Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=2[O:2]1.S(=O)(=O)(O)O.[C:19]([O-])(O)=O.[Na+]>CO>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][CH3:19])=[O:12])=[CH:4][C:3]=2[O:2]1
Reactant: O=C([O-])O
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 86 %

Procedure:
To a solution of 3,4-methylenedioxyphenylacetic acid (4.2 g, 23 mmol) in methanol (50 mL) was added concentrated sulfuric acid (1.5 mL). The mixture was refluxed for 48 h, cooled to room temperature, and neutralized with saturated NaHCO3. The methanol was removed in vacuo. The residue was extracted with 1:1 hexane/EtOAc (2×100 mL). The combined organic phase was washed with water, saturated NaHCO3, and brine, and dried over Na2SO4. The solvent was removed in vacuo to yield the title compound as an oil (3.9 g, 86%). 1H NMR (CDCl3) 6.78-6.72 (m, 3H), 5.95 (s, 2H), 3.69 (s, 3H), 3.54 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:13]([O:20][C:6]1[CH:7]=[C:2]([F:1])[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]=1[F:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)c(OCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 74.2 %

Procedure:
To a solution of 2,4,5-trifluoronitrobenzene (5.4 g, 30.5 mmol) and benzyl alcohol (3.2 mL, 30.5 mmol) in DMF (20 mL) was added K2CO3 (6.33 g, 46.1 mmol). The reaction was stirred at room temperature for 72 hours. Water (60 mL) was added at 0° C. and the resulted mixture was further stirred at 4° C. for 24 hours. The solid was collected by filtration, washed with 30 mL of water, and dried in vacuo at 45° C. to provide the title compound as a pale yellow solid (6.0 g, 74%).
Reaction SMILES: N#N.[CH3:3][S:4]([C:7]1[O:11][C:10]([CH2:12]O)=[CH:9][CH:8]=1)(=[O:6])=[O:5].CCN(CC)CC.C(Cl)[Cl:22]>CN(C1C=CN=CC=1)C>[Cl:22][CH2:12][C:10]1[O:11][C:7]([S:4]([CH3:3])(=[O:6])=[O:5])=[CH:8][CH:9]=1
Reactant: ClCCl
Reactant: CS(=O)(=O)c1ccc(CO)o1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(CCl)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (5-methanesulfonyl-furan-2-yl)-methanol (692 mg, 3.93 mmol) in dry CH2Cl2 (7.0 mL) was treated at 0° C. with Et3N (0.71 mL, 5.11 mmol) followed by DMAP (50 mg, 0.39 mmol) and Ms-C1 (0.37 mL, 4.71 mmol). After stirring at rt for 2 h, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (20 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give 868 mg of crude 2-chloromethyl-5-methanesulfonyl-furan as a yellow oil. 183 mg of this crude material in DMF (0.7 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (90 mg, 0.79 mmol) in DMF (0.7 mL) pre-treated for 1 h with DIPEA (0.27 mL, 1.59 mmol) and the reaction mixture was stirred for 48 h at rt. Water (10 mL), followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (4:6 hept-EA) gave the title compound as a yellow oil: TLC:rf (4:6 hept-EA)=0.36. LC-MS-conditions 02: tR=0.85 min.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH2:29][C:30]2[S:34][CH:33]=[N:32][C:31]=2[Cl:35])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[CH:36](=O)[CH:37]([CH3:39])[CH3:38].C(O)(=O)C.[OH-].[Na+]>ClCCCl>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][CH:25]([N:28]([CH2:29][C:30]2[S:34][CH:33]=[N:32][C:31]=2[Cl:35])[CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:26][CH2:27]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2scnc2Cl)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)CN(Cc1scnc1Cl)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 96.9 %

Procedure:
Add sodium triacetoxyborohydride (24.00 g, 113 mmol) to a stirred solution of 4-{[(4-chloro-thiazol-5-yl)methyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (21.78 g, 65.6 mmol), isobutyraldehyde (9.0 mL, 99.1 mmol), acetic acid (4.0 mL, 69.9 mmol), and 1,2-dichloroethane (260 mL). Stir the reaction for 18 hours at room temperature under nitrogen. Pour the reaction into 2N NaOH (300 mL) and extract with ethyl acetate (3×150 mL). Wash the ethyl acetate with brine (2×150 mL). Dry the ethyl acetate over sodium sulfate and then filter off the sodium sulfate. Concentrate on a rotary evaporator and purify the crude product by flash chromatography on silica gel eluting with 25% ethyl acetate/hexanes to yield 24.67 g (97%) of 