Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH2:20][CH2:19]2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CO.C(OCC)C>C(Cl)Cl>[NH:14]1[CH2:15][CH:16]([N:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:29])[C:25]([F:26])([F:27])[F:28])[CH2:22][CH2:23]2)[CH2:17]1
Reactant: O=C(N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1)C(F)(F)F
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(N1CCN(C2CNC2)CC1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-[4-(1-benzhydryl-azetidin-3-yl)-piperazin-1-yl]-2,2,2-trifluoro-ethanone (2.11 g, 5.23 mmol) in CH2Cl2 (60 mL) was added 1-chloroethyl chloroformate (2.0 mL, 18.35 mmol) at 0° C. under N2. The resulting mixture was stirred at 0° C. for 90 min and then methanol (4 mL) was added. The resulting mixture was refluxed for 1 h. Upon cooling, diethyl ether (50 mL) was added to the mixture. The resulting solid was collected by filtration and dried to yield the title compound, which was used in the next reaction without further purification. MS m/z (M+H+) 238.1.
Reaction SMILES: [C:1]1([N:11]2[C:15]([S:16][CH2:17][C:18]([OH:20])=O)=[N:14][N:13]=[N:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:18](=[O:20])[CH2:17][S:16][C:15]1[N:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[N:12]=[N:13][N:14]=1
Reactant: O=C(O)CSc1nnnn1-c1cccc2ccccc12
Reactant: Nc1ccccc1Cl
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(CSc1nnnn1-c1cccc2ccccc12)Nc1ccccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
2-{{1-(1-Naphthalenyl)-1H-tetrazol-5-yl}thio}acetic acid (500 mg, 1.75 mmol) and 2-chloroaniline (202 μL, 1.92 mmol) were dissolved in dry pyridine (8 mL). This solution was cooled to 0° C. and POCl3 (0.179 mL) was added dropwise. The mixture was stirred at 0° C. for 1 h, quenched with a few drops of water, and concentrated under reduced pressure. The crude product was dissolved in CH2Cl2 (100 mL) and the resulting solution was successively washed with water (2×30 ml) and brine (30 ml), dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (CH2Cl2:(CH3)2CO, 95:5) to afford the title compound (643 mg, 85% yield) as a solid.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]#[C:23][CH:24]2[CH2:26][CH2:25]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CN(C)C=O.[Cu]I>[Si:1]([O:8][CH:9]1[CH2:10][CH2:11][CH:12]([N:15]2[C:16]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:22]=[C:23]2[CH:24]2[CH2:25][CH2:26]2)[CH2:13][CH2:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(Nc2ccccc2C#CC2CC2)CC1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCC(n2c(C3CC3)cc3ccccc32)CC1
Temperature: 25 °C

Procedure:
To a solution of [4-(tert-butyldimethylsilanyloxy)cyclohexyl]-(2-cyclopropylethynylphenyl)amine (3.84 g, 10.4mmol) in N,N-dimethylformamide (60 mL) was added copper(I) iodide (100 mg, 0.525 mmol). After the reaction was refluxed for 48 hours, it was allowed to cool to room temperature, and the solvent was removed in vacuo. The residue was partitioned between water and dichloromethane. The dichloromethane was dried (MgSO4) and concentrated to give a dark residue that was used in the next step with no further purification. LC-MS (C23H35NOSi calc'd 369) m/z 370 (M+H).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C@H:5]2[CH2:4][N:3]1[CH2:11][C:12](C)(C)[C:13]([OH:15])=[O:14].Cl.N[C:20]1(CC(OC)=O)C[CH2:21]1>>[O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C@@H:5]2[CH2:4][N:3]1[C:11]1([CH2:12][C:13]([OH:15])=[O:14])[CH2:21][CH2:20]1
Reactant: CC(C)(CN1C[C@@H]2CNCCN2C1=O)C(=O)O
Reactant: COC(=O)CC1(N)CC1
Agent: Cl
Product: O=C(O)CC1(N2C[C@H]3CNCCN3C2=O)CC1

