Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=[CH:15][C:16]([OH:18])=[O:17])[C:6]([Cl:11])=[CH:7][C:8]=1[O:9]C.B(Br)(Br)Br.ClCCl>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=[CH:15][C:16]([OH:18])=[O:17])[C:6]([Cl:11])=[CH:7][C:8]=1[OH:9]
Reactant: COc1cc(Cl)c(C=CC=CC(=O)O)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)C=CC=Cc1cc(O)c(O)cc1Cl
Temperature: 20 °C
Reaction time: 24 h
Yield: 45.5 %

Procedure:
To a solution containing 0.54 g of the product obtained in Example 35 in 6 ml dichloromethane 6 ml of 1 molar boron tribromide-dichloromethane solution was added and stirred for 24 h at 20° C. The solvent was evaporated in vacuo and 2 N hydrochloric acid was added to the residue. The product was filtered and washed with water. Recrystallization from isopropanol-water yielded 0.22 g (46%) of the product desired, m.p. 203°-206° C.
Reaction SMILES: C([O:3][C:4](=[O:42])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[C:30]([Cl:31])=[CH:29][C:28]([C:32](=[O:34])[CH3:33])=[C:27]([OH:35])[C:26]=2[CH2:36][CH2:37][CH3:38])[C:10]=1[CH2:39][CH2:40][CH3:41])C.[OH-].[Na+]>CO>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:42])=[O:3])=[C:10]([CH2:39][CH2:40][CH3:41])[C:11]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[C:30]([Cl:31])=[CH:29][C:28]([C:32](=[O:34])[CH3:33])=[C:27]([OH:35])[C:26]=1[CH2:36][CH2:37][CH3:38])(=[O:17])[CH3:16]
Reactant: CCCc1c(O)c(C(C)=O)cc(Cl)c1OCCCCCOc1c(C(C)=O)ccc(OCCCC(=O)OCC)c1CCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(O)c(C(C)=O)cc(Cl)c1OCCCCCOc1c(C(C)=O)ccc(OCCCC(=O)O)c1CCC
Yield: 92.1 %

Procedure:
A solution of 0.978 g (0.0016 mole) of 4-[4-acetyl -3-[5-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy]butanoic acid ethyl ester in 50 ml of methanol and 8.1 ml (0.0081 mole) of 1.0N sodium hydroxide was stirred at reflux for 2 hours. Most of the solvent was removed in vacuo and the pH of the residue was adjusted to 2.0. The product was extracted with methylene chloride and the dried (magnesium sulfate) extract was concentrated in vacuo to give 0.850 g (91% of yield) of 4-[4-acetyl-3-[5-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy]butanoic acid as an oil.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](C3C=CC=CC=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([CH3:39])([CH3:38])[C:33]([O:35]CC)=[O:34].C(=O)([O-])[O-].[K+].[K+].[OH-].[K+]>CS(C)=O.CC(=O)CC>[C:1]1([N:8]2[C:9]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([CH3:38])([CH3:39])[C:33]([OH:35])=[O:34])=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=[C:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C)(C)CCCCCCCBr
Reactant: c1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCC(C)=O
Solvent: CS(C)=O
Product: CC(C)(CCCCCCCc1c(-c2ccccc2)nc(-c2ccccc2)n1-c1ccccc1)C(=O)O

