Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][C@H:4]([C@H:9]([OH:13])[CH2:10][CH2:11][CH3:12])[C:5]([O:7]C)=[O:6].O.[OH-].[Li+].S([O-])(O)(=O)=O.[Na+]>O.CO.C1COCC1>[CH3:14][CH:2]([CH3:1])[CH2:3][C@H:4]([C@H:9]([OH:13])[CH2:10][CH2:11][CH3:12])[C:5]([OH:7])=[O:6]
Reactant: CCC[C@@H](O)[C@@H](CC(C)C)C(=O)OC
Agent: O=S(=O)([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCC[C@@H](O)[C@@H](CC(C)C)C(=O)O
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A solution of methyl (2R,3R)-2-(2-methyl-1-propyl)-3-hydroxyhexanoate (6.5 g, 31.9 mmol) in 100 mL of water—MeOH—THF (1:1:4) is treated with lithium hydroxide monohydrate (1.6 g, 38 mmol) and stirred overnight. The reaction mixture is acidified to pH 2 using 1 M aqueous sodium hydrogen sulfate and extracted with two 100-mL portions of EtOAc. The combined organic layers are washed with two 25-mL portions of saturated aqueous sodium chloride, dried over sodium sulfate and filtered, and the solvents are removed under reduced pressure. Purification by flash chromatography on silica gel eluting with 10% EtOAc-hexanes affords 6.0 g (100%) of (2R,3R)-2-(2-methyl-1-propyl)-3-hydroxyhexanoic acid as a gum.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([C:17]([O:19]CC)=[O:18])=[C:15]([S:22][CH:23]3[CH2:28][CH2:27][CH:26]([CH2:29][C:30]([O:32]CC)=[O:31])[CH2:25][CH2:24]3)[N:14]=[C:13]2[CH2:35][CH2:36][CH3:37])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.O1CCCC1>C(O)C>[C:30]([CH2:29][CH:26]1[CH2:25][CH2:24][CH:23]([S:22][C:15]2[N:14]=[C:13]([CH2:35][CH2:36][CH3:37])[N:12]([CH2:11][C:3]3[C:2]([Cl:1])=[CH:10][C:6]4[O:7][CH2:8][O:9][C:5]=4[CH:4]=3)[C:16]=2[C:17]([OH:19])=[O:18])[CH2:28][CH2:27]1)([OH:32])=[O:31]
Reactant: CCCc1nc(SC2CCC(CC(=O)OCC)CC2)c(C(=O)OCC)n1Cc1cc2c(cc1Cl)OCO2
Solvent: C1CCOC1
Solvent: CCO
Product: CCCc1nc(SC2CCC(CC(=O)O)CC2)c(C(=O)O)n1Cc1cc2c(cc1Cl)OCO2
Reaction time: 24 h
Yield: 71.8 %

Procedure:
760 mg of the product of Example 1 is introduced into 20 ml of tetrahydrofuran, 50 ml of ethanol and 25 ml of 2N soda are added and the whole is left for 24 hours at ambient temperature. The tetrahydrofuran and the ethanol are evaporated off then the reaction medium is acidified to pH 1. After extraction with ethyl acetate and evaporating to dryness, the residue is recrystallized from ethanol. 490 mg of expected product is obtained. M.p.=166° C.
Reaction SMILES: [CH2:1]([O:15][C:16]1[S:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C[O-].[Na+:26]>CO>[Na+:26].[CH2:1]([O:15][C:16]1[S:20][C:19]([C:21]([O-:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)s1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)[O-])s1

Procedure:
To 20.4 g (0.06 mole) of 5-tetradecyloxy-2-thiophenecarboxylic acid in 500 ml of methanol is added 5.4 g (0.10 mole) of sodium methoxide. The mixture is refluxed, and the methanol is distilled off being replaced by water. The aqueous solution is cooled, the precipitate collected, and dried to give 5-tetradecyloxy-2-thiophenecarboxylic acid sodium salt.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1)#[CH:2].I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17]>>[C:6]1([CH3:9])[CH:7]=[CH:8][C:3]([C:1]2[O:17][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH:2]=2)=[CH:4][CH:5]=1
Reactant: C#Cc1ccc(C)cc1
Reactant: Oc1ccccc1I
Product: Cc1ccc(-c2cc3ccccc3o2)cc1

