Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>>[CH3:10][O:9][C:3]1[C:4]([O:8][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][O:11]2)=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: C1=COCCC1
Reactant: COc1c(O)cccc1Br
Product: COc1c(Br)cccc1OC1CCCCO1

Procedure:
Treatment of 3-bromo-2-methoxyphenol with dihydropyran and an acid catalyst as described herein affords 2-methoxy-3-tetrahydropyranyloxy-1-bromobenzene.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]([O:18][C:19]2[C:20]([CH3:27])=[N:21][C:22]([NH:25][CH3:26])=[CH:23][CH:24]=2)[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9]1)=O)(C)(C)C.Cl>>[CH3:27][C:20]1[C:19]([O:18][CH:13]([C@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:24][CH:23]=[C:22]([NH:25][CH3:26])[N:21]=1
Reactant: CNc1ccc(OC(CC(C)C)[C@H]2CCN(C(=O)OC(C)(C)C)C2)c(C)n1
Agent: Cl
Product: CNc1ccc(OC(CC(C)C)[C@H]2CCNC2)c(C)n1
Yield: 12 %

Procedure:
Stir a mixture of (3S)-3-[1-(2-methyl-6-methylamino-3-pyridyloxy)-3-methyl-butyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (S-2) and aqueous HCl (4M, 0.261 mL, 1.04 mmol) at room temperature for 1 hour. After full conversion, concentrate the mixture, dissolve in dichloromethane and load the mixture onto a pre-packed SCX column. Wash with dichloromethane followed by methanol. Release the product with 2M NH3 in methanol and concentrate under reduced pressure. Purify the crude residue by reverse phase chromatography (17-43% gradient actonitrile in 0.01 M ammoniumformate in water, 85 mL/min, for 8 min., C18 ODB XBridge column, 30×75 mm, 5 μm) to give 9 mg (12%) of (3S)-3-[1-(2-methyl-6-methylamino-3-pyridyloxy)-3-methyl-butyl]-pyrrolidine (S-2). MS (m/z)=278 [M+1].
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(O)=O)CC1.[CH:26]1([C:29]2[C:30]([O:39][CH2:40][C:41]3([CH3:49])[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34](O)=[O:35])[CH2:28][CH2:27]1.CS(N)(=O)=O.[CH3:55][NH:56][S:57]([NH2:60])(=[O:59])=[O:58]>>[CH:26]1([C:29]2[C:30]([O:39][CH2:40][C:41]3([CH3:49])[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34]([NH:60][S:57](=[O:59])(=[O:58])[NH:56][CH3:55])=[O:35])[CH2:28][CH2:27]1
Reactant: CNS(N)(=O)=O
Reactant: CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)CCC(F)(F)CC1
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: CNS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2(C)CCC(F)(F)CC2)cc1F

Procedure:
Following the procedure as described in Example 158 step 5, and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)methoxy)-benzoic acid with 5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with (methylsulfamoyl)amine, the title compound was obtained (0.13 g, 47%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.77-8.62 (m, 1H), 7.66-7.56 (m, 1H), 6.65-6.51 (m, 1H), 5.30-5.18 (m, 1H), 3.76 (s, 2H), 2.82-2.71 (m, 3H), 2.09-1.73 (m, 7H), 1.69-1.59 (m, 2H), 1.17 (s, 3H), 1.01-0.90 (m, 2H), 0.70-0.61 (m, 2H); MS (ES+) m/z 435.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[CH3:20])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[CH3:20])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Cc1cc(-n2c(C)nc3ccccc32)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(-n2c(C)nc3ccccc32)ccc1N
Yield: 109 %

