Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)=[O:3].I[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=1[C:22]([F:25])([F:24])[F:23]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.CCO>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=2)=[C:15]([C:22]([F:23])([F:24])[F:25])[CH:16]=1)#[N:19]
Reactant: N#Cc1ccc(I)c(C(F)(F)F)c1
Reactant: NC(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: N#Cc1ccc(-c2cccc(C(N)=O)c2)c(C(F)(F)F)c1

Procedure:
The title compound was synthesized from 3-(aminocarbonyl)phenyl boronic acid and 4-iodo-3-(trifluoromethyl)benzonitrile (I-IX-6) according to the procedure described for Ex IX-10, using Pd(PPh3)4 catalyst and PhMe/EtOH (4:1) as organic cosolvents. LC/MS (method A) 2.18 min, m/z 291 (M+H).
Reaction SMILES: O.[C@@H:2]1([N:11]2[C:20]3[C:14](=[C:15]([N+:17]([O-])=[CH:18][N:19]=3)[NH2:16])[N:13]=[CH:12]2)[O:10][C@H:7]([CH2:8][OH:9])[C@@H:5]([OH:6])[C@H:3]1[OH:4].[OH-].[Na+].CO.C(=S)=[S:27]>>[CH:12]1[N:11]([C@@H:2]2[O:10][C@H:7]([CH2:8][OH:9])[C@@H:5]([OH:6])[C@H:3]2[OH:4])[C:20]2[C:14](=[C:15]([NH2:16])[NH:17][C:18]([N:19]=2)=[S:27])[N:13]=1
Reactant: Nc1c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2nc[n+]1[O-]
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 97 %

Procedure:
8.0 g of adenosine 1-oxide monohydrate (26.67 mmol) was refluxed in 5 ml of a 5N sodium hydroxide aqueous solution for 15 minutes. The resulting liquid was neutralized to a pH of 9.0 using Amberlite IRC-50 (H+-type) and then concentrated to a small volume to prepare 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide oxime. To this was added 200 ml of an aqueous solution containing 175 ml of methanol. The pH of the resulting solution was 9. 50 ml of carbon disulfide was further added to the solution, and the mixture was allowed to react in an autoclave at 120° C for 5 hours under autogenous pressure (about 10 Kg/cm2). The orange colored substance formed in the autoclave was removed and concentrated to dryness. The residue was dissolved in 63 ml of 2.5N aqueous ammonia, and any impurities were filtered out. A mixture of n-butanol and acetic acid (125 ml:63 ml) was added to the above filtrate to crystallize the product to obtain 8.20 g of 2-thioadenosine having a melting point of 199° C (with decomposition) in a 97% yield.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[N:8]([CH:21]1[CH2:24][CH2:23][CH2:22]1)[C:9](=[O:20])[C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19].Cl[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1.CCN(C(C)C)C(C)C>CS(C)=O>[CH:21]1([N:8]([C@H:4]2[CH2:5][CH2:6][CH2:7][C@@H:3]2[NH:2][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)[C:9](=[O:20])[C:10]2[C:11]([O:18][CH3:19])=[CH:12][CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH2:24][CH2:23][CH2:22]1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: COc1cccc(OC)c1C(=O)N(C1CCC1)[C@H]1CCC[C@@H]1N
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(OC)c1C(=O)N(C1CCC1)[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1

