Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[N:5][N:6]([CH2:8][C:9]2[NH:10][C:11](=[O:19])[C:12]3[CH:17]=[C:16]([CH3:18])[S:15][C:13]=3[N:14]=2)[CH:7]=1.[H-].[Na+].I[CH3:27].Cl>CN(C=O)C>[OH:1][CH2:2][C:3]1[C:4]([C:20]([F:22])([F:21])[F:23])=[N:5][N:6]([CH2:8][C:9]2[N:10]([CH3:27])[C:11](=[O:19])[C:12]3[CH:17]=[C:16]([CH3:18])[S:15][C:13]=3[N:14]=2)[CH:7]=1
Reactant: CI
Reactant: Cc1cc2c(=O)[nH]c(Cn3cc(CO)c(C(F)(F)F)n3)nc2s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(=O)n(C)c(Cn3cc(CO)c(C(F)(F)F)n3)nc2s1
Temperature: 60 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
2-((4-(Hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-6-methylthieno[2,3-d]pyrimidin-4(3H)-one (240 mg, 0.697 mmol) was dissolved in DMF (5 mL). NaH (17 mg, 0.708 mmol) was added and the reaction mixture heated at 60° C. for 1 h, then allowed to cool to RT before cooling further with an ice/salt bath to 0° C. Iodomethane (1.14 g, 0.50 mL, 8.03 mmol) was added in one portion and the reaction mixture stirred at RT for 1 h, then allowed to warm to RT, before standing overnight. The reaction mixture was acidified with 2M HCl and extracted into EtOAc (×3). The EtOAc layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification by preparative reverse phase HPLC gave the title product as a white solid (76 mg, 0.213 mmol, 31%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].CC1(C)[O:24][C:23](=O)[CH2:22][C:21](=[O:26])[O:20]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:8]=[C:7]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:23]([CH2:22][C:21]([OH:26])=[O:20])=[O:24]
Reactant: Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1Br
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: Cc1ccccc1
Product: O=C(O)CC(=O)Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1Br
Temperature: 88 °C
Reaction time: 8 h

Procedure:
Into a 1-mL round-bottom flask, was placed a solution of 2-bromo-4-[(4-chlorophenyl)carbonyl]aniline (28.62 g, 92.15 mmol, 1.00 equip) in toluene (400 mL), and 2,2-dimethyl-1,3-dioxane-4,6-dione (25.92 g, 179.84 mmol, 2.00 equip). The resulting solution was stirred overnight at 88° C. The solution was cooled to room temperature and the solids were collected by filtration to yield 2-([2-bromo-4-[(4-chlorophenyl)carbonyl]phenyl]carbamoyl)acetic acid as a yellow solid. LCMS (ES, m/z) 396 [M+H]+
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C-:15]#[N:16].[Na+]>C(C(C)=O)C.[Zn].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:12][C:11]([F:14])([F:13])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([C:15]#[N:16])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: [C-]#N
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(F)(F)F
Agent: [Na+]
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCC(C)=O
Product: N#Cc1ccc(S(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
Under an atmosphere of nitrogen, a mixture of 4 g of bis-triphenylphosphine-nickel dichloride, 3 g of triphenylphosphine and 100 ml of MEK was stirred at room temperature for 10 minutes. 1.2 g of activated zinc powder were then added, and the reaction mixture was stirred at 70° C. for 30 minutes. Following this, the mixture was allowed to cool to 25° C., and a solution of 92 g of 4-chloro-trifluoromethanesulphonylbenzene in 50 ml of MEK was added dropwise. The mixture was stirred for 10 minutes, 18.5 g of sodium cyanide were then added and the reaction mixture was stirred at from 65 to 70° C. for 20 h. The conversion after this period of time was greater than 98% (GC). After cooling to RT, the mixture was filtered, the solid filter residue was washed 2× with 30 ml of MEK each time and the combined organic phases were concentrated under reduced pressure. Fractionation under reduced pressure via a 30 cm Vigreux column and heated distillation bridge gave 76 g (85% of theory) of 4-trifluoromethanesulphonylbenzonitrile as a white solid (boiling point at 0.2 mbar: 115° C.). A formation of coupling products was not observed.