Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([Cl:20])[CH:3]=1.[CH:21]1([NH2:25])[CH2:24][CH2:23][CH2:22]1>>[Cl:20][C:4]1[CH:3]=[C:2]([NH:25][CH:21]2[CH2:24][CH2:23][CH2:22]2)[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=1
Reactant: NC1CCC1
Reactant: O=C(Nc1nc2cc(Cl)cc(Cl)n2n1)c1cccnc1
Product: O=C(Nc1nc2cc(Cl)cc(NC3CCC3)n2n1)c1cccnc1
Temperature: 180 °C
Yield: 21 %

Procedure:
The title compound was prepared following procedure described for example 84, but starting from N-(5,7-dichloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B10), 100 mg; 0.32 mmol; 1.0 eq) and cyclobutylamine (139 μL; 1.62 mmol; 5.0 eq) heated at 180° C. for 1800 s after which solvents were evaporated under vacuum, then resuspended in water, filtered and washed with EtOAc to give the title compound as a white solid (23 mg, 21%). HPLC, Rt: 2.95 min. (purity 96.7%). LC/MS, M+(ESI): 342.8, M−(ESI): 340.9.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:35][CH:36]([F:38])[F:37])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([B:26]3[O:30]C(C)(C)C(C)(C)[O:27]3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.I([O-])(=O)(=O)=O.[Na+].C([O-])(=O)C.[NH4+].CC(C)=O>O>[F:38][CH:36]([F:37])[O:35][C:8]1[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([O:2][CH3:1])=[O:39])[N:11]=[C:10]([CH2:17][CH3:18])[C:9]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([B:26]([OH:30])[OH:27])=[CH:24][CH:25]=1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 41 h
Yield: 92.6 %

Procedure:
A mixture of {4-difluoromethoxy-2-ethyl-8-fluoro-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl]quinolin-5-yloxy}acetic acid methyl ester (0.89 g), sodium periodate (1.7 g), ammonium acetate (0.46 g), acetone (23 mL) and water (11 mL) was stirred at room temperature for 41 hours. The mixture was concentrated to low bulk under reduced pressure, and the residue was diluted with water and then extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and than concentrated under reduced pressure to afford title compound (0.70 g).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br:10][CH2:11][CH2:12][CH2:13]Br>[OH-].[Na+]>[Br:10][CH2:11][CH2:12][CH2:13][C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]=1
Reactant: C1=Cc2ccccc2C1
Reactant: BrCCCBr
Agent: [Na+]
Agent: [OH-]
Product: BrCCCC1=CCc2ccccc21
Reaction time: 6 h