Procedure:
To a solution of N-[(1S,2S)-2-aminocyclopentyl]-N-cyclobutyl-2,6-dimethoxybenzamide hydrochloride (Intermediate 18; 200 mg, 0.56 mmol) in dry DMSO (1.9 ml) was added 2-chloro-5-(trifluoromethyl)pyridine (CAS number 52334-81-3; 153 mg, 0.85 mmol) and DIPEA (295 μl, 1.69 mmol). The reaction subjected to microwave irradiation at 150° C. for 2 hours and then was partitioned between ethyl acetate and water. The organics were washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. This was then purified using column chromatography (silica, 0-100% ethyl acetate/petrol) and then further purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:27][CH2:26][C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:28])[C:17]=2[CH2:16]1)=O)(C)(C)C>ClCCl>[CH3:28][N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[CH2:26][CH2:27][NH:15][CH2:16][C:17]1=2
Reactant: Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c2c(c3ccccc31)CCNC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (3.5 ml, 45.23 mmol) was added to a solution of 2-t-butoxycarbonyl-9-methyl-1,2,3,4-tetrahydropyrido[3,4-b]indole (1.848 g, 6.461 mmol) in dichloromethane (25 ml) and stirred at room temperature for 3 hours, diluted with dichloromethane (125 ml), washed with 2M sodium hydroxide (2×50 ml), water and dried (MgSO4). The magnesium sulfate was collected by filtration and the filtrate evaporated in vacuo to give the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:18][C:19]4[N:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[S:16][CH:17]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[Cl:27]N1C(=O)CCC1=O>CN(C=O)C>[Cl:27][C:17]1[S:16][C:15]([NH:18][C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[N:14][C:13]=1[C:11]1[CH:10]=[N:9][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:26][CH:25]=2)[CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(Cn2cc(-c3csc(Nc4ncccn4)n3)cn2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(-c3nc(Nc4ncccn4)sc3Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
According to Scheme 7, Step 1: To a solution of 4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(pyrimidin-2-yl)thiazol-2-amine (0.85 mmol, 0.31 g) in DMF (1 mL) was added 1-chloropyrrolidine-2,5-dione (0.64 mmol, 85 mg). The reaction mixture was stirred for 1 hour at room temperature. The reaction was quenched with a saturated aqueous solution of Na2CO3 and extracted with AcOEt. The combined organic layers were dried over MgSO4, were filtered and were evaporated under reduced pressure to afford 5-chloro-4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(pyrimidin-2-yl)thiazol-2-amine (0.33 mmol, 130 mg, 38%) as an orange solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([C:12]2[O:13][C:14]([CH2:17][N:18]3[CH2:23][C@H:22]([CH3:24])[O:21][C@H:20]([CH3:25])[CH2:19]3)=[N:15][N:16]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[CH:41][CH:40]=[C:39]3[C:35]=2[CH:36]=[CH:37][NH:38]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH3:25][C@H:20]1[O:21][C@@H:22]([CH3:24])[CH2:23][N:18]([CH2:17][C:14]2[O:13][C:12]([C:4]3[CH:3]=[C:2]([C:34]4[CH:42]=[CH:41][CH:40]=[C:39]5[C:35]=4[CH:36]=[CH:37][NH:38]5)[CH:10]=[C:9]4[C:5]=3[CH:6]=[N:7][N:8]4[CH3:11])=[N:16][N:15]=2)[CH2:19]1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: C[C@@H]1CN(Cc2nnc(-c3cc(Br)cc4c3cnn4C)o2)C[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1CN(Cc2nnc(-c3cc(-c4cccc5[nH]ccc45)cc4c3cnn4C)o2)C[C@H](C)O1
Temperature: 110 °C
Yield: 10.1 %

Procedure:
6-Bromo-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-methyl-1H-indazole (50 mg, 0.123 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (32.9 mg, 0.135 mmol), sodium carbonate (39.1 mg, 0.369 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium dichloride) (9.00 mg, 0.012 mmol) were added to a microwave vial and dissolved in 1,4-dioxane (0.5 ml) and water (0.5 ml). The reaction mixture was heated under microwave irradiation at 110° C. for 15 mins. The reaction mixture was passed through a 2 g silica cartridge that was then washed with methanol. The solvent was evaporated under a stream of nitrogen and the residual solid was purified by silica (20 g) cartridge using a gradient of ethyl acetate and cyclohexane to give the title compound as a white solid (5.5 mg).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OCC2C(C3C=CC=C(F)C=3)=NOC=2C)=NC=1.[CH:50]1([NH2:53])[CH2:52][CH2:51]1>>[CH:50]1([NH:53][C:3](=[O:24])[C:4]2[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)=[N:14][O:15][C:16]=3[CH3:17])=[N:6][CH:5]=2)[CH2:52][CH2:51]1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccnc3)noc2C)nc1
Reactant: NC1CC1
Agent: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Product: Cc1onc(-c2cccnc2)c1COc1ccc(C(=O)NC2CC2)cn1
Yield: 83 %

