Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:3]1(=[O:14])=[O:13].[C:15](=O)([O-:17])[O-:16].C[Mg+2].Cl.C(OCC)C>CN(C)C=O>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]([C:15]([OH:17])=[O:16])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:3]1(=[O:13])=[O:14]
Reactant: O=C([O-])[O-]
Reactant: CN1C(=O)Cc2ccccc2S1(=O)=O
Agent: C[Mg+2]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN1C(=O)C(C(=O)O)c2ccccc2S1(=O)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
In a four neck flask equipped with reflux condenser, stirrer, thermometer and calcium drying tube, 1.06 g (0.005 mole) 3,4-dihydro-2-methyl-3-oxo-2H-1,2-benzothiazine 1,1-dioxide and 2.6 g (0.02 mole) methylmagnesiumcarbonate in 20 ml N,N-dimethylformamide were added. The mixture was stirred at 90°-100° C. for 3 hours. The resulting solution was poured quickly into a mixture of 30 ml conc-hydrochloric acid, 70 g ice chips and 200 ml diethylether. After stirring the mixture for 10 minutes, the separated diethylether layer was evaporated in vacuo to obtain 1.25 g of 3,4-dihydro-2-methyl-3-oxo-2H-1,2-benzothiazine-4-carboxylic acid 1,1-dioxide. The obtained compound was dissolved in 20 ml benzene and to the solution, 1.3 ml thionyl chloride and 0.4 ml N,N-dimethylformamide were added.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:26]/[O:27][C:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)/[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([OH:23])=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C1OCCOCCOCCOCCOCCOC1.C([O-])([O-])=O.[K+].[K+].[C:71](=[O:83])([O:79][CH:80](I)[CH3:81])[O:72][CH:73]1[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]1>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:26]/[O:27][C:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)/[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([O:23][CH:80]([O:79][C:71]([O:72][CH:73]4[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]4)=[O:83])[CH3:81])=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(I)OC(=O)OC1CCCCC1
Reactant: C/C=C\C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C/C=C\C1=C(C(=O)OC(C)OC(=O)OC2CCCCC2)N2C(=O)C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Reaction time: 1 h
Yield: 61.8 %

Procedure:
To a mixture of the product of Procedure 7 (35 g, 53.7 mmol) 18-crown-6 (4.0 g, 15 mmol) and well ground K2CO3 (9.45 g, 6.84 mmol) in dry DMF (330 ml) was added dropwise the cyclohexyl 1-iodoethyl carbonate (41 g, 138 mmol) at 0° C. under argon and the mixture was stirred for 1 hr. at 2°-4° C. The mixture was diluted with ethyl acetate (1.5 L) and washed well with water. The organic layer was separated, dried and evaporated under reduced pressure. The residue was chromatographed on a column of silica gel (400 g) and the column was eluted with n-hexane-dichloromethane (2:1 to 0:1). The fractions containing the desired product were combined and evaporated under reduced pressure to afford 27.3 g (62%) of the product as an amorphous powder.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][N:17]=1>C1COCC1>[F:25][C:15]([F:14])([F:24])[C:16]1[N:17]=[CH:18][C:19](/[CH:20]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4])=[CH:22][CH:23]=1
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 101.3 %