Procedure:
Stannous chloride dihydrate (45.9 g) was added portionwise to a stirred solution of 1-(3-methyl-4-nitrophenyl)-2-methylbenzimidazole (9.2 g) in absolute ethanol (200 cm3) under nitrogen. After heating under reflux for 1 hour, the cooled mixture was basified to pH 9 with aqueous 2.5M sodium hydroxide and extracted with chloroform (3×200 cm3). The combined and dried (MgSO4) organic extracts were evaporated in vacuo to give the title compound (8.9 g) which was characterised spectroscopically then used directly in Preparation 12 without further purification.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].O.[F:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[CH:25][C:26]=1[F:27]>O1CCCC1>[C:15]([O:14][C:12]([NH:7][C@H:6]([CH2:10][CH2:9][C:8]([C:24]1[CH:23]=[CH:22][C:21]([F:20])=[C:26]([F:27])[CH:25]=1)=[O:11])[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Fc1ccc([Mg]Br)cc1F
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](CCC(=O)c1ccc(F)c(F)c1)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (6.0 g) in tetrahydrofuran (100 mL), 3,4-difluorophenylmagnesium bromide (0.5 M solution in tetrahydrofuran; 50 mL) was added dropwise at −40° C. over 10 minutes, and the reaction solution was stirred at −40° C. to 0° C. for two hours. Water was added to the solution in small portions, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 8.3 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.[NH2:10][C:11]1[C:16]([F:17])=[CH:15][N:14]=[C:13](Cl)[N:12]=1>CC(O)(C)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][O:9][C:13]1[N:12]=[C:11]([NH2:10])[C:16]([F:17])=[CH:15][N:14]=1
Reactant: Nc1nc(Cl)ncc1F
Reactant: OCc1cccc(Br)c1
Solvent: CC(C)(C)O
Solvent: O
Product: Nc1nc(OCc2cccc(Br)c2)ncc1F
Temperature: 90 °C
Reaction time: 4 h
Yield: 49.3 %

