Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:7].[C:8](Cl)(=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[C:8]([N:3]1[CH2:4][CH2:5][CH2:6][O:1][C:2]1=[O:7])(=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCC(=O)Cl
Reactant: O=C1NCCCO1
Product: CCCCCCCC(=O)N1CCCOC1=O

Procedure:
This compound was prepared following the procedure of Example 1 wherein tetrahydro-2H-1,3-oxazin-2-one was used in place of 2-oxazolidone and octanoyl chloride was used in the place of lauroyl chloride.
Reaction SMILES: C([O:4][CH:5](OC(=O)C)[C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[C:8]([F:13])[CH:7]=1)(=O)C.C(O)C.O.S(=O)(=O)(O)O>CCOCC>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[O:4])=[CH:7][C:8]=1[F:13]
Reactant: CC(=O)OC(OC(C)=O)c1ccc(Br)c(F)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: O=Cc1ccc(Br)c(F)c1

Procedure:
A mixture of 4-bromo-3-fluorobenzylidene diacetate (15 g), ethanol (41 ml), water (41 ml) and concentrated sulphuric acid (4 ml) was heated to reflux for 3 hours. After cooling, ether (300 ml) was added and the aqueous layer separated. The organic phase was washed with saturated sodium carbonate and brine before drying over anhydrous magnesium sulphate and evaporation in vacuo. 4-Bromo-3-fluorobenzaldehyde was obtained as a solid (7.3 g).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[N:10]2[C:11](=[O:21])[C:12]([NH:16][CH:17]3[CH2:20][CH2:19][CH2:18]3)=[N:13][C:14]([Cl:15])=[C:9]2[C@H:8]([CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:7]1)=[O:5])C.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[Cl:15][C:14]1[N:13]=[C:12]([NH:16][CH:17]2[CH2:18][CH2:19][CH2:20]2)[C:11](=[O:21])[N:10]2[C@H:6]([C:4]([OH:5])=[O:3])[CH2:7][C@@H:8]([CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:9]=12
Reactant: CCOC(=O)[C@@H]1C[C@@H](CCCc2ccccc2)c2c(Cl)nc(NC3CCC3)c(=O)n21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@@H]1C[C@@H](CCCc2ccccc2)c2c(Cl)nc(NC3CCC3)c(=O)n21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.8 %

Procedure:
To the ester from Step E (78 mg, 0.18 mmol) dissolved in methanol (1.0 mL) was added LiOH (1.0 M, 0.36 mL). The mixture was stirred at rt for 1.5 h. It was acidified with 5% citric acid, and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4. Evaporation of solvent and lyopholization gave 70 mg white solid used directly in the next Step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([CH:30]=[CH2:31])[C:9]([O:13][C@H:14]3[CH2:18][N:17](C(OC(C)(C)C)=O)[C@H:16]([C:26]([O:28][CH3:29])=[O:27])[CH2:15]3)=[N:10]2)=[CH:5][CH:4]=1.[ClH:32]>O1CCOCC1>[ClH:32].[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([CH:30]=[CH2:31])[C:9]([O:13][C@H:14]3[CH2:18][NH:17][C@H:16]([C:26]([O:28][CH3:29])=[O:27])[CH2:15]3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: C=Cc1cc2ccc(OC)cc2nc1O[C@@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: C=Cc1cc2ccc(OC)cc2nc1O[C@H]1CN[C@H](C(=O)OC)C1

