Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16]1.ClC(Cl)C(Cl)Cl>Cl>[C:5]([C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)c1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)C(Cl)Cl
Product: CC(C)(C)c1ccc(C(=O)CCC(=O)O)cc1
Temperature: 0 °C

Procedure:
Aluminum chloride powder (80.0 g, 600 mmol) was added in portions to a stirred mixture of tert-butylbenzene (40.0 g, 300 mmol) and succinic anhydride (26.7 g, 267 mmol) and 1,1,2,2-tetrachloroethane (100 mL). After all the aluminum chloride had been added, the mixture was poured into a mixture of ice (500 mL) and concentrated hydrochloric acid (100 mL). The organic layer was separated, washed with water (500 mL) and the solvent distilled off. Solid residue was dissolved in hot 15% aqueous solution of sodium carbonate (1000 mL), filtered, cooled and the acid was precipitated with hydrochloric acid (acidified to pH=1). The crude acid was filtered, dried on air and recrystalised from benzene (500 mL) to give 4-(4-tert-butyl-phenyl)-4-oxo-butyric acid as colorless crystals.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][OH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC1(C)N(O)C(C)(C)CC(O)C1>C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH:10]=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCO
Agent: CC1(C)CC(O)CC(C)(C)N1O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCC=O

Procedure:
Solution 1 consisted of 108 g (0.610 mol) of 2-(tert-butyldimethylsilyloxy)ethanol and 5.8 g of 4-hydroxy-TEMPO in 400 ml of ethyl acetate. Flow rates: 48 l/h for solution 1, 30 l/h for solution 2. tert-Butyldimethylsilyloxyacetaldehyde was isolated by fractional distillation of the ethyl acetate phase. B.p.: 74-80° C. (22 mbar).
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.CSC>C1COCC1>[O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[CH2:10][OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OCc1ccccc1Oc1ccccc1
Reaction time: 15 h

Procedure:
To a solution of 2-phenoxybenzoic acid (10.00 g, 46.7 mmol) in THF (250 mL) was added dropwise borane.dimethylsulfide (9.8 mL of a 10.0M solution, 98 mmol). Upon completion of addition, the reaction was stirred for 15 hrs. It was then quenched with aqueous 10% HCl (250 mL) and extracted with ethylacetate (3×250 mL). The organics were combined, dried with MgSO4 and concentrated to afford crude 2-phenoxybenzyl alcohol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[C:5]([F:10])=[CH:4][N:3]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][N:18]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:15]2=[N:16][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[F:11][C:12]1[CH:13]=[C:14]2[C:20]([C:2]3[N:7]=[C:6]([S:8][CH3:9])[C:5]([F:10])=[CH:4][N:3]=3)=[CH:19][N:18]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:31])=[O:32])[C:15]2=[N:16][CH:17]=1
Reactant: CSc1nc(Cl)ncc1F
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CSc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
2-chloro-5-fluoro-4-methylsulfanyl-pyrimidine (1.6 g, 9.0 mmol), 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]yridine, 7a, (2.5 g, 6.0 mmol) and Na2CO3 (1.9 g, 18.0 mmol) were dissolved in DME (37.5 mL) and water (7.5 mL). The mixture was purged with nitrogen for 20 minutes, treated with Pd(PPh3)4, purged with nitrogen for another 20 minutes and heated to reflux overnight. After cooling to room temperature, water (35 mL) was added and the resulting suspension was stirred for 30 minutes. The precipitate was collected by filtration, washed with water and acetonitrile and dried overnight at 50° C., affording 2.3 g (88.5%) of the desired product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.70-8.57 (m, 2H), 8.55-8.42 (m, 2H), 8.09 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 2.76 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([N:5]([CH3:7])[CH3:6])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1(C)C=CC=CC=1.CCOCC>O1CCCC1.C(OCC)(=O)C>[CH3:7][N:5]([CH3:6])[CH2:3][C@@H:2]([NH2:1])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN(C)C(=O)[C@@H](N)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C)C[C@@H](N)Cc1ccccc1
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a solution of (S)-2-amino-N,N-dimethyl-3-phenyl-propionamide (1.0 g, 5.2 mmol) in tetrahydrofuran (10 mL) was added a solution of lithium aluminum hydride in tetrahydrofuran and toluene (3.5 M, 7.4 mL, 26 mmol) dropwise. The mixture was heated to reflux for 4 h after addition and then cooled. Ether (20 mL) was added. Ethyl acetate was added dropwise until all the lithium aluminum hydride was consumed. Sodium hydroxide (1M, 20 mL) was added and the mixture was stirred for 30 min. The mixture was extracted three times with ether. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give (S)—N1,N1-dimethyl-3-phenyl-propane-1,2-diamine (0.60 g, 65%)
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[C:13]([O:15][CH3:16])=[O:14])([O-])=O.[BH4-].[Na+]>CO>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)n1ncc2c([N+](=O)[O-])cccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)n1ncc2c(N)cccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.7 %

