Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][N:5]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)(=[O:8])=[O:7].O.[OH-].[Li+]>C1COCC1>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([N:5]([CH2:4][C:3]([OH:24])=[O:2])[S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)(=[O:7])=[O:8])=[CH:22][CH:21]=1
Reactant: COC(=O)CN(c1ccc(Cl)cc1)S(=O)(=O)c1cccc(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(S(=O)(=O)N(CC(=O)O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [(4-chlorophenyl)-(3-methoxy-benzenesulfonyl)-amino]-acetic acid methyl ester (1.03 g, 2.7 mmol) in THF (20 mL) was added an aqueous solution (10 mL) of lithium hydroxide monohydrate (168 mg, 4.0 mmol) slowly under ice-cooled condition. The reaction mixture was stirred for 2 h at 25° C. THF was evaporated in vacuo and water was added. The mixture was washed with diethyl ether. The aqueous layer was acidified with 1(N) hydrochloride acid to pH 6, and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water, dried (Na2SO4), and evaporated under reduced pressure to yield the title compound as pure solid compound, which used as such in the final coupling reaction. Yield: 810 mg (84%).
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH2:23][O:24][CH2:25][CH2:26][NH:27][C:28]([NH2:30])=[O:29])[CH2:6]1)(=O)C.C[O-].[Na+].C(O)(=O)C>CO.C(OCC)(=O)C>[SH:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH2:23][O:24][CH2:25][CH2:26][NH:27][C:28]([NH2:30])=[O:29])[CH2:6]1
Reactant: CC(=O)S[C@H]1C[C@@H](COCCNC(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: NC(=O)NCCOC[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1.5 h
Yield: 81 %

Procedure:
To a solution of (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-[(2-ureidoethyl)oxymethyl]pyrrolidine (1.01 g) in methanol (20 ml) was added sodium methoxide (28% solution in methanol) (0.5 ml) at -15°-10° C. in a nitrogen stream and the mixture was stirred at the same condition for 1.5 hours. To the mixture was added glacial acetic acid (0.17 ml) at -10°-0° C. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate (50 ml). The solution was washed with water (20 ml), dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (2:98 V/V) to give (2S,4S)-4-mercapto- 1-(4-nitrobenzyloxycarbonyl)-2-[(2-ureidoethyl)oxymethyl]pyrrolidine (0.74 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH3:14])([CH3:13])[C:11]#N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:15].[Na+].C[OH:18]>>[CH2:1]([O:8][CH2:9][C:10]([CH3:14])([CH3:13])[C:11]([OH:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C#N)COCc1ccccc1
Reactant: CO
Reactant: [OH-]
Agent: [Na+]
Product: CC(C)(COCc1ccccc1)C(=O)O

Procedure:
A mixture of 3-benzyloxy-2,2-dimethylpropanenitrile (2.5 g, 13.2 mmol), 10% aqueous sodium hydroxide (10 mL) and methanol (150 mL) was heated 8 hours at reflux and then concentrated. The residue was dissolved in water (30 mL) and the solution was washed with dichloromethane (2×10 mL), treated with 10% hydrochloric acid and extracted with ethyl acetate (4×20 mL). The combined extracts were washed with water and brine, dried (MgSO4) and concentrated to give 3-benzyloxy-2,2-dimethylpropionic acid (1.6 g, 7.5 mmol).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2)(=[O:3])[CH3:2].O.[Br:17]Br>C(O)(=O)C>[Br:17][C:12]1[CH:13]=[CH:14][C:5]([O:4][C:1](=[O:3])[CH3:2])=[C:6]2[C:11]=1[NH:10][C:9](=[O:15])[CH2:8][CH2:7]2
Reactant: BrBr
Reactant: CC(=O)Oc1cccc2c1CCC(=O)N2
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc(Br)c2c1CCC(=O)N2
Reaction time: 2 h
Yield: 74 %

Procedure:
20.5 grams of 5-acetyloxy-3,4-dihydrocarbostyril are dissolved in 200 ml of acetic acid. This solution is stirred under cooling with water and 60 ml of acetic acid solution containing 16 g of bromine are added dropwise over 30 minutes and the reaction is carried out for 2 hours at the same temperature. The reaction mixture is poured into 300 ml of water and allowed to stand for 3 hours and the crystals thus precipitated are separated by filtration, and recrystallized from methanol to obtain 21 g of 8-bromo5-acetyloxy-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with a melting point of 237°-239° C.