Procedure:
To a magnetically stirred mixture of t-BUOK (1.0 M in t-BuOH, 1.36 ml, 1.36 mmol) was added (3-bromophenyl)methanol (0.25 g, 1.36 mmol). To the resulting solution was added 4-amino-2-chloro-5-fluoropyrimidine (0.10 g, 0.68 mmol) and the mixture was capped and stirred at 90° C. for 4 h. The reaction mixture was cooled to room temperature, diluted with water, and the resulting precipitate was collected by filtration. The solid was washed with water, washed with cyclohexane, and dried in a vacuum oven. A CH2Cl2 solution of the compound was loaded onto Biotage SCX column and eluted with CH2Cl2 followed by 2.0 M NH3 in MeOH. The solvent was evaporated under reduced pressure to give the title compound (0.100 g, 49%) as an off-white solid: mp 143-145° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J=2.5 Hz, 1H), 7.61 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.36 (d, J=7.7 Hz, 1H), 7.22 (t, J=7.7 Hz, 1H), 5.28 (s, 2H), 5.20 (br s, 2H); GCMS (EI) m/z 297, 299 (M)+.
Reaction SMILES: Br[C:2](=[CH2:13])[CH2:3][CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C([Li])(C)(C)C.[Li].[F:20][C:21]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:22]=1[CH:23]=[O:24]>C1COCC1>[Si:6]([O:5][CH2:4][CH2:3][C:2](=[CH2:13])[CH:23]([C:22]1[CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[CH:27]=[CH:28][C:21]=1[F:20])[OH:24])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Reactant: C=C(Br)CCO[Si](C)(C)C(C)(C)C
Agent: [Li]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C=C(CCO[Si](C)(C)C(C)(C)C)C(O)c1cc([N+](=O)[O-])ccc1F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of (3-bromobut-3-enyloxy)(tert-butyl)dimethylsilane from step A (3.14 g, 11.83 mmol) in THF (10 mL) at −78° C. was added tert-butyllithium (13.91 mL, 23.65 mmol, 1.70 M solution in hexanes) dropwise over a period of 5 min, and the reaction mixture was stirred at −78° C. for 10 min. The resulting lithium reagent was added dropwise to a solution of 2-fluoro-5-nitrobenzaldehyde (2 g, 11.83 mmol) in THF (10 mL) at −78° C., the reaction mixture was stirred at −78° C. for 20 min. The reaction mixture was then partitioned between ethyl acetate and water, and the organic layer was separated and concentrated to a crude product that was purified by chromatography eluting with 0-20% ethyl acetate/hexanes to give a mixture of starting material and the desired product. This mixture was further purified by preparative TLC eluting with 25% EtOAc/hexanes to give the title compound as a colorless oil (941 mg, 22% yield). 1H NMR (500 MHz, CDCl3) δ 8.57 (1H, m), 8.18 (1H, m), 7.15 (1H, m), 5.52 (1H, br. s), 5.16 (1H, s), 5.09 (1H, s), 4.96 (1H, m), 3.7-3.9 (2H, m), 2.20-2.35 (2H, m), 0.97 (9H, s), 0.17 (3H) and 0.15 (3H, s).
Reaction SMILES: O.[C:2]([NH:9][C@@H:10]([C:15]([OH:17])=O)[CH2:11][CH:12]([CH3:14])[CH3:13])([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3].[CH2:18]([N:20](CC)[CH2:21]C)C.Cl.CNC.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[C:5]([O:4][C:2](=[O:3])[NH:9][C@@H:10]([C:15](=[O:17])[N:20]([CH3:21])[CH3:18])[CH2:11][CH:12]([CH3:14])[CH3:13])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCN(CC)CC
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N(C)C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a solution of Boc-D-leucine monohydrate (2.0 g, 8.0 mmol), triethylamine (5.6 mL, 40.1 mmol), and dimethylamine hydrochloride (1.31 g, 16.0 mmol) in DMF (15 mL) at room temperature was added PyBOP (4.59 g, 8.82 mmol). The reaction mixture was stirred overnight then diluted with EtOAc (50 mL) and washed with water (4×50 mL). The combined organic extracts were dried (Na2SO4) and evaporated under vacuum. The crude residue was purified by SiO2 chromatography (80 g, hexanes/EtOAc, 1:1) to give 1.19 g (58%) of ((R)-1-dimethylcarbamoyl-3-methyl-butyl)-carbamic acid tert-butyl ester as a colorless viscous oil.
Reaction SMILES: [O:1]1[CH:5]=[N:4][C:3]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13](OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[N:2]1.C(O)(C(F)(F)F)=O.[NH2:27][C:28]1[C:33]([N+:34]([O-:36])=[O:35])=C(Cl)[C:31]([Cl:38])=[CH:30][N:29]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CC(O)C>[O:1]1[CH:5]=[N:4][C:3]([CH2:6][N:7]2[CH2:8][CH2:9][N:10]([C:13]3[C:31]([Cl:38])=[CH:30][N:29]=[C:28]([NH2:27])[C:33]=3[N+:34]([O-:36])=[O:35])[CH2:11][CH2:12]2)=[N:2]1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ncon2)CC1
Solvent: ClCCl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Cl)c(N2CCN(Cc3ncon3)CC2)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 64.6 %

Procedure:
To a solution of tert-butyl 4-((1,2,4-oxadiazol-3-yl)methyl)piperazine-1-carboxylate (213 mg, 0.790 mmol) in CH2Cl2 (18 mL) was added TFA (1.8 mL, 23.8 mmol) and the solution was stirred at room temperature for 1½ h. The reaction was concentrated in vacuo, azeotroping with toluene (×2) and dried in vacuum desiccator (containing KOH) overnight to give a yellow oil. The crude oil was dissolved in iPrOH (4.4 mL) and both 2-amino-3-nitro-4,5-dichloropyridine (190 mg, 0.752 mmol) and DIPEA (520 μl, 3.00 mmol) were added. The solution was stirred at 50° C. for 4 h. On cooling, a yellow precipitate dropped out which was filtered, washed with Et2O, dried in vacuo to yield the title compound as a yellow solid (165 mg, 0.486, 65%). The filtrate was concentrated in vacuo to give 715 mg oily yellow solid. Purification was accomplished by flash chromatography on silica gel (4×11) eluting with EtOAc/hexane (40-50%) to yield the title compound (42 mg, 16%) as a yellow solid.
Reaction SMILES: CS([N:5]1[C:9]2=[N:10][CH:11]=[C:12](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:8]2[CH:7]=[CH:6]1)(=O)=O.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:12]1[CH:13]=[C:8]2[CH:7]=[CH:6][NH:5][C:9]2=[N:10][CH:11]=1
Reactant: CC1(C)OB(c2cnc3c(ccn3S(C)(=O)=O)c2)OC1(C)C
Reactant: Brc1ccccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(-c2cnc3[nH]ccc3c2)nc1
Temperature: 80 °C

