Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:9]([N:11]([CH2:13][C:14]([O:16][C@H:17]([CH3:54])[CH2:18][N:19]1[C:23]([CH3:24])=[C:22]([C:25](=[O:46])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[C:43]4[C:38](=[CH:39][C:40]([O:44][CH3:45])=[CH:41][CH:42]=4)[N:37]=[CH:36][CH:35]=3)=[CH:29][N:28]=2)[C:21](=[O:47])[N:20]1[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:15])C)=O)C1C=CC=CC=1>CO.[Pd]>[CH3:9][NH:11][CH2:13][C:14]([O:16][C@H:17]([CH3:54])[CH2:18][N:19]1[C:23]([CH3:24])=[C:22]([C:25](=[O:46])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[C:43]4[C:38](=[CH:39][C:40]([O:44][CH3:45])=[CH:41][CH:42]=4)[N:37]=[CH:36][CH:35]=3)=[CH:29][N:28]=2)[C:21](=[O:47])[N:20]1[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:15]
Reactant: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)CN(C)C(=O)OCc5ccccc5)n(-c5ccccc5)c4=O)nc3)ccnc2c1
Agent: [Pd]
Solvent: CO
Product: CNCC(=O)O[C@H](C)Cn1c(C)c(C(=O)Nc2ccc(Oc3ccnc4cc(OC)ccc34)cn2)c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (R)-1-(4-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-ylcarbamoyl)-2,3-dihydro-5-methyl-3-oxo-2-phenylpyrazol-1-yl)propan-2-yl 2-(N-benzyloxycarbonyl-N-methylamino)acetate (1.0 g, 1.4 mmol) in MeOH (100 mL) was added catalytic amount wet Pd/C (10%, ˜55% w/w water content, 10 mg) under N2 atmosphere. The suspension was degassed under vacuum and then purged with H2. The reaction mixture was stirred at rt for 20 minutes under H2 balloon. The mixture was filtered and the residue was washed with MeOH (35 mL×3). The filtrate used for the next step immediately.
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][SH:7])[CH3:3].[H-].[Na+].[C:12]1([C:18]2[C:22]([N+]([O-])=O)=[N:21][O:20][N+:19]=2[O-:26])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[ClH:1].[C:12]1([C:18]2[C:22]([S:7][CH2:6][CH2:5][N:4]([CH2:8][CH3:9])[CH2:2][CH3:3])=[N:21][O:20][N+:19]=2[O-:26])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1no[n+]([O-])c1-c1ccccc1
Reactant: CCN(CC)CCS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)CCSc1no[n+]([O-])c1-c1ccccc1
Reaction time: 1 h

Procedure:
4.75 g of 2-diethylaminoethyl mercaptan hydrochloride are slowly treated with 3.3 g of a 50% strength sodium hydride in oil suspension in 100 ml of THF under a nitrogen atmosphere. After 1 hour, 5 g of 3-phenyl-4-nitrofuroxan are introduced and the mixture is stirred for 20 hours. The inorganic salts are filtered off with suction and the filtrate is concentrated. The residue is taken up in water and extracted with methylene chloride. After drying and concentrating, the residue is dissolved in ethyl acetate and the product is precipitated by introducing hydrogen chloride and filtered off with suction.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]1[CH2:12][C:13]([O:15]C)=[O:14].[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=[O:14]
Reactant: COC(=O)Cn1c(=O)ccc2cnccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)Cn1c(=O)ccc2cnccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 2-(2-oxo-1,6-naphthyridin-1(2H)-yl)acetate (1.51 g, 6.92 mmol) in THF (10 mL) was added sodium hydroxide (4 mL of a 3 N aqueous solution, 13.8 mmol) and the reaction mixture was stirred at room temperature for 18 h. The resulting solution was diluted with ethyl acetate and washed with water. The aqueous phase was separated, adjusted to pH 2 with aqueous HCl and extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), filtered and concentrated under vacuum to give 2-(2-oxo-1,6-naphthyridin-1(2H)-yl)acetic acid. Retention time (min)=0.368, method [3], MS (ESI) 205.0 (M+H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[OH:20])([CH3:12])([CH3:11])[CH3:10]>CN(C)C=O>[Br:1][C:15]1[CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:14]=1[OH:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(O)c(C(C)(C)C)c1
Solvent: CN(C)C=O
Product: Cc1cc(Br)c(O)c(C(C)(C)C)c1