Reaction SMILES: BrC[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[O:16])=[CH:5][CH:4]=1.[C:24]([O-])(=[O:26])C.[Na+]>C(O)(=O)C>[OH:26][CH2:24][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=2)=[C:10]([C:15]([O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:23])[CH3:21])=[O:16])[CH:11]=1
Reactant: CC(=O)[O-]
Reactant: C[Si](C)(C)CCOC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [Na+]
Solvent: CC(=O)O
Product: C[Si](C)(C)CCOC(=O)c1cc(CO)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.8 g of 4-bromomethyl-2'-(trimethylsilylethoxycarbonyl)biphenyl and 1.17 g of anhydrous sodium acetate are stirred overnight at 65° in glacial acetic acid and then boiled under reflux for 3 hours. The reaction mixture is evaporated, the residue is taken up in ethyl acetate and washed with water and sodium hydrogencarbonate, and the organic phase is dried and concentrated. The residue is introduced into 25 ml of ethanol, 6.3 ml of 1N NaOH are added and the mixture is stirred at room temperature for 30 minutes. It is evaporated in vacuo, and the residue is treated with ethyl acetate, washed with water and brine, dried and evaporated. Flash chromatography (N4) yields 4-hydroxymethyl-2-(trimethylsilylethoxycarbonyl)biphenyl as a colourless oil. 1H-NMR (DMSO): 0 ppm (s, 9H), 0.75 ppm (t, 2H), 4.1 ppm (t, 2H), 4.73 ppm (d, 2H), 5.27 ppm (t, 1H), 7.2-7.7 ppm aromatics.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH3:4].Cl[CH2:18][C:19]([CH:21]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20]>CN(C)C=O>[CH2:3]([O:5][C:6](=[O:16])[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:18][C:19]([CH:21]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[CH:10][CH:9]=1)[CH3:4]
Reactant: O=C(CCl)C1CCCCCCC1
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1ccc(OCC(=O)C2CCCCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
55% Sodium hydride (0.14 g) was stirred with 4-hydroxy-alpha-oxobenzeneacetic acid ethyl ester (0.622 g) in dimethylformamide (8 mL) under argon for 30 minutes and then the solution was treated with 2-chloro-1-cyclooctylethanone (0.53 g) in dimethylformamide (3 mL). The mixture, stirred at room temperature overnight and the at 60° C. for 1 hour, was worked up as in Example 20. The residual oil was purified by flash chromatography over silica gel (3% ethyl acetate in dichloromethane-hexane 1:1 ) to provide of 0.399 g of 4-(2-cyclooctyl-2-oxoethoxy)-alpha-oxobenzeneacetic acid ethyl ester as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CN([C:14]([O:18][N:19]1N=NC2C=CC=N[C:20]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CONC.O>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:19]([O:18][CH3:14])[CH3:20])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(O)cn1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a suspension of 5-hydroxypicolinic acid (1.0 eq), HATU (1.2 eq) and N-methoxymethanamine hydrochloride (1.2 eq) in dry DMF was added DIEtOAc (2.5 eq) dropwise at rt. The mixture was then stirred overnight at rt. After addition with water, the mixture was extracted with CH2Cl2. The extract was dried, concentrated, and purified by column chromatography to give the desired product (87% yield).
Reaction SMILES: [CH:1]([C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:5]([O:15][CH3:16])[C:4]=1[N+:17]([O-:19])=[O:18])=O.[Br-].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:22]1.C(=O)([O-])[O-].[K+].[K+].O>CO.C(O)C>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](/[CH:30]=[CH:1]/[C:3]2[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:5]([O:15][CH3:16])[C:4]=2[N+:17]([O-:19])=[O:18])=[N:22]1
Reactant: COC(=O)COc1ccc(C=O)c([N+](=O)[O-])c1OC
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: COC(=O)COc1ccc(/C=C/c2n[nH]c3ccccc23)c([N+](=O)[O-])c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
Methyl (4-formyl-2-methoxy-3-nitrophenoxy)acetate (2.3 g, 8.5 mmol) obtained in Step 1, (1H-indazol-3-ylmethyl)triphenylphosphonium bromide (4.4 g, 9.4 mmol) and potassium carbonate (2.4 g, 17 mmol) were dissolved in methanol (15 mL) and the solution was stirred at room temperature for 2.0 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was reslurried with ethanol to obtain methyl (E)-{4-[2-(1H-indazol-3-yl)vinyl]-2-methoxy-3-nitrophenoxy}acetate (2.8 g, 87%).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[Cl:12][CH2:13][CH2:14][C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:12][CH2:13][CH2:14][C@H:15]([N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O[C@H](CCCl)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@@H](CCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.4 %

Procedure:
Prepared according to the general procedure described in Srebnik, M.; Ramachandran, P. V.; Brown, H. C. J. Org. Chem. 1988, 53, 2916–2920. A mixture of phthalimide (0.147 g, 1.0 mmol), (R)-(+)-3-chloro-1-phenyl-1-propanol (0.171 g, 1.0 mmol), triphenylphosphine (0.262 g, 1.0 mmol) and diethyl azodicarboxylate (0.174 g, 1.0 mmol) in 5.0 mL of THF was stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo. The residue was washed with pentane (3×50 mL) and the combined pentane extracts were concentrated and chromatographed (silica, hexanes: EtOAc=8:1 as the eluent) to give the desired product (0.121 g, 50%) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.82 (apparent dd, 2H, J=2.9 Hz), 7.70 (apparent dd, 2H, J=2.9 Hz), 7.56 (m, 2H), 7.39–7.27 (m, 3H), 5.64 (apparent dd, 1H, J=7.0, 9.2 Hz), 3.57 (m, 2H), 3.05 (m, 1H), 2.82 (septet, 1H, J=7.0 Hz); ESMS m/e: 300.1 (M+H)+.
