Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25]C(=O)OC(C)(C)C)[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1>Cl.CC(O)C>[ClH:1].[NH2:25][C@@H:21]1[CH2:22][CH2:23][CH2:24][N:19]([C:3]2[C:2]([Cl:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12]([CH:14]4[CH2:15][CH2:16][CH2:17][CH2:18]4)=[O:13])[C:4]=23)[CH2:20]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(NC(=O)C4CCCC4)c23)C1
Agent: Cl
Solvent: CC(C)O
Product: N[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(NC(=O)C4CCCC4)c23)C1
Yield: 212.7 %

Procedure:
(R)-tert-Butyl 1-(5-chloro-3-(cyclopentanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (80 mg, 0.17 mmol) was stirred in 4N HCl in IPA (5 mL) at about 30-40° C. for 24 hours. The reaction was concentrated to dryness to yield (R)—N-(4-(3-aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopentanecarboxamide hydrochloride (72 mg, 115% yield) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[S:23](Cl)(=[O:25])=[O:24].C(N(C(C)C)CC)(C)C.CN(C=O)C>CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:23]([C:19]4[S:18][CH:22]=[CH:21][CH:20]=4)(=[O:25])=[O:24])=[CH:3][CH:4]=3)[N:9]=[CH:10][C:11]=12
Reactant: Nc1ccc(-n2ncc3c(N)ncnc32)cc1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnc2c1cnn2-c1ccc(NS(=O)(=O)c2cccs2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 56.3 %

Procedure:
Title compound 11A, 1-(4-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (36 mg, 1.1 eq, 0.16 mmol), 2-thiophenesulphonylchloride (29 mg, 1.0 eq, 0.16 mmol) and diisopropylethylamine (28 μl, 1.0 eq, 0.16 mmol) were added to DMF (1 ml) and the mixture was stirred for 15 hours at room temperature under an inert atmosphere. Methanol was then added (1 ml) and the solvents were removed in vacuo. The resultant residue was purified by semi-preparative HPLC to yield the title compound as a white solid (35 mg, 0.09 mmol, 75%). LCMS: [M+H]+=373, Rt=1.60 min, 100% purity.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)/[C:5](=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])/[O:4][C:3]1=[O:23].C(N(CC)CC)C.CC(C)(O)C#N>C(#N)C>[CH3:1][C:2]1([CH3:24])[C:11]2[N:10]=[CH:9][CH:8]=[N:7][C:6]=2[C:5](=[O:4])[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:20])([F:21])[F:22])[C:3]1=[O:23]
Reactant: CC1(C)C(=O)O/C(=C\c2ccccc2C(F)(F)F)c2nccnc21
Agent: CC(C)(O)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1(C)C(=O)C(c2ccccc2C(F)(F)F)C(=O)c2nccnc21
Reaction time: 16 h
Yield: 111.8 %

Procedure:
To a stirred solution of 8,8-dimethyl-5-[1-(2-trifluoromethyl-phenyl)-meth-(Z)-ylidene]-5,8-dihydro-pyrano[3,4-b]pyrazin-7-one (0.170 g) in acetonitrile (1.7 ml) at ambient temperature was added triethylamine (0.154 g) and 4□ molecular sieves. After 10 min acetone cyanohydrin (0.013 g) was added and the reaction mixture stirred for 16 hours. The reaction mixture was concentrated and the residue purified by chromatography on silica gel (eluent 5-95% ethyl acetate in isohexane) to give the crude 8,8-dimethyl-6-(2-trifluoromethyl-phenyl)-8H-quinoxaline-5,7-dione (compound E1 of Table E) (0.190 g) which was carried over to the next step.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH:17][CH:16]2[C:33]([OH:35])=O)[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:41][C@@H:40]([CH2:42][CH2:43][NH2:44])[CH2:39][O:38]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:41][C@H:40]([CH2:39][OH:38])[CH2:42][CH2:43][NH:44][C:33]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=2)[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:18]([CH2:29][CH:30]([CH3:31])[CH3:32])[NH:17]1)=[O:35]
Reactant: CC(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: CC1(C)OC[C@H](CCN)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 108.1 %

Procedure:
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 46b (0.6 g, 1.1 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.3 g, 2 mmol), HATU (0.5 g, 1.3 mmol) and iPr2NEt (1.2 g, 9.3 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.6 g, 95%).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Cl:5][CH2:6][CH2:7][NH:8][C:9]([NH:11][CH2:12][CH2:13][Cl:14])=[O:10]>O.C(O)=O>[CH2:7]([NH:8][C:9]([N:11]([N:1]=[O:3])[CH2:12][CH2:13][Cl:14])=[O:10])[CH2:6][Cl:5]
Reactant: O=C(NCCCl)NCCCl
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: O=NN(CCCl)C(=O)NCCCl
Reaction time: 2 h