Procedure:
The product of Example 90A (1.66 g, 7.5 mmol) methanol (20 mL) was treated with BiCl3 (8.2 g, 2.6 mmol) followed by the addition of NaBH4 (1.13 g, 30.5 mmol). The reaction mixture was stirred at room temperature for 20 minutes, filtered through Celite, and the filtrate was evaporated under reduced pressure. The residue was partitioned between ethyl acetate/dilute NaHCO3 solution. The organic phase was separated, dried over MgSO4 filtered and the filtrate concentrated under reduced pressure to provide the title compound (1.2 g). 1H NMR (300 MHz, DMSO-d6) δ 6.1 (s, 2H), 6.41 (dd, 1H), 7.21 (m, 2H), 8.42 (s, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:2]1(/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: C=Cc1ccccc1
Product: C(=C/c1ccccc1)\c1ccccc1

Procedure:
Iodobenzene (32 μL, 0.25 mmol) and styrene (43 μL, 0.375 mmol) were coupled using the procedure described above to give 81% conversion to (E)-stilbene by GC analysis.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[C:12]1[C:16](Br)=[CH:15][S:14][CH:13]=1.Cl>C(OCC)C.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:12]1[C:16]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][S:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC[Mg]Br
Reactant: Brc1cscc1Br
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CCCCCCCCc1cscc1CCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
2 M octylmagnesium bromide (100 milliliters, 0.2 mol) in anhydrous ethyl ether was added to a well-stirred mixture of dichloro[1,3-bis(diphenylphosphino)-propane]nickel(II) (0.2 gram) and 3,4-dibromothiophene (20.16 grams, 0.0833 mol) in 200 milliliters of anhydrous ethyl ether in a 500 milliliter round bottom flask cooled with an ice bath under an inert atmosphere. The nickel complex reacted immediately with the Grignard reagent and the resulting reaction mixture was allowed to warm up to room temperature. An exothermic reaction started within 30 minutes and the ethyl ether began to reflux gently. After stirring for another 2 hours at room temperature, the reaction mixture was refluxed for 6 hours, then cooled in an ice bath, and hydrolyzed with aqueous 2N hydrochloric acid. The organic layer was separated and washed successively with water, brine, and again with water, dried over anhydrous sodium sulfate, and filtered. After evaporation of the solvent, the residue was distilled under reduced pressure through Kugelrohr apparatus to provide 21.3 grams of 3,4-dioctylthiophene as a colorless liquid.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[C:7]([F:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO.O>[Cl:10][C:8]1[C:7]([F:11])=[C:6]([CH:12]2[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15]2)[C:5]([O:23][CH3:24])=[C:4]([CH:1]([OH:3])[CH3:2])[CH:9]=1
Reactant: COc1c(C(C)=O)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c(C(C)O)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110 %