4-{[(4-chloro-thiazol-5-yl)methyl]-isobutyl-amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=388.2 (M+1); 1H NMR (CDCl3): δ=8.65 (s, 1H), 4.21 (br s, 2H), 3.80 (s, 2H), 2.63-2.56 (m, 3H), 2.29 (d, 2H), 1.77-1.65 (m, 3H), 1.50-1.41 (m, 11H), 0.92 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[CH2:25][CH:14]2[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH:13]2[CH2:12]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]2[CH2:25][CH:14]3[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:17][CH:13]3[CH2:12]2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC2CC(N)CC2C1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2CC(Nc3nc(Cl)ncc3Cl)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2,4,5-trichloropyrimidine (1.46 g, 7.96 mmol) and tert-butyl 5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (3.11 g, 13.74 mmol) in EtOH (60 mL) was added Et3N (2.21 g, 21.84 mmol) and the reaction mixture was stirred at rt overnight and then concentrated in vacuo. The residue was dissolved in a mixture of EtOAc (50 mL) and water (50 mL), and extracted with EtOAc (150 mL×3). The combined organic phases were washed with brine (150 mL), dried over anhydrous Na2SO4, then concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/5) to give the title compound as a pale yellow solid (2.97 g, 100%).
Reaction SMILES: [CH:1]1([CH2:10][CH2:11][NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:13][C:14]1([CH3:27])[C:18]2([CH2:22][S:23](Cl)(=[O:25])=[O:24])[C:19]([CH2:21][CH:15]1[CH2:16][CH2:17]2)=[O:20].C(N(CC)CC)C>C(Cl)Cl>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]([CH2:10][CH2:11][NH:12][S:23]([CH2:22][C:18]23[C:14]([CH3:13])([CH3:27])[CH:15]([CH2:16][CH2:17]2)[CH2:21][C:19]3=[O:20])(=[O:25])=[O:24])=[CH:2]1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)Cl)C(=O)C2
Reactant: NCCC1C=Cc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CCC1(CS(=O)(=O)NCCC1=CCc3ccccc31)C(=O)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-(1H-Indene-1-yl)ethyl)amine (190 mg, 1.19 mmol) and (+)-10-camphorsulfonyl chloride (299 mg, 1.19 mmol) were combined in CH2Cl2 (2 ml), treated with triethylamine (87 μl, 120 mg, 1.19 mmol), and the mixture was stirred at ambient temperature overnight. The mixture was chromatographed on a silica gel column eluted with 25% EtOAc in hexane and the product fractions were evaporated to dryness in vacuo to give N-(2-(1H-inden-3-yl)ethyl)-7,7-dimethyl-2-oxobicyclo(2.2.1)heptane-1-methanesulfonamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.CCCCCC.C([Li])CCC.Cl[P:21]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1>O1CCCC1>[CH3:28][C:25]1[CH:24]=[CH:23][C:22]([P:21]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=2)=[CH:27][CH:26]=1
Reactant: Cc1ccc(P(Cl)c2ccc(C)cc2)cc1
Reactant: Cc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(P(c2ccc(C)cc2)c2cccc(C)n2)cc1
Reaction time: 0.17 h
Yield: 50.2 %

Procedure:
After dissolving 2-bromo-6-methylpyridine (23.5 mmol) in 40 ml of tetrahydrofuran, the mixture was cooled in a dry ice-ethanol bath, 1.59 M hexane solution of n-butyllithium (23.5 mmol) was added dropwise while stirring, and stirring was continued for 10 minutes to obtain a reaction mixture. To the obtained reaction mixture there was added chlorobis(4-methylphenyl)phosphine (17.5 mmol) dissolved in 40 ml of tetrahydrofuran, and stirring was continued at room temperature for 2 hours. The reaction solution was quenched with water and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, purification was performed twice by silica gel column chromatography (developing solution: hexane/ethyl acetate=5/1, 9/1), to obtain 2.68 g of bis(4-methylphenyl)(6-methyl-2-pyridyl)phosphine (50% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[CH:4][C:5]([Cl:23])=[C:6]([C:8]2[C:9](=[O:22])[N:10]([CH2:20][CH3:21])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)[CH:7]=1.N1C=CC=CC=1.[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]=[C:39]=[O:40])[CH:33]=1>C1COCC1>[Cl:23][C:5]1[C:6]([C:8]2[C:9](=[O:22])[N:10]([CH2:20][CH3:21])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)=[CH:7][C:2]([NH:1][C:39]([NH:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([F:31])[CH:33]=2)=[O:40])=[C:3]([F:24])[CH:4]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(NC)cc21