Procedure:
To a solution of 1-methanesulfonyl-5-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (300 mg, 0.93 mmol) and 2-bromopyridine (150 mg, 0.95 mmol) in DMF (3 mL) was added aqueous Na2CO3 (2M, 1.9 mL, 3.8 mmol). To this suspension was then added PdCl2(dppf) (60 mg, 0.075 mmol) under N2 atmosphere. The flask was then covered with septa, heated at 80° C. for 9 h, and poured into water (30 mL). The aqueous solution was extracted with ethylacetate (3×30 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated. The resulting residue was dissolved in MeOH (10 mL) and treated with 6N NaOH solution (2 mL) at 50° C. for 3 h. After evaporating the MeOH, the aqueous residue was acidified with 6N HCl to pH=8. The precipitate was collected by filtration, washed with water, and dried on the pump for direct use (100 mg off-white solid, 0.51 mmol). MS (ES+): m/e=196.1 (M+H); LC: 2.04 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27](Cl)[CH:26]=2)=[CH:4][C:5]([F:23])=[C:6]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:12]2=[O:22])=[O:10])[CH:7]=1.[CH3:32][N:33]([CH3:37])[C:34]([NH2:36])=[O:35].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[C:3]([O:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:36][C:34]([N:33]([CH3:37])[CH3:32])=[O:35])[CH:26]=2)=[CH:4][C:5]([F:23])=[C:6]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:12]2=[O:22])=[O:10])[CH:7]=1
Reactant: CN(C)C(N)=O
Reactant: O=C(Nc1cc(Cl)c(Oc2ccnc(Cl)c2)cc1F)N1CCN(C2CCOCC2)C1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN(C)C(=O)Nc1cc(Oc2cc(F)c(NC(=O)N3CCN(C4CCOCC4)C3=O)cc2Cl)ccn1
Temperature: 100 °C
Yield: 44.2 %

Procedure:
A mixture of Example C8 (0.200 g, 0.426 mmol), N,N-dimethyl urea (0.225 g, 2.56 mmol), Cs2CO3 (0.347 g, 1.065 mmol) and Xantphos (0.074 g, 0.128 mmol) in dioxane (3 mL) was sparged with Ar, treated Pd2(dba)3 (0.051 g, 0.055 mmol), sparged again with Ar and heated at 100° C. overnight. The mixture was cooled to RT, treated with brine, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified twice via silica gel chromatography (MeOH/DCM, then MeOH/EtOAc). The material was suspended in 1:1 EtOAc/Et2O, sonicated and the resulting solid collected via filtration to afford N-(5-chloro-4-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)-2-fluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (98 mg, 44%). 1H NMR (400 MHz, DMSO-d6): δ 10.92 (d, J=2.7 Hz, 1 H), 8.91 (s, 1 H), 8.39 (d, J=8.0 Hz, 1 H), 8.10 (d, J=5.7 Hz, 1 H), 7.56 (d, J=11.2 Hz, 1 H), 7.34 (d, J=2.4 Hz, 1 H), 6.56 (dd, J=5.7, 2.4 Hz, 1 H), 3.93-3.86 (m, 3 H), 3.83-3.81 (m, 2 H), 3.47 (m, 2H), 3.37 (m, 2 H), 2.87 (s, 6 H), 1.71 (m, 2 H), 1.59 (m, 2H); MS (ESI) m/z: 521.2 (M+H+).
Reaction SMILES: [C:1]12([OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3](O)([CH2:4]3)[CH2:2]1)[CH2:8]2.[Na].CCCCCCCC.[C:22](O)(=[O:25])[CH:23]=[CH2:24]>S(=O)(=O)(O)O.COC1C=CC(O)=CC=1.O.C1(C)C=CC=CC=1>[C:22]([O:12][C:1]12[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2)(=[O:25])[CH:23]=[CH2:24]
Reactant: C=CC(=O)O
Reactant: OC12CC3CC(C1)CC(O)(C3)C2
Agent: COc1ccc(O)cc1
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: O
Solvent: CCCCCCCC
Solvent: Cc1ccccc1
Product: C=CC(=O)OC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.2 %