Procedure:
Compound 47-A was prepared in analogy to compound Q in Example 19 by using methyl 2-(1-aminocyclopropyl)acetate hydrochloride salt (for its synthesis, refer to: Sandstroem A., et al, Bioorganic & Medicinal Chemistry, 16(10), 5590-5605; 2008) instead of ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]3[S:23][CH:24]=[C:25]([C:27]([O:29]CC)=[O:28])[N:26]=3)[CH:20]=2)[CH2:15][CH2:14]1)=[O:12].[Li+].[OH-].O.Cl>CO.CCOC(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]3[S:23][CH:24]=[C:25]([C:27]([OH:29])=[O:28])[N:26]=3)[CH:20]=2)[CH2:15][CH2:14]1)=[O:12]
Reactant: CCOC(=O)c1csc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CC3)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1csc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CC3)n1
Yield: 14.2 %

Procedure:
The title compound 2-(1-(benzo[d]thiazol-2-ylcarbamoyl)indolin-6-yl)thiazole-4-carboxylic acid (28) was prepared by the following procedure: A mixture of ethyl 2-(1-(benzo[d]thiazol-2-ylcarbamoyl)indolin-6-yl)thiazole-4-carboxylate (28E) (22 mg, 0.05 mmol) and LiOH (12 mg, 0.49 mmol) was stirred in MeOH (2 mL) and water (1 mL) for 20 h. The mixture was diluted with EtOAc (5 mL) and acidified with 1M HCl. The organic layer was isolated, washed with H2O, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by HPLC, to provide 3.0 mg (14%) of the desired product 2-(1-(benzo[d]thiazol-2-ylcarbamoyl)indolin-6-yl)thiazole-4-carboxylic acid (28). LC/MS (APCI): m/z 423.1 (M+H), 844.8 (2M+1).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][NH:7][C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8](=[O:10])[CH3:9])=[CH:11][CH:12]=1
Reactant: CC(=O)NCc1ccc(F)cc1
Reactant: BrCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)N(CCCc1ccccc1)Cc1ccc(F)cc1
Reaction time: 8 h
Yield: 18.6 %

Procedure:
N-(4-fluoro-benzyl)-acetamide (697 mg, 4.17 mmol) was suspended in toluene and treated with 668 mg of 60% NaH (mineral oil) followed by (3-bromopropyl)-benzene (1.27 mL, 8.34 mmol) and the resulting mixture stirred overnight. The mixture was filtered and the solvent removed. The crude product was purified by preparative HPLC (C18, MeOH/H2O-0.1% TFA) to yield 221 mg (19% yield) N-(4-Fluoro-benzyl)-N-(3-phenyl-propyl)-acetamide. HRMS (M+H) calcd for C18H21FNO: 286.1607; found: 286.1603. 1H NMR and 13C NMR show a mixture of rotamers at room temperature. 1H NMR (500 MHz, CDCl3) δ: 1.89 (m), 2.11 (s), 2.16 (s), 2.60 (t, J=7), 3.19 (dd, J=8, 8), 3.41 (dd, J=8, 8), 4.46 (s), 4.54 (s), 6.96-7.32 (overlapping m). 13C NMR (125 MHz, CDCl3) δ: 20.67, 21.21, 28.71, 29.53, 32.77, 33.14, 46.21, 47.25, 48.04, 51.60, 115.48, 115.65, 115.95, 116.12, 116.22, 126.04, 126.44, 128.01, 128.07, 128.28, 128.46, 128.68, 129.94, 130.01, 131.57, 131.59, 132.61, 132.64, 140.32, 141.19, 158.96, 159.28, 161.32, 161.37, 163.28, 163.34, 172.14, 172.46.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:27]([OH:32])[CH2:28][CH2:29][C:30]#[CH:31].[OH-].[Na+]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:31]#[C:30][CH2:29][CH2:28][CH2:27][OH:32]
Reactant: Brc1ccccn1
Reactant: C#CCCCO
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: OCCCC#Cc1ccccn1
Reaction time: 0.08 h

