Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[C:13]([CH3:22])[S:12][C:11]=2[CH:23]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>>[N:24]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[C:13]([CH3:22])[S:12][C:11]=2[CH:23]=1)=[N+:25]=[N-:26]
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(Br)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: Cc1sc2cc(OCCCCN=[N+]=[N-])ccc2c1-c1ccc(Br)cc1

Procedure:
In analogy to the procedures described in examples 49.3 and 49.4, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene (example 27.5) was reacted with sodium azide to yield 6-(4-Azido-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene, which was further reduced with triphenylphosphin and water to yield 4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butylamine as colorless oil, MS: 390 (MH+, 1Br).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([O:15][CH:16]3[CH2:25][CH2:24][C:19]4(OCC[O:20]4)[CH2:18][CH2:17]3)=[CH:10][C:9]=2[F:26])[C:6](=[O:27])[CH:5]=[CH:4][C:3]=1[C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1.Cl>O1CCOCC1.O>[NH2:1][C:2]1[N:7]([C:8]2[C:9]([F:26])=[CH:10][C:11]([O:15][CH:16]3[CH2:25][CH2:24][C:19](=[O:20])[CH2:18][CH2:17]3)=[CH:12][C:13]=2[F:14])[C:6](=[O:27])[CH:5]=[CH:4][C:3]=1[C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1
Reactant: Nc1c(C(=O)c2ccc(F)cc2)ccc(=O)n1-c1c(F)cc(OC2CCC3(CC2)OCCO3)cc1F
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Nc1c(C(=O)c2ccc(F)cc2)ccc(=O)n1-c1c(F)cc(OC2CCC(=O)CC2)cc1F
Reaction time: 18 h
Yield: 85.6 %

Procedure:
To a solution of 6-amino-1-[4-(1,4-dioxa-spiro[4.5]dec-8-yloxy)-2,6-difluoro-phenyl]-5-(4-fluorobenzoyl)-1H-pyridin-2-one (0.55 g, 1.10 mmol) in 1,4-dioxane (10 ml) was added 2M aq HCl (5 ml) at room temperature. Stirring was continued for 18 h. Upon completion of reaction the reaction mixture was diluted with water (10 ml) before evaporation of dioxane under reduced pressure. The residual aqueous solution was extracted with EtOAc (2×10 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated to dryness under reduced pressure to give the desired ketone as a white solid (0.43 g, 86%). LCMS purity 98%, m/z 457 [M+H]+, 1H NMR (400 MHz, CDCl3), δ: 2.05-2.15 (2H, m), 2.25-2.45 (4H, m), 2.55-2.70 (2H, m), 4.65-4.75 (1H, m), 5.85 (1H, d), 6.70-6.75 (2H, m), 7.05-7.15 (2H, m), 7.50-7.65 (3H, m),
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][S:33][CH2:34][CH2:35][CH2:36][C:37]([F:43])([F:42])[C:38]([F:41])([F:40])[F:39])=[CH:26][CH:25]=3)[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1.[OH:44]OS([O-])=O.[K+].O>O1CCCC1.O>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][S:33]([CH2:34][CH2:35][CH2:36][C:37]([F:43])([F:42])[C:38]([F:39])([F:40])[F:41])=[O:44])=[CH:26][CH:25]=3)[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1
Reactant: O=S([O-])OO
Reactant: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCOc1ccc(OCCSCCCC(F)(F)C(F)(F)F)cc1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCOc1ccc(OCCS(=O)CCCC(F)(F)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
(3RS,4RS)-7-Hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-{3-{4-[2-(4,4,5,5,5-pentafluoropentylthio)ethoxy]phenoxy}propyl}thiochroman (11) prepared in Step 8 (110 mg, 0.17 mmol) was dissolved in tetrahydrofuran (5 ml), which was then cooled down to 0° C. Oxone® (monopersulfate compound; DuPont product) (63 mg, 0.1 mmol) and water (3 drops) were added thereto, and the resulting mixture was stirred for 1 hour. Water (2 drops was further added, and the mixture was stirred for 1 hour. Water was added to the reaction solution and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and subjected to silica gel column chromatography to give (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-{3-{4-[2-(4,4,5,5,5-pentafluoropentylsulfinyl)ethoxy]phenoxy}propyl}thiochroman (12) (64.5 mg, yield 57%) as a colorless foamy substance.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[N:27]=[CH:26][N:25]=[C:24]([C:28](O)=[O:29])[CH:23]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.C(OP(C#N)(=O)OCC)C.[NH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C=O)C.CCOC(C)=O.C([O-])(O)=O.[Na+]>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:23]=[C:24]([C:28](=[O:29])[NH:43][C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[N:25]=[CH:26][N:27]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cc(Oc2ccc3c(c2)CCN3C(=O)Nc2cccc(C(F)(F)F)c2)ncn1
Agent: CCOP(=O)(C#N)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1)c1cc(Oc2ccc3c(c2)CCN3C(=O)Nc2cccc(C(F)(F)F)c2)ncn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ice-cooled solution of 400 mg (0.90 mMol) 6-[1-(3-trifluoromethyl-phenylcarbamoyl)-2,3-dihydro-1H-indol-5-yloxy]-pyrimidine-4-carboxylic acid in 4 ml DMF, 402 μl (2.7 mMol) diethyl-cyanophosphonate and 248 μl (2.7 mMol) aniline are added. After stirring the solution for 3 h at rt, another 402 μl diethyl-cyanophosphonate are added and stirring continued for 16 h. Then the mixture is diluted with EtOAc and sat. NaHCO3, the aqueous layer separeted off and extracted twice with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and partially concentrated until crystals are formed. These are filtered and washed with EtOAC/DIPE, yielding the title compound: m.p.: 227-229° C.; MS: [M−1]=518; HPLC: AtRet=17.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([NH:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=2)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.ClC(Cl)(Cl)C(Cl)(Cl)Cl.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C1COCC1.C(Cl)Cl.CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[N:18]3[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]3=[N:16][N:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)NNc2ccc(F)cn2)C1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2nnc3ccc(F)cn23)C1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 72.2 %

