Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[F:29][C:17]([F:16])([F:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2)(=[O:25])=[O:26]
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: CCOC(=O)c1cc2cccc(N)c2[nH]1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cccc(NS(=O)(=O)c3ccccc3C(F)(F)F)c2[nH]1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
To a mixture of ethyl 7-amino-1H-indole-2-carboxylate (4.1 g) and pyridine (60 mL) was added 2-trifluoromethylbenzenesulfonyl chloride (5.0 g) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 18 hr. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate. The solution was washed with aqueous citric acid solution and saturated brine, and filtrated through silica gel. The eluate was concentrated under reduced pressure, and the obtained pale-brown oil was crystallized from ethyl acetate-hexane to give the title compound (7.3 g, yield 88%) as pale-brown crystals. MS: 413 (MH+). melting point: 138-139° C.
Reaction SMILES: [CH2:1]([CH:3]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([CH2:19][CH3:20])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:8][C:7]=1[N+:21]([O-])=O)[CH3:2].C([O-])=O.[NH4+]>CC(O)C>[CH2:1]([CH:3]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([CH2:19][CH3:20])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:8][C:7]=1[NH2:21])[CH3:2]
Reactant: CCCCC(CC)COc1ccc(OCC(CC)CCCC)c([N+](=O)[O-])c1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(C)O
Product: CCCCC(CC)COc1ccc(OCC(CC)CCCC)c(N)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
1,4-Bis(2-ethylhexyloxy)-2-nitrobenzene (11.4 g, 0.03 mol) is dissolved in 2-propanol (100 ml) and degassed under vacuum, purging to nitrogen. 10% (w/w) Pd/C (0.52 g) is added and the mixture heated to 80° C. Water (10 ml) is added, followed by solid ammonium formate (18.9 g, 0.3 mol). After a further 1 hour at 80° C., the reaction mixture is allowed to cool then filtered to remove catalyst, to give a colourless solution which darkened rapidly on standing. The material is used immediately as an isopropanol solution (quant.).
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>O1CCCC1>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31](=[O:32])[O:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][CH2:5][N:4]2[CH2:1][C:2]#[CH:3])=[CH:9][CH:10]=1
Reactant: COc1ccccc1N=C=O
Reactant: C#CCN1CCCc2ccc(O)cc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCN1CCCc2ccc(OC(=O)Nc3ccccc3OC)cc21
Temperature: 35 °C

Procedure:
A mixture of 1-(prop-2-ynyl)-1,2,3,4-tetrahydroquinolin-7-ol (400 mg, 2.14 mM) and triethylamine (0.6 mL) in dry tetrahydrofuran (THF, 5 mL) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, 2-methoxyphenyl isocyanate (427 mg/ml, 3.21 mM) was added at once and then the reaction mixture was further stirred for 48 hours under N2 atmosphere at RT (35° C.). The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product (10e), which was finally chromatographed using chlorophorm-hexane (1:19) to give 10e as solid. Yield: 480 mg, 66.80%.
Reaction SMILES: [O:1]=[C:2]1[CH:8]2[CH2:9][CH2:10][CH:3]1[CH2:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[CH2:7]2.BrCC1C=C(C=CC=1CBr)[C:20]([O:22][CH3:23])=[O:21]>>[O:1]=[C:2]1[CH:8]2[CH2:9][CH2:10][CH:3]1[CH2:4][C:5]1[CH:14]=[CH:13][C:12]([C:20]([O:22][CH3:23])=[O:21])=[CH:11][C:6]=1[CH2:7]2
Reactant: COC(=O)c1ccc(CBr)c(CBr)c1
Reactant: O=C1C2CCC1Cc1ccccc1C2
Product: COC(=O)c1ccc2c(c1)CC1CCC(C2)C1=O

