Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O-:3])=O.[NH4+:4].N.[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([C:20](=O)[CH3:21])[CH:17]=[CH:18][CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.ClC1C=C(Cl)C=CC=1C(=O)C>C(O)=O>[CH:1]([NH:4][CH:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:15]=1)[CH3:21])=[O:3]
Reactant: O=C[O-]
Reactant: CC(=O)c1cccc(OCc2ccccc2)c1
Reactant: [NH4+]
Agent: CC(=O)c1ccc(Cl)cc1Cl
Agent: N
Solvent: O=CO
Product: CC(NC=O)c1cccc(OCc2ccccc2)c1
Reaction time: 7 h

Procedure:
In the same manner as in Example 5 except that 405 q of ammonium formate was placed in the reaction vessel, 569 g of 76% formic acid was placed in the pot of the ammonia absorbing tower, 3'-benzyloxyacetophenone and the pot solution of the ammonia absorbing tower were added to the vessel at 2.54 g/min. and 3-6 g/min. respectively over 3 hours in place of 2',4'-dichloroacetophenone at 0.86 g/min. and the pot solution of the ammonia absorbing tower at 0.48 g/min, and the stirring time after addition was 10 hours in place of 7 hours, the reaction and post treatment were carried out to obtain 497 g of crude N-formyl-1-(3-benzyloxyphenyl)ethylamine (the purity: 97.8%) in place of 2',4'-dichloroacetophenone at 0.86 g/min. and the pot solution of the ammonia absorbing tower at 0.48 g/min.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:2]1.Br[CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:21][CH2:22][OH:23])=[CH:2]1
Reactant: c1ccc(CCCCCCNCc2ccoc2)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCN(CCCCCCc1ccccc1)Cc1ccoc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 2.538 g (9.861 mmol) of N-(3-furylmethyl)-6-phenylhexylamine and 7.39 g (59.2 mmol) of 2-bromoethanol in 50 ml of N,N-dimethylformamide, 13.6 g (98.6 mmol) of potassium carbonate was added, followed by overnight stirring at 90° C. After cooling to room temperature, the reaction mixture was poured into water and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to yield the desired product.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[N:10]=[C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[N:13][C:14]=1Br.[C:32]([Si:34]([CH3:37])([CH3:36])[CH3:35])#[CH:33].O>ClCCCl.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:8][C:9]1[N:10]=[C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[N:13][C:14]=1[C:33]#[C:32][Si:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)n1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)n1nc(-c2nc(C#C[Si](C)(C)C)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 27.5 °C
Reaction time: 18 h