Reactant: O=C=Nc1cccc(F)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cccc(F)c3)c(F)cc2Cl)cc2cnc(NC)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
A 0° C. solution of Example A5 (200 mg 0.58 mmol) and pyridine (68 mg, 0.87 mmol) in THF (20 mL) was treated with 1-fluoro-3-isocyanato-benzene (80 mg, 0.58 mmol), warmed to RT and stirred for 3 h. The mixture was concentrated in vacuo and purified by preparative HPLC to give 1-[4-chloro-5-(1-ethyl-7-methylamino-2-oxo-1,2-dihydro-[1,6]naphthyridin-3-yl)-2-fluoro-phenyl]-3-(3-fluoro-phenyl)-urea (193 mg, 69% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.34 (s, 1H), 8.78 (s, 1H), 8.51 (s, 1H), 8.19 (d, J=8.4 Hz, 1H), 7.85 (s, 1H), 7.87-7.49 (br. s, 1H), 7.59 (d, J=10.8 Hz, 1H), 7.48 (d, J=11.6 Hz, 1H), 7.33 (m, 1H), 7.08 (m, 1H), 6.83 (m, 1H), 6.44 (s, 1H), 4.18 (m, 2H), 2.94 (s, 3H), 1.24 (t, J=6.8 Hz, 3H); MS (ESI): m/z 484.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[F:42][C:43]([F:55])([F:54])[C:44]1[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1>C(#N)C>[F:55][C:43]([F:42])([F:54])[C:44]1[CH:45]=[CH:46][C:47]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:52])=[O:51])=[CH:48][CH:49]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccc(C(F)(F)F)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 27.1 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0310 g, 0.0672 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 4-trifluoromethylbenzenesulfonyl chloride (0.0477 mL, 0.195 mmol) to obtain 4-(4-trifluoromethylbenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0122 g, yield 27%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([F:15])([C:11]([F:14])([F:13])[F:12])[C:4]([F:10])([F:9])[C:5](I)([F:7])[F:6].[CH:18]1[C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=[C:20](I)[CH:19]=1.CS(C)=O>[Cu].O>[F:1][C:2]([F:17])([F:16])[C:3]([F:15])([C:11]([F:14])([F:13])[F:12])[C:4]([F:10])([F:9])[C:5]([F:7])([F:6])[C:20]1[CH:19]=[CH:18][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: FC(F)(F)C(F)(C(F)(F)F)C(F)(F)C(F)(F)I
Agent: [Cu]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1ccc(C(F)(F)C(F)(F)C(F)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 130 °C
Reaction time: 14.5 h
Yield: 29.7 %

Procedure:
A mixture of 3-trifluoromethylperfluorobutyl iodide (19.5 g, 50 mmol), p-iodobenzoic acid (12.4 g, 50 mmol), activated copper (15.9 g, 250 mmol) and dried dimethyl sulfoxide (100 ml) is stirred at 130° C. in an autoclave for 14.5 hours. After cooling, the reaction mixture is poured into water (400 ml), and the precipitated solid material is collected by filtration and dried. Then, the solid material is extracted with ethanol (200 ml), and the ethanol extract is concentrated to yield crude p-(3-trifluoromethylperfluorobutyl)benzoic acid (5.8 g). The crude product is recrystallized from ethanol-water. The melting point of the purified product is 189°-190° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[CH:6][C:5]([OH:15])=[C:4]([I:16])[CH:3]=1.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:44])=[C:22]([S:24]([N:27]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=2[O:42][CH3:43])[C:28]2[S:29][CH:30]=[N:31][N:32]=2)(=[O:26])=[O:25])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:17][C:18]1[C:19]([O:15][C:5]2[CH:6]=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[F:14])[C:2]([Cl:1])=[CH:3][C:4]=2[I:16])=[CH:20][C:21]([F:44])=[C:22]([S:24]([N:27]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=2[O:42][CH3:43])[C:28]2[S:29][CH:30]=[N:31][N:32]=2)(=[O:25])=[O:26])[CH:23]=1
Reactant: Oc1cc(-c2ccccc2F)c(Cl)cc1I