Procedure:
Under nitrogen atmosphere, a dimethylformamide 100 ml solution of N-bromosuccinimide (22.25 g, 125 mmol) was added dropwise at 0° C. to a dimethylformamide 100 ml solution of 2-tert-butyl-4-methylphenol (20.53 g, 125 mmol) with stirring, the resulting reaction mixture was brought up to room temperature and stirred for 5 hours.
Reaction SMILES: [CH2:1]([NH:6][C:7]([C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1)=[O:8])[CH2:2][CH2:3][CH:4]=[CH2:5].[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(#N)C>[CH2:1]([NH:6][C:7]([C:9]1[N:10]=[N:11][C:12]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:13][CH:14]=1)=[O:8])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: C1CNCCN1
Reactant: C=CCCCNC(=O)c1ccc(Cl)nn1
Solvent: CC#N
Product: C=CCCCNC(=O)c1ccc(N2CCNCC2)nn1
Yield: 88.6 %

Procedure:
To a solution of 6-chloropyridazine-3-carboxylic acid pent-4-enylamide synthesized above (1.08 g, 4.79 mmol) in acetonitrile (39 mL) was added piperazine (1.25 g, 14.5 mmol). The reaction mixture was heated to reflux overnight (TLC inindicated the reaction was complete). The mixture was evaporated and the solid residue was dissolved in a mixture of ethyl acetate (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layer were dried over Na2SO4 and concentrated to yield the title compound as a yellow solid (1.169 g, 88.6% yield).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]3)[C:4]=2[O:3][CH2:2]1.[O:24]1[C:28]2[CH:29]=[CH:30][C:31]([NH:33]N)=[CH:32][C:27]=2[O:26][CH2:25]1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]4[N:33]([C:31]5[CH:30]=[CH:29][C:28]6[O:24][CH2:25][O:26][C:27]=6[CH:32]=5)[N:20]=[CH:19][CH:18]=4)=[N:11]3)[C:4]=2[O:3][CH2:2]1
Reactant: NNc1ccc2c(c1)OCO2
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc3c2OCO3)ccc1=O
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=c1ccn(-c2cccc3c2OCO3)nc1-c1ccnn1-c1ccc2c(c1)OCO2

Procedure:
The product was obtained starting from 1-Benzo[1,3]dioxol-4-yl-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-14) and benzo[1,3]dioxol-5-yl-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for example 91. MS: M=403.2 (M+H)+
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9](/[CH:11]=[CH:12]/[C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:8][CH:7]=1)=[O:5])C.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:4]([C:6]1[S:10][C:9](/[CH:11]=[CH:12]/[C:13]2[C:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:8][CH:7]=1)=[O:5])([CH3:27])[CH3:26]
Reactant: CCOC(=O)c1cnc(/C=C/c2c(-c3ccccc3)noc2C)s1
Reactant: CC(C)N
Product: Cc1onc(-c2ccccc2)c1/C=C/c1ncc(C(=O)NC(C)C)s1
Yield: 71 %

Procedure:
As described for example 63b, 2-[(E)-2-(5-methyl-3-phenyl-isoxazol-4-yl)-vinyl]-thiazole-5-carboxylic acid ethyl ester (50 mg, 0.15 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (37 mg, 71%) which was obtained as a white solid. MS: m/e=354.4 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Br:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(Br)ccc1I
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)ccc1-c1ccccc1
Yield: 34.3 %

Procedure:
To methyl 5-bromo-2-iodobenzoate (4.41 g, 13 mmol), phenylboronic acid (1.6 g, 13 mmol), potassium carbonate (3.6 g, 26 mmol), and cesium carbonate (4.2 g, 13 mmol) in DMF (50 mL, sparged with nitrogen) was added palladium(0) tetrakis(triphenylphosphine) (751 mg, 0.65 mmol). The reaction was refluxed 16 h, cooled and washed with water, 1N hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (5% ethyl acetate/hexane) to yield methyl 4-bromo-1,1′-biphenyl-2-carboxylate (1.3 g). To methyl 4-bromo-1,1′-biphenyl-2-carboxylate (500 mg, 1.72 mmol) and Pd(dppf)Cl2—CH2Cl2 (70 mg, 0.086 mmol) in THF (5 mL) was added 1M neopentyl magnesium chloride (5 mL, 5 mmol) slowly at room temperature. The reaction was stirred overnight and then quenched with water. The reaction was diluted in ethyl acetate, and the resulting brown solid was filtered away. The organic layer was washed with water, 1N hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (1% ethyl acetate/hexane) to yield a yellow solid (200 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12]C)=[O:11])=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+]>C(O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)Cc1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(CC(=O)O)cc1