Procedure:
The general procedure was used to convert 4-ethynyl-toluene and 2-iodophenol to the title product. Purification by flash chromatography (10% CH2Cl2 in hexanes as the eluent) gave the analytically pure product as a white solid (268 mg, 64% yield). 1H NMR (300 MHz, CDCl3) δ 7.74 (d, J=8.29, 2H), 7.56-7.48 (m, 2H), 7.28-7.17 (m, 4H), 6.93 (s, 1H), 2.37 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 156.16, 154.75, 138.56, 132.85, 129.47, 127.73, 124.86, 123.97, 122.84, 120.72, 111.07, 100.54, 21.36 Anal. Calcd. for C15H12O: C, 86.51; H, 5.81. Found C, 86.34; H, 5.98. m.p.: 124-125° C. (lit., 3126-128° C.).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:37][CH2:38][CH2:39][O:40][CH3:41])=[C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C)C>[CH3:36][O:35][CH2:34][CH2:33][O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:37][CH2:38][CH2:39][O:40][CH3:41])[N:25]=[CH:24][N:23]=[C:22]2[O:20][C:16]1[CH:15]=[C:14]([NH:13][C:11]([NH:10][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[O:9][N:8]=2)=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCOC
Temperature: 70 °C

Procedure:
According to the procedure described in Example 13B Step 1, a mixture of 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A (0.688 g, 2.5 mmol), 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline from the previous step (0.782 g, 2.5 mmol), and Cs2CO3 (0.977 g, 3 mmol) in isopropanol (15 mL) was heated at 70° C. for 7 hours, to afford 1-{3-[6,7-bis(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}-3-(5-tert-butylisoxazol-3-yl)urea as solid. 1H NMR (300 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.98 (s, 1H), 8.55 (s, 1H), 7.58 (m, 2H), 7.42 (s, 1H), 7.40 (t, 1H), 7.25 (d, 1H), 6.97 (d 1H), 6.47 (s, 1H), 4.34 (m, 4H), 3.77 (m, 4H), 3.38 (s, 3H), 3.36 (s, 3H), 1.27 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:37])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[C:29]([O:30][CH2:31][CH2:32][O:33]C)=[CH:28][CH:27]=[C:26]([F:35])[C:25]=3[F:36])[C:5]2=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:37])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[C:29]([O:30][CH2:31][CH2:32][OH:33])=[CH:28][CH:27]=[C:26]([F:35])[C:25]=3[F:36])[C:5]2=[CH:4][CH:3]=1
Reactant: COCCOc1ccc(F)c(F)c1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2c(OCCO)ccc(F)c2F)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.2 %

Procedure:
To a suspension of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2,3-difluoro-6-(2-methoxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.12 g, 0.22 mmol) prepared in example 101d in dichloromethane (5 mL) at −78° C. was added boron tribromide (1M, 2.19 ml, 2.19 mmol) dropwise. The reaction was gradually warmed up to room temperature and stirred at room temperature for 2 h. Then the crude was diluted with dichloromethane. The organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated. The residue was purified with chromatography (EtOAc) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2,3-difluoro-6-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as white solid (Yield: 46 mg, 39.3%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]1[CH:17]2[CH:12]([CH2:13][NH:14][CH2:15][CH2:16]2)[CH2:11][N:10]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>O1CCCC1>[CH2:1]([N:14]1[CH2:15][CH2:16][CH:17]2[CH2:9][N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:11][CH:12]2[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC2CCNCC2C1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CCN(Cc3ccccc3)CC2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.4 %

