CH2:6][Si:7]([O:12][CH3:13])([O:10][CH3:11])[O:8][CH3:9]>CCCCC>[CH2:6]([Si:7]([O:12][CH3:13])([O:8][CH3:9])[O:10][CH3:11])[CH2:5][CH:4]=[CH2:14]
Reactant: CO[Si](CCC(Cl)CCl)(OC)OC
Agent: N
Agent: [Na]
Solvent: CCCCC
Product: C=CCC[Si](OC)(OC)OC

Procedure:
23 g sodium (1 mole) are placed in a 500 ml flask and approximately 150 ml ammonia condensed in at -70° C. 123.6 g 3,4-dichlorobutyl trimethoxysilane (0.5 mole) is added dropwise to the deep-blue solution produced in the course of 1 hour at -55° C. while the reaction mixture visibly changes color. The ammonia is allowed to evaporate overnight from the colorless, highly viscous suspension produced, the colorless residue combined with 150 ml n-pentane, the NaCl (56.9 g≅97.5% of theory) removed by filtration and 88.2 of a colorless liquid corresponding to the expected amount is obtained after the solvent is drawn off. 75.7 g=85.9% of theory of pure 3-butenyl trimethoxysilane are obtained therefrom by distillation (cf. table 1).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([CH3:12])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1.Br[C:14]([CH3:19])([CH3:18])[C:15](Br)=[O:16]>ClC1C=CC=CC=1>[CH3:18][CH:14]1[CH2:19][C:8]2[C:9](=[CH:10][C:5]([CH3:12])=[CH:6][C:7]=2[CH3:11])[C:15]1=[O:16]
Reactant: CC(C)(Br)C(=O)Br
Reactant: Cc1cccc(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: Cc1cc(C)c2c(c1)C(=O)C(C)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
A 500 μL, 3-neck rounded bottom flask equipped with a magnetic stirring bar and a reflux condenser, was charged under nitrogen with 71.16 g of AlCl3 (0.53 mol) dissolved in 240 mL of chlorobenzene. At room temperature 28.38 mL of m-xylene (0.23 mol) were added dropwise obtaining a light yellow suspension. The flask was then cooled to 0° C. and 28.68 mL of 2-bromoisobutyryl bromide (0.23 mol) were slowly added. At the end of the addition a dark-red slurry was obtained. The reaction mixture was then allowed to warm up to room temperature (r.t.) and stirred for 2 hours. Then it was transferred into a flask containing a solution of 3/1 ice/37% HCl. The organic phase was extracted with Et2O (3×200 mL), the combined organic phases were dried over Na2SO4, filtered and the solvents were removed in vacuo to leave 37.48 g of an orange oil (yield 93.5%). The latter was used as such in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=1)[CH2:3][CH2:4][CH2:5][C:6]([O:8]CC)=[O:7]>[OH-].[Na+]>[O:1]=[C:2]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=1)[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)CCCC(=O)c1cn(-c2cccnc2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCC(=O)c1cn(-c2cccnc2)c2ccccc12

Procedure:
A mixture of 15.0 of 3-(1-oxo-4-ethoxycarbonylbutyl)-N-(3-pyridyl)indole, 100 ml of 0.5N sodium hydroxide is heated under reflux for 16 hours. The solution is acidified to pH of about 6 with hydrochloric and extracted with methylene chloride. The methylene chloride extract is dried over sodium sulfate and evaporated to dryness to give 3-(1-oxo-4-carboxybutyl)-N-(3-pyridyl)-indole, melting point 177°-178°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:82]1[CH2:85][CH2:84][CH2:83]1>CN(C=O)C.[Pd]>[N:82]1([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[C:19]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH2:85][CH2:84][CH2:83]1
Reactant: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Br)cc1
Reactant: C1CNC1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(N2CCC2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of heterocyclyl and heteroaryl substituted phenylsulfonyl derivatives previously described, using 4-Bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide 0.3 g (0.66 mmol), potassium phosphate tribasic monohydrate 0.91 g (3.96 mmol), rac-2,2′-bis (diphenylphosphino)-1,1′-binaphthyl 0.12 g (0.198 mmol), azetidine 0.18 g (3.3 mmol) and Pd (dba)3 60 mg (0.066 mmol) in 3 ml DMF, followed by workup and HPLC purification.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[C:25]([F:27])[C:24]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:23][C:22]=2[O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.O>ClCCl>[CH2:37]([O:36][C:22]1[CH:23]=[C:24]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:25]([F:27])=[CH:26][C:21]=1[CH:18]1[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(F)c(OCc3ccccc3)cc2OCc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Fc1cc(C2CCNCC2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.6 %