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[N:13]1([CH2:19][C:20]([NH:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[O:21])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[NH2:8][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[C:3]([N:16]2[CH2:17][CH2:18][N:13]([CH2:19][C:20]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:21])[CH2:14][CH2:15]2)[C:2]([Br:1])=[CH:7][N:6]=1
Reactant: O=C(CN1CCNCC1)Nc1cccnc1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3cccnc3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 5-bromo-4-chloro-3-nitro-pyridin-2-ylamine (0.126 g, 0.50 mmol) and isopropanol (10 ml) was added 2-(piperazin-1-yl)-N-(pyridin-3-yl)acetamide×3HCl salt (0.180 g, 0.55 mmol) followed by diisopropylethylamine (0.41 ml, 2.36 mmol). The reaction mixture was heated at 45° C. for 18 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 2.5% methanol in ethyl acetate. The title compound was obtained as a yellow solid (0.180 g, 82%); 1H-NMR (500 MHz, DMSO-d6) 2.68 (br s, 4H, piperazine N(CH2)2), 3.14 (br s, 4H, piperazine N(CH2)2), 3.24 (s, 2H, NCH2CO), 6.98 (br s, 2H, NH2), 7.34 (dd, J=8.10, 4.75 Hz, 1H, pyridyl 5-H), 8.06 (d, J=7.50 Hz, 1H, pyridyl 4-H), 8.16 (s, 1H, 6-H), 8.27 (dd, J=4.80, 1.96 Hz, 1H, pyridyl 6-H), 8.78 (d, J=2.30 Hz, 1H, pyridyl 2-H), 9.95 (s, 1H, CONH);
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][N:8]=2)[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:25]1[CH:30]=[C:29]([C:31]2[C:40]3[C:35](=[CH:36][C:37]([O:43][CH3:44])=[C:38]([O:41][CH3:42])[CH:39]=3)[C:34](=[O:45])[N:33]([CH2:46][C:47]3[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=3)[N:32]=2)[CH:28]=[CH:27][N:26]=1.N>CN(C)C=O.[Cu](I)I>[CH3:42][O:41][C:38]1[CH:39]=[C:40]2[C:35](=[CH:36][C:37]=1[O:43][CH3:44])[C:34](=[O:45])[N:33]([CH2:46][C:47]1[CH:48]=[CH:49][N:50]=[CH:51][CH:52]=1)[N:32]=[C:31]2[C:29]1[CH:30]=[CH:25][N:26]=[C:27]([N:9]2[N:8]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:17])[CH:28]=1
Reactant: COc1cc2c(-c3ccnc(Br)c3)nn(Cc3ccncc3)c(=O)c2cc1OC
Reactant: O=c1[nH]nc(-c2cccnc2)c2ccccc12
Agent: I[Cu]I
Agent: N
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cc2c(-c3ccnc(-n4nc(-c5cccnc5)c5ccccc5c4=O)c3)nn(Cc3ccncc3)c(=O)c2cc1OC
Yield: 49.1 %

Procedure:
To a solution of 4-(3-pyridyl)phthalazin-1(2H)-one (167 mg) in dimethylformamide (5 ml) are added successively potassium carbonate (103 mg), copper iodide (70 mg) and 2-bromo-4-[6,7-dimethoxy-2-(4-pyridyl)methyl-phthalazin-1(2H)-on-4-yl]pyridine (335 mg) under nitrogen atmosphere, and the mixture is refluxed for two hours. The reaction mixture is cooled, and thereto is added aqueous ammonia. The mixture is extracted with chloroform, and the extract is washed, dried, concentrated, and purified by silica gel column chromatography (solvent; chloroform:methanol=19:1) to give 4-[6,7-dimethoxy-2-(4-pyridyl)methylphthalazin-1(2H)-on-4-yl]-2-[4-(3-pyridyl)-phthalazin-1(2H)-on-2-yl]pyridine (216 mg).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].C(OC(=O)C)(=O)C.[Cl:12][C:13]([F:26])([F:25])[C:14]1([C:21]([Cl:24])([F:23])[F:22])[O:18][CH:17]([CH2:19]O)[CH2:16][O:15]1>O>[N+:1]([O-:4])([O:3][CH2:19][CH:17]1[CH2:16][O:15][C:14]([C:13]([Cl:12])([F:25])[F:26])([C:21]([Cl:24])([F:22])[F:23])[O:18]1)=[O:2]