Procedure:
In the presence of copper(I) iodide (25 mg) and dichlorobis(triphenylphosphine)palladium(II) (91 mg), triethylamine (0.397 ml) was dropwise added to a mixture of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (1.00 g) and ethynyl(trimethyl)silane (0.716 ml) in 1,2-dichloroethane (20 ml) under ice-cooling. The mixture was stirred at same temperature for one hour and at 25-30° C. for 18 hours. After addition of water, an organic layer was collected, washed with sat. aq. sodium chloride, dried over MgSO4 and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (80:20 v/v) to give a solid. The solid was crystallized from a mixture of acetone and n-hexane to give 6-{5-amino-3-phenyl-6-[(trimethylsilyl)ethynyl]-2-pyrazinyl}-2-isopropyl-3(2H)-pyridazinone (431 mg).
Reaction SMILES: O[NH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:9](=[C:19]3[CH2:25][CH:24]4[N:26]([C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH:21]([CH2:22][CH2:23]4)[CH2:20]3)[C:10]3[C:15]([O:16][C:17]=2[CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[NH:4].C1N=CN([C:38](N2C=NC=C2)=[S:39])C=1.C1C[O:48]CC1>O>[F:29][C:28]([F:31])([F:30])[C:27]([N:26]1[CH:24]2[CH2:23][CH2:22][CH:21]1[CH2:20][C:19](=[C:9]1[C:8]3[CH:7]=[CH:6][C:5]([C:3]4[NH:2][C:38](=[O:48])[S:39][N:4]=4)=[CH:18][C:17]=3[O:16][C:15]3[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:25]2)=[O:32]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: N=C(NO)c1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Reactant: C1CCOC1
Solvent: O
Product: O=C(N1C2CCC1CC(=C1c3ccccc3Oc3cc(-c4nsc(=O)[nH]4)ccc31)C2)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of compound 6a (0.0417 g, 0.094 mmol) and TCDI (0.025 g, 0.14 mmol) in THF (2 mL) was stirred at room temperature for 45 min. The mixture was diluted with H2O (2 mL) and extracted with EtOAc (3×5 mL). The combined organic extracts were washed with H2O (15 mL), dried (MgSO4), and concentrated. The residue was dissolved in THF (2 mL). Boron trifluoride diethyl etherate was added to the solution, and the resulting mixture was stirred at room temperature for 1 h. The mixture was diluted with H2O (2 mL) and extracted with EtOAc (3×5mL). The organic layers were dried (MgSO4), and concentrated. The resultant compound 9a was used in the next reaction without further purification. MS m/z (MH+) 485.8.
Reaction SMILES: [CH2:1]([C:3]1([S:6]([O-:9])(=O)=[O:7])[CH2:5][CH2:4]1)[CH3:2].[K+].S(Cl)([Cl:13])=O.O>C(Cl)Cl.CN(C=O)C>[CH2:1]([C:3]1([S:6]([Cl:13])(=[O:9])=[O:7])[CH2:5][CH2:4]1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCC1(S(=O)(=O)[O-])CC1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC1(S(=O)(=O)Cl)CC1
Temperature: 80 °C
Yield: 138.3 %

Procedure:
To a mixture of potassium 1-ethylcyclopropane-1-sulfonate (0.420 g, 2.23 mmol, Preparation #JJJ.1) in thionyl chloride (3.58 mL, 49.1 mmol) was added DMF (0.016 mL, 0.20 mmol). The reaction was heated at about 80° C. for about 16 h. The reaction was cooled to 0° C. before the slow addition of water (10 mL). The reaction mixture was diluted with DCM (20 mL). The layers were separated and the aqueous portion was extracted with DCM (3×10 mL). The combined organic layers were separated, dried over anhydrous MgSO4, filtered, and concd under reduced pressure to afford crude 1-ethylcyclopropane-1-sulfonyl chloride (0.52 g, 83% yield, 60% purity) as an orange oil: 1H NMR (400 MHz, DMSO) d 2.09 (q, J=7.4, 2H), 1.62-1.60 (m, 2H), 1.45-1.39 (m, 2H), 0.91 (t, J=7.5, 3H).
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]([C:28]4[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=4[Cl:35])[N:22]=[N:23][C:24]=3[CH:25]([CH3:27])[CH3:26])=[CH:14][C:13]=2[CH3:36])[CH:5]=1.[OH-].[Li+].CCCCCC.C(OCC)(=O)C>C1COCC1>[Cl:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([Cl:34])[C:28]=1[N:21]1[C:20]([CH2:19][O:18][C:15]2[CH:16]=[CH:17][C:12]([CH:11]=[CH:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:37])=[O:2])=[C:13]([CH3:36])[CH:14]=2)=[C:24]([CH:25]([CH3:27])[CH3:26])[N:23]=[N:22]1
Reactant: COC(=O)c1cccc(C=Cc2ccc(OCc3c(C(C)C)nnn3-c3c(Cl)cccc3Cl)cc2C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(OCc2c(C(C)C)nnn2-c2c(Cl)cccc2Cl)ccc1C=Cc1cccc(C(=O)O)c1
Temperature: 55 °C