Procedure:
A cold solution of 0.2346 g (3.4 mmole) sodium nitrite in 2 ml water was slowly added to a stirred solution of 0.2727 g (1.47 mmole) 1,3-bis(2-chloroethyl)urea in 2 ml 88% formic acid at 0°. After 2 hours at 0°, 0.1449 g (46.0%) of an oil solid phase was removed. The ir spectrum of this fraction failed to agree with that of BCNU. After 2 days a small amount of crystalline BCNU slowly formed in this oil phase. A methylene dichloride extract of the aqueous phase yielded 0.0943 g (30.0%) of an amber oil whose ir spectrum agreed with that of a known sample of BCNU. Treatment of this oil with 5 ml hexane and cooling to 0° gave crystalline BCNU which formed an oil on warming to ambient temperature.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.[CH3:54][NH:55][C:56]([CH3:104])([C:58]([NH:60][C@H:61]([C:65]([N:67]([C@@H:69]([C@@H:100]([CH3:103])[CH2:101][CH3:102])[C@H:70]([O:98][CH3:99])[CH2:71][C:72]([N:74]1[CH2:78][CH2:77][CH2:76][C@H:75]1[C@H:79]([O:96][CH3:97])[C@@H:80]([CH3:95])[C:81]([NH:83][C@H:84]([C:92]([OH:94])=[O:93])[CH2:85][C:86]1[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=1)=[O:82])=[O:73])[CH3:68])=[O:66])[CH:62]([CH3:64])[CH3:63])=[O:59])[CH3:57]>CN(C=O)C.ClCCl>[O:7]=[C:4]1[CH:5]=[CH:6][C:2](=[O:1])[N:3]1[CH2:8][CH2:9][CH2:10][C:11]([N:55]([CH3:54])[C:56]([CH3:104])([C:58]([NH:60][C@H:61]([C:65]([N:67]([C@@H:69]([C@@H:100]([CH3:103])[CH2:101][CH3:102])[C@H:70]([O:98][CH3:99])[CH2:71][C:72]([N:74]1[CH2:78][CH2:77][CH2:76][C@H:75]1[C@H:79]([O:96][CH3:97])[C@@H:80]([CH3:95])[C:81]([NH:83][C@H:84]([C:92]([OH:94])=[O:93])[CH2:85][C:86]1[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=1)=[O:82])=[O:73])[CH3:68])=[O:66])[CH:62]([CH3:63])[CH3:64])=[O:59])[CH3:57])=[O:13]
Reactant: O=C(O)CCCN1C(=O)C=CC1=O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)CCCN1C(=O)C=CC1=O)C(C)C
Reaction time: 0.5 h