Procedure:
The compound is prepared as described by Makoska in Tetrahedron Letters 38, 4621-4624 (1966) by adding a mixture of 580 g (5 M) indene and 1010 g (5 M) 1,3-dibromopropane to 1500 ml 50% aqueous NaOH containing 50 ml 40% methanolic Triton B. The temperature is held below 55° C. by cooling in an ice bath. After stirring 6 hours the reaction mixture is diluted to 4 l. The layers are separated and the aqueous layer is extracted two times with ether. The combined organic layers are extracted two times with water, dried over MgSO4, filtered and the solvent is removed. The oily product is distilled and redistilled at reduced pressure collecting 432 g (36.6%) boiling 126°-140°/0.1 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([S:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH:24]O>C(O)(=O)C.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([S:17]([C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20])=[O:24])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: OO
Reactant: CC(C)(Sc1ccc2c(-c3ccc(Cl)cc3)noc2c1)C(=O)O
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)(C(=O)O)S(=O)c1ccc2c(-c3ccc(Cl)cc3)noc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
5.56 g (16.0 mmol) of 2-[[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]thio]-2-methylpropionic acid and 6 ml of 30% H2O2 were combined in 200 ml glacial acetic acid. The mixture was stirred at room temperature and monitored by TLC for the disappearance of starting material and the appearance of product. After about four hours the reaction was stopped by diluting with excess 3N HCl. The resulting precipitate was filtered and washed several times with cold toluene to yield white crystals, 3.38 g (58%) of 2-[[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]sulfinyl]-2-methylpropionic acid, m.p. 184°-185° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH3:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:24](O)=[O:25].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[CH3:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)=[N:6][CH:7]=1)=[O:25]
Reactant: CCOC(=O)c1ccc(Oc2ccc(N)cn2)cc1
Reactant: Cc1ccc(C(=O)O)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Oc2ccc(NC(=O)c3ccc(C)c(C)c3)cn2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of ethyl 4-(5-aminopyridin-2-yloxy)benzoate (14.15 g, 54.8 mmol) in DMF (100 mL) were added 3,4-dimethylbenzoic acid (8.23 g, 54.8 mmol), 1-hydroxybenzotriazole monohydrate (8.4 g, 54.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (12.6 g, 65.7 mmol) under ice cooling, and then stirred for 30 minutes under ice cooling and for 17 hours at room temperature. The reaction solution was concentrated under reduced pressure. To the residue was added water (200 mL), and extracted with ethyl acetate (250 mL). The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby yield 16.15 g of the title compound.
Reaction SMILES: [CH2:1]([N:6]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][C:8]([C:17]([O:19]CC)=[O:18])=[N:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].O.[OH-].[Li+].Cl>O1CCCC1.C(OCC)C>[CH2:1]([N:6]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][C:8]([C:17]([OH:19])=[O:18])=[N:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN1N=C(C(=O)OCC)CC1c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCN1N=C(C(=O)O)CC1c1ccccc1
Temperature: 70 °C
Yield: 74 %

Procedure:
To a magnetically stirred solution of ethyl 1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylate (Intermediate (V-1) (11.76 g, 38.74 mmol) in tetrahydrofuran (100 ml) and water (100 ml) was added lithium hydroxide (1.86 g, 77.5 mmol) and the resulting mixture was heated at 70° C. for 1 hour. The reaction mixture was allowed to attain room temperature and diethyl ether (200 ml) and concentrated hydrochloric acid (7 ml) were added. The organic layer was separated, washed three times with water and with brine and subsequently dried over Na2SO4, filtered and concentrated in vacuo to give 1-(n-pentyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylic acid (Intermediate (VI-1) (7.9 g, 74% yield) as an oil. 1H-NMR (400 MHz, CDCl3) δ 0.84 (t, J=7, 3H), 1.15-1.28 (m, 4H), 1.53-1.65 (m, 2H), 2.92 (dd, J=17 and 13, 1H), 3.02-3.11 (m, 1H), 3.18-3.27 (m, 1H), 3.44 (dd, J=17 and 13, 1H), 4.75 t, J=13, 1H), 7.31-7.41 (m, 5H), 7.42-9.00 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.C(=O)(O)[O-].[K+].[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].C1C2C(=CC=CC=2)CCN1>C1C=CC=CC=1>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2)=[O:22]
Reactant: CN1CCc2c(N)cccc2C1
Reactant: O=C(Cl)c1ccccc1F
Agent: O=C([O-])O
Agent: [K+]
Agent: c1ccc2c(c1)CCNC2
Solvent: c1ccccc1
Product: CN1CCc2c(cccc2NC(=O)c2ccccc2F)C1