Procedure:
A mixture of 2,4,5-triphenylimidazole (4.13 g), ethyl 9-bromo-2,2-dimethylnonanoate (10.95 g), potassium carbonate (10 g) and 2-butanone was stirred at reflux for 48 hours. The mixture was filtered, solvent removed under reduced pressure and the residue was chromatographed on silica gel eluted with chloroform to give a clear oil which was dissolved in dimethyl sulphoxide (30 ml) and treated with potassium hydroxide (3 g). The mixture was stirred at 40° C. for 24 hours when the solvent was removed under reduced pressure. Water (50 ml) was added, the pH of the solution was adjusted to 4 and the aqueous was extracted with chloroform (3×50 ml). The chloroform extracts were dried over magnesium sulphate, filtered and the solvent removed to give a solid which was recrystallised from acetonitrile to give 9-(1,2,4-tri-phenylimidazolyl)-2,2-dimethylnonanoic acid as a white crystalline solid, m.p. 119°-120° C.; Found: C, 79.85; H, 7.64; N, 6.23% (C32H36N2O2); Requires: C, 79.96; H, 5.54; N, 5.82%
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH3:12])=[O:10].[NH2:13][CH:14]([C:29]1[N:30]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:31]=[C:32]([CH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][CH3:37])[N:33]=1)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=2)=[CH:18][CH:17]=1>>[CH3:39][C:35]([CH3:38])([CH2:36][CH3:37])[CH2:34][C:32]1[N:33]=[C:29]([CH:14]([NH:13][C:9]([O:11][CH3:12])=[O:10])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=3)=[CH:18][CH:17]=2)[N:30]([C:40]([O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[O:41])[CH:31]=1
Reactant: CCC(C)(C)Cc1cn(C(=O)OC(C)(C)C)c(C(N)Cc2ccc(-c3ccc(F)cn3)cc2)n1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Product: CCC(C)(C)Cc1cn(C(=O)OC(C)(C)C)c(C(Cc2ccc(-c3ccc(F)cn3)cc2)NC(=O)OC)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (0.02 mL, 0.16 mmol) followed by methyl chloroformate (5 μL, 0.05 mmol) were added to an ambient temperature solution of tert-butyl 2-{1-amino-2-[4-(5-fluoropyridin-2-yl)phenyl]ethyl}-4-(2,2-dimethylbutyl)-1H-imidazole-1-carboxylate (24 mg, 0.05 mmol). After stirring at ambient temperature for 1 h, the reaction mixture was quenched with water and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Preparatory plate chromatography eluting with 20% ethyl acetate/hexane afforded tert-butyl 4-(2,2-dimethylbutyl)-2-{2-[4-(5-fluoropyridin-2-yl)phenyl]-1-[(methoxy carbonyl)amino]ethyl}-1H-imidazole-1-carboxylate.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:24])=[O:4].[NH2:25][CH:26]1[CH2:30][CH2:29][O:28][CH2:27]1>>[O:28]1[CH2:29][CH2:30][CH:26]([NH:25][C:3]([C:5]2[S:9][C:8](/[CH:10]=[CH:11]/[C:12]3[C:13]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[N:14][O:15][C:16]=3[CH3:17])=[N:7][C:6]=2[CH3:24])=[O:4])[CH2:27]1
Reactant: COC(=O)c1sc(/C=C/c2c(-c3ccccc3)noc2C)nc1C
Reactant: NC1CCOC1
Product: Cc1nc(/C=C/c2c(-c3ccccc3)noc2C)sc1C(=O)NC1CCOC1
Yield: 43 %

Procedure:
As described for example 68c, 4-methyl-2-[(E)-2-(5-methyl-3-phenyl-isoxazol-4-yl)-vinyl]-thiazole-5-carboxylic acid methyl ester (80 mg, 0.24 mmol) was converted, using 3-amino-tetrahydrofuran instead of isopropylamine, to the title compound (40 mg, 43%) which was obtained as a light yellow solid. MS: m/e=396.3 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][C:14]3=[O:19])=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:20][N:21]2C(=O)C3C(=CC=CC=3)C2=O)[O:3]1.CN.[ClH:34]>CO>[ClH:34].[NH2:21][CH2:20][C@@H:4]1[O:3][C:2](=[O:1])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][C:14]3=[O:19])=[CH:9][CH:8]=2)[CH2:5]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Agent: CN
Agent: Cl
Solvent: CO
Product: NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Temperature: 27.5 °C
Reaction time: 1 h