Procedure:
To a brown solution Intermediate 90a (1.37 g, 4.22 mmol), Ph3P (2.22 g, 8.45 mmol) and Et3N (2.35 mL, 16.9 mmol) in THF (25 mL) at 0° C. was added hexachloroethane (2.00 g, 8.45 mmol) in 3 portions at 1 min intervals. The solution was stirred at 0° C. for 30 min and at RT for 3.5 h. The suspension was filtered and the filter-cake washed with THF (10 mL). The combined organics were applied to an SCX-2 cartridge (50 g), then washed with DCM-MeOH (1:1, 50 mL) and MeOH (50 mL). The product was eluted with 2M NH3 in MeOH (75 mL); concentration in vacuo gave a brown oil that solidified on standing. The solid was dissolved in DCM (10 mL) then Et3N (0.580 mL, 4.16 mmol) and BOC anhydride (454 mg, 2.08 mmol) added sequentially. The solution was stirred at RT for 45 min, then water (10 mL) was added and the aqueous extracted with DCM (5 mL). The combined organics were passed through a hydrophobic frit and concentrated in vacuo to leave a brown gum. FCC, using 2.5-3% MeOH in DCM, gave the title compound as a pale brown solid (933 mg, 73%). LCMS (Method 3): Rt 2.94 min, m/z 207 [MH+—C5H9O2].
Reaction SMILES: [Li]CCCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][N:8]=1.[CH2:14]1[O:16][CH2:15]1>CCOCC.C1COCC1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:14][CH2:15][OH:16])=[CH:9][N:8]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 40.2 %

Procedure:
BuLi (32.2 ml of a 1.6 M solution in hexanes, 52 mmol) added dropwise to a stirred solution of 2,5-dibromopyridine (11.09 g, 46.8 mmol) in Et2O (400 ml) at −78° C. under nitrogen. Upon complete addition the reaction mixture was stirred for 45 min and then a solution of ethylene oxide (6.74 g, 0.14 mol) in THF (70 ml) was added. The reaction mixture was warmed to room temperature, stirred for 1 h and then quenched by addition of NH4Cl solution (sat., 150 ml). The organics were extracted with EtOAc (3×100 ml), washed with brine (100 ml) and dried (MgSO4). The material was concentrated under reduced pressure, whilst simultaneously dry-loading onto silica. The material was purified by column chromatography on silica eluting with Et2O and then EtOAc to give the pure alcohol (3.8 g, 40%).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:7]([Si:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:12][CH2:13][CH:14]=[CH:15][CH2:16][OH:17])([CH3:10])([CH3:9])[CH3:8].C(N(C(C)C)CC)(C)C.CO>CN(C)C1C=CN=CC=1.ClCCl>[C:7]([Si:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:12][CH2:13][CH:14]=[CH:15][CH2:16][O:17][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)[Si](OCC=CCO)(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)OCC=CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C