Procedure:
A stirring solution of 4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butanoic acid (1.2 equivalents), HATU (1.2 equivalents), and Hunig's base (3 equivalents) in DMF and dichloromethane is allowed to stir for 30 minutes. Compound #115 (1 equivalent) is then added as a solution in dichloromethane and DMF. Reaction is monitored by LC-MS. Reaction is concentrated down and purification is completed by Isco medium pressure reverse phase chromatography (Gradient: 5%-100% water in acetonitrile).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=2)[CH:5]=[N:4][C:3]=1[CH:20]=[N:21][OH:22].Cl.BrN1C(=O)CCC1=O.[CH2:32]([O:35][CH3:36])[C:33]#[CH:34]>CN(C)C=O.C(N(CC)CC)C>[CH3:36][O:35][CH2:32][C:33]1[O:22][N:21]=[C:20]([C:3]2[N:4]=[CH:5][N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:8]=3)[C:2]=2[CH3:1])[CH:34]=1
Reactant: C#CCOC
Reactant: Cc1c(C=NO)ncn1-c1cccc(Oc2ccccc2)c1
Agent: Cl
Agent: O=C1CCC(=O)N1Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCc1cc(-c2ncn(-c3cccc(Oc4ccccc4)c3)c2C)no1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
660 mg of 5-methyl-1-(3-phenoxyphenyl)-imidazole-4-carbaldehydoxime, hydrochloride is dissolved in 4 ml of dimethylformamide. At 0° C., 0.28 ml of triethylamine is added and a solution of 360 mg of N-bromosuccinimide in 2 ml of dimethylformamide is instilled within one hour. Then, 1.7 ml of methyl propargyl ether and 0.28 ml of triethylamine are added, and the mixture is stirred for 14 hours at room temperature. 360 mg of N-bromosuccinimide in 2 ml of dimethylformamide and 0.28 ml of triethylamine are again added and the mixture is stirred for 18 hours at room temperature. After the concentration by evaporation, it is mixed with water and extracted with ethyl acetate. The extract that has been concentrated by evaporation is mixed with diethyl ether and filtered. The filtrate is purified by column chromatography. 230 mg (32% of theory) of the title compound is obtained as oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@:4]1([CH2:17][OH:18])[CH2:8][C@H:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5]1.[C:19]1([Se:25]N2C(=O)C3=CC=CC=C3C2=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.B(F)(F)F>C(Cl)Cl>[OH:18][CH2:17][C@:4]12[CH2:8][C@H:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:13])[CH3:14])[C@H:6]([Se:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@H:5]1[O:1][CH2:2][CH2:3]2
Reactant: O=C1c2ccccc2C(=O)N1[Se]c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@@](CO)(CCO)C1
Agent: FB(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1C[C@]2(CO)CCO[C@@H]2[C@H]1[Se]c1ccccc1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a 12-L three-neck round bottom flask equipped with a mechanical stirrer, Claisen adapter with a nitrogen inlet and a temperature probe, and a nitrogen outlet was charged with the product of Step B (382 g, 1.26 mol, 1 eq) and CH2Cl2 (6.5 L). N-(phenylseleno)phthalimide (419 g, 1.39 mol, 1.1 eq) was added followed by BF3 etherate (16 mL, 0.126 mol, 0.1 eq) directly added by graduated cylinder. The reaction steadily climbed from 15° C. to 24° C. and within 10 min, the reaction formed a pink precipitate. Ten min later, the reaction became thick with a white precipitate and the temperature began to decrease. The reaction was checked by HPLC and found to be complete. The reaction was filtered through Celite (removing the phthalimide impurity), the filter cake was washed with CH2Cl2 (750 mL) until the filtrate was no longer orange. The filtrate was transferred to a separatory funnel, washed with aqueous NaOH (0.5 M, 2×1350 mL), brine (2×1 L), and the organic layer was dried over Na2SO4. [A second run was conducted with 382 g of the product of Step B, under the same conditions, and was worked up and combined at this point]. With about 3 L organics left, toluene (3 L, ˜4 mL/g starting material) was added and the evaporation continued. Shortly after the toluene addition, crystallization occurred. The 20-L round bottom flask was transferred to a heating mantel, and the contents heated to 80° C., until the solid dissolved. The flask was transferred back to the rotary evaporator, reference material was used to seed the crystallization, and the flask swirled (no heat) until the product started to crystallize. Ice was added to the bath and the contents of the flask swirled at 15° C. (external temp) for 30 min. The product was filtered, washed with ice-cold toluene and air-dried for 1 h, and afforded the product of Step C. 1H NMR (CHLOROFORM-d) δ: 7.49-7.56 (m, 2H), 7.23-7.29 (m, 3H), 5.05 (br. s., 1H), 4.46 (br. s., 1H), 4.29 (s, 1H), 3.86-3.97 (m, 2H), 3.57-3.69 (m, 3H), 1.98-2.08 (m, 1H), 1.86-1.97 (m, 2H), 1.73-1.86 (m, 2H), 1.41 (s, 9H). Calculated for C19H27NO4Se: 436.1 (M+23). found: 436.1.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([CH3:24])[C:8]([CH3:10])([CH3:9])[O:7][B:6]([C:11]2[CH:23]=[CH:22][C:14]([O:15][CH2:16][C:17](OCC)=[O:18])=[CH:13][CH:12]=2)[O:5]1.O1CCCC1.C(O)C>O>[CH3:9][C:8]1([CH3:10])[C:4]([CH3:3])([CH3:24])[O:5][B:6]([C:11]2[CH:23]=[CH:22][C:14]([O:15][CH2:16][CH2:17][OH:18])=[CH:13][CH:12]=2)[O:7]1
Reactant: CCOC(=O)COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(OCCO)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
Sodium borohydride (0.33 g) was added to a mixture of ethyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-acetate (1.33 g), tetra hydrofuran (10 mL) and ethanol (10 mL). The mixture was stirred at room temperature for 4 hrs, and water was added. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1) to afford the title compound (1.13 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:6]([F:11])([F:10])[CH2:7][CH2:8][CH3:9])=[CH:4][F:5].[FH:14]>>[F:1][C:2]([F:12])([F:13])[CH:3]([C:6]([F:10])([F:11])[CH2:7][CH2:8][CH3:9])[CH:4]([F:14])[F:5]
Reactant: F
Reactant: CCCC(F)(F)C(=CF)C(F)(F)F
Product: CCCC(F)(F)C(C(F)F)C(F)(F)F