Reactant: OCC1COC(C(F)(F)Cl)(C(F)(F)Cl)O1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=[N+]([O-])OCC1COC(C(F)(F)Cl)(C(F)(F)Cl)O1
Reaction time: 0.5 h

Procedure:
34 ml nitric acid (96%) is added slowly to 43 ml chilled acetic anhydride. Then, 14.8 grams of 2,2-bis(chlorodifluoromethyl)-4-hydroxymethyl-1,3-dioxolane, is added dropwise with magnetic stirring over a 30 minute period to the chilled mixed acid (0 to -10° C.). An additional 25 minutes of stirring is allowed. The reaction mixture is drowned in 250 ml of cold tap water forming a small lower liquid layer. Ether extraction (3 × 75 ml) removed the lower layer and all of the yellow coloration. The ether solution is washed several times with water and then dried over Na2SO4, filtered and evaporated on a rotary evaporator. The cloudy residue is redissolved in ether, treated with Na2SO4, decanted and evaporated as before. The bright yellow liquid is redissolved in ether and treated with activated carbon (DARCO G-60), then filtered (colorless), and reevaporated to yield the above named product.
Reaction SMILES: [N+]([C:4]1[CH:18]=[CH:17][C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:6]=2[C:5]=1[CH2:19][C:20]#[N:21])([O-])=O.[OH:22]S(O)(=O)=O.O>O.C(O)(=O)C.[Zn]>[C:11]1([C:9]2[O:10][C:6]3[C:7]([N:8]=2)=[CH:17][CH:18]=[C:4]2[C:5]=3[CH2:19][C:20](=[O:22])[NH:21]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=S(=O)(O)O
Reactant: N#CCc1c([N+](=O)[O-])ccc2nc(-c3ccccc3)oc12
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: O=C1Cc2c(ccc3nc(-c4ccccc4)oc23)N1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of (6-nitro-2-phenyl-benzoxazole-7-yl)-acetonitrile (66 mg 0.23 mmol) (Starting Material 7) was suspended in concentrated H2SO4/H2O (1/1, 2 mL)) and stirred at 100° C. for 30 min. The resulting solution was diluted with water and extracted with ethyl acetate, and the combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give the crude acid. To a solution of the crude acid in acetic acid (3 mL) heated at reflux was added excess zinc dust (120 mg, 1.85 mmol) portionwise during thirty minutes. The mixture was filtered through a Celite® pad and washed with hot DMF. The solvent was removed in vacuo and residue was suspended and stirred for 30 minutes in 3M hydrochloric acid. The insoluble solid material was collected, washed with water, and air dried to give 2-phenyl-6,8-dihydro-oxazolo[5,4-e]indol-7-one. (Yield 17 mg, 30%)
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15](C(OC(C)(C)C)=O)[C:16]1[CH:25]=[CH:24][C:23]2[C:22]3=[CH:26][CH:27]=[N:28][N:21]3[CH2:20][CH2:19][C:18]=2[C:17]=1[C:29]([O:31][CH3:32])=[O:30])=O)(C)(C)C.C(OC(NC1C=CC2C3=CC=NN3CCC=2C=1C(OC)=O)=O)(C)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[NH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:22]3=[CH:26][CH:27]=[N:28][N:21]3[CH2:20][CH2:19][C:18]=2[C:17]=1[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2c1CCn1nccc1-2
Agent: COC(=O)c1c(NC(=O)OC(C)(C)C)ccc2c1CCn1nccc1-2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(N)ccc2c1CCn1nccc1-2
Reaction time: 0.25 h

Procedure:
TFA (1 mL) was added to a mixture of methyl 8-[bis-(tert-butoxycarbonyl)amino]-5,6-dihydropyrazolo[5,1-a]isoquinoline-7-carboxylate and methyl 8-tert-butoxycarbonylamino-5,6-dihydropyrazolo[5,1-a]isoquinoline-7-carboxylate (Intermediate 23, 0.114 g) in DCM (2 mL) and the resultant mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added and the mixture was stirred for 15 minutes, then extracted with DCM, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to give methyl 8-amino-5,6-dihydropyrazolo[5,1-a]isoquinoline-7-carboxylate (0.060 g) as a gum.