Procedure:
To a stirring solution of trimethyl phosphonoacetate (0.510 mL, 3.14 mmol) in THF (15 mL) at 0° C. was added NaH (88.0 mg, 3.3 mmol). After stirring for ca. 20 min, the slurry was allowed to warm to ambient temperature for 10 min, then cooled again to 0° C. To this was added dropwise 6-(trifluoro-methyl)nicotinaldehyde (500 mg, 2.86 mmol), which is commercially available from Oakwood Products, Inc. (1741 Old Dunbar Rd., West Columbia, S.C. 29172), in THF (5 mL) over 2 min. The bath was allowed to expire and the reaction stirred at ambient temperature for ca. 24 h. The reaction was quenched with H2O (50 mL) then diluted with EtOAc (100 mL). The phases were separated and the organics further washed with H2O (2×20 mL), brine (5 mL), dried over MgSO4, filtered and concentrated in vacuo to afford 670 mg 26A in ca. 85% purity as a white solid (86% yield). This was taken forward without further purification. m/z (ES+) M+1=232.1; HPLC tR=1.07 min. 1H NMR (500 MHz, CDCl3) δ 8.84 (dd, J=2.1, 0.6 Hz, 1H), 7.99 (dt, J=8.2, 1.2 Hz, 1H), 7.77-7.65 (m, 2H), 6.59 (d, J=16.2 Hz, 1H), 3.85 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>CO>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)=[CH:16][C:15]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1COc2cc(O)ccc21
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Agent: Cl
Solvent: CO
Product: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 67.8 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 4-methoxy-3-benzyloxybenzaldehyde 1.79 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 1.69 g.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[N+:18]([O-])=O.CN(C)C=O.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>>[NH2:18][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:9]=1[O:8][CH3:7])[C:13]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([F:26])=[CH:28][CH:29]=1)=[O:15]
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccc(F)cc2)cc1N
Yield: 67.4 %

Procedure:
Prepared according to the procedure described for Example 7 using oxalyl chloride (3.0 mL, 34.39 mmol), 4-methoxy-3-nitrobenzoic acid (5.00 g, 25.36 mmol), dimethylformamide (0.5 mL, 6.5 mmol), and 4-fluroaniline (5.0 mL, 52.78 mmol) to afford the product (4.45 g); m.p. 164-167° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11]([CH3:13])=[O:12].[CH:14]([C:17]1[N:18]=[C:19]([C:22](Cl)=[O:23])[S:20][CH:21]=1)([CH3:16])[CH3:15]>O1CCOCC1>[CH:14]([C:17]1[N:18]=[C:19]([C:22]([NH:1][C:2]2[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=2[C:11](=[O:12])[CH3:13])=[O:23])[S:20][CH:21]=1)([CH3:16])[CH3:15]
Reactant: CC(C)c1csc(C(=O)Cl)n1
Reactant: COc1ccc(C(C)=O)c(N)c1C
Solvent: C1COCCO1
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1C
Reaction time: 2 h
Yield: 90 %

Procedure:
A solution of (2-amino-4-methoxy-3-methylphenyl)(methyl)ketone (18.6 g, 104 mmol) in dioxane (50 mL) was added under nitrogen to a suspension of 4-isopropylthiazole-2-carbonyl chloride in dioxane (250 mL). After 2 h at room temperature, the reaction mixture was concentrated to dryness. Then, the residue was partitioned between an aqueous solution of NaHCO3 and AcOEt, organic layer was washed with brine, dried (Na2SO4), and evaporated. The residue was triturated in diisopropyl ether, filtered off and washed with diisopropyl ether to give 30.8 g (90%) of the title product 35.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH2:17])=[CH:12][CH:11]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[CH3:18][C:19]([Mg]Br)=[CH:20][CH3:21].[Cl-].[NH4+]>O1CCCC1>[CH3:18][C:19]1[NH:1][C:4]2=[C:5]([C:10]3[CH:15]=[CH:14][C:13]([CH:16]=[CH2:17])=[CH:12][CH:11]=3)[N:6]=[CH:7][CH:8]=[C:9]2[C:20]=1[CH3:21]
Reactant: C=Cc1ccc(-c2ncccc2[N+](=O)[O-])cc1
Reactant: CC=C(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=Cc1ccc(-c2nccc3c(C)c(C)[nH]c23)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 3-nitro-2-(4-vinylphenyl)pyridine (4.9 g, 21.6 mmol) prepared in Preparation 9 in anhydrous tetrahydrofuran (150 ml) was cooled to −78° C. and 1-methyl-1-propenyl magnesium bromide (0.5M in anhydrous tetrahydrofuran solution; 130 ml) was slowly added thereto. The reaction mixture was stirred for 1 hour at the same temperature, slowly warmed to room temperature, and then stirred overnight. 20% (w/v) ammonium chloride solution was added to the reaction mixture, which was then extracted with ethyl acetate. The reaction mixture was dried on anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography and then crystallized with ethyl ether to give 612 mg of the titled compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)=O>CCO>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: NC(=S)c1ccc(F)cc1
Solvent: CCO
Product: Cc1ccc(-c2csc(-c3ccc(F)cc3)n2)cc1
Temperature: 25 °C
Yield: 44.3 %