Procedure:
Isobutyryl chloride (10.4 mL, 98.04 mmol) was added drop wise to a stirred and a cooled (0° C.) solution of the product of Example 5E (61.28 mmol), diisopropylethyl amine (21.3 mL, 122.56 mmol), and 4-dimethylaminopyridine (0.30 g, 3.0 mmol) in dry dichloromethane (150 mL). The resulting solution was allowed to stir at 0° C. for five hours. After the completion of reaction (monitored by TLC), methanol (5 mL) was added to quench excess acid chloride. The solvent was removed under reduced pressure and the resulting slurry was partitioned using diethyl ether (200 mL) and saturated NH4Cl (100 mL). The organic layer was washed successively with 20% NaHSO4, NaHCO3, brine, and it was dried over MgSO4. After removal of solvent, the crude oil was purified over silica gel column using 10% diethyl ether in hexanes to give the title compound as a colorless oil: (20.5 g, 84% over 2 steps).
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH2:6].[C:7]1([CH:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](Cl)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[O:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH:6][C:14](=[O:15])[CH:13]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1nnco1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: O=C(Nc1nnco1)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, light yellow solid, m.p. 131-132° C. and MS: m/e=279.2 (M+) was prepared in accordance with the general method of example 44a from [1,3,4]oxadiazol-2-ylamine and 2,2-diphenylacetic acid chloride.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([NH:13][C@H:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].[NH:35]([C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48])[CH2:36][C:37]([O:39]N1C(=O)CCC1=O)=O>>[NH:35]([C:47]([O:49][CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:48])[CH2:36][C:37]([NH:1][C@H:2]([C:11]([NH:13][C@H:14]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:39]
Reactant: O=C(CNC(=O)OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Product: CC(C)[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C

Procedure:
A diester such as H-Gly-Asp(OtBu)-Val-OtBu can be prepared by condensing Z-Asp(OtBu)-OH and H-Val-OtBu to give Z-Asp(OtBu)-Val-OtBu, hydrogenolyzing the latter, coupling the resulting H-Asp(OtBu)-Val-OtBu with Z-Gly-OSu to give Z-Gly-Asp(OtBu)-Val-OtBu and hydrogenolyzing the latter.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:15]([CH3:17])[CH3:16])[CH2:10][C:11](OC)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:15]([CH3:17])[CH3:16])[CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: [BH4-]
Agent: [Li+]
Product: CC(C)[C@@H](CCO)NC(=O)OC(C)(C)C
Yield: 93 %

Procedure:
Methyl (R)-3-(tert-butoxycarbonylamino)-4-methylpentanoate (1.62 g, 6.6 mmol) was treated with lithium borohydride in a manner analogous to Method B8a, Step 2 to afford (R)-3-(tert-butoxycarbonylamino)-4-methylpentanol (93%).
Reaction SMILES: [C:1]([N:9]=C=O)(=[O:8])C1C=CC=CC=1.C(O[C:15]([C:17]1[O:32][C:20]2=[N:21][C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:23][C:24]([CH3:25])=[C:19]2[C:18]=1[NH2:33])=[O:16])C.CC[O-].[Na+].C(O)C>CC(C)=O.O>[CH3:25][C:24]1[C:19]2[C:18]3[NH:33][C:1](=[O:8])[NH:9][C:15](=[O:16])[C:17]=3[O:32][C:20]=2[N:21]=[C:22]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:23]=1
Reactant: CCOC(=O)c1oc2nc(-c3ccccc3)cc(C)c2c1N
Reactant: O=C=NC(=O)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(-c2ccccc2)nc2oc3c(=O)[nH]c(=O)[nH]c3c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
1.0 g (6.8 mmol) benzoylisocyanate is added to 1.0 g (3.4 mmol) 3-amino-4-methyl-6-phenyl-furo[2,3-b]pyridine-2-carboxylic acid ethyl ester (described in Wagner G., Prantz J. Pharmazie 1990, 45, 213-214) in 20 ml absolute acetone and stirred at room temperature for 30 minutes. The solvent is removed and the precipitate precipitated after the addition of water is sucked off and dried. The resulting precipitate is refluxed with 0.46 g (6.8 mmol) NaOEt and 20 ml ethanol for 15 min. Then, 20 ml water is added, the precipitate is sucked off, washed with some ethanol and dried. 0.85 g (85%) 9-methyl-7-phenyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-2,4-dione is obtained
Reaction SMILES: [CH2:1]([N:8]([CH2:17][CH2:18]O)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Br:46])C(=O)C1>C(Cl)Cl.CCOCC>[CH2:1]([N:8]([CH2:17][CH2:18][Br:46])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CN(CCO)Cc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN(CCBr)Cc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 50.2 %