Procedure:
5-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (5.0 g) prepared as in Example 4 was dissolved in dry benzene (75 ml) and 0.5 g of dry potassium bicarbonate was added. A 0.1 mole excess of 2-fluorobenzoyl chloride was dissolved in dry benzene (75 ml) and this solution was added to the solution of the tetrahydroisoquinoline. A white precipitate formed immediately. The mixture was refluxed for 1 hour to insure that the reaction had gone to completion. The precipitate was collected by vacuum filtration and washed with 10% sodium carbonate solution followed by water. The washings were discarded and the remaining residue was recrystallized from ethyl acetate to yield 6.8 g of the desired product as white crystals, m.p. 112°-112.5° C.
Reaction SMILES: [CH3:1][S:2]([O-:4])=[O:3].[Na+].Br[C:7]1[N:11]2[CH2:12][CH2:13][N:14]([CH3:31])[C:15]3([CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:17][CH2:16]3)[C:10]2=[CH:9][CH:8]=1>[Cu]I.CS(C)=O>[CH3:31][N:14]1[C:15]2([CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:19][CH2:20]2)[C:10]2=[CH:9][CH:8]=[C:7]([S:2]([CH3:1])(=[O:4])=[O:3])[N:11]2[CH2:12][CH2:13]1
Reactant: CS(=O)[O-]
Reactant: CN1CCn2c(Br)ccc2C12CCN(C(=O)OCc1ccccc1)CC2
Agent: [Cu]I
Agent: [Na+]
Solvent: CS(C)=O
Product: CN1CCn2c(ccc2S(C)(=O)=O)C12CCN(C(=O)OCc1ccccc1)CC2
Temperature: 90 °C
Yield: 52.1 %

Procedure:
A mixture of sodium methanesulfinate (293 mg, 2.87 mmol), benzyl 6-bromo-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (1.00 g, 2.39 mmol), CuI (296 mg, 1.55 mmol) and DMSO (5 mL) was heated at 90° C. in a pressure vessel for 20 hours. The mixture was cooled and was partitioned between ether (10 mL) and water (10 mL). The organic layer was separated and the aqueous layer was extracted with ether (3×5 mL). The combined organic layers were washed with brine (2×10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography utilizing a gradient of 0-50% ethyl acetate in CH2Cl2 to yield benzyl 2-methyl-6-methylsulfonyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (520 mg, 52%) as a white solid. ESI-MS m/z calc. 417.2, found 418.3 (M+1)+; Retention time: 1.27 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.45-7.30 (m, 5H), 6.88 (d, J=4.1 Hz, 1H), 6.01 (d, J=3.9 Hz, 1H), 5.15 (s, 2H), 4.28-4.15 (m, 2H), 4.09-3.89 (m, 2H), 3.40-3.16 (m, 4H), 3.10 (s, 3H), 2.37 (s, 3H), 2.20-2.02 (m, 2H), 1.89-1.66 (m, 2H).
Reaction SMILES: Cl[C:2]([F:7])([F:6])[C:3]([O-])=O.[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:28]([C@H:33]1[CH2:38][CH2:37][C@H:36]([C@H:39]2[CH2:44][CH2:43][C@H:42]([C:45](=O)C)[CH2:41][CH2:40]2)[CH2:35][CH2:34]1)[CH2:29][CH2:30][CH2:31][CH3:32].CCCCCCC>CN(C=O)C>[F:6][C:2]([F:7])=[CH:3][CH2:45][C@H:42]1[CH2:43][CH2:44][C@H:39]([C@H:36]2[CH2:37][CH2:38][C@H:33]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:34][CH2:35]2)[CH2:40][CH2:41]1
Reactant: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(C)=O)CC2)CC1
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: CN(C)C=O
Product: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](CC=C(F)F)CC2)CC1
Temperature: 80 °C