Procedure:
Prepared using the procedure described for 11-oxo-5,6,7,8,9,10-hexahydro-6,9-methanobenzocyclooctene (Justus Liebigs Ann. Chem. 1961, 650, 115) using methyl 3,4-bis(bromomethyl)benzoate in place of 1,2-bis(bromomethyl)benzene.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:70][C:71]1[CH:77]=[CH:76][C:74]([NH2:75])=[CH:73][CH:72]=1>CN(C=O)C>[CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:75][C:74]2[CH:76]=[CH:77][C:71]([F:70])=[CH:72][CH:73]=2)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:2]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: Nc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)Nc3ccc(F)cc3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.3 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27.3 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and 4-fluoroaniline (8.64 uL, 0.08 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (10 mg, 27%). LC-MS m/z 615 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([CH:16]2[CH2:18][CH:17]2[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:11][C:10]=1[F:25])C1C=CC=CC=1>CCOC(C)=O.CCO.[Pd]>[F:15][C:14]1[CH:13]=[C:12]([CH:16]2[CH2:18][CH:17]2[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:11]=[C:10]([F:25])[C:9]=1[OH:8]
Reactant: CCOC(=O)CC1CC1c1cc(F)c(OCc2ccccc2)c(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CC1CC1c1cc(F)c(O)c(F)c1
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a solution of ethyl 2-(2-(4-(benzyloxy)-3,5-difluorophenyl)cyclopropyl)acetate (505) (0.782 g, 2.25 mmol) in EtOAc/EtOH (5 mL/10 mL) was added 159 mg of 10% Pd/C, and the mixture was stirred under a hydrogen balloon overnight. After filtration through celite and washing with EtOH, the filtrate was concentrated in vacuo to afford 0.508 g of desired product (506) as a pale-yellow liquid. The product was sufficiently pure to be used directly in subsequent couplings. 1H NMR (400 MHz, CDCl3) δ: 6.67 (d, J=8.4 Hz, 2H), 4.96 (br, 1H), 4.23-4.05 (m, 2H), 2.50-2.26 (m, 2H), 1.70-1.66 (m, 1H), 1.33-1.19 (m, 4H), 0.97-0.79 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([CH:15]3[CH2:19][CH:18]([OH:20])[CH:17]([OH:21])[CH2:16]3)=O)[CH2:9][CH2:8]2)=[C:4]([CH3:24])[CH:3]=1.B.CO>O1CCCC1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH:15]3[CH2:16][CH:17]([OH:21])[CH:18]([OH:20])[CH2:19]3)[CH2:11][CH2:12]2)=[C:4]([CH3:24])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1OC1CCN(C(=O)C2CC(O)C(O)C2)CC1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Cl)ccc1OC1CCN(CC2CC(O)C(O)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
4-{[4-(4-Chloro-2-methylphenoxy)piperidin-1-yl]carbonyl}cyclopentane-1,2-diol (32.0 g) was dissolved in tetrahydrofuran (100 mL) and stirred, at room temperature, under nitrogen. Borane (1 M solution in THF; 300 mL) was added dropwise and then the reaction mixture was heated under reflux for 2 h. The reaction mixture was allowed to cool slightly and methanol (60 mL) was added carefully. Heating was resumed and continued overnight. The reaction mixture was concentrated in vacuo and the residue was purified using SCX resin:Non-basic impurities were eluted with methanol then product was eluted with 0.7 M ammonia in methanol. Solvent was removed in vacuo to give the title compound (30 g) as a mixture of 2 stereoisomers.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[CH3:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[O:9][CH2:10][CH2:11][OH:12]>>[S:1]([O:12][CH2:11][CH2:10][O:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[CH3:6])(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)Cl
Reactant: Cc1ccccc1OCCO
Product: Cc1ccccc1OCCOS(N)(=O)=O
Yield: 53 %

Procedure:
The title compound was prepared by procedures of Example 33 from sulfamoyl chloride and 2-(2-methylphenoxy)ethanol in 53% yield as an off-white solid, mp 81.5°-83° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][NH2:9])[CH:3]=1.[CH:10]([N:13]=[C:14]=[O:15])([CH3:12])[CH3:11]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][NH:9][C:14]([NH:13][CH:10]([CH3:12])[CH3:11])=[O:15])[CH:3]=1
Reactant: CC(C)N=C=O
Reactant: NNc1cc(Br)ccn1
Solvent: ClCCl
Product: CC(C)NC(=O)NNc1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(4-bromopyridin-2-yl) hydrazine (0.376 g, 2.00 mmol) in 10 mL of DCM at 0° C. was added isopropyl isocyanate (0.216 mL, 2.20 mmol). The heterogeneous mixture was allowed to warm up to RT and stir. A white precipitate appeared and after 1 h the solid was collected by filtration and washed with DCM to afford 1-(4-bromopyridin-2-yl)-4-isopropylsemicarbazide as a white solid. MS (ESI, pos. ion) m/z: 273.2 (M+1).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:17][SnH:18]([CH3:20])[CH3:19]>C1(C)C=CC=CC=1.CC(C)=O>[C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Sn:18]([CH3:20])([CH3:19])[CH3:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: C[SnH](C)C
Reactant: C=CCCCCS(=O)(=O)c1ccc(C)cc1
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)CCCCCC[Sn](C)(C)C)cc1