Procedure:
In a four neck round bottom flask, charged methanol (2900 ml), 2-([(5S)-2-Oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione (290 g), and 40% aqueous methylamine (265 g) at 25 to 30° C. Reaction mass is stirred for 1 h at 25 to 30° C. and then heated to 60 to 65° C., and maintained at same temperature for 4 h. Reaction mixture then cooled to 25 to 30° C. and added conc. hydrochloric acid (290 ml, pH should be 1 to 2) and stirred for 30 minutes. Obtained solid is filtered off and washed by chilled methanol (290 ml).
Reaction SMILES: C(#N)C.[Br:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:16][CH2:17][CH2:18][OH:19])[C:14]=1[CH3:15])[C:8]([O:10][CH3:11])=[O:9].S([O-])([O-])(=O)=O.[Na+].[Na+].[F:27][C:28]([F:36])(S(F)(=O)=O)C(O)=O>O>[Br:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:16][CH2:17][CH2:18][O:19][CH:28]([F:36])[F:27])[C:14]=1[CH3:15])[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: COC(=O)c1cc(Br)c(C)c(CCCO)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(Br)c(C)c(CCCOC(F)F)c1
Temperature: 50 °C

Procedure:
To an acetonitrile (0.6 M) suspension of methyl 3-bromo-5-(3-hydroxypropyl)-4-methylbenzoate (1 eq.) from the previous step and sodium sulfate (0.2 eq.) was added dropwise at 50° C. difluoro(fluorosulfonyl)acetic acid (1 eq.) over a period of 10 min. After the completion of addition, the reaction suspension was heated at 50° C. for another 16 h. The reaction mixture was then cooled to RT, poured into water and extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.CC([O-])=[O:27].[K+]>CC(O)=O.O>[F:22][C:21]([F:24])([F:23])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:4]=[N:3][C:2]([OH:27])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1
Reactant: CC(=O)[O-]
Reactant: FC(F)(F)c1ccccc1OC1CCN(c2ccc(Cl)nn2)CC1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1
Reaction time: 3 h

Procedure:
A solution of 3-chloro-6-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyridazine (100 mg, 0.28 mmol) and KOAc (55 mg, 0.56 mmol) in AcOH/H2O (1:1, 2 mL) was heated at 150° C. After 3 h, the solvent was evaporated and the mixture diluted with water (2 mL), extracted with (3×2 mL) EtOAc and dried over Na2SO4. Evaporation of the solvent followed by purification Combiflash chromatography (SiO2, eluant 5% MeOH/EtOAc) afforded the desired product. 1H NMR (500 MHz, acetone-d6): δ 1.86-1.93 (m, 2H), 2.10-2.14 (m, 2H), 3.33-3.39 (m, 2H), 3.54-3.60 (m, 2H), 4.88-4.90 (m, 1H), 6.77 (d, 1H), 7.10 (t, 1H), 7.34 (d, 1H), 7.49 (d, 1H), 7.59-7.65 (m, 2H). MS (+ESI) m/z 340 (MH+).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]1[CH2:44][CH2:43][N:42]([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:48]3[CH2:47][CH2:46][CH:45]([N:42]4[CH2:41][CH2:40][N:39]([CH3:38])[CH2:44][CH2:43]4)[CH2:50][CH2:49]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CN1CCN(C2CCNCC2)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCN(C)CC2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 1-methyl-4-piperidin-4-yl-piperazine (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C39H51Cl2N6O2 [(M+H)+] 705.3445, observed 705.3445.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][C:43]([CH3:48])([CH3:47])[C:44](O)=[O:45])[CH2:10]2)=[CH:5][CH:4]=1.[CH2:49]([O:56][C:57]([N:59]1[CH2:64][CH2:63][CH:62]([NH2:65])[CH2:61][CH2:60]1)=[O:58])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>>[CH2:49]([O:56][C:57]([N:59]1[CH2:64][CH2:63][CH:62]([NH:65][C:44](=[O:45])[C:43]([CH3:47])([CH3:48])[CH2:42][C@@H:11]2[CH2:10][C@H:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]2[S:32]([C:35]2[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=2)(=[O:33])=[O:34])[CH2:61][CH2:60]1)=[O:58])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)NC4CCN(C(=O)OCc5ccccc5)CC4)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
According to general procedure D, 224 mg of 3-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionic acid (from example 65b) and 87 mg of 4-amino-piperidine-1-carboxylic acid benzyl ester are used to afford the title compound as a colourless oil. Rf=0.18 (EtOAc-heptane 1:1); Rt=5.53.
Reaction SMILES: Cl.[N:2]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][CH2:6][NH:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.C(N(CC)CC)C.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>ClCCl>[CH:26]1([C:29]([N:5]2[CH2:6][CH2:7][N:2]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3][CH:4]2[C:8]([O:10][CH3:11])=[O:9])=[O:30])[CH2:28][CH2:27]1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)C1CC1
Reaction time: 0.58 h
Yield: 103.4 %

