Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:30]=[C:29]([Cl:31])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:27][CH2:26][CH2:25][C:24]4[NH:23][N:22]=[CH:21][C:20]3=4)[C:15]2=[O:28])=[C:11]([Cl:32])[CH:10]=1)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[Cl:31][C:29]1[CH:30]=[C:9]([OH:8])[CH:10]=[C:11]([Cl:32])[C:12]=1[CH2:13][C@@H:14]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:27][CH2:26][CH2:25][C:24]3[NH:23][N:22]=[CH:21][C:20]2=3)[C:15]1=[O:28]
Reactant: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1C1CCCc2[nH]ncc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C1[C@H](Cc2c(Cl)cc(O)cc2Cl)CCN1C1CCCc2[nH]ncc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
To a solution of (R)-3-(4-benzyloxy-2,6-dichloro-benzyl)-1-(4,5,6,7-tetrahydro-1H-indazol-4-yl)-pyrrolidin-2-one (1.32 g) in ethanol (50 mL), add palladium hydroxide on carbon (10%, 0.65 g). Stir the mixture under hydrogenation (50 psi) at room temperature for 3 hours. Filter the mixture through celite. Remove the solvent in vacuo to afford 0.93 g of the title compound. MS (m/z): 380 (M+).
Reaction SMILES: O[C:2]1[C:15]2[C@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@:9]3([OH:21])[CH2:10][CH2:11][C:12](=[O:20])[CH2:13]4)[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C1(OC2NN=NN=2)C=CC=CC=1>>[OH:21][C@:9]12[C@@H:8]3[N:18]([CH3:19])[CH2:17][CH2:16][C@:14]1([C:15]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[CH2:7]3)[CH2:13][C:12](=[O:20])[CH2:11][CH2:10]2
Reactant: CN1CC[C@]23CC(=O)CC[C@@]2(O)[C@H]1Cc1cccc(O)c13
Agent: c1ccc(Oc2nnn[nH]2)cc1
Product: CN1CC[C@]23CC(=O)CC[C@@]2(O)[C@H]1Cc1ccccc13

Procedure:
Conversion of 4,14-dihydroxy-6-keto-N-methylmorphinan into the phenyltetrazolyl ether followed procedures given in Example 1, and the removal of the phenyltetrazolyl ether group followed procedures given in Example 2, affording 14-hydroxy-6-keto-N-methylmorphinan, m.p. 143°-144°, [α]D26 --137.9 (c 0.94, CHCl3).
Reaction SMILES: C([N:4]1[CH2:10][CH2:9][CH2:8][N:7]([CH3:11])[C:6]2[N:12]=[CH:13][CH:14]=[CH:15][C:5]1=2)(=O)C.[OH-].[Na+]>Cl>[CH3:11][N:7]1[CH2:8][CH2:9][CH2:10][NH:4][C:5]2[CH:15]=[CH:14][CH:13]=[N:12][C:6]1=2
Reactant: CC(=O)N1CCCN(C)c2ncccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN1CCCNc2cccnc21
Yield: 96.2 %

Procedure:
A solution of 1-acetyl-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepine (1.7 g) in 6N hydrochloric acid (60 ml) was heated at 100° C. for 6 hours. After cooling, the mixture was basified with aqueous sodium hydroxide and extracted with ethyl acetate. The extracted organic layer was washed with brine and dried over sodium sulfate and concentrated in vacuo. The residue was washed with hexane to give 5-methyl-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepine (1.3 g).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(#N)C>[N:14]1([CH:2]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)C(Br)c1ccc(C)cc1
Reactant: C1CCNCC1
Solvent: CC#N
Product: COC(=O)C(c1ccc(C)cc1)N1CCCCC1
Yield: 10.7 %

Procedure:
To a solution of methyl 2-bromo-2-p-tolylacetate (2.50 g, 10.3 mmol) in acetonitrile, was added piperidine (2.06 ml, 20.6 mmol) and the mixture was reacted for 2 hours at room temperature. The solvent was evaporated and the resulting crude was portioned between water and EtOAc. The aqueous phase was extracted with EtOAc, the organic phases were combined, dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (petroleum ether/EtOAc=9/1) to obtain methyl 2-(piperidin-1-yl)-2-p-tolylacetate (273 mg, 21% yield) as a colourless oil.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:14])[CH2:8][CH2:9][O:10][CH:11]([CH3:13])[CH3:12])(=[O:3])[CH3:2]>C(O)C.[Ni]>[C:1]([O:4][CH2:5][CH2:6][CH:7]([CH3:14])[CH2:8][CH2:9][O:10][CH:11]([CH3:13])[CH3:12])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC=C(C)CCOC(C)C
Agent: [Ni]
Solvent: CCO
Product: CC(=O)OCCC(C)CCOC(C)C
Reaction time: 20 h