Procedure:
A nitrogen-purged 1-L three-neck flask equipped with a stirrer, a thermometer and a dropping funnel was charged with 16.4 g (107.7 mmol) of sodium chlorodifluoroacetate, 28.3 g (107.7 mmol) of triphenylphosphine and 200 ml of DMF, and the mixture was heated up to 80° C. while stirring. A solution of 15.0 g (53.9 mmol) of 1-(trans-4-(trans-4-pentylcyclohexyl)-cyclohexyl)acetaldehyde dissolved in 100 ml of DMF was added dropwise at 80 to 110° C., and the solution was stirred at 100° C. for 2 hours. The reaction mixture was transferred into a 2-L beaker, and 500 ml of heptane was added thereto. Insoluble materials were separated by filtration by means of a glass filter, and 300 ml of water was added thereto. The separated heptane layer was washed twice with 300 ml of water and dried over anhydrous magnesium sulfate. The solvent was distilled of under reduced pressure, and then the concentrated residue was purified by means of a silica gel column chromatography with heptane as a developing solvent to obtain 14.1 g of 1,1-difluoro-3-(trans-4-(trans-4-pentylcyclohexyl)cyclohexyl)-1-propene.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]23[CH2:18][CH:16]([CH2:17]2)[C:15](=[O:19])[NH:14][C:13]3=[O:20])=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH2:21](Br)[CH:22]=[CH2:23]>CN(C)C=O>[CH2:23]([N:14]1[C:15](=[O:19])[CH:16]2[CH2:17][C:12]([C:9]3[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:11][CH:10]=3)([CH2:18]2)[C:13]1=[O:20])[CH:22]=[CH2:21]
Reactant: O=C1NC(=O)C2(c3ccc([N+](=O)[O-])cc3)CC1C2
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.36 g of sodium hydride is added to a solution of 2.46 g of 1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 25 ml of N,N-dimethylformamide and the whole is stirred at room temperature for 30 minutes. 1.27 ml of allyl bromide dissolved in 10 ml of N,N-dimethylformamide are then added dropwise thereto. When the reaction is complete, the reaction mixture is freed of N,N-dimethylformamide. The residue is partitioned between ethyl acetate and water, and the organic phase is dried over magnesium sulphate and, after concentration by evaporation and subsequent recrystallisation from ethyl acetate/petroleum ether, the product is obtained having a melting point of 146°-147°.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([O:19]C)=[O:18])=[CH:12][C:11]=3[CH:21]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][C:11]=3[CH:21]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C1=Cc2cc(-c3ccc(C)s3)ccc2OCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
In THF (10.5 ml) and methanol (5.2 ml) was dissolved methyl 7-(5-methyl-2-thienyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (525 mg), and to the mixture was added 1N sodium hydroxide (10.5 ml). The mixture was stirred at room temperature for 2 hours. Under reduced pressure, the organic solvent was removed, and to the residue was added ethyl acetate. The mixture was extracted with water, and to the aqueous layer was added 6N hydrochloric acid to make the solution pH 4-5, which was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed to give 7-(5-methyl-2-thienyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (410 mg).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([N+:23]([O-:25])=[O:24])=[C:6]([C:8]([C:21]#[N:22])([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)C(OCC)=O)[N:7]=1.Cl>[OH-].[Na+]>[NH2:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([N+:23]([O-:25])=[O:24])=[C:6]([CH:8]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]#[N:22])[N:7]=1
Reactant: CCOC(=O)C(C#N)(Cc1ccccc1)c1nc(N)[nH]c(=O)c1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#CC(Cc1ccccc1)c1nc(N)[nH]c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
A solution of 2-Amino-α-cyano-1,6-dihydro-5-nitro-α-(phenylmethyl)-6-oxo-4-pyrimidineacetic acid, ethyl ester as prepared above (2.0 g) in 1N NaOH (100 mL) is stirred at room temperature for 1 h and is acidified with 4N HCl (30 mL). The precipitate is collected by filtration and dried under vacuum to give 2-Amino-1,6-dihydro-5-nitro-6-oxo-α-(phenylmethyl)-4-pyrimidineacetonitrile (600 mg, 36%). ##STR13##
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=O)[C:3]=1[OH:10].Cl[CH2:12][C:13](=[O:15])[CH3:14].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:13]([C:14]1[O:10][C:3]2[C:2]([Br:1])=[CH:9][CH:8]=[CH:7][C:4]=2[CH:5]=1)(=[O:15])[CH3:12]
Reactant: O=Cc1cccc(Br)c1O
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cc2cccc(Br)c2o1
Temperature: 60 °C