Procedure:
As another example, 2-trifluoromethyl-1,1,1,3,3-pentafluoro-2-hexanol may be prepared by fluorinating commercially available 3-hexanone to form 3,3-difluorohexane which may then be dehydrogenated to form 3,3-difluoro-2-hexene. CF3 may then be reacted with the 3,3-difluoro-2-hexene to form 2-trifluoromethyl-1,3,3-trifluorohexane which may then be dehydrogenated to form 2-trifluoromethyl-1,3,3-trifluoro-1-hexene. The 2-trifluoromethyl-1,3,3-trifluoro-1-hexene may then be reacted with hydrogen fluoride to form 2-trifluoromethyl-1,1,3,3-tetrafluorohexane which may then be dehydrogenated to form 2-trifluoromethyl-1,1,3,3-tetrafluoro-1-hexene which may then be fluorinated to form 2-trifluoromethyl-1,1,1,2,3,3-hexafluorohexane. The 2-trifluoromethyl-1,1,1,2,3,3-hexafluorohexane may then be hydrolyzed to form 2-trifluoromethyl-1,1,1,3,3-pentafluoro-2-hexanol.
Reaction SMILES: [C:1]1([CH:11]=[C:12]2[CH2:17][C:16](=[O:18])[O:15][C:13]2=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>ClCCl>[C:1]1([CH:11]=[C:12]([CH2:17][C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])[C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C1COCCN1
Reactant: O=C1CC(=Cc2cccc3ccccc23)C(=O)O1
Solvent: ClCCl
Product: O=C(O)C(=Cc1cccc2ccccc12)CC(=O)N1CCOCC1
Yield: 80.5 %

Procedure:
The solution of 1.00 g of the 2-(1-naphthylmethylene)succinic anhydride and 0.37 g of morpholine in 31 ml of dry dichloromethane was stirred for 2 hours at room temperature. The reaction mixture was evaporated under reduced pressure, and the residue was triturated with a mixture of ethyl acetate, benzene and hexane (1/1/1 by volume) to obtain 1.10 g of 2-(1-naphthylmethylene)-3-(morpholinocarbonyl)propionic acid as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH2:17]([CH:21]([N:28]1[C:36]2[C:31](=[CH:32][C:33](/[C:37](/[CH3:42])=[CH:38]/[C:39](O)=[O:40])=[CH:34][CH:35]=2)[CH:30]=[CH:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH3:20]>>[CH2:17]([CH:21]([N:28]1[C:36]2[C:31](=[CH:32][C:33](/[C:37](/[CH3:42])=[CH:38]/[C:39]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:40])=[CH:34][CH:35]=2)[CH:30]=[CH:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: CCCCC(c1ccccc1)n1ccc2cc(/C(C)=C/C(=O)O)ccc21
Product: CCCCC(c1ccccc1)n1ccc2cc(/C(C)=C/C(=O)Nc3ccccc3OCCCC(=O)O)ccc21

Procedure:
0.61 g of compound 42 was obtained in a similar manner to those described in the Examples 1 and 2 using 1.28 g of ethyl 4-(2-aminophenoxy)butyrate and 1.0 g of 3-[1-(α-butylbenzyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:21](O)[C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[F:30])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C>CO>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[F:30])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(O)c1cc(F)c(F)cc1F
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)Cc1cc(F)c(F)cc1F
Yield: 79.9 %