Procedure:
A mixture of 2-bromopyridine (5 g, 31.6 mmol), palladium (II) acetate (5 mg), copper (I) iodide (5 mg), triphenylphosphine (5 mg) in triethylamine (40 ml) was deaerated with argon for 5 minutes. After 4-pentyn-1-ol (3.49 ml, 37.9 mmol) was added, the solution was rapidly heated to reflux under argon and conditions maintained for 22 hours. On cooling, the mixture was poured into 2M sodium hydroxide (ca. 30 ml) and extracted thoroughly with ethyl acetate. Evaporation of the dried (magnesium sulphate) extracts gave an oil, which was flash chromatographed on silica using 60% ethyl acetate/chloroform. Fractions with Rf of about 0.12 on evaporation gave the title alcohol as a pale brown oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:33])([F:32])[C:10]1[N:14]2[N:15]=[C:16]([N:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH2:17][CH2:18][C:13]2=[N:12][N:11]=1>C(Cl)Cl>[N:19]1([C:16]2[CH2:17][CH2:18][C:13]3[N:14]([C:10]([C:9]([F:8])([F:32])[F:33])=[N:11][N:12]=3)[N:15]=2)[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2=Nn3c(nnc3C(F)(F)F)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1nnc2n1N=C(N1CCNCC1)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
TFA (5 mL) was added to tert-butyl 4-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazine-1-carboxylate (1.88 g, 5.02 mmol) in DCM (5 mL). The resulting solution was stirred at ambient temperature for 30 minutes then added to a SCX column. The desired product was eluted from the column using 2M ammonia in methanol and the solvents were evaporated to dryness to give 6-(piperazin-1-yl)-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine (1.360 g, 99%) as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][C:8]([CH3:13])([CH3:12])[CH:9]3[O:11][CH:10]3[C:5]=2[CH:4]=1)#[N:2].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=[O:22].[H-].[Na+].O>CS(C)=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][C:8]([CH3:13])([CH3:12])[C@@H:9]([OH:11])[C@H:10]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]3=[O:22])[C:5]=2[CH:4]=1)#[N:2]
Reactant: O=C1CCCCN1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCCCC2=O)[C@@H]1O
Reaction time: 6 h

Procedure:
6-Cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-benzo[b]pyran and 2-piperidone were stirred in dimethyl sulphoxide under nitrogen at room temperature. Sodium hydride (81% dispersion in mineral oil) was added during 5 mins. and the reaction stirred for a further 6 hours. Addition of water, extraction with ethyl acetate, drying of the organic phase with magnesium sulpate, filtration, evaporation and recrystallisation from ethyl acetate gave 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-piperidinyl)-2H-benzo[b]pyran-3-ol was prepared, as crystals of m.p. 155° C.
Reaction SMILES: C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.[CH:18]1[C:30]2[CH:29]([C:31](O)=[O:32])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1.Cl.[NH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38]>C(Cl)Cl.O>[CH:18]1[C:30]2[CH:29]([C:31]([NH:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[O:32])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)C1c2ccccc2-c2ccccc21
Reactant: COC(=O)CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CNC(=O)C1c2ccccc2-c2ccccc21
Reaction time: 20 h
Yield: 93.2 %