Procedure:
To a solution of 3-(2-(4-(3-(2,6-dichloro-phenyl)-5-isopropyl-3-H-(1,2,3)triazol-4ylmethyoxy)-2-methyl-phenyl)-vinyl)-benzoic acid methyl ester (0.025 g, 0.046 mmol) in THF (3 mL) is added lithium hydroxide (0.005 g, 0.21 mmol). The reaction mixture is heated to 55° C. The reaction is determined to be incomplete due to the presence of starting material by TLC (1:1 hexane/ethyl acetate). An additional amount of lithium hydroxide (0.050 g) is added and the reaction is heated to 60° C. for 3 h. The reaction is quenched with aqueous 1 N HCl and is extracted with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound. ES/MS m/e 521.8 (M+1).
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:7][CH:8]=1.[C:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)#N.[Cl-].[NH4+].CC[O:25]CC>C1C=CC=CC=1>[F:10][C:9]([F:12])([F:11])[C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)=[O:25]
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: CCOCC
Reactant: N#Cc1ccncc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: c1ccccc1
Product: O=C(c1ccncc1)c1cccc(C(F)(F)F)c1
Reaction time: 8 h
Yield: 55 %

Procedure:
To a cold Grignard reagent prepared from 27 g (1.1 moles) of magnesium and 240 g (1.07 moles) of 3-bromobenzotrifluoride in 300 ml of dry ether and 150 ml of benzene, was added dropwise over a period of three hours a solution of 100 g (0.96 mole) of 4-cyanopyridine in 300 ml of benzene and 200 ml of ether. After being allowed to stand overnight at room temperature, the mixture was warmed for thirty minutes and then decomposed by adding 700 ml of saturated ammonium chloride solution. The ether-benzene layer was separated and extracted with 10% hydrochloric acid. The acid layer was separated and made basic with 20% sodium hydroxide and extracted with ether. The ether layer was dried over sodium sulphate. The ether solution was concentrated and the residual oil distilled to give 137 g (55%) of 4-(m-trifluoromethylbenzoyl)pyridine. Boiling point 97°-100° C/0.1 mm Hg. nD22 = 1.5380.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[N:13]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>Cl.O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][NH2:13])=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Br)cc1C(F)(F)F
Temperature: -10 °C
Reaction time: 3 h

Procedure:
A suspension of 25.6 g (0.11 mol) 4-bromo-2-(trifluoromethyl)-aniline in 125 ml of conc. hydrochloric acid is cooled to −10° C. and a solution of 7.7 g (0.11 mol) sodium nitrite in 125 ml of water is added. The reaction mixture is stirred for 3 hours at −10 to −5° C., then a solution of 103 g (0.46 mol) tin-(II)-chloride-dihydrate in 125 ml of conc. hydrochloric acid is added dropwise. The mixture is stirred for 1 hour at −5° C. The precipitate formed is suction filtered and washed with water. The aqueous mother liquor is extracted with petroleum ether, then made basic with sodium hydroxide. The precipitate formed is extracted with diethyl ether. The organic phase is dried and evaporated to dryness. Yield: 12.9 g
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(N(CC)CC)C.[OH:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=O.[CH:25]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[C:26]1=O)[CH2:32]2>C1COCC1.O>[OH:14][C:15]1[CH:16]=[C:17]([CH2:18][O:20][CH2:21][C:25]23[CH2:34][CH:29]4[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]4)[CH2:26]2)[CH2:32]3)[CH:22]=[CH:23][CH:24]=1
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: COC(=O)c1cccc(O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Oc1cccc(COCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
[(3-Hydroxyphenyl)methoxymethyl]adamantane (1a) was prepared as described in my previous application Ser. No. 224,681, filed Jul. 27, 1988. A 500-mL flask was fitted with a reflux condenser, a 125-mL addition funnel, and nitrogen line. The apparatus was dried by means of a hot air gun and nitrogen purging. Dry THF (40 mL) was added and the flask cooled in an ice bath. TiCl3 (1.5 g, 10 mmol) was added rapidly followed by LAH (0.19 g, 5 mmol) in portions with stirring. The cooling bath was removed and the black mixture was allowed to warm to room temperature. Triethylamine (0.7 mL, 5 mmol) was added to the stirred suspension and refluxed for 15 min. After this period, a solution of methyl 3-hydroxybenzoate (152 mg, 1 mmol) and 2-adamantanone (300 mg, 2 mmol) in 20 mL of dry THF was added dropwise to the refluxing mixture over 15 min. Refluxing was continued for an additional 15 min after which the reaction was cooled to room temperature and diluted with 100 mL of distilled water. The aqueous solution was extracted with 3×50 mL portions of ethyl acetate. The combined organic layer was washed with water, dried over MgSO4, and concentrated. Chromatography over silica with 15% ethyl acetate/hexane gave 240 mg (89%) of 1a as a white solid: mp 133°-4° C.; 1H NMR (CDCl3) δ1.64-1.96 (m, 12H), 2.65 (s, 1H), 3.24 (s, 1H), 3.32 (s, 3H), 5.25 (s, 1H, OH exchange with D2O), 6.70-7.30 (m, 4H); 13C NMR (CDCl3) δ28.45, 30.36, 32.36, 37.30, 39.18, 39.33, 57.82, 114.60, 116.16, 122.19, 129.24, 137.24, 155.62; MS m/e (rel intensity) 271 (20, M+1), 270 (100, M), 253 (7.3), 213 (35.1), 121 (41.7), 93 (9.4); Exact mass: calcd 270.1619, found 270.1616. ##STR21##
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.Cl.[CH3:16][NH:17][O:18][CH3:19].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([N:17]([O:18][CH3:19])[CH3:16])=[O:14]
Reactant: O=C(O)c1ccc2ccccc2c1Br
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.7 %