Procedure:
In accordance with the method described in Example 6, except that 43.94 g (3S)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxy-4-(2,4,5-trifluorophenyl)butyrate and an equal amount of anhydrous ethanol were used to replace (3S)-3-(tert-butoxycarbonylamino)-4-hydroxy-4-(2,4,5-trifluorophenyl)n-butyl ester and methanol respectively, 33.83 g (R)-benzyl 3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butyrate (yield: 77%) was obtained using the same method.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([N:27](C)[C:28](=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[CH3:36][C:37]1[N:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1>>[CH3:36][C:37]1[N:42]=[CH:41][C:40]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([NH:27][CH3:28])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:8]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)=[O:21])[CH:7]=2)=[CH:39][CH:38]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: Cc1ccc(B(O)O)cn1
Product: CN[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2ccc(C)nc2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (S)-tert-butyl (1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (Stage 102.1) and (6-methylpyridin-3-yl)boronic acid. LC-MS (Condition 6) tR=0.8 min, m/z=472.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][C:16]=1[C:24]([F:27])([F:26])[F:25]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[C:16]([C:24]([F:26])([F:25])[F:27])[CH:17]=2)=[O:23])=[C:4]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)[CH:3]=1
Reactant: Nc1ccc(Cl)cc1-c1nnn[nH]1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc(Cl)cc1-c1nnn[nH]1
Yield: 79.7 %

Procedure:
4-Chloro-2-(1H-tetrazol-5-yl)-phenylamine (500 mg) dissolved in toluene (15 ml) was treated with 4-chloro-3-trifluoromethylphenylisocyanate (600 mg) and stirred for a week. The precipitated product was filtered and then acid/base extracted and re-precipitated in aq. acid in a manner analogous to that described for 1-[4-Chloro-2-(1H-tetrazol-5-yl)-phenyl]-3-(3,5-dichloro-phenyl)-urea (Compound 12) to give 1-[4-Chloro-2-(IH-tetrazol-5-yl)-phenyl]-3-(4-chloro-3-trifluoromethyl-phenyl)-urea as a white solid (850 mg). Mp.=245-247° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]([C:15]2[C:23]3[C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[S:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH:12]=[C:11]([Br:28])[C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[K+]>CO>[Br:1][C:2]1[CH:14]=[C:13]([C:15]2[C:23]3[C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[S:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH:12]=[C:11]([Br:28])[C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1c(Br)cc(-c2cccc3sc4ccccc4c23)cc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1c(Br)cc(-c2cccc3sc4ccccc4c23)cc1Br
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of [2,6-dibromo-4-(dibenzothiophen-1-yl)-phenoxy]-acetic acid, ethyl ester (0.324 g, 0.623 mmol) in tetrahyodrofuran (15 mL) and methanol (5 mL) was added an aqueous solution of potassium hydroxide (1N, 0.75 mL, 0.75 mmol, 1.2 eq) dropwise at room temperature. After stirring 2.5 hours at room temperature the solvents were removed and the residue was combined with water (50 mL) and was acidified with 10% aqueous hydrochloric acid. After stirring 0.5 hours the white solid was filtered. Trituration with petroleum ether and recrystallization from aqueous acetic acid with hot filtration gave a white solid which was dried in vacuo at 100° C. for 5 hours to provide the title compound as a white solid: (0.155 g, 51%); mp 212-213° C.; NMR (DMSO-d6): δ 13.19 (broad s, 1H), 8.11 (dd, J=8, 1 Hz, 1H), 8.04 (dm, 1H), 7.78 (s, 2H), 7.55 (dd, J=8, 7 Hz, 1H), 7.45 (ddd, J=8, 7, 1 Hz, 1H), 7.31 (dd, J=7 Hz, 1H), 7.27 (ddd, J=8, 7, 1 Hz, 1H), 7.10 (dm, 1H), 4.67 (s, 2H); MS (+FAB): [M+], 2 bromine isotope pattern, 490 (61%), 492 (100%), 494 (57%); Anal. Calc. for C20H12Br2O3S: C, 48.81, H, 2.46, N, 0.00. Found: C, 48.99, H, 2.24, N, 0.07.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:12]=[C:11]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:10]=2)[CH:6]=[CH:5][CH:4]=1.CCN(CC)CC.[O:36](S(C)(=O)=O)[S:37]([CH3:40])(=[O:39])=[O:38]>C(Cl)Cl>[CH3:40][S:37]([OH:39])(=[O:38])=[O:36].[OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:12]=[C:11]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:10]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Agent: COc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(CO)n3)c2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O

Procedure:
To a suspension of 6-hydroxymethyl-4′-(4-methoxyphenyl)-2,2′:6′,2″-terpyridine (38.5 mmol) in CH2Cl2 (175 mL) and Et3N (50 mmoles) at 8° C. is added a solution of (CH3SO2)2O (48 mmol) in 50 mL of CH2Cl2 over 10-15 minutes. The reaction mixture is then extracted with cold water, dried over Mg2SO4, filtered, and concentrated under high vacuum nearly to dryness. The residue is treated with ethyl acetate, and the desired product is collected by filtration, washed with ethyl acetate, and dried under vacuum.