Procedure:
600 g of 1-acetoxy-5-isopropoxy-3-methyl-2-pentene are hydrogenated in 2000 cc of ethanol with 60 g of Raney nickel at 71 atmospheric pressure and 70°C for 24 hours. After this period, another 30 g of catalyst are added and hydrogenation is effected under the same conditions for a further 20 hours. After filtration, the reaction mixture is evaporated and the residue is distilled. Gas-chromatographically pure 1-acetoxy-5-isopropoxy-3-methyl-pentane is obtained. B.P.: 106°-108°/12 mm Hg. nD20 = 1.4286
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.CN1CCOCC1.CN(C)C=O.Cl.[NH2:31][CH2:32][CH:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:34][CH2:35][CH2:36][C:37](O)=[O:38]>C(OCC)(=O)C.O>[C:40]1([CH:33]2[CH2:32][NH:31][C:37](=[O:38])[CH2:36][CH2:35][CH2:34]2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: NCC(CCCC(=O)O)c1ccccc1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CCCC(c2ccccc2)CN1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
27.6 ml of diphenylphosphoryl azide and then 37.5 ml of N-methylmorpholine were added to 260 ml of dimethylformamide containing 26.0 g of 6-amino-5-phenylhexanoic acid hydrochloride [prepared as described in step (c) above] in an ice-bath. The reaction mixture was stirred for 3.5 hours at room temperature, and then dissolved in 0.5 liter of ethyl acetate and 0.5 liter of water. The ethyl acetate layer was separated, washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was subjected to silica gel column chromatography using a 2:1 by volume mixture of ethyl acetate and methylene chloride as eluent, to give 4.0 g of the title compound as crystals, melting at 153.5°-154.5° C. (with decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([CH3:18])[CH2:9][O:10][Si](C(C)(C)C)(C)C)=[CH:4][CH:3]=1.Cl.CO>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:19])([CH3:18])[CH2:9][OH:10])=[CH:6][CH:7]=1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Agent: Cl
Solvent: CO
Product: CC(C)(CO)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
To a solution of [2-(4-bromophenyl)-2-methylpropoxy](tert-butyl)dimethylsilane (500 mg, 1.46 mmol) in MeOH (5 mL) was added dropwise HCl/MeOH (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction was concentrated to give a crude residue, which was purified by column chromatography to give the title compound (250 mg, 75%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.38 (d, 2H), 7.19 (d, 2H), 3.50 (s, 2H), 1.23 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[CH:29][C:30]([CH3:33])=[N:31][CH:32]=1>>[CH3:33][C:30]1[N:31]=[CH:32][C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:28][CH:29]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1ccc(Br)cn1
Product: Cc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 5-bromo-2-methyl-pyridine [CAS 3430-13-5; commercially available] (237 mg, 1.1 mmol) according to general procedure II. Obtained as a light brown solid (230 mg, 52%). MS (ISP) 447.2 [(M+H)+]; mp 195° C.
Reaction SMILES: CO/[N:3]=[C:4](\[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)/[CH2:5][N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1.O.[OH-].[Na+].C(OCC)C>C1COCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:4]([NH2:3])[CH2:5][N:6]2[CH:10]=[CH:9][CH:8]=[N:7]2)=[CH:12][CH:13]=1
Reactant: CO/N=C(/Cn1cccn1)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: NC(Cn1cccn1)c1ccc(Cl)cc1
Yield: 55 %