Reaction SMILES: Cl.CN(C)CCCC(N=C=N)C.[CH2:13]([O:20][C:21]1[CH:38]=[CH:37][C:36]([Br:39])=[CH:35][C:22]=1[CH2:23][N:24]([C:27]1[S:28][C:29]([C:32]([OH:34])=O)=[CH:30][N:31]=1)[CH2:25][CH3:26])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:40]1([S:46]([NH2:49])(=[O:48])=[O:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CN(C)C=O.O>[CH2:13]([O:20][C:21]1[CH:38]=[CH:37][C:36]([Br:39])=[CH:35][C:22]=1[CH2:23][N:24]([C:27]1[S:28][C:29]([C:32]([NH:49][S:46]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)(=[O:48])=[O:47])=[O:34])=[CH:30][N:31]=1)[CH2:25][CH3:26])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ncc(C(=O)O)s1
Reactant: NS(=O)(=O)c1ccccc1
Agent: CC(CCCN(C)C)N=C=N
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ncc(C(=O)NS(=O)(=O)c2ccccc2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(3--Dimethylaminopropyl)ethylcarbodiimide hydrochloride (0.85 g) was added to a stirred mixture of 2-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylamino]thiazole-5-carboxylic acid (1 g), benzenesulphonamide (0.35 g), 4-dimethylaminopyridine (0.27 g) and triethylamine (0.225 g) in N,N-dimethylformamide (100 mL) and the mixture was stirred at ambient temperature for 16 hours. Water (30 mL) was added to the reaction mixture which was then extracted three times with ethyl acetate (20 mL each time). The combined ethyl acetate extracts were washed consecutively with aqueous 2N HCL (3×10 mL), aqueous saturated NaHCO solution (3×10 mL) and water (10 mL) and dried. The residue obtained on evaporation of the solvent was filtered through silica using ethyl acetate as eluant. The solvent was evaporated and on trituration with diethyl ether the residue gave 2-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylamino]-N-(phenylsulphonyl)thiazole-5-carboxamide, yield 0.358 g, mp 140°-145° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=O.Cl>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(c1)CC(=O)N2
Temperature: 140 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a solution of 5-methoxyisatin (10.62 g, 60 mmol) in DMSO (30 mL) was added N2H4.×H2O (hydrazine hydrate, 6 mL, 120 mmol) dropwise over 5 min (exothermic). After addition, the resulting mixture was heated at 140° C. (oil temp.) for 2 h and then cooled to rt. After diluting with H2O (30 mL), 6 M HCl (12 mL, 72 mmol) was added and the resulting mixture was stirred for 1 h at rt. Ice (30 mL) was added and the reaction mixture was stirred O/N at rt. The precipitate formed was collected by suction filtration, rinsed with H2O, then dried to give the 5-methoxyoxindole (6.523 g) as a brown solid. (about 10% impurity being the oxime from starting material 5-methoxyisatin) 1H NMR (400 MHz, d6-DMSO) 6.78 (s, 1H), 6.85 (s, 1H), 6.72-6.79 (m, 2H), 3.39 (s, 3H); ESI 164.0 [M+H]+, calcd for [C9H9NO2+H]+ 164.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>C1COCC1.C(OCC)C>[C:11]([Si:8]([CH3:10])([CH3:9])[O:5][CH2:4][CH2:3][CH2:2][NH2:1])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCCN
Reaction time: 1 h
Yield: 91.6 %

Procedure:
A solution of 7.4 g (98 mmol) 3-aminopropanol in 10 ml THF was added at room temperature to a suspension of 4.12 sodium hydride (60%; 103.2 mmol) in 140 ml THF. The mixture was stirred for 1 hour and then 16.28 g (108 mmol) tert-butyl-dimethylsilylchloride was added and vigorous stirring was continued for 1 hour. The mixture was diluted with 300 ml diethylether and washed successively with 100 ml of aqueous K2CO3 (10%), 100 ml of water and 100 ml of brine, dried over MgSO4 and evaporated to give 17 g of light yellow crude product. This product was dissolved in ethyl acetate/hexane 1/10 and filtered through a pad of silica gel. The filtrate was concentrated in vacuo to give 13 g (70%) of the desired product as a colorless oil.