Procedure:
To a solution of Compound 4 (2.94 g, 11.1 mmol) in anhydrous CH2Cl2 (40 mL) at 0° C. was added PPh3 (3.49 g, 13.3 mmol). NBS (2.37 g, 13.3 mmol) was added portionwise into the reaction mixture over 1 h. The resulting mixture was stirred at 0° C. for 30 minute after which the ice bath was removed, and the reaction mixture was stirred for 3 h. The resulting mixture was evaporated into an orange solid. The residue was dissolved in ether (100 mL). The solution was filtered, and the filtrate was evaporated and washed with ether again (3 times). The resulting clear filtrate was evaporated to give a white solid. The residue was then dissolved in ether (100 mL) and was passed through a short silica gel column to eliminate as much of the leftover PPh3 as possible. The resulting pure fractions (according to TLC analysis) were collected and dried overnight. The residue was on column chromatography eluted with 5% EtOAc in hexanes to provide Compound 5 (1.83 g, 50.4%) was collected at the ratio ethyl acetate to hexane as 1:11. 1H NMR (CDCl3) δ 1.47 (s, 9H), 3.10 to 3.18 (m, 2H), 3.31 (s, 2H), 3.30 to 3.40 (m, 2H), 3.88 (s, 2H), 7.20 to 7.38 (m, 5H); 13C NMR (CDCl3) δ 28.12, 30.47, 55.14, 55.85, 57.99, 80.96, 127.17, 128.26, 128.69, 138.74, 170.48. HRMS (Positive ion FAB) Calcd for C15H23N4O2Br [M+H]+ m/z 328.0929. Found: [M+Na]+ m/z 328.0912.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH2:9][C:10]#[CH:11])=[CH:6][C:5]([N:12]2[C:20](=[O:21])[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[C:13]2=[O:22])=[C:4]([F:23])[CH:3]=1.[N:24]([O-])=O.[Na+].O>C(O)(=O)C>[F:23][C:4]1[C:5]([N:12]2[C:13](=[O:22])[C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:20]2=[O:21])=[CH:6][C:7]2[N:8]([CH2:9][C:10]#[CH:11])[N:24]=[N:1][C:2]=2[CH:3]=1
Reactant: O=N[O-]
Reactant: C#CCNc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C#CCn1nnc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc21
Reaction time: 0.17 h
Yield: 11.5 %

Procedure:
2-[4-Amino-2-fluoro-5-(2-propynylamino)phenyl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.59 g) was dissolved in acetic acid (1.9 ml), and sodium nitrite (0.13 g) was added thereto at a temperature of 10° to 15° C. After stirring for 10 minutes, the reaction mixture was admixed with water and extracted with ethyl acetate. The extract was washed with water and an aqueous solution of sodium bicarbonate, dried and concentrated. The residue was purified by silica gel thin layer chromatography using a mixture of ethyl acetate and hexane (1:2 by volume) as an eluent to give 2-[5-fluoro-1-(2-propynyl)benzotriazol-6-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.07 g) as a resinous material.
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.[F:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][NH:17][C:18]([C@@H:20]2[CH2:25][CH2:24][CH2:23][CH2:22][N:21]2[CH3:26])=O)=[N:14][CH:15]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CO>[F:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:18]([C@@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][N:21]3[CH3:26])=[N:17][N:16]=2)[CH:15]=1
Reactant: CN1CCCC[C@H]1C(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCCC[C@H]1c1nnc2ccc(F)cn12
Reaction time: 1.5 h
Yield: 41.9 %