Procedure:
To a solution of tert-butyl 3-(3-acetyl-5-chloro-6-fluoro-2-methoxyphenyl)azetidine-1-carboxylate (0.17 g, 0.48 mmol) in methanol (3 mL) cooled at 0° C. was added sodium tetrahydroborate (0.022 g, 0.57 mmol). The mixture was stirred at room temperature for 1 hour, then diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated to give the desired product (0.19 g). LCMS calculated for C17H23ClFNO4Na (M+Na)+: m/z=382.1. found: 382.0.
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH:13]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[Cl:28])[C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])(=[O:12])=[O:11])=[CH:6][N:5]=1.ClCCl.C(OCC)(=O)C>[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C>[Cl:28][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:22]=1[CH:13]([C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])[S:10]([C:7]1[CH:8]=[CH:9][C:4]([F:1])=[N:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: [F-]
Reactant: O=S(=O)(c1ccc(Cl)nc1)C(c1cc(F)ccc1F)c1ccncc1Cl
Agent: [Br-]
Agent: [K+]
Agent: c1ccc([P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=S(=O)(c1ccc(F)nc1)C(c1cc(F)ccc1F)c1ccncc1Cl
Temperature: 25 °C
Yield: 6.9 %

Procedure:
Potassium fluoride (94 mg, 1.60 mmol) and tetraphenylphosphonium bromide (134 mg, 0.32 mmol) were added to a solution of 2-chloro-5-[(3-chloropyridin-4-yl) (2,5-difluorophenyl)methylsulfonyl]pyridine (66 mg, 0.16 mmol) in acetonitrile (2 ml). The resulting mixture was heated under reflux for 16 hours. The reaction mixture was cooled to room temperature. Dichloromethane was added and the mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column and a fraction obtained from the elution portion with hexane:ethyl acetate=17:3 was concentrated under reduced pressure, whereby the title compound (4.5 mg, 0.011 mmol, 7%) was obtained as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][NH2:13])=[CH:3]1.[C:18]([OH:28])(=[O:27])[C@@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[OH:20]>CCOCC>[C:18]([OH:28])(=[O:27])[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[OH:20].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][NH2:13])=[CH:3]1
Reactant: O=C(O)[C@H](O)c1ccccc1
Agent: CCCCC(CN)c1cn(C)c2ccccc12
Solvent: CCOCC
Product: O=C(O)C(O)c1ccccc1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
24 g (0.104 mol) of 2-(1-methyl-3-indolyl)hexylamine, prepared under the conditions of Example 1, and 15.8 g (0.104 mol) of (R)-(-)-mandelic acid are dissolved in 600 cm3 of ether; after 3 hours of stirring at 20° C., the solid formed is drained and dried (m.p. 92°-100° C., quantity=23.1 g).
Reaction SMILES: [C:1]1([CH2:11]O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:14].C(=O)(O)[O-].[Na+].[OH-].[Na+]>C(Cl)Cl>[Br:14][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: BrP(Br)Br
Reactant: OCc1cccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: BrCc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1-naphthylmethanol (3.2 g) was taken up in CH2Cl2 (10 mL) and cooled to 0° C. Phosphorus tribromide (25 mL, 1 M in CH2Cl2) was added drop wise and allowed to stir at RT for 2 h. Saturated sodium bicarbonate and sodium hydroxide was added slowly until alkaline. The organic layer was separated, dried over sodium sulfate, and evaporated under reduced pressure to give an off-white solid (4.4 g). Proton NMR was sufficient for the next step.
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16](=[O:23])[CH2:17][CH2:18][CH2:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OCCOCCO)C.[Pd]>[C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:20]3=[CH:19][CH:18]=[CH:17][C:16]=5[OH:23])=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCCc2c1c1cccc3c1n2C(c1ccccc1)CO3
Agent: [Pd]
Solvent: CCOCCOCCO
Product: Oc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 195 °C
Yield: 47.1 %

Procedure:
A mixture of 1-phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one (0.0586 g, 0.193 mmol) and 10% Pd/C (0.058 g) in 2-(ethoxyethoxy)ethanol (1 mL) is heated at 190-200° C. for 4 h and then cooled and partitioned between dichloromethane and water. The organic layers are dried over magnesium sulfate, filtered, and the filtrate is concentrated and the residue chromatographed on silica gel using ethyl acetate/hexane (20/80) to give 0.0274 g of 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19]([C:21]1([C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)[CH2:23][CH2:22]1)=[O:20])[CH3:17].C(=O)(O)[O-].[Na+]>COCCOC.O.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>[CH2:16]([O:18][C:19]([C:21]1([C:24]2[CH:29]=[CH:28][C:27]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]=[O:15])=[CH:4][CH:3]=3)=[CH:26][CH:25]=2)[CH2:22][CH2:23]1)=[O:20])[CH3:17]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C=O)cc3)cc2)CC1
Temperature: 85 °C