Procedure:
A solution of 1-t-butyl 2-methyl (2S,4R)-4-[(7-methoxy-3-vinylquinolin-2-yl)oxy]pyrrolidine-1,2-dicarboxylate (0.85 g, 1.98 mmol) in 4M HCl in dioxane (10 mL) was stirred at RT for two hours. The reaction mixture was concentrated, and the product was used with no further purification. LRMS (M+H-tBu)+=329.3.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N:21]1[CH:22]=[CH:23][N:24]2[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][C:25]=12.C(N(CC)C(C)C)(C)C>C(#N)C>[N:21]1[CH:22]=[CH:23][N:24]2[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:2]3[C:3]4[CH2:11][N:10]([C:12]5[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=5[C:14]#[N:15])[CH2:9][CH2:8][C:4]=4[N:5]=[CH:6][N:7]=3)=[CH:26][C:25]=12
Reactant: NCc1ccn2ccnc2c1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(NCc4ccn5ccnc5c4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (300 mg, 1.05 mmol) and imidazo[1,2-a]pyridin-7-ylmethanamine (400 mg, 2.31 mmol) in acetonitrile (10 mL) and N,N-diisopropylethylamine (1.0 mL, 5.7 mmol) was subjected to microwave irradiation at 185° C. for 2.5 h. The reaction mixture was concentrated and purified by semi-preparative HPLC (100×20.2 mm, C18 column; 30-60% CH3CN-water [10 mM Et2NH]) to yield a light yellow solid.
Reaction SMILES: CO.[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[C:35]([NH2:40])[CH:36]=[CH:37][CH:38]=5)[CH:33]=[CH:32][C:31]4=[O:41])[CH2:24][CH2:23]3)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1.[C:42](=O)([O-])[O-].[Na+].[Na+].S(OC)(OC)(=O)=O>O>[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[C:35]([NH:40][CH3:42])[CH:36]=[CH:37][CH:38]=5)[CH:33]=[CH:32][C:31]4=[O:41])[CH2:24][CH2:23]3)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(N)cccc32)CC1
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: CO
Product: CNc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.6 %

Procedure:
To 1.5 mL of a methanol solution containing 280 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-amino-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 0.5 mL of water, 83 mg of sodium carbonate and 99 mg of dimethyl sulfate were added, and stirred at room temperature for 3 days. The insoluble material was filtered off, and the solvent was removed under reduced pressure, and purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate: methanol=10:1], to give 65 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-(N-methylamino)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow oil.
Reaction SMILES: [F:1]/[C:2](/[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:3]/[CH2:4][NH:5]C(=O)OC(C)(C)C.[ClH:21]>C(OCC)C>[ClH:21].[F:1]/[C:2](/[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:3]/[CH2:4][NH2:5]
Reactant: CC(C)(C)OC(=O)NC/C=C(/F)COc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: NC/C=C(/F)COc1ccccc1
Reaction time: 68 h
Yield: 46 %

Procedure:
To a solution of (E)-tert-butyl 3-fluoro-4-phenoxybut-2-enylcarbamate (0.026 g, 0.09 mmol) in diethyl ether (3 mL) was added HCl (2 M solution in diethyl ether; 0.23 mL) dropwise. The reaction mixture was then sealed and allowed to stand for 68 hours. The solvent was removed under reduced pressure, dissolved in methanol (2 mL), filtered, and the methanol removed. The resultant gum was dried at 60° C. to afford (E)-3-fluoro-4-phenoxybut-2-en-1-amine hydrochloride (0.009 g, 46%) as an off-white solid; m.p.=113-116° C.; 1H-NMR (200 MHz, CD3OD): δppm: 3.69 (2H, d, J 8.2 Hz), 4.75 (2H, d, J 17.8 Hz), 5.51 (1H, dt, J 18.2, 8.6 Hz), 6.91-7.03 (3H, m), 7.22-7.35 (2H, m).
Reaction SMILES: [Li+].[OH-].[OH:3][CH:4]([CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1)/[CH:5]=[CH:6]/[C@H:7]1[CH2:11][CH2:10][C:9](=[O:12])[C@@H:8]1[CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=1.Cl>C1COCC1>[OH:3][CH:4]([CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1)/[CH:5]=[CH:6]/[C@H:7]1[CH2:11][CH2:10][C:9](=[O:12])[C@@H:8]1[CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(CC[C@H]2C(=O)CC[C@@H]2/C=C/C(O)Cc2ccc3ccccc3c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CC[C@H]2C(=O)CC[C@@H]2/C=C/C(O)Cc2ccc3ccccc3c2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
LiOH (240 mL, 0.24 mmol, 1 M) was added to a solution of methyl 4-(2-((1R,2R)-2-((E)-3-hydroxy-4-(naphthalen-2-yl)but-1-en-1-yl)-5-oxocyclopentyl)ethyl)benzoate (21 mg, 0.047 mmol) in THF (2.5 mL). The mixture was stirred at 60° C. overnight, cooled to room temperature and then 1 M HCl (20 mL) was added. The resulting mixture was extracted with CH2Cl2 (3×20 mL) and the combined organic solution was washed with brine and then was dried (Na2SO4), filtered and evaporated. Purification by preparative thin layer chromatography (10% methanol/CH2Cl2) gave the title compound (13 mg).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:3]1=2.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([Cl:22])=[O:19])=[CH:16][C:3]1=2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1ccccc1CO2
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc2c(c1)C(=O)c1ccccc1CO2