Procedure:
A mixture of 5.0 g (24.9 mmol) of 3-bromo-salicylaldehyde, 3.0 g (32.3 mmol, 2.6 mL) of chloroacetone and 12 g (37.2 mmol) of Cs2CO3 in 30 mL of dry DMF was heated to 60° C. overnight. After cooling at room temperature, water (100 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was directly recrystallized from hexane to afford 2-acetyl-7-bromo benzo[b]furan as a pale orange crystal.
Reaction SMILES: C([Mg]Br)=C.[Cl:5][CH2:6][CH2:7][CH2:8][Si:9]([CH3:12])(C)Cl.[CH2:13]1[CH2:17]OC[CH2:14]1>>[Cl:5][CH2:6][CH2:7][CH2:8][SiH2:9][CH:12]=[C:13]([CH3:17])[CH3:14]
Reactant: C[Si](C)(Cl)CCCCl
Reactant: C1CCOC1
Agent: C=C[Mg]Br
Product: CC(C)=C[SiH2]CCCCl
Reaction time: 2 h
Yield: 66.49 %

Procedure:
To a stirred solution of 1 M vinyl magnesium bromide in THF (9.1 L), 3-chloropropyl dimethylchlorosilane (1.5 Kg) was added over the period of 3 hr through an addition. The reaction mixture stirred further for 2 hr. Added D.M water (9.1 L) and separated the organic layer. The hazy aqueous layer was filtered through hyflo bed and extracted with dichloromethane (3.0 L). The dichloromethane extract was mixed with organic layer and evaporated to dryness to give yellow liquid which was distilled using a Vigreaux column to get pure colorless title product (0.986 Kg)
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:10].[Na+]>S(=O)(=O)(O)O>[C:2]1([CH2:1][C:8]([NH2:9])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: N#CCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
Benzyl cyanide (5 g, 42.7 mmol) was added slowly to concentrated sulfuric acid (20 ml) cooled by water-ice bath. The solution was stirred overnight. The reaction mixture was poured into ice water and neutralized with 20% NaOH. The aqueous phase was extracted by ethyl acetate (3×15 mL). The combined organic layers were washed with water (3×10 mL) and brine (3×10 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate and hexane to give the title compound (4.5 g, 78%). 1H NMR (400 MHz, DMSO-d6) δ 7.54 (s, 1H), 7.20-7.32 (m, 5H), 6.87 (s, 1H), 3.38 (s, 2H).
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+].[Na+].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21]Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][S:1]([OH:4])(=[O:3])=[O:2])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=S([O-])[O-]
Reactant: BrCc1ccccc1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: O
Product: O=S(=O)(O)Cc1ccccc1OCc1ccccc1
Temperature: 0 °C
Yield: 7.6 %

Procedure:
Sodium sulfite (4.2 g) was added to a stirred mixture of 1-benzyloxy-2-bromomethyl-benzene (8.9 g), tetrabutylammonium iodide (59 mg) and water (150 ml). The mixture was warmed to reflux for overnight. As the mixture cooled to 0° C., it was acidified by 6N HCl. Extraction by ethyl acetate (100 ml×6) was performed (some remained in the aqueous layer). The combined organic phases were dried over MgSO4. The filtrate was concentrated on vacuo. The product was triturated by ethyl ether to give (2-Benzyloxy-phenyl)-methanesulfonic acid (678 mg, 8%). 1H NMR (400 MHz, DMSO-D6): δ 3.82 (s, 2 H) 5.09 (s, 2 H) 6.86 (t, J=7.45 Hz, 1 H) 6.96 (d, J=8.08 Hz, 1 H) 7.14 (t, J=7.83 Hz, 1 H) 7.32 (d, J=7.33 Hz, 1 H) 7.38 (t, J=7.33 Hz, 2 H) 7.46 (d, J=9.09 Hz, 1 H) 7.52 (d, J=7.07 Hz, 2 H).
Reaction SMILES: [C:1]12([CH2:11][C:12]3[NH:13][C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][C:16]=3[C:17](O)=[O:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([O:33][C:34](=[O:42])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([NH2:41])[CH:36]=1)C1C=CC=CC=1.CNC[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.O.O1CCOCC1>O>[C:1]12([CH2:11][C:12]3[NH:13][C:14]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:15][C:16]=3[C:17]([NH:41][C:37]3[CH:36]=[C:35]([CH:40]=[CH:39][CH:38]=3)[C:34]([OH:33])=[O:42])=[O:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)c1cc(-c2ccccc2)[nH]c1CC12CC3CC(CC(C3)C1)C2
Reactant: Nc1cccc(C(=O)OCc2ccccc2)c1
Agent: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(NC(=O)c2cc(-c3ccccc3)[nH]c2CC23CC4CC(CC(C4)C2)C3)c1