Procedure:
The procedure described in Example 5 was employed except that 10.1 g (42.5 mmoles) of 5-hexenyl p-tolyl sulfone and 14.0 g (85 mmoles) of trimethyltin hydride were the reactants. The reaction mixture was irradiated for 232 hours. The excess trimethyltin hydride was allowed to evaporate from the reaction mixture under a flow of nitrogen. The unreacted 5-hexenyl p-tolyl sulfone was removed from the reaction mixture by distillation at 1×10-3 mm Hg leaving 3.25 g of crude product. Column chromatography of the distillation residue over silica gel, employing toluene and 1% acetone in toluene as eluents, afforded an oil, 6-(p-tolylsulfonyl)hexyltrimethylstannane. The presence of both the sulfonyl and trimethyltin moieties was indicated by the strong infrared absorption bands at 1315 cm-1, 1300 cm-1, 1285 cm-1 and 1140 cm-1 (--SO2 --) and 760 cm-1 [(CH3)3Sn--]. NMR showed the following:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.[CH:12]1([CH2:15]Br)[CH2:14][CH2:13]1>>[CH:12]1([CH2:15][O:9][CH2:8][CH2:7][O:6][C:5]2[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:14][CH2:13]1
Reactant: OCCOc1ccc(Br)cc1
Reactant: BrCC1CC1
Product: Brc1ccc(OCCOCC2CC2)cc1

Procedure:
Prepared by the method of Example 10 (b) using 2-(4-bromophenoxyl)ethanol and cyclopropylmethyl bromide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([Cl:14])([Cl:13])[Cl:12])[NH:8][C:7](=[O:15])[C:6]=2[CH:16]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:17]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([Cl:14])([Cl:13])[Cl:12])[NH:8][C:7](=[O:15])[C:6]=2[CH:16]=1)(=[O:19])[CH3:18]
Reactant: O=C1NC(C(Cl)(Cl)Cl)Oc2ccc(O)cc21
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc2c(c1)C(=O)NC(C(Cl)(Cl)Cl)O2

Procedure:
3,4-Dihydro-6-hydroxy-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazin-4-one (prepared as described in Example 3--5.0 g.) and acetic anhydride (250 ml.) were stirred for 40 hours at room temperature, the mixture was filtered, and the solid product was washed with acetic anhydride, then diethyl ether, to give 6-acetoxy-3,4-dihydro-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazin-4-one, m.p. 201°-203° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([O:26]C)=O)=[CH:15][C:13]=2[N:14]=1.[F:28][C:29]1[C:35]([F:36])=[C:34]([F:37])[CH:33]=[CH:32][C:30]=1[NH2:31].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:31][C:30]3[CH:32]=[CH:33][C:34]([F:37])=[C:35]([F:36])[C:29]=3[F:28])=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: COC(=O)c1cc2nc(Nc3c(C)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Reactant: Nc1ccc(F)c(F)c1F
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)Nc3ccc(F)c(F)c3F)c3c(c2[nH]1)CC(C)(C)O3
Yield: 48.2 %