Procedure:
To a mixture of 1-bromo-2-naphthoic acid (1.04 g, 4.14 mmol, TCI America) and N,O-dimethylhydroxylamine hydrochloride (0.465 g, 4.76 mmol) in N,N-dimethylformamide (10 mL,) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.11 g, 4.76 mmol). After stirred at room temperature for 10 minutes, N,N-diisopropylethylamine (2.16 mL, 12.4 mmol) was added to the resulting mixture. The reaction was stirred at room temperature for 2 h, quenched with water, and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was concentrated and the residue was purified on silica gel, eluting with 0% to 50% ethyl acetate in hexane, to give the desired product (1.08 g, 88%). LCMS calculated for C13H13BrNO2(M+H)+: m/z=294.0; found: 294.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[O:9][C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11](O)=[O:12])=[CH:4][CH:3]=1.Cl.[NH2:26][CH2:27][C:28]#[N:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl>CN(C=O)C.CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[O:9][C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([NH:29][CH2:28][C:27]#[N:26])=[O:12])=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](OC(c1ccc(F)cc1)c1ccc(Br)cc1)C(=O)O
Reactant: N#CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CC(C)C[C@H](OC(c1ccc(F)cc1)c1ccc(Br)cc1)C(=O)NCC#N
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (2S)-2-[(4-bromophenyl)(4-fluorophenyl)methoxy]-4-methylpentanoic acid of step 4 (0.35 mmol, 151 mg) in DMF (3 mL) was added aminoacetonitrile hydrochloride (0.38 mmol) and HATU (0.38 mmol, 145 mg). Diisopropylethylamine (0.96 mmol, 123 mg) was added last, the mixture was stirred at r.t. for 3 days. Ether was added, followed by 1 N HCl. The mixture was separated after agitation. The organic extract was washed with 0.1 N HCl, water and brine and dried over anhyd. MgSO4. Concentration of the organic extracts followed by chromatography gave the title amide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(N(CC)CC)C>[CH3:25][S:26]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:10]=1)(=[O:28])=[O:27]
Reactant: CCOC(=O)C(Cc1ccc(OCCO)cc1)Oc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc(OCCOS(C)(=O)=O)cc1)Oc1ccccc1