Reaction SMILES: ClC(Cl)(Cl)Cl.C(#N)C.[CH3:9][O:10][CH2:11][CH2:12][O:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C@@H:24]1[O:26][C@H:25]1[CH2:27][OH:28].I([O-])(=O)(=O)=[O:30].[Na+]>O.O.O.[Ru](Cl)(Cl)Cl.O>[CH3:9][O:10][CH2:11][CH2:12][O:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C@@H:24]1[O:26][C@H:25]1[C:27]([OH:30])=[O:28]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COCCOCOCCCCCCCC[C@@H]1O[C@H]1CO
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COCCOCOCCCCCCCC[C@@H]1O[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.5 ml of tetrachloromethane, 2.5 ml of acetonitrile, 3.9 ml of water, 1.5 mmol of the alcohol 5, 4.5 mmol of sodium periodate and 5 mol % of ruthenium(III) chloride trihydrate are combined in this sequence, and the mixture is stirred overnight at room temperature. The batch is evaporated, and the residue is taken up in 10 ml of saturated NaCl solution and 8 ml of CH2Cl2. The phases are separated, the aqueous phase is extracted with CH2Cl2, the combined organic phases are washed with saturated NaCl solution and dried over MgSO4, and the solvent is removed in vacuo. The oxiranecarboxylic acid obtained is employed without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[CH2:14]([CH:17]1[CH2:22][CH2:21][CH:20]([CH:23]2[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]2)[CH2:19][CH2:18]1)[CH2:15][CH3:16].Cl>CCOCC.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:26]2([OH:29])[CH2:25][CH2:24][CH:23]([CH:20]3[CH2:21][CH2:22][CH:17]([CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19]3)[CH2:28][CH2:27]2)=[CH:3][CH:4]=1
Reactant: CCCC1CCC(C2CCC(=O)CC2)CC1
Reactant: Brc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CCCC1CCC(C2CCC(O)(c3ccc(Br)cc3)CC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
106 g (0.45 mol) of 1,4-dibromobenzene are initially introduced in 400 ml of Et2O at −45° C., and 275 ml (0.45 mol) of n-BuLi (15% soln. in hexane) are metered in. After 30 min at this temperature, a solution of 100 g (0.45 mol) of 4′-propylbicyclohexyl-4-one in 200 ml of Et2O is added dropwise, and the mixture is warmed to 0° C. After 1 h, water and dil. hydrochloric acid are added to the batch, and the organic phase is separated off. The aqueous phase is extracted with MTBE, and the combined organic phases are washed with water and subsequently dried using sodium sulfate. The solution is concentrated to completion, and the residue is used without further purification for the following reaction.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8](NC)[CH3:9].[C:12]1(=[O:22])[O:17][C:15](=O)[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[CH2:23]([N:25](CC)CC)C>C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH3:9])[CH2:23][N:25]1[C:12](=[O:22])[C:13]2=[CH:21][CH:20]=[CH:19][CH:18]=[C:14]2[C:15]1=[O:17]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCN(CC)CC
Reactant: CNC(C)CCCCCCBr
Solvent: Cc1ccccc1
Product: CC(CCCCCCBr)CN1C(=O)c2ccccc2C1=O

Procedure:
8-Bromo-2-methylaminooctane is treated with phthalic anhydride in toluene in the presence of triethylamine under reflux. The solvent is removed in vacuo. The residue, when triturated with water, acidified with hydrochloric acid and crystallized from alcohol will yield N-(8-bromo-2-methyloctyl)phthalimide.