Procedure:
The title compound was prepared by following the procedure as described for Example-137 by using methyl 2-[(2-chloro-6-methylphenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-35, 0.200 g, 0.414 mmol) and 2,3,4-trifluoroaniline (0.090 g, 0.602 mmol), trimethyl aluminium (2M solution in toluene) (1 mL) and dry toluene (5.0 mL) to afford 0.100 g of the desired product. 1HNMR (DMSO-d6): δ 1.55 (s, 6H), 2.24 (s, 3H), 3.13 (s, 2H), 7.25-7.43 (m, 4H), 7.52 (s, 1H), 8.24 (m, 1H), 9.10 (m, 1H), 10.06 (s, 1H), 10.96 (m, 1H): MS [M+H]+: 501.04.
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]([F:32])=[CH:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]3[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[CH:19]=[C:18]([CH:25]([CH3:27])[CH3:26])[C:17]=3[O:28][CH2:29][CH2:30][CH3:31])[C:9]=2[CH:8]=1)C.C1COCC1.[Li+].[OH-]>CO>[F:32]/[C:5](=[CH:6]/[C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]3[CH:21]=[C:20]([CH:22]([CH3:23])[CH3:24])[CH:19]=[C:18]([CH:25]([CH3:26])[CH3:27])[C:17]=3[O:28][CH2:29][CH2:30][CH3:31])[C:9]=2[CH:8]=1)/[C:4]([OH:33])=[O:3]
Reactant: CCCOc1c(-c2cccc3sc(C=C(F)C(=O)OCC)cc23)cc(C(C)C)cc1C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCOc1c(-c2cccc3sc(/C=C(/F)C(=O)O)cc23)cc(C(C)C)cc1C(C)C
Temperature: 25 °C

Procedure:
A mixture of 0.450 mmol of 2-fluoro-3-[4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-prop-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at room temperature, the mixture was acidified to pH=2 and extracted with ethyl acetate. The organic layer was dried over MgSO4 and after evaporation of the solvents, the crude acid was recrystallized from acetonitrile. (E)-2-Fluoro-3-[4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-prop-2-enoic acid was isolated as a white solid. 1H-NMR (CDCl3), δ: 7.83 (d, J=7.7 Hz, 1H), 7.49 (broad s, 1H), 7.46 (s, 1H), 7.42 (t, J=7.0 Hz, 2H), 7.18 (d, J=2.1 Hz, 1H), 7.00 (d, J=2.1 Hz, 1H), 3.42 (dt, J=13.7, 6.8 Hz, 1H), 3.32 (m, 1H), 3.19 (m, 1H), 2.92 (dt, J=13.8, 6.9 Hz, 1H), 1.29 (m, 14H), 1.22 (m, 2H), 0.45 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:22])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:5]2[N:6]([N:8]=[C:9](N)[N:10]=2)[CH:7]=1.BrC1C(C)=C(C2C=CC=C(C(F)(F)F)C=2)C([Cl:30])=NC=1>>[Br:1][C:2]1[C:3]([CH3:22])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:5]2[N:6]([N:8]=[C:9]([Cl:30])[N:10]=2)[CH:7]=1
Reactant: Cc1c(Br)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: Cc1c(Br)cnc(Cl)c1-c1cccc(C(F)(F)F)c1
Product: Cc1c(Br)cn2nc(Cl)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 6-bromo-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (Int. 2, 356 mg, 0.959 mmol) using a similar method to that employed in Intermediate 14 (130 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5]([CH2:8][CH:9]([O:30][CH3:31])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)(=[O:7])=[O:6].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[CH3:31][O:30][CH:9]([CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1)[CH2:8][S:5]([CH2:4][CH2:3][CH2:2][O:1][S:40]([CH3:39])(=[O:42])=[O:41])(=[O:7])=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: COC(COCCCCCCCCCCCCC1CCCCC1)CS(=O)(=O)CCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(COCCCCCCCCCCCCC1CCCCC1)CS(=O)(=O)CCCOS(C)(=O)=O
Yield: 100 %

Procedure:
In 100 ml of dichloromethane are dissolved 8.9 g of 2-methoxy-3-(12-cyclohexyldodecyloxy)propyl 3-hydroxypropyl sulfone and 3.7 ml of triethylamine, to which 3.0 g of methanesulfonyl chloride is added dropwise with stirring under ice cooling. After 2 hours stirring at room temperature, the reaction solution is washed with water, an aqueous sodium bicarbonate solution and water, and dried. The solvent is then distilled off under reduced pressure to leave 10.4 g of the captioned compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[C@H:7]([N:11]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:8][CH2:9]O)([CH3:4])([CH3:3])[CH3:2].[I:36]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>ClCCl.CO>[C:1]([O:5][C:6](=[O:35])[C@H:7]([N:11]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:8][CH2:9][I:36])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H](CCO)N(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H](CCI)N(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.4 %