Procedure:
In a similar manner to that described in Reference example 3(g), a reaction was carried out using ethyl 3-[4-(2-hydroxyethoxy)phenyl]-2-phenoxypropionate (3.27 g), which is the product of Reference example 4(e), triethylamine (2.07 ml) and methanesulfonyl chloride (0.84 ml) and the reaction mixture was treated to afford the desired compound (4.20 g) as a syrup.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][C:8]1([C:13]2[CH:18]=[CH:17][C:16]([N:19]([C:21](=[O:42])[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[CH3:39])=[O:31])=[C:25]([O:40][CH3:41])[CH:24]=3)[CH3:20])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.ClCCl>O>[CH3:41][O:40][C:25]1[CH:24]=[C:23]([CH2:22][C:21]([N:19]([CH3:20])[C:16]2[CH:17]=[CH:18][C:13]([C:8]3([CH2:7][C:6]([OH:43])=[O:5])[CH2:12][CH2:11][CH2:10][CH2:9]3)=[CH:14][CH:15]=2)=[O:42])[CH:28]=[CH:27][C:26]=1[NH:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:39])=[O:31]
Reactant: COc1cc(CC(=O)N(C)c2ccc(C3(CC(=O)OC(C)(C)C)CCCC3)cc2)ccc1NC(=O)Nc1ccccc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1cc(CC(=O)N(C)c2ccc(C3(CC(=O)O)CCCC3)cc2)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.9 %

Procedure:
[1-{4-[{2-[3-Methoxy-4-[3-o-tolyl-ureido]-phenyl]-acetyl}-methyl-amino]-phenyl}-cyclopentyl]-acetic acid tert-butyl ester [0.18 g, Reference Example 8(b)] was treated with a mixture of trifluoroacetic acid (6 mL), dichloromethane (1.2 mL) and water (0.75 mL)and the resulting solution was then stirred at room temperature, under argon, for 1.5 hours. The amber coloured reaction mixture was evaporated and the residue was chased twice with toluene (20 mL) to yield an amber gum. This gum was triturated with pentane and the solid obtained was washed with pentane and then dried at 60° C., under vacuum, to give the title compound (0.13 g) as a pale yellow solid, m.p. softens at 100° C. then slowly melts from 118–150° C.
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)[CH3:2].[Li+].CCC[CH2-].C(#N)C.[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]>C1COCC1.O>[NH2:20][C:19]([C:18]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:17]=1[Cl:16])=[CH:2][C:1]#[N:4]
Reactant: N#Cc1ccc(Cl)cc1Cl
Reactant: CC(C)NC(C)C
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: N#CC=C(N)c1ccc(Cl)cc1Cl
Reaction time: 0.17 h

Procedure:
90 g (889.46 mmol) of diisopropylamine are introduced into 1660 ml of THF at −70° C. in a three-necked flask with mechanical stirrer under argon. 124.66 ml of N-butyllithium solution (2.5M in hexane, 758.66 mmol) are added dropwise at a rate such that the temperature does not rise above −60° C. The mixture is stirred for 10 min and then a solution of 32.22 g (784.82 mmol) of acetonitrile in 340 ml of THF is slowly added dropwise, and the suspension is stirred for 30 min. Then a solution of 90 g (523.21 mmol) of 2,4-dichlorobenzonitrile in 340 ml of THF is added dropwise, and the mixture is stirred at −70° C. for 20 min. It is allowed slowly to reach RT and is stirred at RT for a further 16 h. 600 ml of water are added, most of the THF is distilled off, and water and dichloromethane are added. The organic phase is washed with sat. aqueous sodium chloride solution. Removal of the solvent results in dark crystals which are purified by stirring with diethyl ether. 76.5 g (69% of theory) of the product are obtained as a solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH2:11][C:12]([OH:14])=[O:13].[N:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1)=[C:23]=[S:24]>CC#N.CCN(C(C)C)C(C)C>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:23]([NH:22][C:25]1[CH:26]=[CH:27][C:28]([S:31](=[O:33])(=[O:32])[NH2:34])=[CH:29][CH:30]=1)=[S:24])[CH2:11][C:12]([OH:14])=[O:13]
Reactant: NCCCCCCCCN(CC(=O)O)Cc1ccccn1
Reactant: NS(=O)(=O)c1ccc(N=C=S)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1ccc(NC(=S)NCCCCCCCCN(CC(=O)O)Cc2ccccn2)cc1