Procedure:
A solution of methyl 4-cyanophenylacetate (23.9 g; 0.136 mol) in ethanol (250 mL) was stirred at room temperature and a solution of sodium hydroxide (6.0 g; 0.15 mol) in water (25 mL) was added. After 2 hours the ethanol was removed in vacuo. Ethyl acetate (300 mL) and 5% aqueous HCl (300 mL) were added and the layers were separated. The aqueous layer was extracted with ethyl acetate (300 mL) and the combined organic layers were dried (MgSO4) and evaporated in vacuo to give the acid (21.6 g; 99%) which was used without further purification.
Reaction SMILES: [H-].[Na+].[I-].C[S+](C)C.[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([CH:13]2[O:15]C2)=[CH:11][CH:10]=1>>[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([CH:13]=[O:15])=[CH:11][CH:10]=1
Reactant: Clc1ccc(C2CO2)cc1
Agent: C[S+](C)C
Agent: [H-]
Agent: [I-]
Product: O=Cc1ccc(Cl)cc1

Procedure:
Following the procedure of Example 6 and employing 42.0 g. of 57% sodium hydride/mineral oil, 200 g. (1.0 mol) of trimethylsulfonium iodide and 70.4 g. (0.50 mol) of p-chlorobenzaldehyde there is obtained p-chlorostyrene oxide.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[F:29]>>[Cl:22][C:23]1[CH:24]=[C:25]([C:2]2[S:6][C:5]([S:7]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:12]=3)(=[O:9])=[O:8])=[CH:4][CH:3]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2ccc(F)c(Cl)c2)s1
Yield: 31 %

Procedure:
The product was prepared according to General Procedure 3, described in Example 22, using 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.055 mmol) and 3-chloro-4-fluorophenyl-boronic acid (10 mg, 0.06 mmol). The title compound was obtained in 31% yield (6.7 mg). MS (ESI+) calcd mass for C17H11ClFN5O2S2 435.002672, found 435.002662.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:19][CH2:20]OC)[CH2:11][CH2:10][N:9]([C:12](=[O:18])[CH2:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:8][CH2:7]1)=[O:5])C.[Cl-].C[Al+]C.[F:27][C:28]([F:38])([F:37])[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1>CCCCCCC>[CH:15]1([CH2:14][CH2:13][C:12]([N:9]2[CH2:8][CH2:7][C:6]3([C:4](=[O:5])[N:34]([C:33]4[CH:35]=[CH:36][C:30]([O:29][C:28]([F:27])([F:37])[F:38])=[CH:31][CH:32]=4)[CH2:20][CH2:19]3)[CH2:11][CH2:10]2)=[O:18])[CH2:16][CH2:17]1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C1(CCOC)CCN(C(=O)CCC2CC2)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCCC
Product: O=C(CCC1CC1)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Yield: 15.9 %

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(3-cyclopropyl-propionyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.1 g), dimethylaluminium chloride in heptane (0.9 molar, 0.71 ml) and 4-trifluoromethoxyanilin (0.057 g) to give the desired 8-(3-cyclopropyl-propionyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (0.021 g) as an off-white solid. MS (ESI): 449.17 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:7]([CH3:14])[N:6]=1)=[O:4].O1CCOCC1.S(=O)(=O)(O)O>O>[CH3:13][O:12][C:10]([C:8]1[N:7]([CH3:14])[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:9]=1)=[O:11]
Reactant: COC(=O)c1cc(C(=O)OC)n(C)n1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(C(=O)O)nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
1-Methyl-1H-pyrazole-3,5-dicarboxylic acid dimethyl ester (640, 3.7 g, 19.0 mmol) was combined with 1,4-dioxane (20 mL) and water (60 mL). Concentrated sulfuric acid (1.0 mL) in 2 mL of water was added to the solution. After the reaction was stirred at reflux overnight, it was cooled to room temperature and concentrated until precipitation began. The obtained mixture was left standing overnight. The resulting solid was filtered and dried under reduced pressure. The collected aqueous fractions were extracted with ethyl acetate. The organic portion was dried over anhydrous sodium sulfate and concentrated. Additional solid was crystallized from ethyl acetate to give the desired compound (641, 2.33 g, 68%). MS (ESI) [M+H+]+=185.0, melting point 175° C.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[O:13][C:12]([CH2:14]O)=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.C(Cl)[Cl:24]>CN(C1C=CN=CC=1)C>[Cl:24][CH2:14][C:12]1[O:13][C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)=[CH:10][CH:11]=1
Reactant: ClCCl
Reactant: CC1(c2ccc(CO)o2)OCCO1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Product: CC1(c2ccc(CCl)o2)OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-yl]-methanol (3.50 g, 19.00 mmol) in dry CH2Cl2 (35.0 mL) was treated at 0° C. with Et3N (3.44 mL, 22.80 mmol) followed by DMAP (232 mg, 1.90 mmol) and Ms-C1 (1.77 mL, 22.80 mmol). After stirring at rt for 2 h, the reaction mixture was quenched with water (40 mL), extracted with CH2Cl2 (40 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced. Purification of the residue by FC (8:2:0.1 hept-EA-Et3N) gave the title compound as a yellow oil: TLC:rf (4:1 hept-EA)=0.35.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:29])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:29])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:22]([O:27][CH3:28])[CH:21]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(CC(=O)Nc2cccc(C3CCC(C(C)(C)C)CC3)c2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(CC(=O)Nc2cccc(C3CCC(C(C)(C)C)CC3)c2)cc1OC
Yield: 75.8 %