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (0.5 g, 1.88 mmol) was mixed with 1-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester (0.72 g, 2.07 mmol) and sodium bicarbonate (0.553 g, 6.58 mmol) in DME (5 mL) and H2O (2.5 mL). The reaction was purged with N2 (g) then bis(triphenylphosphine)palladium(II) dichloride (0.066 g, 0.094 mmol) was added and the reaction was heated to 85° C. overnight. After cooling to room temperature the reaction was submitted to standard aqueous workup the purified by silica gel chromatograph (0-20% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([C:30](=[O:32])[CH3:31])=[C:24]([OH:33])[CH:23]=1.C([O-])(O)=O.[Na+]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[C:27]([O:28][CH3:29])=[CH:26][C:25]([C:30](=[O:32])[CH3:31])=[C:24]([OH:33])[CH:23]=4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C(C)=O)c(O)cc1OCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(C(C)=O)c(O)cc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 13.1 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.2 g, 19 mmol), 1-[4-(3-chloropropoxy)-2-hydroxy-5-methoxyphenyl]ethanone (5.0 g, 19 mmol), NaHCO3 (1.8 g, 20 mmol) and acetonitrile (120 mL) was stirred and refluxed for 16 hours. The reaction was filtered and the filtrate was concentrated to a dark oil. The oil was taken up in anhydrous ether and ethereal HCl was added to precipitate 8.7 g of an off-white hydrochloride salt. A 2.0 g sample of the salt was converted to its free base and chromatographed by preparative HPLC (silica gel with 5% MeOH/CH2Cl2 as eluent). Concentration of the desired fractions gave 1.1 g of a white solid, which was recrystallized from EtOH to yield 0.85 g of the product, m.p. 122°-124° C.
Reaction SMILES: [NH2:1][CH:2]1[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[N+]([O-])(O)=[O:13]>OS(O)(=O)=O>[NH2:1][CH:2]1[CH:3]2[CH2:11][CH:7]3[CH2:6][C:5]([OH:13])([CH2:10][CH:9]1[CH2:8]3)[CH2:4]2
Reactant: O=[N+]([O-])O
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: O=S(=O)(O)O
Product: NC1C2CC3CC1CC(O)(C3)C2

Procedure:
This know material (CAS 62058-13-3) was made according to Klimova et al., Khimiko-Farmatsevticheskii Zhurnal (1986), 20(7), 810-815 by hydroxylation of 2-aminoadamantane with HNO3 in H2SO4. 2-amino-5-hydroxyadamantane was obtained as a 2:1 mixture of the (Z) and (E) diasteromers.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[OH:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]([O:20][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:19])=[CH:14][CH:15]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1ccc(O)cc1)OCc1ccccc1
Reaction time: 15 h
Yield: 88.2 %