Procedure:
280 μl (3.7 mmol, 10 eq) of trifluoroacetic acid are added to a solution of 184 mg (0.37 mmol, 1 eq) of 4-(2,4-bis(benzyloxy)-5-fluorophenyl)piperidine-1-carboxylic acid tert-butyl ester in 3 ml of dichloromethane. The reaction medium is stirred at ambient temperature for 1 hour. The reaction medium is treated with 10 ml of water and then extracted with dichloromethane. The organic phases are combined, washed with a saturated solution of sodium hydrogen carbonate and then with a saturated solution of sodium chloride, dried over magnesium sulphate and evaporated. 150 mg of 4-(2,4-bis(benzyloxy)-5-fluorophenyl)piperidine are obtained. Yield=100%.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][CH:32]([O:35][CH2:36][CH:37]=C)[CH2:31][CH2:30]1.I([O-])(=O)(=O)=[O:40].[Na+].CC(C)=O.C(#N)C>C(OCC)(=O)C.O.[Os]=O>[OH:40][CH2:37][CH2:36][O:35][C@H:32]1[CH2:33][CH2:34][C@H:29]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:11][CH:10]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)[CH2:30][CH2:31]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCOC1CCC(n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3)c(CCC)n3ncnc23)CC1
Agent: O=[Os]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCO)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4′-({5-oxo-4-[4-(prop-2-en-1-yloxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (1.1 g), osmium oxide (7% immobilized catalyst, 0.48 g), sodium periodate (2.4 g), acetone (15 mL), acetonitrile (15 mL) and water (15 mL) was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate and water, and insoluble material was filtered off through celite. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in methanol (20 mL), sodium borohydride (0.13 g) was added, and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.23 g, 20%).
Reaction SMILES: C(O[C:4](=[O:14])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[CH:8]=[N:7][CH:6]=1)C.[OH-].[Na+].Cl.[NH:18]([O:20][CH3:21])[CH3:19].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CCO.CN(C=O)C>[CH2:12]([O:11][C:9]1[CH:8]=[N:7][CH:6]=[C:5]([CH:10]=1)[C:4]([N:18]([O:20][CH3:21])[CH3:19])=[O:14])[CH3:13]
Reactant: CCOC(=O)c1cncc(OCC)c1
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CCOc1cncc(C(=O)N(C)OC)c1
Reaction time: 1 h

Procedure:
To a solution of 16-2 (15 g, 72 mmol) in EtOH (100 mL) was added 1N NaOH (80 ml, 80 mmol). After stirring for 1 h, the solvents were evaporated and the residue was dissolved in 1N HCl (80 ml, 80 mmol) and then concentrated, azeotroped with CH3CN to give the crude acid. The crude acid was suspended in DMF (200 mL) and then treated with HCl.HN(Me)OMe (13.9 g, 144 mmol), EDC (15.1 g, 79.2 mmol), HOBT (9.6 g, 72 mmol) and NMM (60 mL, 576 mmol). The mixture was stirred for 18 hours and then concentrated. The residue was dissolved in ethyl acetate, washed with 10% K2CO3, brine, dried (MgSO4), and concentrated to give amide 16-3 as a brown oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:12])[CH3:11])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH3:27]>[Cu]Br>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH3:27])[C:10](=[O:12])[CH3:11])[CH3:2]
Reactant: CCc1ccccc1Br
Reactant: CCc1ccccc1NC(C)=O
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1ccccc1N(C(C)=O)c1ccccc1CC
Temperature: 200 °C
Yield: 67 %

Procedure:
The mixture of the N-(2-ethylphenyl)acetamide (7.35 g, 45.03 mmol), anhydrous K2CO3 (6.22 g, 45.03 mmol), copper(I) bromide (452.2 mg, 3.15 mmol) in 1-bromo-2-ethylbenzene was stirred and heated to 200° C. under argon for 48 h. After cooling the reaction mixture was poured into ice-H2O and extracted with ethyl acetate (2×500 mL), the combined organics were washed with brine, dried over anhydrous (K2CO3), filtered and concentrated to dryness. The crude product was purified using an ISCO machine using a ethyl acetate-hexane gradient to afford the product, N,N-bis(2-ethylphenyl)acetamide (8.1 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]([OH:22])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.OCC([C:28]1[C:33]([N+:34]([O-])=O)=[C:32]([CH3:37])[CH:31]=[CH:30][C:29]=1[S:38]([NH2:41])(=[O:40])=[O:39])(C)C>>[OH:22][CH2:20][C:19]([NH:41][S:38]([C:29]1[CH:30]=[CH:31][C:32]([CH3:37])=[C:33]([NH:34][C:20]([C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH:14]4[CH2:15][CH2:16]4)=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][C:10]=23)=[O:22])[CH:28]=1)(=[O:39])=[O:40])([CH3:18])[CH3:10]
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Reactant: Cc1ccc(S(N)(=O)=O)c(C(C)(C)CO)c1[N+](=O)[O-]
Product: Cc1ccc(S(=O)(=O)NC(C)(C)CO)cc1NC(=O)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.28) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-4-methyl-benzenesulfonamide (example B.11) according to general procedure II. Pale-yellow solid. MS (ISP) 554.3 [(M+H)+].