Procedure:
N-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-4-hydroxy-3-methoxyphenylacetamide (130 mg) and ethyl bromoacetate (84 mg) are dissolved in acetone, and thereto is added potassium carbonate (180 mg), and the reaction solution is heated under reflux for 18 hours. The reaction solution is filtered, and the filtrate is concentrated. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give N-[3-(4-tert-butylcyclohexan-1-yl)phenyl]-4-ethoxycarbonylmethyloxy 3-methoxyphenylacetamide (120 mg). This product is dissolved in methanol (2 ml), and thereto is added 2 M aqueous sodium hydroxide solution (1 ml), and the mixture is stirred at 25° C. for 1 hour. The mixture is neutralized with acetic acid, and water is added thereto. The mixture is extracted with chloroform, and the organic layer is dried over sodium sulfate. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: gradient from 0% to 25% chloroform/methanol) to give the desired compound (45 mg).
Reaction SMILES: C1C=CC(I(OC(C(F)(F)F)=O)OC(C(F)(F)F)=O)=CC=1.[C:22]([O:26][C:27]([N:29](C(OC(C)(C)C)=O)[C:30]1[N:31]=[CH:32][C:33]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH:47]3[CH2:52][CH2:51][CH2:50][N:49]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:48]3)(=[O:46])=[O:45])=[CH:40][CH:39]=2)=[N:34][C:35]=1[C:36]#[CH:37])=[O:28])([CH3:25])([CH3:24])[CH3:23].[OH:67][C:68]1[CH:76]=[CH:75][CH:74]=[CH:73][C:69]=1/[CH:70]=[N:71]/[OH:72]>CO.O>[C:22]([O:26][C:27]([NH:29][C:30]1[N:31]=[CH:32][C:33]([C:38]2[CH:39]=[CH:40][C:41]([S:44]([CH:47]3[CH2:52][CH2:51][CH2:50][N:49]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:48]3)(=[O:45])=[O:46])=[CH:42][CH:43]=2)=[N:34][C:35]=1[C:36]1[O:72][N:71]=[C:70]([C:69]2[CH:73]=[CH:74][CH:75]=[CH:76][C:68]=2[OH:67])[CH:37]=1)=[O:28])([CH3:24])([CH3:25])[CH3:23]
Reactant: C#Cc1nc(-c2ccc(S(=O)(=O)C3CCCN(C(=O)OC(C)(C)C)C3)cc2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O/N=C/c1ccccc1O
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ncc(-c2ccc(S(=O)(=O)C3CCCN(C(=O)OC(C)(C)C)C3)cc2)nc1-c1cc(-c2ccccc2O)no1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
PIFA was added to a stirred solution of tert-butyl 3-[4-[5-[bis(tert-butoxycarbonyl)amino]-6-ethynyl-pyrazin-2-yl]phenyl]sulfonylpiperidine-1-carboxylate (150 mg,) and (E)-2-hydroxybenzaldehyde oxime in MeOH/water (0.4 mL) and the reaction mixture stirred at ambient temperature for 1.5 hours. A further portion of PIFA was added and the reaction mixture stirred at ambient temperature for a further 1.5 hours. The reaction mixture was partitioned between ethylacetate and water and the layers separated. The aqueous layer was extracted with ethylacetate (×1) and the combined organic extracts dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 24 g column, eluting with 0 to 50% Petroleum/Petroleum Ether, loaded in DCM) to give tert-butyl 3-((4-(5-((tert-butoxycarbonyl)amino)-6-(3-(2-hydroxyphenyl)isoxazol-5-yl)pyrazin-2-yl)phenyl)sulfonyl)piperidine-1-carboxylate as an off-white solid (142 mg, 78%). LC/MS m/z 722.1 [M−56+1]+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[F:12].[Li]CCCC.CN([CH:21]=[O:22])C>C1COCC1>[F:12][C:3]1[C:4]2[O:9][CH2:8][CH2:7][O:6][C:5]=2[CH:10]=[CH:11][C:2]=1[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: Fc1c(Br)ccc2c1OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1F)OCCO2
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 21.9 %