Procedure:
As described for example 89, 6-(5-methyl-3-pyridin-3-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (130 mg, 0.4 mmol), instead of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, using cyclopropylamine instead of 2,2,2-trifluoroethylamine, was converted to the title compound (117 mg, 83%) which was obtained as an off white solid. MS: m/e=351.4 [M+H]+.
Reaction SMILES: [OH-].[Na+].[Cl:3][CH2:4][CH2:5][CH2:6][CH:7]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:8]([O:10]CC)=[O:9].C(O)C.O>C1COCC1.C(OCC)C>[Cl:3][CH2:4][CH2:5][CH2:6][CH:7]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)C(CCCCl)C1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)C(CCCCl)C1CCOCC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 74.1 %

Procedure:
A 5 N sodium hydroxide solution (1.6 ml) was added to a solution of ethyl 5-chloro-2-(tetrahydropyran-4-yl)-valerate (672 mg) in THF (2.5 ml)-ethanol (7.5 ml), and the reaction solution was stirred at room temperature for four days. Water and diethyl ether were added to the reaction solution, and the aqueous layer was separated. The aqueous layer was washed with diethyl ether again. Then, 5 N hydrochloric acid (1.6 ml) and ethyl acetate were added to the aqueous layer, and the organic layer was separated. The ethyl acetate extraction layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain crude 5-chloro-2-(tetrahydropyran-4-yl)valeric acid (442 mg).
Reaction SMILES: [CH2:1]([N:5]([CH:10]1[CH2:14][S:13](=[O:16])(=[O:15])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]1=2)[S:6]([CH3:9])(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].[N+:21]([O-])([O-:23])=[O:22].[Na+]>S(=O)(=O)(O)O>[CH2:1]([N:5]([CH:10]1[CH2:14][S:13](=[O:15])(=[O:16])[C:12]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:11]1=2)[S:6]([CH3:9])(=[O:7])=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: O=[N+]([O-])[O-]
Reactant: CCCCN(C1CS(=O)(=O)c2ccccc21)S(C)(=O)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCCN(C1CS(=O)(=O)c2cc([N+](=O)[O-])ccc21)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.2 %

Procedure:
At -10° C., 0.5 g (1.6 mmol) of N-butyl-N-(1,1-dioxo-2,3-dihydro-1H-benzo[b]thiophen-3-yl)methanesulfonamide (Example 5) was dissolved in 5 ml of concentrated sulfuric acid and admixed with 0.15 g (1.8 mmol) of sodium nitrate, and the mixture was stirred at RT for 20 h. The reaction mixture was poured into 50 ml of ice-water, stirred for 30 minutes, filtered off with suction, washed neutral with water and dried under reduced pressure. This procedure gave 0.5 g of N-butyl-N-(6-nitro-1,1-dioxo-2,3-dihydro-1H-benzo[b]thiophen-3-yl)-methanesulfonamide; m.p. 52-55° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[C:10](=[O:19])[NH:11][C:12]([CH2:15][CH2:16][CH2:17][CH3:18])=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:26]([O:30][C:31]([C:33]1[C:34]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45]Br)=[CH:41][CH:40]=2)=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[C:26]([O:30][C:31]([C:33]1[C:34]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45][N:11]3[C:12]([CH2:15][CH2:16][CH2:17][CH3:18])=[CH:13][CH:14]=[C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:20])[C:10]3=[O:19])=[CH:41][CH:40]=2)=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCCCc1ccc(CNC(=O)OC(C)(C)C)c(=O)[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCc1ccc(CNC(=O)OC(C)(C)C)c(=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 46.5 %