Procedure:
The benzyl ester of the title compound was prepared by reacting 2-adamantan-1-ylmethyl-5-phenyl-1H-pyrrole-3-carboxylic acid (Example 1, step c) with 3-amino-benzoic acid benzyl ester according to the procedure of Example 1, step d. This was converted to the title compound using the procedure of Example 1, step e. 1H NMR (300 MHz, d6-DMSO) 11.19 (1H, s), 9.62 (1H, s), 8.37 (1H, s), 7.97 (1H, d) 7.66 (2H, d), 7.58 (1H, d), 7.39 (3H, m), 7.16 (2H, m), 2.84 (2H, s), 1.88 (3H, br s), 1.54 (12H, m). The product was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 62.82; H, 7.38; N, 5.82%; C36H47N3O8.2.0 H2O requires: C, 63.04; H, 7.50; N, 6.12%.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].CC(C)=O.[OH:9][N:10]=[C:11]([CH3:26])[CH2:12][N:13]([S:22]([CH3:25])(=[O:24])=[O:23])[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21]>C(N(CC)CC)C>[CH3:1][NH:2][C:3]([O:9][N:10]=[C:11]([CH3:26])[CH2:12][N:13]([S:22]([CH3:25])(=[O:24])=[O:23])[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])=[O:4]
Reactant: CN=C=O
Reactant: CC(CN(c1c(C)cccc1C)S(C)(=O)=O)=NO
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CNC(=O)ON=C(C)CN(c1c(C)cccc1C)S(C)(=O)=O
Reaction time: 8 h

Procedure:
Methyl isocyanate (1.2 ml) was added to an acetone solution of N-[2-hydroxyiminopropyl]-2',6'-dimethylmethanesulphonanilide (2.7 g) containing triethylamine (0.05 ml). The mixture was allowed to stand at room temperature overnight, then evaporated to a viscous oil which slowly solidified on standing. Recrystallisation from ethylacetate/60°-80° petrol gave colourless crystals of N-[2-(methylcarbamoyloxyimino)propyl]-2',6'-dimethylmethanesulphonanilide. Yield 3.0 g (91%). Melting point 130°-134°.
Reaction SMILES: [N:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)=[N:3][C:2]=1[N:29]1[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]1.C(O)(C(F)(F)F)=O>>[N:29]1([C:2]2[N:3]=[C:4]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:5]3[CH2:11][CH2:10][CH2:9][C:8]4[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=4[C:6]=3[N:1]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3c(c(N4CCN(C(=O)OC(C)(C)C)CC4)n2)CCCc2ccccc2-3)CC1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c(c1)CCCc1c-2nc(N2CCNCC2)nc1N1CCNCC1
Temperature: 60 °C

Procedure:
The product from Example 103C (71 mg, 0.13 mmol) was treated with TFA (2 mL), heated at 60° C. for 1 minute, concentrated, dissolved in 1:1 MeOH: CH2Cl2 (2 mL), diluted with CH2Cl2 (25 mL), washed with 1 M NaOH (10 mL) and the layers were separated. The aqueous layer was extracted with CH2Cl2 (25 mL) and the combined organic layers were dried (MgSO4), filtered, concentrated and purified by chromatography on silica gel eluting with 10 and 40% (9:1 MeOH:concentrated NH4OH) in CH2Cl2 to provide the title compound. 1H NMR (CD3OD) δ 2.24-2.40 (m, 4H), 2.65 (t, J=6.5 Hz, 2H), 3.27-3.32 (m, 4H), 3.37-3.42 (m, 4H), 3.66-3.70 (m, 4H), 4.07-4.12 (m, 4H), 7.27-7.31 (m, 1H), 7.32-7.43 (m, 2H), 7.72-7.76 (m, 1H); MS (M+H)+ m/z at 365.