Procedure:
To a solution cooled to 0° C. of 10.0 g (35.6 mmol) of 1-tert-butyl 3-methyl piperazine-1,3-dicarboxylate hydrochloride (CAS 129799-08-2) in 350 ml of dichloromethane are added 11.0 ml (79.1 mmol) of triethylamine and then, over 35 minutes, 3.6 ml (40 mmol) of cyclopropylcarbonyl chloride dissolved in 50 ml of dichloromethane. The medium is stirred from 0° C. to room temperature over 4 hours 30 minutes and is then washed with twice 40 ml of water and dried over sodium sulfate. The solvent is evaporated off under reduced pressure and the residue is chromatographed on a column of 90 g of silica gel, eluting with a mixture of 5 to 50% ethyl acetate in dichloromethane, to give 11.5 g 1-tert-butyl 3-methyl 4-cyclopropanecarbonylpiperazine-1,3-dicarboxylate in the form of a viscous oil.
Reaction SMILES: Br[C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]([N+:12]([O-:14])=[O:13])=[C:2]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:7]=1
Reactant: C1CCNC1
Reactant: Cc1cc(Br)c([N+](=O)[O-])cc1[N+](=O)[O-]
Product: Cc1cc(N2CCCC2)c([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
A mixture of 5-bromo-2,4-dinitrotoluene (2.61 g, 10 mmol) and pyrrolidine (2.49 g, 35 mmol) was heated at 90°-100° C. for 2 hours. The resulting dark brown oil was combined with cracked ice and the precipitated solids filtered off, washed with water, and vacuum dried. Purification was carried out by flash chromatography of the solids on a silica gel column using chloroform/hexane (50:50) as eluant. Evaporation of the eluants afforded 17 as orange needles: 2.0 g (82%) yield; mp 142° C.; TLC (chloroform), Rf =0.82; IR (KBr pellet) 1606, 1566, 1510, 1369, 1350, 1334, 1301, 1276, 1130, 833 cm-1 ; 1H NMR (dimethyl sulfoxide-d6) δ8.83 and 8 53 (2H, 2×s, aromatic protons), 3.27 (4H, m, methylenes adjacent to pyrrolidine N), 2.61 (3H, s, methyl), 1.99 (4H, m, other pyrrolidine methylenes); mass spectrum (EI mode) m/z 251 (P+), 234 (P+ -OH). Anal. Calcd for C11H13N3O4 : C, 52.58; H, 5.21; N, 16.72. Found: C, 52.51; H, 5 27; N, 16.64.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([C:45]2[CH:46]=[C:47]3[C:52](=[C:53]([CH:55]([N:57]([C:59]4[CH:64]=[C:63]([F:65])[CH:62]=[C:61]([F:66])[CH:60]=4)[CH3:58])[CH3:56])[CH:54]=2)[O:51][C:50]([N:67]2[CH2:72][CH2:71][O:70][CH2:69][CH2:68]2)=[CH:49][C:48]3=[O:73])=[O:44])[CH2:39][CH2:38]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[F:66][C:61]1[CH:60]=[C:59]([N:57]([CH3:58])[CH:55]([C:53]2[CH:54]=[C:45]([C:43]([N:40]3[CH2:39][CH2:38][CH:37]([OH:36])[CH2:42][CH2:41]3)=[O:44])[CH:46]=[C:47]3[C:52]=2[O:51][C:50]([N:67]2[CH2:72][CH2:71][O:70][CH2:69][CH2:68]2)=[CH:49][C:48]3=[O:73])[CH3:56])[CH:64]=[C:63]([F:65])[CH:62]=1
Reactant: CC(c1cc(C(=O)N2CCC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC2)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1cc(F)cc(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(c1cc(C(=O)N2CCC(O)CC2)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1cc(F)cc(F)c1
Reaction time: 2 h