Procedure:
(6-Butyl-2-oxo-1,2-dihydropyridin-3-ylmethyl)carbamic acid t-butyl ester (200 mg, 0.71 mmol) was dissolved in THF (5 mL) and cooled to −5° C. n-Butyllithium (285 μL, 2.5M solution in hexanes, 1 eq) was added, and the mixture was stirred at −5° C. for 5 minutes. 4′-Bromomethylbiphenyl-2-carboxylic acid t-butyl ester (247 mg, 1 eq) was added, and solution was warmed to reflux and stirred for 72 hours. The solution was allowed to cool, the solvent evaporated and the residue purified by silica gel chromatography (3:1 hexanes:EtOAc) to yield intermediate (25a) as a white solid (180 mg, 330 μmol). MS m/z: [M+H+] calcd for C33H43N2O5, 547.7; found 547.3.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17]Cl>>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[CH:6]=[O:7]
Reactant: COCCOCCl
Reactant: COc1cc(C=O)ccc1O
Product: COCCOCOc1ccc(C=O)cc1OC
Yield: 36.2 %

Procedure:
The hydroxyl group of 4-hydroxy-3-methoxybenzaldehyde (1.4 g) was protected by use of 2-methoxyethoxymethyl chloride (1.7 g) in accordance with (production process 1), to thereby produce 3-methoxy-4-methoxyethoxymethoxybenzaldehyde (0.8 g, yield: 31%). The thus-produced 3-methoxy-4-methoxyethoxymethoxybenzaldehyde (0.8 g) and 3,4-dimethoxybenzyl cyanide (0.6 g) were subjected to condensation in accordance with process A of (production process 2), to thereby yield an MEM form of the target product. Subsequently, the protective group was removed from the MEM form in accordance with (production process 3), to thereby produce the target product (0.5 g, yield: 51%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:14])([C:11](=[O:13])[CH3:12])[CH3:10])=[CH:5][CH:4]=1.[O:15]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[F:30])[CH:25]=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[K+]>CO>[O:15]([C:22]1[CH:23]=[C:24]([CH:25]=[CH:12][C:11](=[O:13])[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)([CH3:14])[CH3:10])[CH:27]=[CH:28][C:29]=1[F:30])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(C(C)(C)C(C)=O)cc1
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(C)(C)C(=O)C=Cc2ccc(F)c(Oc3ccccc3)c2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 32.6 %

Procedure:
A mixture of 7.6 g of 2-(4-methoxyphenyl)-2-methyl-3-butanone, 8.5 g of 3-phenoxy-4-fluorobenzaldehyde, 30 ml of methanol and 2 g of KOH was stirred at 60° C. for two hours. In the same manner as described in (a) of (1) of Synthesis Example 1, the reaction mixture was treated to give 5 g of 1-(3-phenoxy-4-fluorophenyl)-4-(4-methoxyphenyl)-4-methyl-1-penten-3-one.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]2)=[CH:5][C:4]=1[C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:20]=2[N:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:52][NH:53][CH:54]1[CH2:58][CH2:57][N:56]([CH3:59])[CH2:55]1>>[CH3:52][N:53]([CH:54]1[CH2:58][CH2:57][N:56]([CH3:59])[CH2:55]1)[C:15]([CH:12]1[CH2:11][CH2:10][N:9]([C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[C:4]([C:18]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:20]=4[N:19]=3)[CH:5]=2)[CH2:14][CH2:13]1)=[O:17]
Reactant: Cc1ccc2[nH]c(-c3cc(N4CCC(C(=O)O)CC4)ccc3Cl)nc2c1
Reactant: CNC1CCN(C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1ccc2[nH]c(-c3cc(N4CCC(C(=O)N(C)C5CCN(C)C5)CC4)ccc3Cl)nc2c1
Temperature: 35 °C
Yield: 34.3 %