Procedure:
To a solution of the crude product of 4-fluorothiobenzamide (2.0 g, 12.9 mmol) in EtOH (30 ml) is added 2-bromo-4′ methylacetophenone (2.75 g, 12.9 mmol). The mixture is heated to reflux for 24 hours. The course of the reaction is followed by thin layer chromatography. Upon completion of the reaction the solution is cooled to room temperature and the white precipitate filtered and dried under vacuum to yield 2-(4′-fluorophenyl)-4-(p-tolyl) thiazole (1.54 g, 54%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:33]=[CH:32][C:11]([C:12]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][C:21]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([OH:24])[CH2:20][CH2:19]2)=O)=[O:13])=[CH:10][CH:9]=1.O>O1CCCC1>[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH:12]([OH:13])[CH2:14][CH2:15][CH2:16][N:18]2[CH2:19][CH2:20][C:21]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([OH:24])[CH2:22][CH2:23]2)=[CH:32][CH:33]=1
Reactant: O=C(CCC(=O)N1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OC(CCCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2.0 g of lithium aluminum hydride and 50 ml of tetrahydrofuran, was gradually added a solution of 5.0 g of 1-[β-(p-fluorobenzoyl)propionyl]-4-(p-chlorophenyl)-4-hydroxypiperidine in 40 ml of tetrahydrofuran. The mixture was stirred at room temperature for one hour, and at 60°to 65°C for 4 hours. Then 15 ml of cold water was added dropwise to the reaction mixture while the mixture was kept below 20°C in an ice bath. The precipitate was filtered off and the tetrahydrofuran was removed from the filtrate by distillation under reduced pressure. The residue was kept cooled for 2 hours and the solid matter was collected by filtration, washed with water, and dried to obtain 1-(p-fluorophenyl)-4-[4-(p-chlorophenyl)-4-hydroxypiperidino]-1 -butanol, melting at 128° - 130°C.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[C:11]([O:13][CH2:14][O:15][CH3:16])[CH:10]=[C:9]([Br:17])[CH:8]=1.CN([CH:21]=[O:22])C.O>CCOCC>[Br:17][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([O:13][CH2:14][O:15][CH3:16])[CH:10]=1)[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: COCOc1cc(Br)cc(Br)c1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: COCOc1cc(Br)cc(C=O)c1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
n-BuLi (8.34 mL of a 1.6 M solution in Et2O, 13.34 mmol) was added dropwise to a solution cooled to −78° C. of 1,3-dibromo-5-methoxymethoxy-benzene (3.59 g, 12.13 mmol) in anhydrous Et2O (40 mL) under a nitrogen atmosphere. The solution was aged at −78° C. for 45 m, anhydrous DMF (1.03 mL, 13.34 mmol) was added, and the reaction mixture was slowly warmed to RT. The mixture was poured into H2O (50 mL), and the aqueous phase was extracted with Et2O (2×75 mL). The combined organic fractions were washed with brine (50 mL) and dried over anhydrous MgSO4. The solvents were evaporated, and the remaining oil was purified by flash chromatography over silica gel (0% to 10% EtOAc/hexanes) to afford 2.18 g (74%) of 3-bromo-5-methoxymethoxy-benzaldehyde (113b).
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][N:12]4[C:18]=3[CH2:17][N:16](CC3C=CC(OC)=CC=3OC)[C:15](=[O:30])[C:14]3[CH:31]=[C:32]([CH3:35])[CH:33]=[CH:34][C:13]4=3)[O:6][N:5]=2)[CH2:3][CH2:2]1.FC(F)(F)S(O)(=O)=O>C(Cl)Cl.FC(F)(F)C(O)=O>[CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][N:12]4[C:18]=3[CH2:17][NH:16][C:15](=[O:30])[C:14]3[CH:31]=[C:32]([CH3:35])[CH:33]=[CH:34][C:13]4=3)[O:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(CN2Cc3c(-c4nc(C5CC5)no4)ncn3-c3ccc(C)cc3C2=O)c(OC)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)C(=O)NCc1c(-c3nc(C4CC4)no3)ncn1-2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-5-(2,4-dimethoxy-benzyl)-8-methyl-4,5-dihydro-2,5,10b-triaza-benzo[e]azulene-6-one (17.5 g, 37.1 mmol) was suspended in CH2Cl2 (100 mL), cooled in ice, and diluted slowly with trifluoroacetic acid (85.2 mL). The resulting solution was treated at 5° C. with trifluoromethanesulfonic acid (4.9 mL, 55.7 mmol). The red solution was stirred at room temperature for 4 h. The mixture was then evaporated and dissolved in CH2Cl2 (100 mL), washed with sodium hydrogen carbonate (10%, 2×50 mL) and the organic layer was dried (Na2SO4) and evaporated. Digestion in EtOAc (100 mL) followed by the slow addition of hexane (100 mL). The solid obtained was washed twice with EtOAc: Hexane (1:1, 2×20 mL). Yield: 9.3 g (78%) m/z 321 (M).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([O:13][C:14](=[O:39])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:24]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:23]=[C:22]1[CH3:38])[CH3:12].I[CH2:41][CH3:42]>C1COCC1>[CH2:11]([O:13][C:14](=[O:39])[CH:15]([CH2:41][CH3:42])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:24]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:23]=[C:22]1[CH3:38])[CH3:12]
Reactant: CCOC(=O)CCCCCCn1c(C)nc(-c2ccccc2)c1-c1ccccc1
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)CCCCCn1c(C)nc(-c2ccccc2)c1-c1ccccc1