Procedure:
Next, 30.44 g of oxepincarboxylic acid III obtained above was allowed to react with 30 ml of thionyl chloride in 200 ml of toluene by heating under reflux for one hour. Concentration of the reaction mixture to dryness under reduced pressure gave 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-carboxylic acid chloride IV in a quantitative yield. One half of this acid chloride IV was added to 300 ml of ethanol, and the mixture was stirred at room temperature for three hours and concentrated under reduced pressure. The residue was dissolved in chloroform, and the solution was washed with a saturated aqueous solution of sodium bicarbonate, dehydrated and concentrated to dryness to obtain 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-carboxylic acid ethyl ester V in a quantitative yield. Recrystallization from n-hexane gave pure crystals having a melting point of 104°-105° C. IR spectrum (KBr tablet, cm-1): 2980, 1710, 1650, 1610, 1250, 1010.
Reaction SMILES: CN1CCN(C[C:9]2[CH:37]=[CH:36][C:12]([C:13]([NH:15]C3C=CC(C)=C(NC4N=C(C5C=NC=CC=5)C=CN=4)C=3)=[O:14])=[CH:11][CH:10]=2)CC1.OC1C(C(O)=O)=CC2C(C=1)=CC=CC=2.O>C(O)C>[C:13]([NH2:15])(=[O:14])[C:12]1[CH:36]=[CH:37][CH:9]=[CH:10][CH:11]=1
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Agent: O=C(O)c1cc2ccccc2cc1O
Solvent: CCO
Solvent: O
Product: NC(=O)c1ccccc1

Procedure:
A mixture of 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamide (4.94 g, 10 mmol) and 4,4′-methylenebis[3-hydroxy-2-naphthoic acid (Fluka, Buchs, Switzerland; 3.88 g, 10 mmol) in ethanol (50 mL) is heated. Water (25 mL) is then added. Upon cooling, the product crystallises and is filtered-off and dried to afford 4-[(4-methyl-1-piperazinyl)methyl]-N-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamide, pamoate as a pale-yellow solid, having the following analytical properties: Analysis found: C, 69.12; H, 5.62; N, 10.88%; H2O, 2.50%. Calculated for C52H47N7O7-1.26 H2O: C, 69.04; H, 5.52; N, 10.84%; H2O, 2.51%.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:19][O:20][C:21]1[CH:37]=[CH:36][C:24]([CH2:25][N:26]2[CH:30]=[C:29]([C:31](OCC)=[O:32])[CH:28]=[N:27]2)=[CH:23][CH:22]=1.C(OCC)C.[OH-].[Na+]>O1CCCC1>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:10][C:9]=1[CH2:19][O:20][C:21]1[CH:37]=[CH:36][C:24]([CH2:25][N:26]2[CH:30]=[C:29]([CH2:31][OH:32])[CH:28]=[N:27]2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cnn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CO)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
Lithium aluminium hydride (323 mg) was added to a mixture of ethyl 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazole-4-carboxylate (3.55 g), diethyl ether (25 ml), and tetrahydrofuran (25 ml) at 0° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into a 1N aqueous sodium hydroxide solution, which was extracted with diethyl ether. The diethyl ether layer was washed with water and then with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The crystals obtained were filtrated to obtain [1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]methanol (2.93 g, yield: 92%). This was recrystallized from ethyl acetate-hexane. Melting point: 100–101° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10](I)=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([CH3:23])[O:22][CH2:21][CH2:20][O:19]4)=[CH:14][CH:13]=3)[N:8]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:5]2=[N:6][CH:7]=1.[Li][C:33](C)(C)C.CI.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([CH3:33])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([CH3:23])[O:22][CH2:21][CH2:20][O:19]4)=[CH:14][CH:13]=3)[N:8]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:5]2=[N:6][CH:7]=1
Reactant: CC1(c2ccc(-c3c(I)c4nc(Br)cnc4n3COCC[Si](C)(C)C)cc2)OCCO1
Reactant: [Li]C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(-c2ccc(C3(C)OCCO3)cc2)n(COCC[Si](C)(C)C)c2ncc(Br)nc12
Temperature: -75 °C
Reaction time: 0.08 h
Yield: 66.9 %