Reaction SMILES: [C:1]1([C:7]23[CH2:16][CH:11]4[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]4)[CH2:8]2)[CH2:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=[O:19])C>C(OC(=O)C)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[OH:19][C:11]12[CH2:12][CH:13]3[CH2:15][CH:9]([CH2:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([CH2:14]3)[CH2:16]1)[CH2:10]2
Reactant: c1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Product: OC12CC3CC(C1)CC(c1ccccc1)(C3)C2
Temperature: 4 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
To a solution of 0.03 mol chromiumtrioxide in 20 ml glacial acetic acid and 20 ml acetic anhydride, add 0.0095 mol of 1-phenyl adamantane at 0° C. and stir for 24 hours at 4° C. Pour the reaction mixture onto water and extract with three portions of pentane. Wash the organic phase with saturated sodium chloride solution, dry over magnesium sulfate, filter and evaporate to dryness under vacuum. Hydrolize the residue with 20 ml of 2N NaOH and 50 ml of methanol. Subsequently, remove the methanol under vacuum and dilute the residue with water. Then extract with three portions of ether. Dry the organic phase, filter and evaporate to dryness under vacuum. Recrystallize the residue from cyclohexane. (Yield: 50%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([CH2:9][C:10]([Cl:12])=[CH2:11])[C:5]([O:7][CH3:8])=[O:6].Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH3:8][O:7][C:5](=[O:6])[C:4]([CH2:9][C:10]([Cl:12])=[CH2:11])([C:3]([O:2][CH3:1])=[O:13])[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: C=C(Cl)CC(C(=O)OC)C(=O)OC
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: C=C(Cl)CC(CC(=O)OC(C)(C)C)(C(=O)OC)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A mixture of the title compound of Example 2A (519.6 g, 2.564 mol) and tert-butyl bromoacetate (500 g, 2.564 mol) was added dropwise over 30 min to a stirred mixture of 10N aqueous NaOH (2.56 L, 25.6 mol) and benzyltriethylammonium chloride (2.56 g, 11.2 mmol) at 10°. The reaction mixture was stirred at room temperature for 2 h and then diluted with Hex (750 mL). The organic phase was separated and washed serially with H2O (100 mL) and brine (2×100 mL), dried (MgSO4), and concentrated under reduced pressure to give the title compound (822 g, 100% yield) which was used without further purification for the next step (Example 2C). 1H NMR (400 MHz, CDCl3) δ5.32 (d, J=1.4 Hz, 1H), 5.20 (broad s, 1H), 3.75 (s, 6H), 3.25 (broad s, 2H), 3.06 (s, 2H), 1.43 (s, 9H). MS (FAB) m/z 321 (MH+).