Procedure:
(Scheme 3 (O)) This compound was obtained using the procedures as described above. The following scales and reagents were used: 7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptanoic acid ethyl ester (390 mg, 1 mmole), Sodium bis(trimethylsilyl)amide (1M in THF) (1.2 ml, 1.2 mmole), Iodoethane (0.4 ml, 779.8 mg, 5 mmole), anhydrous THF (10 ml). Product was obtained (100 mg, 24%). 1H NMR (CDCl3): δ0.88 (t, 3H), 1.23 (m, 4H), 1.33 (t, 3H), 1.54 (m, 4H), 1.68 (b, 1H), 2.04 (s, 1H), 2.17 (m, 1H), 2.49 (s, 3H), 3.709 (t, 2H), 4.15 (m, 2H), 7.19 (m, 3H), 7.42 (m, 3H), 7.46 (m, 4H). 13C NMR (CDCl3): δ12.0, 13.9, 14.6, 25.7, 26.6, 27.0, 30.5, 31.9, 44.0, 47.3, 60.2, 126.1, 126.7, 128.2, 128.7, 129.2, 131.3. Anal. Calcd. for C27H34N2O2: C, 77.48; H, 8.19; N, 6.69. Found: C, 77.34; N, 8.01; N, 6.56. Mass Spec: 419.32 (MH+).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:10][CH:9]1[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[C:13]([C:22]2[CH:31]=[C:30]3[C:25]([C:26]([CH3:36])([CH3:35])[CH2:27][C:28](=[O:34])[N:29]3[CH2:32][CH3:33])=[CH:24][C:23]=2[CH3:37])[CH:12]=1)=[O:7])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:32]([N:29]1[C:30]2[C:25](=[CH:24][C:23]([CH3:37])=[C:22]([C:13]3[CH:12]=[C:11]([CH:9]4[CH2:10][CH:8]4[C:6]([OH:7])=[O:5])[CH:16]=[CH:15][C:14]=3[O:17][C:18]([F:20])([F:19])[F:21])[CH:31]=2)[C:26]([CH3:36])([CH3:35])[CH2:27][C:28]1=[O:34])[CH3:33]
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C4CC4C(=O)OC(C)(C)C)ccc3OC(F)(F)F)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C4CC4C(=O)O)ccc3OC(F)(F)F)cc21