Procedure:
Method Q—Step a To a mixture of 1-[4-chloro-3-(5-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidine-4-carboxylic acid hydrochloride (obtained as described in general method 3,4, step e) (0.01 g, 0.25 mmol) in dcm (2 mL), HATU (0.10 g, 0.26 mmol), TEA (0.07 mL, 0.53 mmol) and methyl-(1-methyl-pyrrolidin-3-yl)-amine (0.03 g, 0.31 mmol) were added. The reaction mixture was heated at 35° C. overnight, cooled to room temperature, washed with ammonium chloride solution (2 mL), filtered through a phase separator and organic phase was filtered by SCX column (eluent: first dcm:MeOH/1:1 then NH3 in MeOH (2N)). This work up was done using the Zinsser Speedy (version 6.1.3). The crude was then purified by flash chromatography (eluent: gradient from EtOAc to EtOAc:NH3 in MeOH (2N)/10:1) to obtain 0.04 g of the title compound (37%). 1H-NMR (400 MHz, CD3OD): δ 1.76-1.93 (5H, m), 2.08-2.23 (2H, m), 2.36-2.48 (6H, m), 2.51-3.09 (9H, m), 3.83-3.86 (2H, m), 5.13-5.20 (1H, m), 7.09-7.13 (2H, m), 7.38-7.40 (3H, m), 7.51 (1H, bs); m/z 466 (M+H)+, retention time (method b)=2.30 (10 min run)
Reaction SMILES: C[N:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH2:3]1.[Mn]([O-])(=O)(=O)=O.[K+].[C:14](=O)([O-:16])[O-:15].[Na+].[Na+]>O>[N:2]1[CH:7]=[CH:6][C:5]([C:14]([OH:16])=[O:15])=[N:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CN1C=CC=NC1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccncn1
Yield: 11 %

Procedure:
3-Methyl-pyrimidine (9.41 g, 100 mmol), potassium permanganate (26.9 g) and sodium carbonate (10.6 g) was refluxed in water (100 ml) for 72 h followed by filtration through celite. The filtrate was washed with several portions of DCM and EtOAc before acidification with conc. HCl. The formed precipitate was collected and washed with water to yield 1.37 g of the title compound as a white solid. 1H NMR (DMSO-d6) d (ppm): 13.94 (br. s, 1H), 9.37 (d, 1H), 9.07 (d, 1H), 8.01 (dd, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8]P(=O)(OC)OC)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH2:20]([N:22]1[C:27]2[CH:28]=[C:29]([C:33]3[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=3[O:41][C:42]([F:45])([F:44])[F:43])[CH:36]=O)[C:30]([CH3:32])=[CH:31][C:26]=2[C:25]([CH3:47])([CH3:46])[O:24][C:23]1=[O:48])[CH3:21]>C1COCC1.CN1C(=O)N(C)CCC1.C1COCC1>[C:1]([O:5][C:6](=[O:7])[CH:8]=[CH:36][C:35]1[CH:38]=[CH:39][C:40]([O:41][C:42]([F:45])([F:43])[F:44])=[C:33]([C:29]2[C:30]([CH3:32])=[CH:31][C:26]3[C:25]([CH3:46])([CH3:47])[O:24][C:23](=[O:48])[N:22]([CH2:20][CH3:21])[C:27]=3[CH:28]=2)[CH:34]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN1C(=O)OC(C)(C)c2cc(C)c(-c3cc(C=O)ccc3OC(F)(F)F)cc21
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCN1C(=O)OC(C)(C)c2cc(C)c(-c3cc(C=CC(=O)OC(C)(C)C)ccc3OC(F)(F)F)cc21
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 36.8 %

Procedure:
A flask charged with 0.23 mL (2.5 mmol) of dimethyl t-butoxycarbonyl-methylphosphonate in 8.75 mL of dry THF/DMPU (10:1). The flask was cooled to −78° C. where 1.78 mL (0.9 mmol, 2.5M hexanes) of n-butyl lithium was added slowly via syringe. The reaction mixture was stirred at −78° C. for 10 minutes and then a solution of 0.35 g (0.86 mmol) of Compound 14E in 3 mL of dry THF was added. After warming to room temperature and an additional 20 minutes of stirring, the reaction was quenched with 3 mL of water and then partitioned with 10 mL of saturated ammonium chloride and 20 mL of ethyl acetate, The water layer was further extracted with ethyl acetate (2×15 mL) and the combined organic layers were then washed with brine (10 mL), dried over magnesium sulfate, filtered and excess solvent was removed on the rotary evaporator. The crude product was purified by flash chromatography (3.5:1 EtOAc/Hexanes) to give 0.16 g (41%) of the product as a white solid. MS (electrospray): mass calculated for C23H22F3NO5, 449.15; m/z found 450, [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:18]2[CH:22]=[N:21][N:20]=[C:19]2[CH2:23][N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])=[C:8]([CH:17]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])([O-:3])=[O:2].[Br:35]N1C(=O)CCC1=O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:18]2[C:19]([CH2:23][N:24]3[C:25](=[O:34])[C:26]4=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]4[C:28]3=[O:29])=[N:20][N:21]=[C:22]2[Br:35])=[C:8]([CH:17]=1)[C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10])([O-:3])=[O:2]
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1-n1cnnc1CN1C(=O)c2ccccc2C1=O
Reactant: O=C1CCC(=O)N1Br
Product: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1-n1c(Br)nnc1CN1C(=O)c2ccccc2C1=O