Procedure:
Benzyl bromide (5.7 g, 33.09 mmol) was added to a suspension of 3-(4-hydroxyphenyl)propanoic acid (5.0 g, 30.08 mmol) and anhydrous potassium carbonate (8.31 g, 60.17 mmol) in anhydrous DMF (60 ml), and the mixture was stirred for 15 hr. The reaction mixture was diluted with water and was extracted with ethyl acetate, and the organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was chromatographed on silica gel column (hexane:ethyl acetate=8:2) to give the title compound as an oil (6.8 g, yield 88%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C@@H:15]1[C@:19]([Si:21]([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([OH:20])[C@@H:18]([CH2:38][O:39][C:40]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[O:17][C@H:16]1[N:63]1[C:72]2[N:71]=[CH:70][N:69]=[C:67]([NH2:68])[C:66]=2[N:65]=[CH:64]1)=[O:7])#[N:2].[C:73](C1NN=NN=1)(=[O:80])[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1.CC(C)=O.C(Cl)Cl>CCOC(C)=O>[C:73]([NH:68][C:67]1[C:66]2[N:65]=[CH:64][N:63]([C:72]=2[N:71]=[CH:70][N:69]=1)[C@@H:16]1[O:17][C@H:18]([CH2:38][O:39][C:40]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[C@@:19]([Si:21]([C:34]([CH3:35])([CH3:36])[CH3:37])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([OH:20])[C@H:15]1[O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][CH2:4][CH2:3][C:1]#[N:2])=[O:7])(=[O:80])[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1
Reactant: O=C(c1ccccc1)c1nnn[nH]1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(N)ncnc43)[C@H](OCCCCCNC(=O)OCCC#N)[C@@]2(O)[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)[C@H](OCCCCCNC(=O)OCCC#N)[C@@]2(O)[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
A solution of compound 54 (0.25 g, 0.25 mmol) and benzoyl-tetrazole (0.09 g, 0.50 mmol) in anhydrous CH2CN (0.5 mL) was stirred in a preheated bath at 65° C. for 1.5 h. After this time, the TLC (10% CH3COCH3/CH2Cl2) that the reaction was complete. The reaction mixture was cooled to room temperature and taken up in EtOAc (30 mL) washed with aq saturated sodium bicarbonate solution (2×15 mL) and water (15 mL) dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using 10% CH3COCH3/CH2Cl2 as the eluent and the appropriate fractions were combined and concentrated to give a colorless foam, yield (0.105 g, 50%). 1H NMR (CDCl3) d 11.21 (s, 1H), 8.58 and 8.56 (2s, 2H), 8.04 (d, 2H, J=7.3 Hz), 7.70-7.09 (m, 22H), 6.78 (d, 4H, J=8.0 Hz), 6.23 (d, 1H, J=4.6 Hz), 4.73-4.69 (m, 1H), 4.44-4.39 (m, 1H), 4.30-4.20 (m, 1H), 4.10 (t, 2H, J=6.1 Hz), 3.71 (s, 6H), 3.25-2.79 (m, 8H), 1.39-1.02 (m, 15H).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:8]([F:17])=[CH:9][C:10]([N+:14]([O-])=O)=[C:11]([NH2:13])[CH:12]=1.[H][H]>CO.[Pd]>[CH3:18][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([NH2:13])[C:10]([NH2:14])=[CH:9][C:8]=1[F:17]
Reactant: CN(C)CCCOc1cc(N)c([N+](=O)[O-])cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCOc1cc(N)c(N)cc1F
Yield: 104.3 %

Procedure:
3.8 g of 5-(3-dimethylaminopropoxy)-4-fluoro-2-nitrophenylamine in solution in 100 mL of methanol are hydrogenated under 1 bar of hydrogen pressure in the presence of 400 mg of palladium-on-charcoal at 25° C. for 16 hours. The reaction crude is filtered through celite and the filtrate is concentrated under vacuum in a rotary evaporator. 3.5 g of 4-(3-dimethylaminopropoxy)-5-fluorobenzene-1,2-diamine are isolated in the form of a black oil. 1H NMR (400 MHz, DMSO-d6, δ in ppm): 1.75 (m, 2H); 2.13 (m, 6H); 2.32 (m, 2H); 3.84 (m, 2H); 4.3 (m, 4H); 6.32 (m, 2H).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH2:6]([NH:14][C:15](=[O:17])[CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[C:15]([NH:14][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:10][CH:9]=1)(=[O:17])[CH3:16]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)NCCc1ccccc1
Solvent: ClCCl
Product: CC(=O)NCCc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
30.6 ml chlorosulfonic acid were added in one portion to 25.0 g N-phenethyl-acetamide. The reaction mixture was stirred at room temperature for one hour, then 100 ml dichloromethane were added and the reaction mixture was poured on ice water. The organic layer was separated washed twice with 50 ml brine and then dried over MgSO4. The solvent was removed in vacuo to obtain 22.0 g 4-(2-Acetylamino-ethyl)-benzenesulfonyl chloride as a white solid.