Procedure:
A solution of Compound 40A in CH2Cl2 (2 mL) and TFA (1 mL) was stirred at r.t. overnight after which the solvent was removed in vacuo to obtain the desired product (Compound 40) as pale yellow powder (0.036 g). The compound is racemic (i.e. mixture of both enantiomers). The designated “trans” stereochemistry merely describes the relative stereochemistry for the two substituents on the cyclopropane ring. MS (electrospray): mass calculated for C25H26F3NO4, 461.18; m/z found 462 [M+H]+.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[C:8]([I:14])[CH:7]=1.O>ClCCl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([I:14])[CH:7]=1
Reactant: COc1ccc(Cl)cc1I
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(Cl)cc1I
Temperature: 20 °C

Procedure:
Boron tribromide (1349 g) was added to a solution of 4-chloro-2-iodoanisole (1025 g) in dichloromethane (10.3 L) under nitrogen at such a rate that the temperature remained at 0-5° C. The solution was then warmed to 20° C. and stirred for c. 19 h until the reaction was complete by HPLC. This organic solution was added to water (8.2 L) and the mixture was cooled to 5° C. to 10° C. DCM (770 ml) was added and the resulting biphasic mixture was then stirred at 5° C. for 15 min before being warmed to 22° C. and then finally stirred at 22° C. for 20 min before separating the phases. The separated organic phase was washed with aqueous saturated sodium bicarbonate (3.1 L), water (3.1 L) and then evaporated on a Buchi to give the title compound. (963.6 g)
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C(=S)=S>[C:5]([C:16]1[CH:17]=[CH:18][C:13]([Br:12])=[CH:14][CH:15]=1)(=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: Brc1ccccc1
Reactant: CCCCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCCCC(=O)c1ccc(Br)cc1
Temperature: 0 °C

Procedure:
104.5g (0.76mol) of anhydrous aluminum chloride and 92.1g (0.76mol) of valeroylchloride were added to 350ml of carbon disulfide chilled at 0° C. To the resulting mixture with chilling and stirring, 100g (0.64mol) of bromobenzene was added and the solution was stirred at room temperature for 24 hours. After completion of the reaction, the resulting mixture was added to 400ml of cold 4N hydrochloric acid and the aluminum chloride complex was decomposed. Then the organic layer was extracted with chloroform and washed with water and the solvent was removed by distillation. The residue was distilled under reduced pressure to yield 95g of 4-pentanoylbromobenzene having a b.p. 105° to 110° C./2mmGn.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][N:43]([CH:46]4[CH2:49][O:48][CH2:47]4)[CH2:42][C@@H:41]3[CH3:50])=[CH:36][N:35]=2)[C:30](=[O:51])[N:29]([CH3:52])[CH:28]=1)(=O)C.O.[Li+].[OH-]>C1COCC1>[F:26][C:9]1[CH:8]=[C:7]([C:27]2[CH:32]=[C:31]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([N:40]4[CH2:45][CH2:44][N:43]([CH:46]5[CH2:47][O:48][CH2:49]5)[CH2:42][C@@H:41]4[CH3:50])=[CH:36][N:35]=3)[C:30](=[O:51])[N:29]([CH3:52])[CH:28]=2)[C:6]([CH2:5][OH:4])=[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])[CH:10]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(N4CCn5c(cc6c5CCCC6)C4=O)c3CO)cn(C)c2=O)nc1
Yield: 40.8 %