Procedure:
0.777 g of benzylbromide (4.54 mmol) were added dropwise to a mixture of 1.028 g of commercially available tert-butyl hexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (4.54 mmol), 1.883 g potassium carbonate (13.62 mmol) and a spatula tip of 18-crown-6 in 25 ml of tetrahydrofurane. The reaction mixture was stirred for 16 h at room temperature, filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane, the organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated to yield 1.413 g of product that was used in the subsequent step without further purification.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:10]#CC(=O)CCCCC>>[CH:4]1([C:3](=[O:9])[C:2]#[CH:1])[CH2:10][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: C#CC(O)CCCCC
Reactant: C#CC(=O)CCCCC
Product: C#CC(=O)C1CCCCC1

Procedure:
In like manner, but replacing the 3-cyclohexylprop-1-yn-3-ol with oct-1-yn-3-ol, oct-1-yn-3-one was prepared. C. Similarly, but starting with other appropriate 3-hydroxy-1-alkynes, prepared as shown above, the following 3-oxo-1-alkynes are prepared:
Reaction SMILES: CN(C)C=O.[H-].[Na+].[NH:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.Br[C:14]1[CH:23]=[C:22]2[C:17]([C:18]([CH3:31])=[CH:19][C:20](=[O:30])[N:21]2[CH2:24][CH:25]2[O:29][CH2:28][CH2:27][O:26]2)=[CH:16][CH:15]=1>[Cu]=O.O.C(Cl)(Cl)Cl>[O:26]1[CH2:27][CH2:28][O:29][CH:25]1[CH2:24][N:21]1[C:22]2[C:17](=[CH:16][CH:15]=[C:14]([N:8]3[CH:12]=[CH:11][N:10]=[CH:9]3)[CH:23]=2)[C:18]([CH3:31])=[CH:19][C:20]1=[O:30]
Reactant: c1c[nH]cn1
Reactant: Cc1cc(=O)n(CC2OCCO2)c2cc(Br)ccc12
Agent: O=[Cu]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(=O)n(CC2OCCO2)c2cc(-n3ccnc3)ccc12
Temperature: 142.5 °C
Reaction time: 0.17 h

Procedure:
To 0.7 mL of an N,N-dimethylformamide solution containing 74 mg of 60% sodium hydride, 0.14 g of imidazole was added at room temperature, and the mixture was stirred for 10 minutes. Thereto were added 0.20 g of 7-bromo-1-(1,3-dioxolan-2-ylmethyl)-4-methylquinolin-2(1H)-one and 17 mg of copper(II) oxide, and the mixture was heated to 140 to 145° C. and stirred for 40 minutes. Thereto was further added 2 mL of N,N-dimethylformamide, and the mixture was further stirred for 1 hour. The reaction mixture was cooled to room temperature, then chloroform and water were added thereto, and the insoluble material filtered off. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=10:1] to obtain 77 mg of a brown oily substance, 1-(1,3-dioxolan-2-ylmethyl)-7-(1H-imidazol-1-yl)-4-methylquinolin-2(1H)-one.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][C:14]=1[F:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl>[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][Cl:3])=[CH:15][C:14]=1[F:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(OCc2ccccc2)c(F)c1
Solvent: ClCCl
Product: Fc1cc(CCl)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (5 mL) was added to solution of (4-benzyloxy-3-fluoro-phenyl)methanol (CAB03017, 6.80 g, 29.28 mmol) in dichloromethane (50 mL). The solution was stirred for 1 h at room temperature and concentrated under reduced pressure. Then diethyl ether (100 mL) and water (20 mL) were added. The organic layer was separated, washed with conc. sodium bicarbonate solution (10 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in dichloromethane (5 mL) and precipitated by addition of hexane (ca 50 mL). The precipitate was filtered off and dried under high vacuum. Yield: 7.01 g (95%) white powder. 1H-NMR (400 MHz, CDCl3) δ=4.52 (s, 2H, —CH2Cl), 5.15 (s, 2H), 6.96 (dd, J=8.2, 8.2 Hz, 1H), 7.04-7.06 (m, 1H), 7.15 (dd, J=11.7, 2.4 Hz, 1H), 7.31-7.45 (m, 5H). LRMS (FAB+): 91 (100), 215.0 (10), 250.0 (16, [M]+).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:19]#[CH:20])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[CH3:23]COC(C)=O>C1COCC1>[C:1]([N:8]([C@@H:9]([C:19]#[CH:20])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH3:23])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CCOC(C)=O
Reactant: C#C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C