Reaction SMILES: [Sn](Cl)Cl.[NH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-])=O)=[CH:7][N:6]=1.[OH-].[Na+].CO.C(Cl)Cl>Cl>[NH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([NH2:12])=[CH:7][N:6]=1
Reactant: Cc1cc(N)ncc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(N)ncc1N
Temperature: 90 °C

Procedure:
To a solution of tin(II) chloride (4.95 g, 26.12 mmol) in concentrated hydrochloric acid (13.0 mL) was added 2-amino-5-nitro-4-picoline (1.0 g, 6.53 mmol) and heated at 90° C. for 24 h. The reaction was cooled to room temperature, made basic with 5N NaOH, extracted with ethyl acetate, dried (Na2SO4), and evaporated to give a solid. The crude material was subjected to silica gel chromatography using 10% methanol/methylene chloride as eluant to give the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=3)[CH2:12][CH2:11]2)=[N:2]1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH2:31][C:32](Cl)=[O:33]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:32](=[O:33])[CH2:31][C:27]4[S:26][CH:30]=[CH:29][CH:28]=4)=[CH:23][CH:24]=3)[CH2:14][CH2:15]2)=[N:2]1
Reactant: O=C(Cl)Cc1cccs1
Reactant: Nc1ccc(CCCN2CCN(c3nsc4ccccc34)CC2)cc1
Product: O=C(Cc1cccs1)Nc1ccc(CCCN2CCN(c3nsc4ccccc34)CC2)cc1

Procedure:
N-{4-[3-(4-1,2-Benzoisothiazol-3-yl-piperazin-1-yl)-propyl]-phenyl}-2-thiophen-2-yl-acetamide was prepared according to the procedure outlined in Example 1, starting with 4-[3-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-propyl]-phenylamine (200 mg) and 2-thiopheneacetyl chloride (0.069 mL). The resultant white solid was purified using an ISCO autocolumn eluting with 80% ethyl acetate in hexanes. N-{2-[3-(4,1,2-Benzoisothiazol-3-yl-piperazin-1-yl)-propyl]-phenyl}-2-(4-chloro-phenyl)-acetamide was isolated in 100% purity @ 254 nm; LCMS (APCI): 477 [M+H]+.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5]P(=O)(OC)OC.[CH3:17][O:18][C:19](=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[C:31](=[O:32])[CH2:30][CH2:29][CH2:28][C@@H:27]1[CH:33]=O>C1COCC1>[CH3:17][O:18][C:19](=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[C@@H:27](/[CH:33]=[CH:5]/[C:4](=[O:3])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:28][CH2:29][CH2:30][C:31]1=[O:32]
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Reactant: COC(=O)CCCCCCN1C(=O)CCC[C@@H]1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCC(=O)/C=C/[C@H]1CCCC(=O)N1CCCCCCC(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
Sodium hydride (60% dispersion in oil, 7.2 mg, 0.18 mmol) was added to a solution of dimethyl 2-oxoheptylphosphonate (47 mg, 0.19 mmol) in THF (1 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm to rt. After 1 h at rt, the solution was recooled to 0° C. and 7-((R)-2-formyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester (crude, prepared in accordance with Example 29, step 5, ˜0.20 mmol) in THF (1 mL) was added via cannula. The reaction was allowed to warm to rt. After 17 h at rt, the reaction was quenched with aqueous acetic acid (50%, 5 mL) and extracted with EtOAc (3×10 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 59 mg (90%) of 7-[(R)-2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-heptanoic acid methyl ester.
Reaction SMILES: O[CH:2]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH:26]2[O:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:19][CH:18]=1)[CH2:3][CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][C:9]=1[CH3:10].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>O>[CH3:10][C:9]1[O:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][C:5]=1[CH2:4][CH2:3][CH2:2][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH:26]2[O:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:19][CH:18]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCC(O)c1ccc(CCCC2OC(=O)NC2=O)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1oc(-c2ccccc2)nc1CCCc1ccc(CCCC2OC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
A mixture of 5-[3-[4-[1-hydroxy-3-(5-methyl-2-phenyl-4-oxazolyl)propyl]phenyl]propyl]-2,4-oxazolidinedione (0.14 g), triethylsilane [(C2H5)3SiH] (0.075 g) and trifluoroacetic acid (2 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured over water, neutralized with an aqueous solution of sodium hydrogen carbonate and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and then concentrated under reduced pressure; the residue was purified by silica gel column chromatography. From the fraction eluted with chloroform-methanol (100:3), 5-[3-[4-[3-(5-methyl-2-phenyl-4-oxazolyl)propyl]phenyl]propyl]-2,4-oxazolidinedione (0.11 g, 82%) was obtained, which was then recrystallized from ether-methanol to yield colorless needles having a melting point of 119°-120° C.