Procedure:
Borane tetrahydrofuran complex (15.00 mL, 15.00 mmol) was added to a stirred solution of (Z) and (E)-1-(4-chlorophenyl)-2-(1H-pyrazol-1-yl)ethanone O-methyl oxime (Intermediate 91) (0.749 g, 3 mmol) dissolved in THF (30 mL) at room temperature under argon. The resulting solution was stirred under reflux for 3 hours. The mixture was cooled in an ice/water bath and water (25 ml) was carefully added followed by 20% NaOH (25 ml). The resulting biphasic mixture was refluxed overnight with vigorous magnetic stirring and allowed to cool. Diethyl ether was added and the layers were separated. The organic layer was further extracted with diethyl ether dried over MgSO4, filtered and evaporated to give the crude product (741 mg, 55%). This was used directly in the following reaction.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][C:7](O)=O)[N:3]=[CH:2]1.[NH2:10][C:11]1[C:12](=[O:33])[N:13]([CH2:30][CH2:31][CH3:32])[C:14](=[O:29])[N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[C:16]=1[NH2:17]>>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:15]2[C:16]3[N:17]=[C:7]([CH2:6][C:4]4[N:3]=[CH:2][S:1][CH:5]=4)[NH:10][C:11]=3[C:12](=[O:33])[N:13]([CH2:30][CH2:31][CH3:32])[C:14]2=[O:29])=[CH:21][CH:22]=1)([O-:28])=[O:27]
Reactant: CCCn1c(=O)c(N)c(N)n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: O=C(O)Cc1cscn1
Product: CCCn1c(=O)c2[nH]c(Cc3cscn3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O

Procedure:
By the method of Example 2, 4-thiazolylacetic acid is reacted with 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(4-thiazolyl)methyl]xanthine. By methods well known in the art, 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(4-thiazolyl)methyl]xanthine is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-1-propyl-8-[(4-thiazolyl)methyl]xanthine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=5)[C:33](O)=[O:34])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.COC1C=CC(CN(CC2C=CC(OC)=CC=2)C2N=CC(C3C4CCN(C5C=CC(C(O)=O)=CC=5)C=4N=C(N4CCOCC4)N=3)=CN=2)=CC=1.[CH3:99][N:100]1[CH2:105][CH2:104][NH:103][CH2:102][CH2:101]1>>[CH3:47][O:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][N:8]([CH2:7][C:6]2[CH:48]=[CH:49][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[C:32]([C:33]([N:103]6[CH2:104][CH2:105][N:100]([CH3:99])[CH2:101][CH2:102]6)=[O:34])[CH:36]=[CH:37][CH:38]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:41][CH:42]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(C(=O)O)c3)cn2)cc1
Reactant: CN1CCNCC1
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(C(=O)N4CCN(C)CC4)c3)cn2)cc1
Yield: 72.2 %

Procedure:
Using 3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (38.2 mg, 0.0579 mmol) obtained in Step A in Example 1-D-53 instead of 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid, and N-methylpiperazine (13.0 μl, 0.116 mmol) instead of 3-(aminomethyl)pyridine, in the same manner as Step B in Example 1-D-19, amidation was carried out, to obtain a crude product of {3-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone as a yellow liquid (31 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-54) as a yellow powder (20.0 mg, 68%).
Reaction SMILES: [CH3:1][CH:2]([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:3][CH3:4].CO.C[O-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>O1CCCC1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:8][S:5]([CH:2]([CH2:3][CH3:4])[CH3:1])(=[O:7])=[O:6])=[O:23])=[CH:17][CH:16]=1
Reactant: CCC(C)S(N)(=O)=O
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(C)S(=O)(=O)NC(=O)Nc1ccc(Cl)cc1
Yield: 18.6 %

Procedure:
The method of Example 10 was followed with 2-butanesulfonamide (6.85 g), methanol (250 ml), sodium methoxide (2.7 g), tetrahydrofuran (250 ml) and 4-chlorophenyl isocyanate (7.7 g) with the resulting solid being recrystallized from ethyl acetate to give 2.7 g of white crystals with a melting point of 172-174° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[I:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23].C(N(CC)CC)C>CN(C=O)C>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[CH:4]([NH:3][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([I:12])=[C:14]([N+:22]([O-:24])=[O:23])[CH:15]=1)[CH2:5]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C(Cl)c1ccc(I)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC1CN2CCC1CC2)c1ccc(I)c([N+](=O)[O-])c1
Yield: 22.5 %