Procedure:
(S)-2-(N-Boc-N-Methylamino)-1-(-tert-butyldimethylsilyloxy)-but-3-yne was synthesized according to Method Y above by the treatment of (S)-N-Boc-2-amino-1-(-tert-butyldimethylsilyloxy)-but-3-yne (190 mg, 0.64 mmol) (Example 115B) with NaH (18 mg, 0.76 mmol) and Mel (180 mg, 1.27 mmol) in THF (5 mL). The product was obtained after silica gel column chromatography with a 0-10% EtOAc in hexanes gradient. (Yield 190 mg, 95%).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH2:19]([NH2:21])[CH3:20]>O>[CH2:19]([NH:21][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][N:7]=1)[CH3:20]
Reactant: COc1ccc2nc(-c3ccc(F)nc3)sc2c1
Reactant: CCN
Solvent: O
Product: CCNc1ccc(-c2nc3ccc(OC)cc3s2)cn1
Temperature: 100 °C

Procedure:
In a microwave vial were added 2-(6-fluoropyridin-3-yl)-6-methoxy-1,3-benzothiazole (75 mg, 0.289 mmol), water (1.2 mL) and ethylamine in water (70%, 1.2 mL) and the reaction was heated in a microwave oven at 100° C. for 5 min. The precipitated product was filtered off, washed with water and dried in a desicator over P2O5 to yield the product (67 mg) as a white solid. 1H NMR δ ppm 8.62 (d, 1H) 7.95 (dd, 1H) 7.82 (d, 1H) 7.64 (d, 1H) 7.23 (t, 1H) 7.07 (dd, 1H) 6.57 (d, 1H) 3.83 (s, 3H) 3.33-3.40 (m, 2H) 1.16 (t, 3H); MS m/z (M+H) 286.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].[O:9]=[O+][O-]>CO>[CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].[OH:9][CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=[O+][O-]
Agent: C=Cc1ccccn1
Solvent: CO
Product: OCc1ccccn1
Yield: 78.1 %

Procedure:
12 liters of a solution of 1250 [lacuna] of vinylpyridine (12 mol) in methanol were prepared, and a 1 molar solution of vinylpyridine in methanol was ozonized analogously to Example 3, a concentration of 20 g of vinylpyridine per liter being maintained in the ozonolysis by metered addition. A total of 12 l of solution and thus 12 mol of vinylpyridine were fed in. All of the ozone introduced was taken up. The resulting peroxide solution was stored in a deep-freeze at −30° C. and used for a further continuous ozonolysis at a vinylpyridine content of about 2 g/l. The total ozone consumption was, at 570 g or 98.9% of theory, somewhat lower than in Example 18. The resulting peroxide solution was hydrogenated analogously to Example 17. After work-up analogously to Example 18, 1024 [lacuna] (78.1% of theory) of hydroxymethylpyridine were obtained.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[S:17][C:16]([C:18]([C@H:20]2[CH2:25][CH2:24][C@H:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]2)=[CH2:19])=[N:15][CH:14]=1>C(Cl)Cl>[Br:12][C:13]1[S:17][C:16]([C:18]2([C@H:20]3[CH2:25][CH2:24][C@H:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]3)[CH2:19][O:9]2)=[N:15][CH:14]=1
Reactant: C=C(c1ncc(Br)s1)[C@H]1CC[C@H](C(=O)OCC)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@H](C2(c3ncc(Br)s3)CO2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
mCPBA (130 mg, 0.582 mmol) was added was added to a solution of ethyl trans-4-[1-(5-bromo-1,3-thiazol-2-yl)ethenyl]cyclohexanecarboxylate (182 mg, 0.529 mmol) in DCM (3 ml) at 0° C. The mixture was then allowed to stir at room temperature for 17 h, diluted with dichlormethane and washed with sodium hydroxide (2M in H2O). The aqueous layer was extracted with DCM and the combined organic layers were washed with brine, dried, concentrated in vacuo. The residue was purified on silica gel (0-15% EtOAc in hexane) to afford ethyl trans-4-[2-(5-bromo-1,3-thiazol-2-yl)oxiran-2-yl]cyclohexanecarboxylate. MS ESI calc'd. for C14H18BrNO3S [M+H]+ 360. found 360.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:7][C:6]=1[O:22]CC(C)=C)([CH3:4])([CH3:3])[CH3:2]>CN(C)C1C=CC=CC=1>[C:18]([C:8]1[C:7]2[CH2:2][C:1]([CH3:4])([CH3:3])[O:22][C:6]=2[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:10][C:9]=1[O:11][C:12](=[O:17])[C:13]([CH3:15])([CH3:16])[CH3:14])([CH3:21])([CH3:19])[CH3:20]
Reactant: C=C(C)COc1cc(C(C)(C)C)c(OC(=O)C(C)(C)C)cc1C(C)(C)C
Solvent: CN(C)c1ccccc1
Product: CC1(C)Cc2c(c(C(C)(C)C)cc(OC(=O)C(C)(C)C)c2C(C)(C)C)O1
Yield: 179.2 %