Reaction SMILES: C(N=C=NC(C)C)(C)C.[OH:10][C:11]1[C:12]([C:17]([OH:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=1.[F:20][C:21]1[C:26](O)=[C:25]([F:28])[C:24]([F:29])=[C:23]([F:30])[C:22]=1[F:31]>C(Cl)Cl.O>[OH:10][C:11]1[C:12]([C:17]([O:19][C:26]2[C:25]([F:28])=[C:24]([F:29])[C:23]([F:30])=[C:22]([F:31])[C:21]=2[F:20])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)c1ncccc1O
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: CC(C)N=C=NC(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ncccc1O
Reaction time: 12 h

Procedure:
At 20-25° C. 13 g of N,N′-diisopropylcarbodiimide (DIC) were added dropwise to a solution of 14 g of 3-hydroxypyridine-2-carboxylic acid and 18.5 g of pentafluorophenol in 700 ml of CH2Cl2. After the reaction had ended (about 40 min), the solution was allowed to stand at 20-25° C. for about 12 hours. The solvent was removed, and the residue formed was then taken up in water and the solution was extracted with CH2Cl2. The organic phase gave, after drying and removal of the solvent, 29 g of the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.O.[C:9]([C:13]1[CH:50]=[CH:49][C:16]2[NH:17][C:18]([CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:28][CH:29]3[C@H:33]4[O:34]C(C)(C)[O:36][C@H:32]4[C@H:31]([N:39]4[C:43]5[N:44]=[CH:45][N:46]=[C:47]([NH2:48])[C:42]=5[CH:41]=[CH:40]4)[CH2:30]3)[CH:25]([CH3:27])[CH3:26])=[N:19][C:15]=2[CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>C(Cl)Cl>[NH2:48][C:47]1[C:42]2[CH:41]=[CH:40][N:39]([C@@H:31]3[CH2:30][CH:29]([CH2:28][N:24]([CH2:23][CH2:22][CH2:21][CH2:20][C:18]4[NH:17][C:16]5[CH:49]=[CH:50][C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:14][C:15]=5[N:19]=4)[CH:25]([CH3:27])[CH3:26])[C@@H:33]([OH:34])[C@H:32]3[OH:36])[C:43]=2[N:44]=[CH:45][N:46]=1
Reactant: CC(C)N(CCCCc1nc2cc(C(C)(C)C)ccc2[nH]1)CC1C[C@@H](n2ccc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(CCCCc1nc2cc(C(C)(C)C)ccc2[nH]1)CC1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
TFA (0.75 ml) followed by water (0.1 ml) was added to a solution of 7-[(3aS,4R,6aR)-6-({[4-(5-tert-butyl-1H-1,3-benzodiazol-2-yl)butyl](propan-2-yl)amino}methyl)-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine in DCM (1.5 ml) and stirred at 50° C. for 2 hours. The reaction mixture was then evaporated in vacuo. MeOH (2 ml) was added to the residue and cooled to 0° C. This was basified with 7N ammonia in MeOH (3 ml) and then evaporated to dryness. The product was filtered though a short silica gel column, eluting with 7N ammonia in MeOH:DCM (5/95-1/9). This gave separation of two products plus a mixture of both. The mixed fractions were combined and purified on a prep. TLC plate, eluting twice with 7N ammonia in MeOH:DCM (1:9) to give a white solid (39 mg, 56%); MS (ESI+) for C30H43N7O2. m/z 534.48 [M+H]+; HPLC purity 98% (ret. time, 4.68 min); 1H NMR (250 MHz, MeOD) δ ppm 8.05 (1H, s), 7.48 (1H, s), 7.34-7.43 (1H, m), 7.22-7.31 (1H, m), 7.17 (1H, d, J=3.50 Hz), 6.59 (1H, d, J=3.50 Hz), 4.77-4.90 (1H, m), 4.29 (1H, dd, J=7.08, 5.86 Hz), 3.95 (1H, t, J=5.33 Hz), 3.09 (1H, s), 2.91 (2H, t, J=7.39 Hz), 2.64-2.78 (1H, m), 2.44-2.63 (3H, m), 2.14-2.41 (2H, m), 1.75-1.98 (2H, m), 1.48-1.68 (3H, m), 1.35 (9H, s), 1.04 (6H, dd, J=12.33, 6.55 Hz).