Procedure:
A solution of the title E compound, (2R)-[t-butoxycarbonyl(4′-chlorobiphenyl-4-sulfonyl)amino]4-hydroxybutyric acid t-butyl ester (2.0 g, 9.58 mmol) in 50 mL dichloromethane is sequentially treated with iodine (2.88 g, 14.37 mmol), triphenylphosphine (3.72 g, 14.37 mmol) and imidazole (0.97 g, 14.37 mmol) at RT. After 2 h, 20 mL of methanol are added and the reaction mixture is stirred at RT for 30 min further. The solvent is evaporated and the product is purified by chomatography on silica gel (eluant; 1/19—EtOAc/hexane) to afford 2.46 g (78%) of (2R)-[t-butyloxycarbonyl(4′-chlorobiphenyl-4-sulfonyl)amino]-4-iodobutyric acid t-butyl ester.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][C:6]([C:10](=[O:12])[CH3:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:13]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[Cl:13][C:3]1[C:4]2=[N:5][C:6]([C:10](=[O:12])[CH3:11])=[CH:7][CH:8]=[C:9]2[NH:1][CH:2]=1
Reactant: CC(=O)c1ccc2[nH]ccc2n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc2[nH]cc(Cl)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To 1-(1H-pyrrolo[3,2-b]pyridin-5-yl)ethanone (2.80 g, 17.48 mmol) in anhydrous DMF (27 mL) at 0° C. was added a solution of N-chlorosuccinimide (2.50 g, 18.36 mmol) dissolved in anhydrous DMF (54 mL). The reaction mixture was stirred at 0° C. for 1 h and then at RT for 18 h. The reaction mixture was diluted with EtOAc, and the organic layer was washed with sat'd. aq. NaHCO3 solution, water and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by SiO2 chromatography eluting with EtOAc/heptane. Trituration with DCM/heptane afforded 3.35 g (98.59%) of 1-(3-chloro-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanone as a white solid. 1H NMR (400 MHz, DMSO) δ 11.96 (br s, 1H), 8.01 (d, J=2.9 Hz, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.88 (d, J=8.6 Hz, 1H), 2.71 (s, 3H); MS (ESI) m/z: 195.2 [M+1]+.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][P:7]([CH2:27][NH2:28])([CH2:9][CH:10]([C:15](=[O:26])[NH:16][C@H:17]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=O)[O:37][C:35](=[O:36])[C:34]2=[CH:40][CH:41]=1>>[CH3:5][O:6][P:7]([CH2:27][N:28]1[C:38](=[O:37])[C:33]2=[CH:32][C:31]([O:30][CH3:29])=[CH:41][CH:40]=[C:34]2[C:35]1=[O:36])([CH2:9][CH:10]([C:15](=[O:26])[NH:16][C@H:17]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8]
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN)OC
Reactant: COc1ccc2c(c1)C(=O)OC2=O
Solvent: CC(=O)O
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN1C(=O)c2ccc(OC)cc2C1=O)OC
Yield: 50.4 %

Procedure:
In a manner analogous to that described in Example 3(A), from 0.45 g of (aminomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid methyl ester acetate and 0.185 g of 4-methoxyphthalic anhydride, there was obtained 0.274 g of [(4-methoxyphthalimido)methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid methyl ester in the form of colorless foam.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:16][NH2:17])([CH3:15])[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:18](O)C>>[OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:16][NH2:17])([CH3:15])[C:11]([O:13][CH2:14][CH3:18])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COC(=O)C(C)(Cc1ccc(O)c(O)c1)NN
Reactant: CCO
Product: CCOC(=O)C(C)(Cc1ccc(O)c(O)c1)NN

Procedure:
Following the procedure for preparation of compound 107, and substituting methanol with ethanol, provided the title compound, which was used in the next reaction without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24]O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.C(P(CCCC)CCCC)CCC.[NH:50]1[CH:54]=[N:53][CH:52]=[N:51]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][N:50]4[CH:54]=[N:53][CH:52]=[N:51]4)=[CH:22][N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: c1nc[nH]n1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2CO)ccc1OCc1nc(-c2ccco2)oc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2Cn2cncn2)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 15 h
Yield: 39.8 %

Procedure:
To a mixture of {3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}methanol (0.50 g), tributylphosphine (0.40 g), 1H-1,2,4-triazole (0.14 g) and tetrahydrofuran (50 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.50 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 1-({3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}methyl)-1H-1,2,4-triazole as crystals (0.22 g, yield 41%) from a fraction eluted with ethyl acetate-methanol (50:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 149-150° C.