Procedure:
1.2 ml of triethylamine and 1.31 g of 1-hydroxybenzotriazole were successively added, under ice-cooling, to a solution of 1.5 g of fluorene-9-carboxylic acid and 0.90 g of methyl glycinate hydrochloride in 50 ml of methylene chloride, followed by further adding 10 minutes later 1.64 g of water-soluble carbodiimide hydrochloride. The resultant mixture was stirred at 0° C. for 0.5 hour and, then at room temperature for 20 hours. The reaction mixture was washed with 5% hydrochloric acid, saturated sodium bicarbonate, and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by a silica gel column chromatography (eluting solution: chloroform-methanol) to give 1.87 g of methyl N-(9-fluorenylcarbonyl)glycinate.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[O:18][C:19]([CH3:30])=[C:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:21]=4)=[C:13]([NH:31][CH:32]([CH3:34])[CH3:33])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[H-].[Na+].[CH3:37][C:38](OC(C)=O)=[O:39]>O1CCCC1>[C:38]([N:22]([C:20]1[N:21]=[C:17]([C:14]2[CH:15]=[N:16][C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]4[N:3]=[CH:2][S:1][C:5]=4[CH:6]=3)=[CH:12][C:13]=2[NH:31][CH:32]([CH3:34])[CH3:33])[O:18][C:19]=1[CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])(=[O:39])[CH3:37]
Reactant: Cc1oc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)nc1NC(=O)OC(C)(C)C
Reactant: CC(=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(C(=O)OC(C)(C)C)c1nc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)oc1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of tert-butyl 2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazol-4-ylcarbamate (Example 106) (20 mg, 0.042 mmol) in Tetrahydrofuran (5 mL) was cooled to 0° C. and treated with NaH (0.042 mmol). Stirred the reaction mixture at 0° C. for 10 min. Added Ac2O (0.042 mmol) to the reaction mixture and stirred at 0° C. for 0.5 h. The reaction mixture was quenched with ice pieces and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, filtered and concentrated to afford tert-butyl acetyl(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazol-4-yl)carbamate. LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA in water; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min; retention time: 0.90 min; LCMS (ES-API), m/z 523.6 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH:7]([CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8](O)=O)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1.C=O.Cl>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:21])[C:7]([CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH2:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(CCOCc1ccccc1)C(=O)O
Agent: C=O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: C=C(CCOCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of 2-(2-benzyloxyethyl) malonic acid mono tert-butyl ester (23.9 g, 81.2 mmol), piperidine (1.31 mL, 13.2 mmol), and paraformaldehyde (3.7 g, 123 mmol) in pyridine (160 mL) was heated at a temperature of 70° C. for 3 hours. After cooling to room temperature, the mixture was poured over ice. The mixture was acidified using 6N HCl solution and then extracted twice with ether; the extracts were combined, washed with brine, dried over MgSO4 and concentrated under vacuum to leave an oil. The oil was chromatographed on silica gel using 6% ethyl acetate in hexane to afford 2-(2-benzyloxyethyl)acrylic acid tert-butyl ester as a clear oil, 18.51 g (87%).
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:17][C:16]3=[CH:18][NH:19][C:14]4[C:15]3=[C:10]([CH:11]=[CH:12][N:13]=4)[C:9]2=[O:20])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:28]([CH2:30][C:31](ON1C(=O)CCC1=O)=[O:32])#[N:29]>CCO>[CH3:1][C:2]1([N:8]2[CH2:17][C:16]3=[CH:18][NH:19][C:14]4[C:15]3=[C:10]([CH:11]=[CH:12][N:13]=4)[C:9]2=[O:20])[CH2:7][CH2:6][N:5]([C:31](=[O:32])[CH2:30][C:28]#[N:29])[CH2:4][CH2:3]1
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Reactant: CC1(N2Cc3c[nH]c4nccc(c34)C2=O)CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1(N2Cc3c[nH]c4nccc(c34)C2=O)CCN(C(=O)CC#N)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 49.4 %