Procedure:
Hexachloroethane (505 mg, 2.14 mmol) was added portionwise over 5 min at RT to a stirred mixture of Intermediate 120a (270 mg, 1.07 mmol), triethylamine (595 μL, 4.28 mmol) and triphenylphosphine (560 mg, 2.14 mmol) in THF (10 mL). The reaction mixture was stirred for 1.5 h and then diluted with methanol and loaded onto an SCX cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3 in MeOH and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-8% [2M NH3 in MeOH] in EtOAc to give the title compound (105 mg, 42%). 1H NMR (400 MHz, CDCl3): 1.34-1.51 (1H, m), 1.62-1.92 (5H, m), 2.00 (3H, s), 2.20 (1H, td, J=11.4, 3.7 Hz), 3.06 (1H, m), 3.87 (1H, dd, J=10.9, 3.3 Hz), 7.18 (1H, ddd, J=9.8, 7.6, 2.3 Hz), 7.71 (1H, ddd, J=9.9, 5.0, 0.7 Hz), 8.75-7.79 (1H, m).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.FC(F)(F)S([O-])(=O)=O.[N:17]1([S:22](N2C=C[NH+](C)C2)(=[O:24])=[O:23])[CH:21]=[CH:20][N:19]=[CH:18]1>>[N:17]1([S:22]([N:6]2[CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5]2)(=[O:24])=[O:23])[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: C[NH+]1C=CN(S(=O)(=O)n2ccnc2)C1
Reactant: OCC1CCNCC1
Agent: O=S(=O)([O-])C(F)(F)F
Product: O=S(=O)(N1CCC(CO)CC1)n1ccnc1

Procedure:
[1-(Imidazole-1-sulfonyl)-piperidin-4-yl]-methanol was prepared in accordance with step A of the general method described in example 76 from 4-(hydroxymethyl)-piperidine and 3-(1H-imidazol-1-ylsulfonyl)-1-methyl-1H-imidazolium trifluoromethanesulfonate; MS: m/e=246.5 (M+H+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:10]=[C:9]([CH:11]=[CH2:12])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].C(=O)(O)[O-].[Na+].Cl.[NH2:21][OH:22]>CC(O)C.C(OCC)(=O)C>[OH:22][N:21]=[C:5]([NH2:6])[C:4]1[CH:7]=[CH:8][C:9]([CH:11]=[CH2:12])=[CH:10][C:3]=1[C:2]([F:14])([F:13])[F:1]
Reactant: C=Cc1ccc(C#N)c(C(F)(F)F)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: C=Cc1ccc(C(N)=NO)c(C(F)(F)F)c1
Temperature: 85 °C
Yield: 87.6 %

Procedure:
To a mixture of 2-(trifluoromethyl)-4-vinylbenzonitrile (450 mg, 2.282 mmol) and sodium bicarbonate (767 mg, 9.13 mmol) in 2-propanol (10 mL) was added hydroxylamine hydrochloride (317 mg, 4.56 mmol). The reaction mixture was heated at 85° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with H2O. The organic layer was dried with MgSO4, filtered, and concentrated to give 460 mg of N′-hydroxy-2-(trifluoromethyl)-4-vinylbenzimidamide. MS (m+1)=231. HPLC Peak RT=0.78 minutes (Analytical Method B).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][NH2:34])[CH2:28][CH2:27]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:34][CH2:33][CH2:32][N:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NCCN1CCOCC1
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCCN3CCOCC3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and 2-morpholinoethanamine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5][CH:4]=1>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:10]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1c1ccc(OC)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1C(c2ccccc2)c2ccccc2C1c1ccc(OC)cc1
Reaction time: 24 h

Procedure:
To a solution of ethyl (RS)-1-(4-methoxyphenyl)-3-phenylindene-2-carboxylate (5.75 g, 15 mmol) in EtOAc (150 ml) was added 5% palladium on activated carbon (600 mg). The resulting suspension was stirred under an atmosphere of H2 for 1 d, then was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to afford the title compound, which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[H-].[Na+].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.C(Cl)(Cl)Cl>CN(C)C=O>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]1=[O:1]
Reactant: BrCCCCBr
Reactant: Oc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=c1ccc2ccccc2n1CCCCBr
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 6424.9 %

Procedure:
2-hydroxyquinoline (0.29 g, 2.0 mmoles) was dissolved in 4 ml of dimethylformamide, 60% sodium hydride (80 mg, 2.0 mmoles) was added to the solution, and the mixture was stirred at 60° C. for 30 minutes and then cooled to room temperature. 1,4-dibromobutane (2.16 g, 10 mmoles) was further added, and the resulting mixture was stirred at 60° C. for 4 hours. After chloroform was added to the reaction mixture, insolubles were removed by filtration, the filtrate was washed with water, and the solvent was evaporated. The residue thus obtained was purified by chromatography on a silica gel column to give 36 g (yield 64%) of the title compound as an oil.