Procedure:
At room temperature, to a solution of 106a (153 mg 0.22 mmol) in THF/iPA/H2O (6 mL/6 mL/2 mL) was added LiOH (70 mg, 2.9 mmol) while stirring. This mixture was stirred for 0.5 h. Then, H2O (20 mL) was added and the mixture was extracted with EA (30 mL×3). The combined organic layer was dried with Na2SO4 and concentrated to give a yellow solid, which was further purified by reverse-phase prep-HPLC to afford 106 as a white solid (60 mg, 42% yield). LCMS: [M+H]+ 668. 1H NMR (500 MHz, CDCl3) δ 8.57 (dd, J=2.0, 7.0, 1H), 7.97 (s, 1H), 7.85 (s, 1H), 7.48 (t, J=2.5, 1H), 7.33 (d, J=7.0, 1H), 7.16 (d, J=8.0, 1H), 6.96 (dd, J=2.5, 9.0, 1H), 6.87 (s, 1H), 6.83 (d, J=9.0, 1H), 4.69-4.72 (m, 4H), 4.55 (d, J=11.5, 1H), 4.29-4.38 (m, 2H), 4.14-4.20 (m, 3H), 3.90-3.93 (m, 1H), 3.71 (s, 3H), 3.57 (s, 1H), 3.48 (s, 1H), 3.09-3.14 (m, 2H), 2.52-2.61 (m, 7H), 2.23 (s, 1H), 1.88-1.91 (m, 2H), 1.79-1.81 (m, 2H), 0.99 (d, J=5.0, 3H)
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N:11]1([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]1.I[CH2:32][CH:33]=[CH2:34]>C1COCC1>[CH2:34]([C:14]1([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12][N:11]([C:21]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:16][CH2:15]1)[CH:33]=[CH2:32]
Reactant: COC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C=CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OC)CCN(C(=O)OCc2ccccc2)CC1
Temperature: -50 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
Lithium bis(trimethylsilyl)amide (LiHMDS) in THF (1.0 M, 45 mL) was added to a solution of 1-benzyl 4-methyl piperidine-1,4-dicarboxylate (10.0 g, 0.0360 mol) at −78° C. The reaction mixture was slowly warmed to −50° C. and kept at this temperature for 10 min, and then re-cooled to −78° C. 3-Iodo-1-propene (4.95 mL, 0.0541 mol) was added slowly. After the addition, the mixture was allowed to warm slowly to room temperature and kept at room temperature for 3 hours. The mixture was carefully quenched (the pH was adjusted to 4) with 1N HCl solution, and ethyl acetate (200 mL) was added. The organic layer was separated and washed with water, NaHCO3 (7.5%), brine, dried over MgSO4, and filtered. The filtrate was concentrated. The residue was purified by flash chromatography with 20% ethyl acetate in hexane to give 1-benzyl 4-methyl 4-allylpiperidine-1,4-dicarboxylate (10.4 g, 90.9%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([O:16]CC)=[O:15])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([CH2:20][CH3:21])[C:3]=1[C:22]([NH2:24])=[O:23].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](OC)=O)=[CH:29][CH:28]=1.[O-]CC.[Na+].CC(O)=O>C(O)C>[Cl:13][C:12]1[CH:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=[C:8]([Cl:19])[C:7]=1[N:6]1[C:2]2=[N:1][C:34]([CH2:33][C:30]3[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)=[N:24][C:22](=[O:23])[C:3]2=[C:4]([CH2:20][CH3:21])[NH:5]1
Reactant: CCOC(=O)c1cc(Cl)c(-n2nc(CC)c(C(N)=O)c2N)c(Cl)c1
Reactant: COC(=O)Cc1ccc(OC)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1[nH]n(-c2c(Cl)cc(C(=O)O)cc2Cl)c2nc(Cc3ccc(OC)cc3)nc(=O)c1-2
Yield: 75.1 %

Procedure:
Part D: To a stirred solution of 500 mg (1.35 mmol) of 5-amino-3-ethyl-1-(2,6-dichloro-4-carboethoxyphenyl)pyrazole-4-carboxamide in 10 mL ethanol was added 1.45 g (8.1 mmol) of methyl 4-methoxyphenylacetate followed by 2.6 mL (8.1 mmol) of 2.66 M sodium ethoxide in ethanol. The reaction was heated at relux for 18 h and then 10% aq. HOAc was added. After stirring an additional hour at relux, the heat was removed and the reaction solution was poured into ice water, stirred 10 min. and filtered. The solid was washed with water and diethyl ether and dried to give 480 mg (75%) of 1-(2,6-dichloro-4-carboxyphenyl)-3-ethyl-6-(4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one, mp 277° C. Mass Spec.: (ES−) 471 (M−H)−.