Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:30]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[S:35]([C:31]2[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=2)(=[O:37])=[O:36])[CH:7]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3cnccn3)cc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3cnccn3)cc2)S(=O)(=O)c2cccnc2)c1

Procedure:
The title compound of Step B was prepared from 3-{3-[(4-pyrazin-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, of Step A, and pyridine-3-sulfonyl chloride hydrochloride, of Preparation 2, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 8.99 (s, 1H), 8.80 (d, 1H), 8.62 (s, 1H), 8.51 (d, 1H), 8.06 (m, 1H), 7.89 (d, 2H), 7.43 (m, 1H), 7.23 (m, 2H), 7.15 (m, 1H), 7.06 (d, 1H), 6.92 (d, 1H), 6.86 (s, 1H), 4.42 (s, 2H), 4.37 (s, 2H), 3.65 (s, 3H), 2.82 (t, 2H), 2.50 (t, 2H); MS 502 (M+1).
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[NH:5])#[N:2].[ClH:14].[CH2:15]([NH2:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1(C)C=C(C)C=C(C)C=1>[ClH:14].[CH2:7]([NH:6][C:4]([NH:3][C:1]([NH:27][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[NH:2])=[NH:5])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#CNC(=N)NCc1ccccc1
Reactant: CCCCCCCCCCCCN
Agent: Cl
Solvent: Cc1cc(C)cc(C)c1
Product: CCCCCCCCCCCCNC(=N)NC(=N)NCc1ccccc1
Yield: 52.3 %

Procedure:
To 20 g of N1 -cyano-N3 -benzyl-guanidine and 25.4 g of dodecylamine hydrochloride, 200 ml of mesitylene was added, which was heated and refluxed for 2 hours. After reaction, by the same operation as in Example 1, 23.7 g of the captioned compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]2=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(OC(=O)C1C=CC(CN2C3C=CC=CC=3C3C2=CC=CC=3)=CC=1)C>>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:11]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]2[C:12]1=[CH:13][CH:14]=[C:2]([Br:1])[CH:3]=2)[CH3:25]
Reactant: CCOC(=O)CCCCCBr
Reactant: Brc1ccc2[nH]c3c(c2c1)CCCC3
Agent: CCOC(=O)c1ccc(Cn2c3ccccc3c3ccccc32)cc1
Product: CCOC(=O)CCCCCn1c2c(c3cc(Br)ccc31)CCCC2

Procedure:
Compound 31 was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazole (30) (1.50 g, 6.00 mmol) and ethyl 6-bromohexanoate (1.34 g, 6.00 mmol) using the procedure described above for compound 28 as a solid (1.453 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[NH:18][C:12]3=[N+:13]([O-])[CH:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:21])=O.[OH-].[Na+]>>[Cl:21][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:18][C:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:10][C:11]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cccc2cc(CCc3ccccc3)[nH]c21
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccnc2[nH]c(CCc3ccccc3)cc12
Temperature: 0 °C
Yield: 56.3 %