Procedure:
2-Bromo-7-iodo-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (1.0 g, 1.6 mmol, Preparation #5, Step A) in THF (12 mL) was cooled to about −75° C. then t-BuLi (1.7 M in hexanes, 1.05 mL, 1.79 mmol) was added keeping the temperature about −70 and −75° C. The mixture was stirred for about 5 min at about −75° C. Additional t-BuLi (1.7 M in hexanes, 0.286 mL, 0.487 mmol) was added and the mixture was stirred an additional 15 min. The mixture was treated with MeI (0.461 g, 3.24 mmol) then the temperature of the mixture was raised to about 15° C. over about 10 min. The mixture was stirred at about 20° C. overnight then saturated aqueous NH4Cl (5 mL) was added. The mixture was stirred for about 15 min at about 20° C. then the material was partitioned between EtOAc (50 mL) and water (20 mL). The layers were separated and then the aqueous layer was extracted with EtOAc (10 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The material was purified by flash chromatography with a 25 g silica gel column and eluted with 0 to 40% EtOAc/heptane to provide 2-bromo-7-methyl-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (0.54 g, 66%): LC/MS (Table 2, Method g) Rf=2.25 min; MS m/z 504, 506 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:26][C:25](=[O:27])[NH:24][S:23]2(=[O:29])=[O:28])=[C:18]([O:30]CC2C=CC=CC=2)[CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.O.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:26][C:25](=[O:27])[NH:24][S:23]2(=[O:29])=[O:28])=[C:18]([OH:30])[CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCCC1CCc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1

Procedure:
A solution of 2-{2-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester in 2 mL of ethanol/water (1:1) is hydrogenated over 10% Pd/C at 1 atm for 2 h. The catalyst is removed by filtration through Celite and the solvent is removed under reduced pressure to give the title compound: LC rt 1.52 (method A); (M−1)−=438.
Reaction SMILES: [Cl:1][CH2:2][C:3]1([CH3:9])[O:7][C:6](=[O:8])[NH:5][CH2:4]1.Br[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1>[Cl:1][CH2:2][C:3]1([CH3:9])[O:7][C:6](=[O:8])[N:5]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)[CH2:4]1
Reactant: CC1(CCl)CNC(=O)O1
Reactant: Clc1ccc(Br)nc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC1(CCl)CN(c2ccc(Cl)cn2)C(=O)O1
Temperature: 85 °C
Reaction time: 12 h
Yield: 38.8 %

Procedure:
A mixture of 5-(chloromethyl)-5-methyl-1,3-oxazolidin-2-one (1.50 g, INTERMEDIATE 16), 2-bromo-5-chloropyridine (1.92 g), cesium carbonate (4.89 g), bispalladium tribenzylideneacetone (1.37 g) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.30 g) in 25 ml of dioxane was stirred at 85° C. for 12 h. The sample was then cooled to room temperature, and filtered through a plug of silica gel (15×15 ml) of silica gel eluting with ethyl acetate. The eluent then was concentrated in vacuo and purified via column chromatography on a Biotage Horizon 65i column eluting with 0% ethyl acetate in hexanes (1 column volume), followed by a gradient to 60% ethyl acetate in hexanes (over 10 column volumes), and held at 60% ethyl acetate for 4 column volumes to provide the title compound (1.01 g, 39%). Mass spectrum (ESI) 262.9 (M+2).). 1H NMR (500 MHz, CDCl3): δ 8.27 (d, J=2.5 Hz, 1), 8.21 (d, J=8.9 Hz, 1H), 7.68 (dd, J=8.9, 2.5 Hz, 1H), 4.31 (d, J=10.8 Hz, 1H), 3.95 (d, J=10.7 Hz, 1H), 3.73 (d, J=11.7 Hz, 1H), 3.63 (d, J=11.7 Hz, 1H), 1.66 (s, 3H).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([O:17]C)[CH:15]=[CH:16][C:11]=2[CH:10]=1)=[O:8].[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([OH:17])[C:15]([C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:20]=3[Cl:19])=[CH:16][C:11]=2[CH:10]=1)=[O:8]
Reactant: COC(=O)C1=Cc2ccc(OC)cc21
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)C1=Cc2cc(C(=O)c3ccc(Cl)cc3Cl)c(O)cc21