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3cc(-c4ccccc4F)c(Cl)cc3I)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6-Chloro-2′-fluoro-4-iodobiphenyl-3-ol (Preparation 94, 651 mg, 1.75 mmol) was added to a mixture of 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 16, 671 mg, 1.85 mmol) and potassium carbonate (967 mg, 7.00 mmol) in dimethylsulfoxide (17.5 mL) and the mixture stirred at room temperature for 18 hours. The reaction was quenched by addition of 0.75 N aq. sodium hydroxide (30.0 mL) and ethyl acetate (30 mL). The aqueous layer was separated and extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with brine (10 mL), dried over MgSO4, filtered and evaporated. The residue was purified on silica, eluting with ethyl acetate:heptanes (3:7) to give the title compound as a mixture of regioisomers (930 mg, 67%). Further purification by preparative HPLC using acetonitrile/water as eluent (5/95-95/5, Phenomenex Luna C18 5 u 110 A 21.2×150 mm) gave the title compound (600 mg, 43%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][C@H:17]2[CH2:21][CH2:20][CH2:19][O:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:33]=[CH:32][N:31]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[N:30]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][C@H:17]2[CH2:21][CH2:20][CH2:19][O:18]2)[C:13]([NH:28][C:29]2[CH:33]=[CH:32][N:31]([CH2:34][C:35]([OH:37])([CH3:36])[CH3:38])[N:30]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCCO2)C(=O)O)cc1Cl
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(C[C@H]2CCCO2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-furan-2(R)-yl)-propionic acid (168 mg, 0.51 mmol) was dissolved in methylene chloride (10 mL) and N,N-dimethylfomamide (one drop) and cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 291 μL, 0.58 mmol) which produced gas evolution and it was then stirred at 0° C. for 15 minutes and 30 min at 25° C. After this time, the reaction was concentrated in vacuo to ⅓ of the original volume. In a separate flask a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in Example 80, 86 mg, 0.56 mmol), 2,6-lutidine (84 μL, 0.76 mmol) and methylene chloride (10 mL) was cooled to 0° C. in an ice bath. To this solution was then added the solution of the prepared acid chloride diluted with another portion of methylene chloride (2 mL) dropwise. After addition was complete the reaction was then allowed to warm to 25° C. and stirred for 16 hours. After this time the reaction was diluted with methylene chloride (10 mL) and washed with a saturated aqueous sodium bicarbonate solution (1×20 mL) and the aqueous layers were than extracted with methylene chloride (2×10 mL). The combined organic layers were then washed with a 1 N aqueous hydrochloric acid solution (1×20 mL) and then dried over sodium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (12 g column, 70% ethyl acetate/hexanes to 90% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-furan-2(R)-yl)-propionamide (155 mg, 65%) as a mixture of roughly 1:1 mixture of diastereomers as a white foam: ES-HRMS m/e calcd for C21H28N3O5SCl (M+H)+ 470.1511, observed 470.1504; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.02, 1.03 (2×s, 6H, 2×CH3), 1.37-1.52 (m, 1H, CH of CH2), 1.64-1.99 (m, 4H, 4×CH of CH2), 2.08-2.40 (m, 1H, CH of CH2), 3.34, 3.35 (2×s, 3H, SO2CH3), 3.43-3.77 (m, 3H, OCH2 and OCH), 3.86 (brs, 2H, NCH2), 3.97-4.12 (m, 1H, ArCH), 4.62, 4.63 (2×s, 1H, OH), 6.43 (m, 1H, Ar), 7.49 (m, 1H, Ar), 7.59 (2×dd, Jo=8.2 Hz, Jm=1.7 Hz, 1H, Ar), 7.69 (2×d, Jm=1.7 Hz, 1H, Ar), 7.99 (2×d, Jo=8.2 Hz, 1H, Ar), 10.75, 10.81 (2×s, 1 H, NH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)[CH3:14].[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH:37]=O)=[N:29]1>CO.N1CCCCC1>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](/[CH:37]=[C:8]2\[O:9][C:5]3[C:4]([CH:13]([N:15]4[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]4)[CH3:14])=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:29]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1C(C)N1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1C(C)N1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
A solution of tert-butyl 4-[1-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)-ethyl]piperazine-1-carboxylate (0.091 g, 0.24 mmol) in methanol (3.0 mL) was added with 1H-indazole-3-carboxaldehyde (0.039 g, 0.27 mmol). Then, the mixture was added with 5 drops of piperidine, and then the mixture was stirred at 60° C. for 1 hour. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (100:0→97:3)) to obtain tert-butyl (Z)-4-(1-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}ethyl)piperazine-1-carboxylate (0.10 g, 85%).