Procedure:
Adamantyl acrylate is synthesized by the method described in JP-2001-106650-A. That is, 86.4 g (513 mmol) of 1,3-adamantane diol containing sodium in an amount of 0.05% by weight, 400 ml of toluene, 400 ml of n-octane, 108 g (1,500 mmol) of acrylic acid, 1.23 g of strong sulfuric acid, and 0.37 g p-methoxyphenol are placed in a separable flask equipped with a stirrer, a thermometer, a Dean-Stark water separator, a Dimroth condenser, an air introduction tube, and a separating valve provided on the bottom side. Reaction is conducted for five hours in a reflux state at 112° C. while inspiring a small amount of air to the flask. During the reaction, produced water is removed by using the Dean-Stark water separator. The reaction liquid is cooled down to room temperature followed by filtration of insoluble matters. 840 g of 5% by weight sodium hydroxide solution is admixed and separated. Thereafter, the organic phase is washed with 400 ml of water six times. The organic phase is condensed with a reduced pressure, filtered, and dried to obtain 83.8 g of adamantyl acrylate of white powder.
Reaction SMILES: C(OC([NH:8][C:9](=[O:22])[C@H:10]([CH2:12][S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[NH2:11])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][S:13][CH2:12][C@@H:10]([C:9]([NH2:8])=[O:22])[NH2:11])=[CH:20][CH:19]=1
Reactant: Cc1ccc(CSC[C@H](N)C(=O)NC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(CSC[C@H](N)C(N)=O)cc1

Procedure:
Treat the product of Step 1 (2.79 g) in CH2Cl2 (40 ml) with trifluoroacetic acid (10 ml) at room temperature for 18 hr. Concentrate the reaction mixture in vacuo. Dissolve the residue in CH2Cl2 and concentrate in vacuo (twice). Dissolve the white solid in EtOAc and extract with 10% sodium bicarbonate solution. Dry (MgSO4) the EtOAc and concentrate in vacuo to give the title compound, a white solid (1.53 g) m.p. 94°-95°, [α]D26 =-1.3° (MeOH).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Sc1ccc(Br)cc1
Yield: 89.7 %

Procedure:
Following the procedure indicated in Example 49b 47 g of a limpid pale yellow oil are prepared from 29 g (0.150 mol) of p-bromothiophenol and 32.2 g (0.165 mol) of ethyl 2-bromo-2-methylpropionate; subsequent purification of this oil (by distillation under reduced pressure) gives 40.8 g of ethyl 2-(p-bromophenylthio)-2-methylpropionate.
Reaction SMILES: [CH2:1]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@H:9]([C@H:17]([OH:26])[CH:18]([N+:23]([O-])=O)[CH2:19][CH2:20][CH:21]=[CH2:22])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C.[Zn]>[NH2:23][CH:18]([CH2:19][CH2:20][CH:21]=[CH2:22])[C@@H:17]([OH:26])[C@@H:9]([N:8]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=CCCC([C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1)[N+](=O)[O-]
Agent: Cl
Agent: [Zn]
Solvent: CCO
Product: C=CCCC(N)[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 1 h

Procedure:
Add powdered Zn (1.56 g, 24 mmol) portionwise at 0-5° C. to a stirred suspension of the (2S,3S)-2-dibenzylamino-4-nitro-1-phenyloct-7-en-3-ol mixture (2.7 g, 6 mmol) in a mixture of ethanol (20 mL) and concentrated HCl (20 mL). Stir for 1 h. Filter the reaction mixture and concentrate the filtrate under reduced pressure. Dilute residue with water and add concentrated ammonium hydroxide. Extract with dichloromethane. Wash the organic layer with water, dry (magnesium sulfate), and concentrate under reduced pressure to give the mixture of amines (1.5 g, 60%).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4](S([O-])=O)=[CH:3][CH:2]=1.[Na+].Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O-2].[Ca+2]>CN1CCCC1=O>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:2]=1
Reactant: Brc1ccccc1
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Ca+2]
Agent: [Na+]
Agent: [O-2]
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2ccccc2)cc1