Procedure:
In a manner analogous to that described in Example 5, starting from 26.6 g of aluminium trichloride, 9.61 g of 5-methoxybenzocyclobutene-1-carboxylic acid methyl ester and 20.95 g of 2,4-dichlorobenzoyl chloride there is obtained 4-(2,4-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid methyl ester having a melting point of 99°-100°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1)#[CH:2].[CH3:13][O:14][C:15](=[O:37])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]#[C:27][C:28]2[CH:33]=[C:32]([Br:34])[CH:31]=[C:30](Br)[CH:29]=2)=[CH:20][C:19]=1[CH3:36]>CN(C=O)C.C(N(CC)CC)C.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.[Cu]I>[CH3:13][O:14][C:15](=[O:37])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]#[C:27][C:28]2[CH:29]=[C:30]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][CH:4]=3)[CH:31]=[C:32]([Br:34])[CH:33]=2)=[CH:20][C:19]=1[CH3:36]
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(Br)c2)cc1C
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(C#Cc3ccc(C(F)(F)F)cc3)c2)cc1C
Temperature: 75 °C

Procedure:
A mixture of 1-ethynyl-4-trifluoromethyl-benzene (149 mg, 0.88 mmol), {4-[3-(3,5-dibromo-phenyl)-prop-2-ynyloxy]-2-methyl-phenoxy}-acetic acid methyl ester (412 mg, 0.88 mmol, intermediate 2), Pd(PPh3)2Cl2 (101 mg, 0.088 mmol), CuI (46 mg, 0.246 mmol) in dry DMF (2 ml) and triethylamine (2 ml) was heated in a microwave own for 20 min. at 75° C. in a sealed tube. The reaction mixture was filtered through Decalite and the filtrate was evaporated. The residue was purified on column chromatography using methylene chloride/heptanes mixtures to give (4-{3-[3-bromo-5-(4-trifluoromethyl-phenylethynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester in 94 mg (19%) yield.
Reaction SMILES: [ClH:1].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12](O)[CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22](O)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].Cl>CC(=O)CC>[ClH:1].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][C:19](=[C:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:20][CH2:21]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: Cl
Solvent: CCC(C)=O
Product: CC(C)(C)c1ccc(C=CCCN2CCC(=C(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
A mixture of 63.4 g (0.134 mole) of α-(p-tert-butylphenyl)-4-(α-hydroxy-α-phenylbenzyl)-1-piperidinebutanol hydrochloride, 400 ml of 37% HCl, and 250 ml of butanone was refluxed under a nitrogen atmosphene for 17 hours. The solvent and excess acid were removed under vacuum. The mixture was extracted into toluene, and a precipitate formed upon addition of ether. After cooling, the precipitate was collected by filtration, washed with ether and recrystallized from ethyl acetate to give the desired product, M.P. 224°-231° C.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:36])([CH3:35])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:24]=[C:25]([O:27]CC2C=CC=CC=2)[CH:26]=1)[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH2:22][CH3:23])[N:18]=1)=[O:15])[CH3:9])([CH3:4])[CH3:3]>C1COCC1>[CH3:1][C:2]([Si:5]([CH3:36])([CH3:35])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:24]=[C:25]([OH:27])[CH:26]=1)[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH2:22][CH3:23])[N:18]=1)=[O:15])[CH3:9])([CH3:4])[CH3:3]
Reactant: CCn1ccc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Solvent: C1CCOC1
Product: CCn1ccc(NC(=O)c2cc(O)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
A solution of 3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-(1-ethyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide (2.40 g, 4.71 mmol) and THF (80 mL) was evacuated and purged with Argon (×3). Palladium on carbon (10%, 422 mg) was added and reaction mixture was evacuated and finally purged with hydrogen gas. Reaction mixture was left to stir at ambient temperature under hydrogen for 16 hours. Pd/C was filtered off and concentrated in vacuo to give the product as a colourless oil (1.87 g, 95%).