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34](=[O:38])[N:35]([CH3:37])[CH3:36])[CH2:24][CH:23]2[OH:39])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34](=[O:38])[N:35]([CH3:36])[CH3:37])[CH2:24][C:23]2=[O:39])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: CN(C)C(=O)c1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN(C)C(=O)c1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(=O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-[2-(N,N-dimethylcarbamoyl)phenyl]piperidin-3-ol (1.8 g) obtained in Step 2 in 10 ml of dimethylsulfoxide (DMSO), was added 2 ml of triethylamine. The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (1.8 g) was added slowly to the reaction mixture, which was then stirred for about 2 hours at room temperature. The reaction mixture was diluted with 50 ml of ethyl acetate, washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 1.2 g of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7](=O)[C:8]3[CH:13]=[C:12]([CH3:14])[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)[C:8]3[CH:13]=[C:12]([CH3:14])[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1
Reactant: Cc1cc2c(s1)Oc1cc(Cl)ccc1NC2=O
Reactant: CN1CCNCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cc1cc2c(s1)Oc1cc(Cl)ccc1N=C2N1CCN(C)CC1

Procedure:
In the same manner as in Example 125 and using 8-chloro-2-methylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 8-chloro-2-methyl-4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepine is obtained.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[CH3:14][O:15][C:16](=[O:27])[C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1Cl>O1CCOCC1>[CH3:14][O:15][C:16](=[O:27])[C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: Oc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cc([N+](=O)[O-])ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
A mixture of phenol (5.64 g, 60 mmol) and potassium t-butoxide (6.74 g, 60 mmol) in 50 mL 1,4-dioxane was stirred at room temperature for 0.5 h. To the mixture was added 2-chloro-5-nitro-benzoic acid methyl ester (10.78 g, 50 mmol) and the mixture was refluxed overnight. The solvent was evaporated and the residue was purified by chromatography with EtOAc:hexanes, 1:4, as eluant, yielding (11.739 g, 86%) 5-nitro-2-phenoxy-benzoic acid methyl ester. A mixture of 5-nitro-2-phenoxy-benzoic acid methyl ester (2.0 g, 7.32 mmol) in 30 mL ethanol and Pd/C (200 mg) were hydrogenated at 40 psi overnight to yield 5-amino-2-phenoxy-benzoic acid methyl ester (1.672 g, 94%). A mixture of 5-amino-2-phenoxy-benzoic acid methyl ester (0.95 g, 3.9 mmol) and hydrazine (4 mL, 80%) was refluxed for 4 h to yield 5-amino-2-phenoxy-benzoic acid hydrazide (0.722 g, 76%). The title compound was prepared from 5-amino-2-phenoxy-benzoic acid hydrazide and 3-trifluoromethyl-benzaldehyde by a procedure similar to Example 22. 1H NMR (CDCl3): 10.81 (s, 1H), 8.15 (s, 1H), 8.0 (s, 1H), 7.98 (d, J=7.5 Hz, 1H), 7.66 (s, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.53 (t, J=7.2 Hz, 1H), 7.40 (m, 2H), 7.19 (t, J=7.5 Hz, 1H), 7.07 (d, J=7.8, 2H), 6.80 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH2:8][C:7]([CH3:12])([CH3:11])[C:6]=2[CH:5]=[C:4]([CH:13]=[O:14])[CH:3]=1.[O-:15][Mn](=O)(=O)=O.[K+]>CC(C)=O.O>[Br:1][C:2]1[C:10]2[O:9][CH2:8][C:7]([CH3:11])([CH3:12])[C:6]=2[CH:5]=[C:4]([C:13]([OH:15])=[O:14])[CH:3]=1
Reactant: CC1(C)COc2c(Br)cc(C=O)cc21
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)COc2c(Br)cc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
A solution of 7-bromo-3,3-dimethyl-2,3-dihydro-benzofuran-5-carbaldehyde (14.61 g, 57.29 mmol) in acetone (80 mL) was added at room temperature to KMnO4 (9.05 g, 57.29 mmol) dissolved in water (200 mL). The reaction mixture was stirred at room temperature overnight filtered over celite then H2SO4 in water was added and the solution extracted with ethyl acetate. The organic layer was further washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give 9.9 g of 7-bromo-3,3-dimethyl-2,3-dihydro-benzofuran-5-carboxylic acid (64%). 1H NMR (300 MHz; CDCl3): 1.40 (s, 6H), 4.44 (s, 2H), 7.79 (s, 1H), 8.13 (s, 1H). c. 7-bromo-3,3-dimethyl-2,3-dihydro-benzofuran-5-carbaldehyde.