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])=[CH:3][CH:4]([OH:6])[CH3:5].N1C=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH2:19]>C(OC)(C)(C)C>[C:14]([O:6][CH:4]([CH:3]=[C:2]([CH3:1])[CH2:7][CH2:8][CH:9]=[C:10]([CH3:11])[CH3:12])[CH3:5])(=[O:19])[CH2:15][CH2:16][CH3:17]
Reactant: c1ccncc1
Reactant: O
Reactant: CC(C)=CCCC(C)=CC(C)O
Solvent: COC(C)(C)C
Product: CCCC(=O)OC(C)C=C(C)CCC=C(C)C
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 76 %

Procedure:
A flask was charged with 4,8-dimethyl-3,7-nonadien-2-ol CAS 67845-50-5 (20 grams), buryric anhydride (25 grams) and pyridine (12.5 grams). The mixture was stirred and heated to 100° C. The reaction was held at 100° C.±1° C. for 90 minutes and then cooled to room temperature. The reaction mixture was diluted with water (100 milliliters) and methyl t-butyl ether, washed several times with water until neutral pH, dried over sodium sulfate and concentrated to furnish 34.4 grams of crude product. After distillation by Kugelruhr 23.4 g of the product, 76% yield, were obtained and confirmed by 1H NMR.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][CH2:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][O:19][C:20](=[O:23])[CH2:21][NH2:22].C(OCC)C>CCCCCC>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([NH:22][CH2:21][C:20]([O:19][CH3:18])=[O:23])=[O:16])[CH2:10][CH2:11][CH2:12][CH3:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OC
Yield: 92.6 %

Procedure:
The title compound was prepared by the general method of Example 1 using 15.0 g (65 mmol) of t-butoxycarbonyl-D-norleucine (Boc-D-Nle) and 8.1 g (65 mmol) of glycine methyl ester hydrochloride. Trituration of the product oil with diethyl ether and (Skellysolve B) produced 18.2 g of the title compound as a pale yellow solid. Structure assignment was supported by elemental analysis.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:4]([CH3:31])=[C:5]([C:26]([CH3:30])=[CH:27][C:28]=1[CH3:29])[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:32]([O:36][C:37](=[O:48])[CH:38]=[C:39]([CH3:47])[CH:40]=[CH:41][CH:42]=[C:43]([CH:45]=O)[CH3:44])[CH2:33][CH2:34][CH3:35].C1OC1CC>>[CH2:32]([O:36][C:37](=[O:48])[CH:38]=[C:39]([CH3:47])[CH:40]=[CH:41][CH:42]=[C:43]([CH3:45])[CH:44]=[CH:6][C:5]1[C:26]([CH3:30])=[CH:27][C:28]([CH3:29])=[C:3]([Cl:2])[C:4]=1[CH3:31])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCOC(=O)C=C(C)C=CC=C(C)C=O
Reactant: Cc1cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1Cl
Agent: CCC1CO1
Agent: [Cl-]
Product: CCCCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)cc(C)c(Cl)c1C

Procedure:
16 g of 3-chloro-2,4,6-trimethyl-benzyl-triphenylphosphonium chloride and 10 g of 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid butyl ester are heated to boiling with stirring after the addition of 40 g of 1,2-butylene oxide. The 1,2-butylene oxide is slowly distilled off. The reaction mixture is stirred for 30 minutes at 80°-82° C, then cooled and thoroughly extracted with hexane. The hexane extract is shaken out 5 times with 50 ml of methanol/water 70:30 parts by volume each time, then dried over sodium sulphate and evaporated under reduced pressure to produce 9-(3-chloro-2,4,6-trimethyl-phenyl),3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid butyl ester as a residue.