Procedure:
A solution of 3.08 g (24.4 mmol) of 3-aminoquinuclidine dihydrochloride, 7.60 g (24.4 mmol) of 4-iodo-3-nitrobenzoyl chloride, 9.88 g (97.6 mmol) of triethylamine in 150 ml of DMF was stirred at room temperature overnight. The solvent was distilled off in a rotary evaporator, the residue was taken up in 200 ml of dichloromethane, and 200 ml of a saturated sodium bicarbonate solution were added. The organic phase was dried over sodium sulfate, and the solvent was distilled off in vacuo. 2.20 g (22.5%) of the desired title compound were obtained.
Reaction SMILES: CN(C1C2C[C@@H]3C(C(=O)C=2C(O)=CC=1)=C(O)[C@@]1(O)[C@H]([C@H](N(C)C)C(O)=C(C(N)=O)C1=[O:18])C3)C.C[C@]1(O)[C@@H]2C(=C(O)[C@]3(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]3C2)C(=O)C2C(O)=CC=C(Cl)C1=2.C[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](NC(N)=N)[C@@H](O)[C@@H]2NC(N)=N)[C@H](O[C@@H]2O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]2NC)[C@@]1(O)C=O.CC[O:109][C:110]([C@@H:112]([NH:120]C(C1C=CC=CC=1)=O)[CH2:113][CH2:114][CH2:115][N:116]=[C:117](N)[NH2:118])=[O:111]>>[NH2:120][C@H:112]([C:110]([OH:109])=[O:111])[CH2:113][CH2:114][CH2:115][NH:116][C:117]([NH2:118])=[O:18]
Reactant: CN(C)c1ccc(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]3(O)C(O)=C1C2=O
Reactant: CCOC(=O)[C@H](CCCN=C(N)N)NC(=O)c1ccccc1
Agent: CN(C)[C@@H]1C(O)=C(C(N)=O)C(=O)[C@@]2(O)C(O)=C3C(=O)c4c(O)ccc(Cl)c4[C@@](C)(O)[C@H]3C[C@@H]12
Agent: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Product: NC(=O)NCCC[C@H](N)C(=O)O

Procedure:
Inhibition constants were determined for minocycline, chlortetracycline, and streptomycin using standard kinetic analyses. Briefly, the compounds were incubated in Reaction Buffer containing various concentrations of BAEE (0-20 mM) for 10 minutes at 37° C. PAD4 (0.2 μM) was then added to initiate the reaction and allowed to proceed for 6 additional minutes. Reactions were then quenched by flash freezing in liquid N2 and the amount of Cit produced was quantified. The data obtained for streptomycin, minocycline and chlortetracycline were fit to equations 2 and 3,
Reaction SMILES: [C:1]1([C:12]([NH:14][CH:15]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][C:44]([F:49])([F:48])[CH:45]([F:47])[F:46])[CH:38]=2)[CH:16]([C:18]2[CH:35]=[CH:34][C:21]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[OH:17])=[O:13])[C:6]2[CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO>[C:1]1([C:12]([NH:14][CH:15]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][C:44]([F:48])([F:49])[CH:45]([F:46])[F:47])[CH:38]=2)[CH:16]([C:18]2[CH:35]=[CH:34][C:21]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[OH:17])=[O:13])[C:6]2[CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(COc2ccc(C(O)C(Cc3cccc(OC(F)(F)C(F)F)c3)NC(=O)c3cccc4c3C=CCCC4)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(COc2ccc(C(O)C(Cc3cccc(OC(F)(F)C(F)F)c3)NC(=O)c3cccc4c3C=CCCC4)cc2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4-[(4-{(1RS,2SR)-2-[(6,7-dihydro-5H-benzo[a][7]annulen-1-ylcarbonyl)amino]-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl}phenoxy)methyl]-benzoate (260 mg, 0.384 mmol) in methanol (10 ml) was added 2N aqueous sodium hydroxide solution (0.38 ml, 0.76 mmol), and the mixture was stirred at 60° C. overnight. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (100 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the objective substance (209 mg, 82%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:15][C:16]1[CH:20]=[C:19]([NH2:21])[N:18]([C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH:24]=[CH:25][CH:26]=[N:27]3)[N:17]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:21][C:19]2[N:18]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[CH:24]=[CH:25][CH:26]=[N:27]4)[N:17]=[C:16]([CH3:15])[CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(N)n(-c2cccc3ncccc23)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc(OC(C)C)cc2)n(-c2cccc3ncccc23)n1
Temperature: 80 °C
Yield: 8.2 %