Procedure:
4-(4-Methylpiperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one (21 mg, 0.078 mmol) and triethylamine (0.032 mL, 0.233 mmol) were dissolved in EtOH (4 mL) and cooled to 0° C. and allowed to stir for 10 min. Then 2,5-dioxopyrrolidin-1-yl 2-cyanoacetate (17 mg, 0.093 mmol) dissolved in EtOH (1 mL) was added dropwise and the mixture was allowed to stir for 30 min at 0° C. The solution was concentrated in vacuo and purified via preparative HPLC 10% to 40% B in A and gave 13 mg of the title compound as its TFA salt. 1H NMR (400 MHz, CD3OD) δ 7.61 (m, 1H), 7.43 (m, 1H), 5.08 (s, 2H), 3.90 (m, 2H), 3.72 (m, 1H), 3.61-3.62 (m, 1H), 3.51-3.52 (m, 2H), 2.65-2.69 (m, 1H), 2.51-2.57 (m, 1H), 2.22-2.26 (m, 1H), 2.10-2.12 (m, 1H), 1.66 (s, 3H). [M+H] found 338.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][C:14](=[O:22])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1.NC1C(C(OCC)=[O:31])=NC=CC=1.C1C=CC(CC(Cl)=O)=CC=1.CC1(C(F)(F)F)OO1.FC(F)(F)C(C)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[N+:6]([O-:31])[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([NH:13][C:14](=[O:22])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]=1
Reactant: CCOC(=O)c1ncccc1N
Reactant: CCOC(=O)c1ncc(Cl)cc1NC(=O)Cc1ccccc1
Agent: CC(=O)C(F)(F)F
Agent: CC1(C(F)(F)F)OO1
Agent: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)c1c(NC(=O)Cc2ccccc2)cc(Cl)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 96 h
Yield: 4 %

Procedure:
Ethyl 5-chloro-3-(phenylacetamido)picolinate (153) was formed by reacting ethyl 3-aminopicolinate and phenacetyl chloride under the conditions described in Example 3. The amide (153) (10.0 mg, 0.0324 mmol) was added to a CH2Cl2 solution (10 mL) of methyl(trifluoromethyl)dioxirane, generated from 2.5 mL of 1,1,1-trifluoroacetone using the procedure of Mello et al. (Mello et al., J. Amer. Chem. Soc. 111:6749-6757 (1989)). The solution was stirred at rt in a bomb protected from light. After 4 days, the solvent was removed and the residue chromatographed by prep TLC (silica GF). Eluting with hexanes-EtOAc (1:4), the band at Rf =0.45 was removed and triturated with MeOH (40 mL) overnight. The mixture was filtered and the filtrate rota-evaporated to dryness, leaving a white residue (0.4 mg, 4%). 1H NMR (CDCl3): δ1.26 (t, J=7.2, 3, CH3CH2), 3.75 (s, 2, benzylic), 4.10 (q, J=7.2, 2, CH3CH2O), 7.37 (m, 5, phenyl), 7.98 (d, J=0.9, 1, py), 8.44 (s, 1, py); LRMS (m/z):336 (5), 335 (5), 334 (M+, 20), 274 (15), 273 (10), 272 (55), 260 (10), 226 (10), 180 (10), 156 (10), 154 (30), 126 (10), 117 (20), 91 (100), 65 (15); HRMS Calcd for C16H15ClN2O4 : 334.0720, Found: 334.0729; HPLC: 77%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17][OH:18])[CH2:13][C:12]=2[CH:11]=[CH:10][C:9]=1[Cl:19].[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:18][CH2:17][CH:14]2[CH2:13][C:12]3[CH:11]=[CH:10][C:9]([Cl:19])=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:16]=3[O:15]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1Cc2ccc(Cl)c(-c3ccccc3Cl)c2O1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3ccc(Cl)c(-c4ccccc4Cl)c3O2)cc1
Yield: 86.2 %