Procedure:
Tetrabutylammonium fluoride (1N in THF) (7.83 mL, 7.83 mmol) was added dropwise to a stirred solution of 6-(4-(tert-butyldiphenylsilyloxy)piperidine-1-carbonyl)-8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-2-morpholino-4H-chromen-4-one (3 g, 3.92 mmol, enantiomer 2 in Example 7.0a, [α]D20°: −102° dissolved in THF (20 mL) at RT under nitrogen and stirred for 2 hrs. The mixture was evaporated to dryness, diluted with DCM, washed with water. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (80 g) eluting with 3 to 7% MeOH in DCM. The solvent was evaporated to dryness to give a foam which was triturated in ether (2-5 mL). The resulting white solid was collected by filtration and dried to give 8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-6-(4-hydroxypiperidine-1-carbonyl)-2-morpholino-4H-chromen-4-one enantiomer 2 (1.7 g, 82%) as a white solid. Mass Spectrum: M+H° 528. [α]D20°: +7° in MeCN.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:27])=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15]3)=N[CH:13]=2)=[CH:4][CH:3]=1.[CH2:31]([C@@H]1COC(=O)N1C(=O)[C@H](CS(N1CCN(C2C=CC(C3C=CC(F)=CC=3)=CN=2)CC1)(=O)=O)C(C)C)C1C=CC=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:31][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:27])=[O:26])(=[O:21])=[O:22])[CH2:16][CH2:15]3)=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)O
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1)C(=O)O
Yield: 59 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methylbutyric acid, from 4-(R)-benzyl-3-(2-(R)-{4-[5-(4-fluorophenyl)pyridin-2-yl]piperazine-1-sulfonyl methyl}-3-methylbutyryl)-oxazolidin-2-one (0.167 g), to yield the title compound as a white solid (0.072 g, 59%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.Cl.[CH3:15][O:16][NH2:17].C(=O)([O-])O.[Na+]>C(O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:17][O:16][CH3:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: CON
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=NOC)c1csc(N)n1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
In 10 ml of 50% aqueous ethanol is dissolved 200 mg of ethyl 2-aminothiazol-4-yl-glyoxylate, followed by the addition of 166 mg of O-methylhydroxylamine hydrochloride and, then, 168 mg of sodium hydrogen carbonate. The mixture is stirred in a closed vessel at 70° C. for 5 hours. The reaction mixture is concentrated under reduced pressure and the residue is diluted with 10 ml of water and extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried. The ethyl acetate is then distilled off to obtain ethyl 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate as crystals. Based on NMR and other data, this product is found to be an 83:17 mixture of syn- and anti-isomers.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=[C:21]([NH:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[N:20]=3)=[CH:13][CH:12]=2)=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:4].[OH-].[Na+].Cl>O1CCOCC1>[CH3:33][CH:32]([CH3:34])[CH2:31][CH2:30][NH:29][C:21]1[N:20]=[C:19]([NH:18][CH2:17][C:14]2[CH:13]=[CH:12][C:11]([C:6]3[C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:16][CH:15]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1
Reactant: COC(=O)c1ccccc1-c1ccc(CNc2nc(NCCC(C)C)nc3ccccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)CCNc1nc(NCc2ccc(-c3ccccc3C(=O)O)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 10 mL of dioxane was added 0.159 g of 4'-[[[2-[(3-methylbutyl)amino]-4-quinazolinyl]amino]methyl][1,1'-biphenyl]-2-carboxylic acid methyl ester and 2 mL of 0.5N aqueous sodium hydroxide. The resulting solution was stirred at room temperature for 72 hours. All solvents were moved and the residue was neutralized with 0.1N hydrochloric acid. The resulting precipitate was collected, washed with water and dried. (0.14 g, 93%) (M.P.=195°-205° C., decomp): 1H NMR (DMSO-d6, 300 MHz) δ8.43 (bs, 1H), 8.03 (m, 1H), 7.70 (m, 1H), 7.59 (m, 1H), 7.45 (m, 5H), 7.21 (m, 3H), 7.01 (m, 1H), 6.50 (bs, 1H), 4.78 (d, 2H), 3.50 (m, 2H), 1.60 (m, 1H), 1.40 (m, 2H), 0.85 (d, 6H); negative FAB MS m/e 439 (M-H). Anal. Calcd for C27H28N4O2 ·1/2HCl: C, 70.69; H, 6.26; N, 12.53. Found: C, 70.77; H, 6.20; N, 12.53.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C=O)C>[N:17]1([CH2:16][CH2:15][CH2:14][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][NH:8][C:9]3=[O:12])=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: ClCCCN1CCCC1
Reactant: O=C1NCCc2ccc(O)cc21
Solvent: CN(C)C=O
Product: O=C1NCCc2ccc(OCCCN3CCCC3)cc21