Procedure:
A stirred mixture of 4-isopropoxybenzene-1-sulfonyl chloride (0.10 g, 0.52 mmol) and 3-methyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (prepared from Example 4 step b, 0.10 g, 0.44 mmol) in pyridine (2 mL) was heated at 80° C. for 1 h. After cooling to room temperature, aqueous saturated sodium bicarbonate was added to the reaction mixture and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 2-10% methanol in dichloromethane), followed by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.015 g, 0.036 mmol, 8%). 1H NMR (400 MHz, CDCl3) δ 8.58 (dd, J=2.0, 4.0 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H), 7.61 (dd, J=7.6, 8.4 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.48 (d, J=1.6 Hz, 1H), 7.25-7.21 (m, 2H), 7.14 (dd, J=0.8, 7.2 Hz, 1H), 6.74 (d, J=2.4 Hz, 1H), 6.72 (d, J=2.0 Hz, 1H), 6.25 (s, 1H), 4.57 (hept, J=6.0 Hz, 1H), 2.33 (s, 3H), 1.39 (d, J=6.4 Hz, 6H); MS: (ES) m/z calculated for C23H23N4O3S [M+H]+ 423.2. found 423.0.
Reaction SMILES: O[CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[C:7](=[O:16])[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=1.C1C=CC=CC=1.P(Br)(Br)[Br:26].O>C1(C)C=CC=CC=1>[Br:26][CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[C:7](=[O:16])[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=1
Reactant: O=C1Nc2ccccc2Sc2cc(CO)ccc21
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: O=C1Nc2ccccc2Sc2cc(CBr)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 4.43 gm. of the alcohol of Step A in 100 cc. of benzene and add 1 cc (10.5 mmole) of phosphorous tribromide. Stir at room temperature for 1 hour, add water and then dilute with toluene. Wash three times with water, dry and strip to a solid residue.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([CH3:18])([CH:15]([CH3:17])[CH3:16])[C:12](=[O:14])[CH3:13].[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:13][C:12](=[O:14])[C:11]([CH3:18])([CH3:10])[CH:15]([CH3:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)C(C)(C)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C(C)(C)C(=O)C=Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
44.4 g (0.316 mol) of 4-chlorobenzaldehyde and 40 5 g (0.316 mol) of 3,3,4-trimethyl-pentan-2-one are dissolved in a mixture of 100 ml of ethanol and 10 ml of water, and a solution of 0.9 g of sodium hydroxide in 10 ml of water is added. The mixture is initially stirred for 1 hour at room temperature, then 0.4 g of solid sodium hydroxide is added and the mixture is stirred for a further 16 hours. The precipitate which results is filtered off with suction and then washed with water. 33.1 g (42% of theory) of 1-(4-chlorophenyl)-4,4,5-trimethyl-1-hexen-3-one are obtained in the form of a low melting, oily-crystalline product. ##STR24##
Reaction SMILES: C([Li])CCCCC.CC1(C)CCCC(C)(C)N1.[N:18]1([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH:22]=[CH:21][CH:20]=[N:19]1.[CH2:31]([Sn:35](Cl)([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH3:34]>C1COCC1>[CH2:40]([Sn:35]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:36][CH2:37][CH2:38][CH3:39])[C:22]1[N:18]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[N:19]=[CH:20][CH:21]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: N#Cc1ccc(-n2cccn2)cc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccnn1-c1ccc(C#N)cc1
Temperature: 10 °C
Reaction time: 0.33 h

Procedure:
Hexyl lithium (2.3 M in hexanes) (16.96 mL, 39.01 mmol) was added to a stirred solution of 2,2,6,6-tetramethyl-piperidine (6.85 mL, 40.63 mmol) in dry THF (15 mL) at −30° C. and the resulting suspension was stirred for 20 minutes. The suspension was allowed to warm to 10° C. to aid dissolution and was added, via cannula, to a solution of 4-pyrazol-1-yl-benzonitrile (5.50 g, 32.51 mmol, prepared according to Bioorganic & Medicinal Chemistry Letters, 2006, 16(11), 2955-2959, which is incorporated herein by reference in its entirety) in THF (85 mL) at −78° C., keeping the internal reaction temperature<-50° C. The resulting reaction mixture was stirred at −75° C. for 4 hrs and tributyl tin(IV) chloride (9.08 mL, 33.49 mmol) was added keeping the internal reaction temperature<-60° C. during addition. The reaction mixture was stirred at −60° C. for 1.5 rsh then allowed to warm to RT. The resulting solution was quenched by addition of EtOAc (100 mL) and then washed with water (2×50 mL) followed by saturated brine (50 mL). The organic extract was dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was purified by flash chromatography, eluting with a gradient of 0-5% EtOAc in pentane to give the title compound as an amber oil that solidified on standing (10.11 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:29][CH2:30]CS([O-])(=O)=O)[CH2:13][C:12](=[O:14])[N:11]([C:15](=[O:28])[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:37]1([C:43]2([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:29][CH2:30][N:46]3[CH2:45][CH2:44][C:43]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47]3)[CH2:13][C:12](=[O:14])[N:11]([C:15](=[O:28])[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)CC2=O)cc(OC)c1OC
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: COc1cc(C(=O)N2CC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)CC2=O)cc(OC)c1OC

Procedure:
Prepare according to the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-5-oxo-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.