Procedure:
Under a nitrogen stream, a solution of 0.48 g of 2,5-di-t-butyl-4-trimethylacetoxy-1-(2-methyl-2-propenyloxy)benzene in 5 ml of dimethylaniline was refluxed overnight. The solution was allowed to attain room temperature and concentrated under reduced pressure, then extracted with ethyl acetate and 5% hydrochloric acid. The organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 0.5% ethyl acetate) to give 0.43 g of 4,7-di-t-butyl-2,2-dimethyl-5-trimethylacetoxy-2,3-dihydrobenzofuran as a colorless solid.
Reaction SMILES: [I-].[Cl:2][C:3]1[CH:19]=[CH:18][C:6]2[S:7][C:8](=[N+:10](C)C3C=CC=CC=3)[S:9][C:5]=2[CH:4]=1.Cl.N[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[Cl:2][C:3]1[CH:19]=[CH:18][C:6]2[S:7][C:8](=[N:10][CH:23]([CH3:22])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[S:9][C:5]=2[CH:4]=1
Reactant: CCOC(=O)CCCN
Reactant: C[N+](c1ccccc1)=c1sc2ccc(Cl)cc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(C)N=c1sc2ccc(Cl)cc2s1
Yield: 31.9 %

Procedure:
A solution of 5-chloro-N-methyl-N-phenyl-1,3-benzodithiol-2-iminium iodide (12.59g), 4-aminobutanoic acid, ethyl ester, hydrochloride (5.02g), and anhydrous sodium carbonate (3.18g) in 300 ml of anhydrous dimethylformamide is heated at 120° C under nitrogen for three hours. The reaction mixture is poured into water (1000 ml) and extracted with three 200 ml portions of benzene. The combined benzene extracts are washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The resultant crude product is chromatographed on silica gel (1000 ml) eluting with 1) pentane (1000 ml), 2) pentane/dichlormethane (1:1, 4000 ml) and 3) dichloromethane (9000 ml). The fractions containing product with Rf =0.4 (silica gel, 1% ethyl acetate/dichloromethane) are concentrated in vacuo. The resultant solid is recrystallized from pentance to yield 3.02g of the title compound, melting point 60°-61° C.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:16]=2[CH:32]=1)(C)(C)C>FC(F)(F)C(O)=O.O>[C:26]1([N:17]2[C:16]3[CH:32]=[C:12]([O:11][CH2:10][CH2:9][O:8][CH2:7][C:6]([OH:33])=[O:5])[CH:13]=[CH:14][C:15]=3[N:19]=[C:18]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)COCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Reaction time: 48 h