Procedure:
7-(3-Pyrrolidin-1-yl-propoxy)-3,4-dihydro-2H-isoquinolin-1-one is prepared from 7-hydroxy-3,4-dihydro-2H-isoquinolin-1-one (0.48 g, 2.94 mmol) in a manner substantially analogous to Procedure A except DMF is used in place of dioxane and 1-(3-Chloro-propyl)-pyrrolidine is used instead of N-(3-chloropropyl)piperidine. Following aqueous workup, the crude material is purified by flash chromatography (Biotage 40M SiO2, elute 90/10/1 CH2Cl2/MeOH/NH4OH) to give the title compound as an off-white solid (0.17 g, 21%). MS (ES+) 275.1
Reaction SMILES: [CH3:1][C:2]1([CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH:5]=[C:4]([CH3:8])[O:3]1.[CH:18]#[N:19]>N1C=CC=CC=1>[CH3:8][C:4]1([C:18]#[N:19])[CH2:5][CH2:6][CH2:7][C:2]([CH3:1])([CH2:9][O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:3]1
Reactant: CC1=CCCC(C)(COCc2ccccc2)O1
Reactant: C#N
Solvent: c1ccncc1
Product: CC1(C#N)CCCC(C)(COCc2ccccc2)O1
Reaction time: 16 h

Procedure:
A mixture of 15.0 g 3,4-dihydro-2,6-dimethyl-2-[(phenylmethoxy)methyl]-2H-pyran, 1.75 g liquid hydrogen cyanide, and 0.1 g pyridine sealed in a 30 ml glass bomb was kept at 150° C. for 16 hours. The resulting dark brown solution was distilled (Kugelrohr) to give 15.7 g colorless product, bp 112°-118° C. (0.01 torr), as an isomeric mixture, ca 4:6, cis:trans, based on NMR spectrum in CDCl3.