Procedure:
3.56 g (20 mmol) of sodium p-toluenesulfinate, 3.14 g (20 mmol) of bromobenzene, 11.2 g (200 mmol) of calcium oxide, 60 ml of N-methyl-2-pyrrolidone and each catalyst compound and each organophosphorus compound ligand indicated in Table 2 were placed in 100 ml round bottom flask and reacted at 150° C. in a nitrogen gas stream for 6 hours, respectively. After the completion of the reaction, the amount of 4-methylbiphenyl formed was analyzed by means of high performance liquid chromatography. The results are shown in Table 2.
Reaction SMILES: N.[CH3:2][C:3]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH2:11][CH2:10][C:9]=2[CH3:16])[O:5]N=1.[Na].[Cl-].[NH4+]>C(O)(C)(C)C.O1CCCC1>[CH3:16][C:9]1[CH2:10][CH2:11][CH2:12][C:13]([CH3:14])([CH3:15])[C:8]=1[C:6](=[O:5])[CH:7]=[CH:3][CH3:2]
Reactant: CC1=C(c2cc(C)no2)C(C)(C)CCC1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CC=CC(=O)C1=C(C)CCCC1(C)C
Yield: 85.3 %

Procedure:
To a mixture of liquid ammonia (500 ml), tetrahydrofuran (30 ml), tert-butanol (2.796 g) and 3-methyl-5-[2,6,6-trimethyl-cyclohex-1-en-1-yl]-isoxazole (2.593 g; 12.65 millimoles), kept under stirring, there was added sodium metal until the solution acquired a steady blue colour. The reaction mixture was stirred for 15 more minutes, solid ammonium chloride was added thereto until complete discolouration, and the ammonia was then evaporated under a stream of argon. After having added 50 ml of ether and 300 ml of a concentrated ammonium chloride solution in water, the mixture was extracted with two fractions of 300 ml of ether and 150 ml of chloroform, respectively. The combined organic extracts were dried over magnesium sulphate, concentrated under reduced pressure and dissolved in 50 ml of toluene containing traces of p-toluene-sulphonic acid. The thus obtained mixture was refluxed for 24 hours, concentrated in vacuo and then distilled to yield 2.074 g (yield 84%) of 2,6,6-trimethyl-1-[but-2-enoyl]-cyclohex-1-ene; b.p. 55°/0.04 Torr. The analytical data of the obtained product were identical with those of a pure sample prepared by one of the known methods.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][CH:14]=[C:15]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[N:16]=2)=[CH:8][CH:7]=1.[CH3:25][CH:26]1[CH2:30][CH2:29][CH2:28][NH:27]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[CH3:25][CH:26]1[CH2:30][CH2:29][CH2:28][N:27]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][CH:14]=[C:15]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[N:16]=2)=[CH:8][CH:7]=1
Reactant: CC1CCCN1
Reactant: O=C(c1coc(-c2ccc(OCCCCl)cc2)n1)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC1CCCN1CCCOc1ccc(-c2nc(C(=O)N3CCOCC3)co2)cc1
Yield: 37 %

Procedure:
4-({2-[4-(3-chloropropoxy)phenyl]-1,3-oxazol-4-yl}carbonyl)morpholine i35 (0.26 g, 0.75 mmol, 1 eq) is reacted with 2-methylpyrrolidine (0.11 ml, 1.13 mmol, 1.5 eq) in the presence of potassium carbonate (0.2 g, 1.5 mmol, 2 eq) and a catalytic amount of sodium iodide in refluxing acetonitrile (15 ml) overnight. The solvent is then evaporated, and the residue taken up in ethyl acetate and washed two times with an aqueous solution of sodium hydrogenocarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated under vacuum. Purification by chromatography over silicagel (eluent: dichloromethane/methanol/ammonia 96:3.6:0.4) affords 0.11 g of 4-[(2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1,3-oxazol-4-yl)carbonyl]morpholine 90.