Procedure:
Treatment of 1-bromo-2-chlorobenzene (5.0 g, 26.88 mmol) with (2-chloro-6-methyoxyphenyl)boronic acid (15.6 g, 80.64 mol) generally according to the procedure described for Intermediate 37 afforded 5.0 g (73%) of 6-chloro-2′-chlorobiphenyl-2-yl methyl ether. Treatment of 6-chloro-2′-methylbiphenyl-2-yl methyl ether with hydrogen bromide (60 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 395 afforded a brown oil. The oil was reacted with sodium hydride (1.05 g, 26.35 mmol) and allyl bromide (3.19 g, 26.35 mmol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-6-chloro-2′-chlorobiphenyl-2-ol. Treatment of 3-allyl-6-chloro-2′-chlorobiphenyl-2-ol (2.8 g, 10.03 mmol) with m-chloroperoxybenzoic acid (4.6 g, 15.0 mmol, 77%) and potassium carbonate (1.6 g, 12.0 mmol) generally according to the procedure described for Intermediate 9 afforded 2.2 g (74%) of (±)-[7-(2-chlorophenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment (±)-[7-(2-chlorophenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol (1.6 g, 5.42 mmol) with p-toluenesulfonyl chloride (1.55 g, 8.13 mmol) generally according to the procedure described for Intermediate 10 gave 2.1 g (86%) of (±)-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.2 g, 0.44 mmol) with sodium azide (0.2 g, 3.08 mmol) generally according to the procedure described for Intermediate 98 afforded 0.14 g, (99%) of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-chloro-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-chloro-2,3-dihydro-1-benzofuran (0.14 g, 0.43 mmol) in tetrahydrofuran (10 mL) with polymer-supported triphenylphosphine (0.3 g, 1.14 mmol) generally according to the procedure described for Example 154 provided 0.036 g (24%) of (±)-{[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 221-223° C.
Reaction SMILES: O.[C:2]([NH:5][O-:6])(=[O:4])[CH3:3].[K+].[Cl:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:11][CH:10]=1.[K+].[Br-]>COCCO>[C:2]([NH:5][O:6][CH2:16][CH2:15][CH2:14][O:13][C:12]1[CH:11]=[CH:10][C:9]([Cl:8])=[CH:19][CH:18]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)N[O-]
Reactant: Clc1ccc(OCCCBr)cc1
Agent: [Br-]
Agent: [K+]
Solvent: COCCO
Solvent: O
Product: CC(=O)NOCCCOc1ccc(Cl)cc1
Temperature: 50 °C
Yield: 105.8 %

Procedure:
To a solution of 0.91 kg (8.0 moles) of potassium acetohydroxamate hydrate in 4.96 kg of 2-methoxyethanol solution was added 1650 g (6.62 moles) of 3-(4-chlorophenoxy)propyl bromide. An additional 200 mL of 2-methoxyethanol was added and the reaction mixture was heated 2 hours at 50° C. After cooling to room temperature the KBr was removed by filtration and washed with 100 mL of 2-methoxyethanol. The filtrate and washings were concentrated on a rotovap, diluted with 1.0 L of EtOAc, and washed with a 600 mL and a 400 mL portion of water before concentration at high vacuum to yield 1707 g of crude 3-(4chlorophenoxy)propyl acetohydroxamate which was used without further purification. This crude material was dissolved in 5.0 L of methanol and 640 g of conc. HCl was added. After 15 hr the starting material was consumed, as determined by TLC utilizing the diazonium spray. The mixture was concentrated at oil pump vacuum to give 1537 g of crude product which was used without further purification. A sample recrystallized from EtOAc melted 115-116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.Cl.Cl.[Cl:15][C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C>C(O)CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:25]3[CH2:24][CH2:23][N:22]([C:18]4[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=4)[CH2:27][CH2:26]3)[N:10]=2)[CH:7]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Agent: Cl
Solvent: OCCO
Solvent: CCN(CC)CC
Product: Clc1cccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)c1
Yield: 58.5 %

Procedure:
Following the general procedure of Example 11 and making noncritical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 4, Step 1; 0.354 g), 1-(3-chlorophenyl)piperazine dihydrochloride (Aldrich; 0.475 g), triethylamine (0.552 g), and ethylene glycol (2 mL) give 0.372 g of the title compound after chromatography (silica gel, methanol/dichloromethane, 4/96) and crystallization from dichloromethane/hexane; mp 148-149° C.; MS m/z 360; IR (mineral oil) 1594, 1340, 1073, 1218, 1502 cm-1. 1H NMR (CDCl3) δ2.71, 3.23, 3.76, 6.79, 6.86, 7.14, 7.52, 7.53, 8.14.