Procedure:
Following the procedure of Example 2, 5-nitro-2-[3-phthalimidomethyl-4H-1,2,4-triazol-4-yl]benzophenone is reacted with N-bromosuccinimide to form 5-nitro-2-[3-bromo-5-phthalimidomethyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [N+:1]([C:4]1[CH:57]=[CH:56][CH:55]=[CH:54][C:5]=1[CH2:6][O:7][C:8]([CH:10]([PH:35]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[N:11]1[CH:14]([CH2:15][CH2:16][OH:17])[CH:13]([CH:18]([NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])=[O:22])[CH3:19])[C:12]1=[O:34])=[O:9])([O-:3])=[O:2].CC(C)=[O:60].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O.C(Cl)Cl>[N+:1]([C:4]1[CH:57]=[CH:56][CH:55]=[CH:54][C:5]=1[CH2:6][O:7][C:8]([CH:10]([PH:35]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[N:11]1[C@@H:14]([CH2:15][C:16]([OH:60])=[O:17])[C@H:13]([CH:18]([NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])=[O:22])[CH3:19])[C:12]1=[O:34])=[O:9])([O-:3])=[O:2]
Reactant: CC(NC(=O)OCc1ccccc1[N+](=O)[O-])C1C(=O)N(C(C(=O)OCc2ccccc2[N+](=O)[O-])[PH](c2ccccc2)(c2ccccc2)c2ccccc2)C1CCO
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(NC(=O)OCc1ccccc1[N+](=O)[O-])[C@@H]1C(=O)N(C(C(=O)OCc2ccccc2[N+](=O)[O-])[PH](c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CC(=O)O
Reaction time: 0.17 h

Procedure:
1-(o-Nitrobenzyloxycarbonyltriphenylphosphoranylmethyl)-3-(1-o-nitrobenzyloxycarbonylaminoethyl)-4-(2'-hydroxyethyl)-2-azetidinone (0.1582 g, 0.20 mmol) (cf. Example 43, Step I) is dissolved in 5 ml acetone cooled to 0°. Jones Reagent (0.12 ml, 4N solution) is added dropwise over 3 minutes and the resulting solution is stirred at 0° for 10 minutes. Isopropanol (0.05 ml) is added and the mixture stirred for another 2 minutes. The reaction mixture is diluted with CH2Cl2 and filtered. The filtrate is washed with saturated NaCl aqueous solution, dried and evaporated to give 0.132 g of crude acid which is used without further purification in the next step.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl.[CH2:15]([NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)[CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>COCCOC>[CH2:15]([NH:29][C:30]1[CH:31]=[CH:32][C:33]([C:34]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:35])=[CH:37][CH:38]=1)[CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCCCCCCCC=CCCCNc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCCCCCC=CCCCNc1ccc(C(=O)C(C(=O)OCC)C(=O)OCC)cc1

Procedure:
A solution of 26.6 g. of diethyl malonate and 10 ml. of 1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1,2-dimethoxyethane under argon. A solution of 17.3 g. of 4-(1-tetradec-4-enylamino)benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is refluxed for 4.5 hours, cooled, poured on ice, acidified, and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. Addition of a small amount of ethanol to the residue gives a solid which is filtered and discarded. The ethanol filtrate is concentrated and the residue is recrystallized from ether to yield diethyl 4-(1-tetradec-4-enylamino)benzoylmalonate.