Procedure:
50 mg of 2-[2-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]ethoxy]acetic acid-tert-butyl ester was dissolved in 0.5 ml of trifluoroacetic acid and stirred for 48 hours. Then, it was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was chromatographed on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12])=[CH:5]2.Br[CH2:20][CH2:21][OH:22].C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:14][CH2:15][N:16]([CH2:20][CH2:21][OH:22])[CH2:17][CH2:18]1)=[O:12])=[CH:5]2
Reactant: OCCBr
Reactant: O=C(c1cc2cc(Cl)ccc2[nH]1)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(c1cc2cc(Cl)ccc2[nH]1)N1CCN(CCO)CC1
Temperature: 60 °C
Yield: 42.8 %

Procedure:
The product from Step B (1.0 g) was dissolved in CH3CN (10 mL) and treated with 2-bromoethanol (0.5 g) and then K2CO3 (0.8 g). The resulting mixture was heated at 60° C. overnight. The mixture was cooled to ambient temperature, filtered, and concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography (0-10% methanol/dichloromethane) to give the title compound (0.5 g). 1H NMR (400 MHz, CDCl3): δ 10.09 (br s, 1H), 7.61 (d, J=2.0 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.23 (dd, J=2.0, 8.8 Hz, 1H), 6.69 (d, J=0.8 Hz, 1H), 3.95 (br m, 3H), 3.72-3.69 (m, 2H), 2.67-2.64 (m, 4H), 2.52 (br s, 3H). MS (electrospray): exact mass calculated for C15H18ClN3O2, 307.78; m/z found, 308.1 [M+H]+.
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[S:3][C:2]=1[C:10]([O-:12])=O.[Na+].Cl.[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27])[CH:20]=[CH:19]2>>[ClH:15].[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([S:26]([N:29]1[CH2:30][CH2:31][N:32]([C:10]([C:2]3[S:3][C:4]4[CH:5]=[N:6][CH:7]=[CH:8][C:9]=4[N:1]=3)=[O:12])[CH2:33][CH2:34]1)(=[O:27])=[O:28])[CH:20]=[CH:19]2
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: O=C([O-])c1nc2ccncc2s1
Agent: Cl
Agent: [Na+]
Product: O=C(c1nc2ccncc2s1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1

Procedure:
In a similar manner to Example 4 except for the use of sodium thiazolo[5,4-c]pyridine-2-carboxylate and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:18]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[C:3]=12.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36]>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:18]3[CH2:22][CH2:21][NH:20][CH2:19]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:35](=[O:36])[C:34]4[CH:38]=[CH:39][CH:40]=[C:32]([C:31]([F:30])([F:41])[F:42])[CH:33]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CC[C@H](n2nc(-c3ccc(N)cc3)c3c(N)ncnc32)C1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(NC(=O)c3cccc(C(F)(F)F)c3)cc1)nn2[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (S)-tert-butyl 3-(4-amino-3-(4-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate (0.075 g, 0.17 mmol) in CH2Cl2 (10 mL) was cooled in an ice-water bath. To this, 3-(trifluoromethyl)benzoyl chloride (0.025 mL, 0.17 mmol) diluted in CH2Cl2 (5 mL) was added dropwise. The reaction was allowed to warm to room temperature and left stirring for 4 hours, yielding the benzamide derivative (ESI-MS m/z [M+H]+ found 568.5, calculated 568.6). Boc-deprotection was completed through the addition of formic acid (5 mL) and concentrated HCl (0.5 mL) added dropwise directly to the reaction mixture. The reaction mixture was left stirring for 12 hours and then was concentrated in vacuo, resuspended in 50:50 H2O—CH3CN, and purified on a C18 column in CH3CN/H2O/0.1% TFA (1-100% gradient) to afford AD70. ESI-MS m/z [M+H]+ found 468.5, calculated 468.2.