Procedure:
A solution of 6-bromo-5-fluoro-2,3-dihydro-1,4-benzodioxin (146 mg, 0.627 mmol) in THF (5 ml) at −78° C. was treated with n-BuLi (0.551 ml, 1.378 mmol) under a nitrogen atmosphere and stirred at −78° C. for 15 min before treatment with a solution of DMF (0.243 ml, 3.13 mmol) in THF) (2.00 ml). The reaction was stirred for 10 min at −78° C. and then the reaction was allowed warm to rt over 10 min and stirred at rt for 0.5 h. Reaction was treated with 2M HCl (20 ml) and extracted with ethyl acetate (3×100 ml). The organic extracts were evaporated, dried (MgSO4), filtered, evaporated, chromatographed (0-100% EtOAC:Cyclohexane) to give product as a white solid (25 mg, 22%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][CH2:6][CH:7]([OH:22])[CH2:8][NH:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[NH2:20])=[CH:15][CH:14]=1.Cl.[C:27](OC(=O)C)(=[O:29])[CH3:28].[OH-].[Na+]>O>[C:27]([NH:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][CH2:6][CH:7]([OH:22])[CH2:8][NH:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[NH2:20])=[CH:15][CH:14]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1ccc(OCCNCC(O)COc2cccc(N)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1cccc(OCC(O)CNCCOc2ccc(C(N)=O)cc2)c1

Procedure:
An aqueous mixture consisting of 10 g. of 1-(3-aminophenoxy)-3-[2-(4-carbamoylphenoxy)ethylamino]propan-2-ol in 150 ml. of water was adjusted to pH 4-5 with dilute hydrochloric acid and then stirred vigorously for several minutes in order to effect complete solution. At this point, 3 g. of acetic anhydride were added to the mixture in a dropwise manner and the pH of the resulting solution was simultaneously maintained within the aforestated pH range by means of dilute aqueous sodium hydroxide. After further stirring the spent reaction mixture for a period of 1 hour, it was subsequently basified with additional dilute aqueous sodium hydroxide solution and the resulting solid precipitate with formed at this point was thereafter collected by means of suction filtration to give 1-(3-acetamidophenoxy)-3-[2-(4-carbamoylphenoxy)ethylamino]propan-2-ol as a white crystalline base, m.p. 164°-165°C. The analytical sample was then recrystallized from aqueous ethanol, but the melting point remained constant.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([F:14])[C:3]=1[C@H:4]1[O:6][CH2:5]1.[Br-:15].[Li+].P([O-])([O-])([O-])=O>O1CCCC1.[Ni](Br)Br>[Br:15][CH2:5][C@@H:4]([C:3]1[C:2]([F:1])=[C:10]([F:11])[C:9]([F:12])=[C:8]([F:13])[C:7]=1[F:14])[OH:6]
Reactant: Fc1c(F)c(F)c([C@@H]2CO2)c(F)c1F
Reactant: [Br-]
Agent: Br[Ni]Br
Agent: O=P([O-])([O-])[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O[C@@H](CBr)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.1 %

Procedure:
To an ice-cooled solution of 1.05 g of (R)-(+)-2,3,4,5,6-pentafluorostyrene oxide in 10 ml of tetrahydrofuran, was added dropwise a solution of Li2NiBr4, which was prepared by adding 2.19 g of nickel (II) bromide to a suspension of 1.74 g of lithium bromide in 20 ml of tetrahydrofuran. After completion of addition, the solution was stirred for 15 hours at room temperature. The resulted reaction mixture was poured into a 0.05 mol phosphate buffer, and was extracted with ether. The resultant extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 1.02 g of (R)-(-)-2-bromo-1-(pentafluorophenyl)ethanol containing 15% of (+)-2-bromo-2-(pentafluorophenyl)ethanol.