Procedure:
2-((pyridin-2-ylmethyl)(8-(3-(4-sulfamoylphenyl)thioureido)octyl)amino)acetic acid. A solution of tert-butyl 2-((8-(tert-butoxycarbonylamino)octyl)(pyridin-2-ylmethyl)amino)acetate (0.449 g, 1.0 mmol) in DCM (4 mL) and TFA (4.0 mL) was stirred at room temperature for overnight. The solvent was evaporated to afford 2-((8-aminooctyl)(pyridin-2-ylmethyl)amino)acetic acid. A solution of the above product 2-((8-aminooctyl)(pyridin-2-ylmethyl)amino)acetic acid, 4-isothiocyanatobenzenesulfonamide (0.278 g, 1.3 mmol) in CH3CN (40 mL) and DIPEA (3.0 mL) was stirred at 50° C. under nitrogen for 48 h. The solvent was evaporated under reduced pressure to give a crude product, which was purified by Amberchrom™ eluting with acetonitrile/water to give 2-((pyridin-2-ylmethyl)(8-(3-(4-sulfamoylphenyl)thioureido)octyl)amino)acetic acid (0.500 g) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.65 (d, J=4.4 Hz, 1H), 8.11 (s, 1H), 7.94 (td, J=7.6, 1.6 Hz, 1H), 7.70 (d, J=8.8 Hz, 2H), 7.63 (d, J=8.8 Hz, 2H), 7.57 (d, J=7.6 Hz, 1H), 7.50-7.47 (m, 1H), 7.26 (s, 2H), 4.53 (s, 2H), 4.14 (s, 2H), 3.44-3.40 (m, 2H), 3.14-3.08 (m, 2H), 1.64-1.24 (m, 1 H); ESMS m/z: 508.3 (M+H)+.
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@@:12]1([CH2:16][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[C@H:14]([CH3:15])[O:13]1.C([S:25][C@@H:26]1[CH2:31][O:30][C@@H:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:28][CH2:27]1)(=O)C>CO.C(O)C>[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@:12]([OH:13])([C@H:14]([S:25][C@@H:26]1[CH2:27][O:28][C@@H:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:30][CH2:31]1)[CH3:15])[CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1cccc(F)c1F
Reactant: CC(=O)S[C@H]1CO[C@H](c2ccccc2)OC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: C[C@@H](S[C@H]1CO[C@H](c2ccccc2)OC1)[C@](O)(Cn1cncn1)c1cccc(F)c1F

Procedure:
0.29 ml (1.4 mmol) of a 4.9 M solution of sodium methoxide in methanol were added to a solution of 1.77 g (7.1 mmol) of (2R,3S)-2-(2,3-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane [prepared as described in Step 7(iv) above] and 2.20 g (9.2 mmol) of trans-5-(acetylthio)-2-phenyl-1,3-dioxane [prepared as described in Japanese Patent Application (Kokai) Hei 8-333350] in 20 ml of ethanol. The resulting mixture was then heated under reflux for 7 hours. After cooling the reaction mixture, it was partitioned between ethyl acetate and an aqueous ammonium chloride solution. The organic layer was washed with saturated aqueous sodium chloride solution and concentrated under reduced pressure to afford 3.65 g of the crude title compound. An aliquot (0.28 g) of the crude residue was purified by chromatography on a silica gel (15 g) column using a 2:5 mixture of ethyl acetate and hexane as eluent to afford 0.21 g of the title compound.