Procedure:
A mixture of 2-(2-phenylethyl)-1H-pyrrolo[2,3-b]pyridine 7-oxide (1.17 g, 4.91 mmol) and phosphorus oxychloride (9.73 g) was heated under reflux for 2 hr. The reaction mixture was poured into ice water, and the mixture was neutralized with sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-0/1) and washed with hexane to give the title compound (0.71 g, yield 56%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]([OH:9])=O)[CH2:2][CH2:3][CH3:4].[NH2:10][C:11]1[N:16]=[N:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>>[CH2:1]([O:5][CH2:6][C:7]([NH:10][C:11]1[N:16]=[N:15][C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:23](=[O:24])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[CH2:21][CH2:22]2)=[CH:13][CH:12]=1)=[O:9])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: CCCCOCC(=O)O
Product: CCCCOCC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 2, making variations only as required to use butoxyacetic acid in place of benzyloxyacetic acid to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (40.8% yield). 1H NMR (300 MHz, CDCl3) δ 9.19, 8.35, 7.72, 7.55, 7.33, 7.03, 4.05, 3.94, 3.60, 3.31, 1.64, 1.43, 0.93. MS (ES+) m/z 465.6 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:14])[C:3]=1[SH:15].C(N(CC)CC)C.Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26]>C(Cl)Cl>[OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:14])[C:3]=1[S:15][CH2:24][C:25](=[O:26])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: O=c1oc(-c2ccccc2)cc(O)c1S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CSc1c(O)cc(-c2ccccc2)oc1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-hydroxy-3-mercapto-6-phenyl-2-pyrone (0.175, 0.840 mmol, prepared as in R. F. Harris, J. E. Dunbar, U.S. Pat. No. 3,818,046) in CH2Cl2 (3.0 mL) under an N2 atmosphere was treated with triethylamine (0.12 mL, 0.84 mmol) followed by bromoacetophenone (0.167 g, 0.840 mmol). The mixture was allowed to stir for 30 min. at ambient temperature then the solvent removed in vacuo. The residue was then diluted with diethyl ether and extracted with saturated Na2CO3 (3×50 mL). The aquous layers were then combined, acidifed with conc. HCl, and extracted with CH2Cl2 (3×100 mL). The organic layers were combined, dried with Na2SO4, and the solvent removed in vacuo to give the title compound (0.066 g, m.p. 164°-166° C.) which was dried in vacuo. 1H NMR (300 MHz, CDCl3) δ 9.900 (bs, 1 H), 7.970 (d, 2 H, J=7.1 Hz), 7.810 (d, 2 H, J=8 Hz), 7.615 (t, 1 H, J=4 Hz), 7.505-7.443 (m, 5 H), 6.619 (s, 1 H), 4.334 (s, 2 H).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[NH2:13][C@H:14]([CH2:16][OH:17])[CH3:15].C(N(CC)CC)C>ClCCl>[OH:17][CH2:16][CH:14]([NH:13][C:8]([C:7]1[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=1)=[O:9])[CH3:15]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: C[C@H](N)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CO)NC(=O)c1cn(C)nc1C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
At 0° C., a solution of 38.9 g 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.2 mol) in 100 ml dichloromethane is added dropwise to a stirred solution of 15 g alaninol (0.2 mol) and 25 g triethylamine (0.25 mol) in 400 ml dichloromethane. The reaction mixture is stirred for 1 h at ambient temperature and then allowed to stand for 3 h at ambient temperature. After removal of the solvent the residue is purified by flash chromatography over silica gel 400 g (eluent: ethyl acetate/methanol 19:1). 42 g (90% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (2-hydroxy-1-methyl-ethyl)-amide is obtained in form of a solid (mp. 81-87° C.).
Reaction SMILES: [Br:1][CH2:2][C:3]([CH:5]1[CH:10]2[CH:8]([C:9]2([CH3:12])[CH3:11])[C:7](=[O:13])[O:6]1)=[O:4].C(Cl)Cl.C(Cl)(Cl)Cl.[Br:21]Br>O>[Br:1][CH:2]([Br:21])[C:3]([CH:5]1[CH:10]2[CH:8]([C:9]2([CH3:11])[CH3:12])[C:7](=[O:13])[O:6]1)=[O:4]
Reactant: CC1(C)C2C(=O)OC(C(=O)CBr)C21
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC1(C)C2C(=O)OC(C(=O)C(Br)Br)C21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
0.125 g of (1R-(1 α, 4 β, 5α))-4-(bromoacetyl)-6,6-dimethyl-3-oxabicyclo [3.1.0] hexan-2-one of Example 3 were mixed under an inert ga atmosphere with 1 ml of methylene chloride and 1 ml of chloroform. 50 μl of bromine were added slowly at +25° to 30° C. and the mixture was stirred for 48 hours at ambient temperature. Water was added, followed by decanting and extracting with methylene chloride. The organic phase was dried and the solvent was evaporated under reduced pressure to obtain 0.199 g of the crude expected product in the form of an oil.
Reaction SMILES: I[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:9]([Si:11]([CH2:19][CH3:20])([CH2:17][CH3:18])[C:12]#[C:13][CH2:14][CH2:15][OH:16])[CH3:10].[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O.CCOC(C)=O.CCOCC>[CH2:19]([Si:11]([CH2:9][CH3:10])([CH2:17][CH3:18])[C:12]1[NH:8][C:3]2=[N:4][CH:5]=[CH:6][CH:7]=[C:2]2[C:13]=1[CH2:14][CH2:15][OH:16])[CH3:20]
Reactant: CC[Si](C#CCCO)(CC)CC
Reactant: Nc1ncccc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: CC[Si](CC)(CC)c1[nH]c2ncccc2c1CCO
Temperature: 100 °C
Reaction time: 15 h
Yield: 79.6 %

Procedure:
A mixture of 3-iodopyridin-2-amine (0.46 g, 2.09 mmole), 4-(triethylsilyl)but-3-in-1-ol (0.58 g, 3.14 mmole), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane (0.083 g, 0.105 mmole), lithium chloride (0.086 g, 2.09 mmole) and sodium carbonate (0.44 g, 4.18 mmole) in DMF (21 ml) was stirred under nitrogen for 15 hours at 100° C. The reaction mixture was cooled to RT, EtOAc/ether (1:1) was added and the mixture was poured into H2O. The two-phase suspension was filtered through filter earth. After separating the phases the aqueous phase was extracted with EtOAc (2×). The organic phases were combined and washed with H2O and with saturated NaCl solution and dried over MgSO4. After filtering off the drying agent the solvents were removed on a rotary evaporator. Column chromatography of the residue (n-hexane/EtOAc=2:1, then n-hexane/EtOAc=1:1) yielded 2-(2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanol (0.46 g, 80%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[Cl:26][CH2:27][CH2:28][CH2:29][CH2:30]I>>[Cl:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([OH:10])=[O:9]
Reactant: ClCCCCI
Reactant: O=C(O)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)C(CCCCCl)c1ccccc1
Yield: 97.8 %

Procedure:
Step AAO (1): 2-Phenylacetic acid (2.19 g, 16.1 mmol) was deprotonated with NaHMDS 2.0 M in THF (18.1 mL, 36.2 mmol) and reacted with 1-chloro-4-iodobutane (3.87 g, 17.7 mmol) using a procedure analogous to Step AC (1) to afford 6-chloro-2-phenylhexanoic acid (3.57 g, quantitative yield) as a pale yellow oil. LC-MS (M−H)− 225.1. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.25-7.39 (5 H, m), 3.58 (1 H, t, J=7.6 Hz), 3.52 (2 H, t, J=6.7 Hz), 2.12 (1 H, dddd, J=13.4, 10.5, 7.8, 5.5 Hz), 1.73-1.90 (3 H, m), 1.34-1.54 (2 H, m).
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8](Br)[CH:9]=[CH2:10].C1(=O)OCC1.BrCCCCCCCCC=C>>[CH2:10]([CH:2]1[CH2:3][CH2:4][CH2:5][O:6][C:1]1=[O:7])[CH:9]=[CH2:8]
Reactant: O=C1CCCCO1
Reactant: C=CCBr
Agent: C=CCCCCCCCCBr
Agent: O=C1CCO1
Product: C=CCC1CCCOC1=O
Yield: 70 %

Procedure:
9.81 g of tetrahydro-3-(2-propenyl)-2H-pyrane-2-one of interest were prepared in the same manner as in Preparation Example 2Z-3 except that 10.01 g (100.0 mmol) of δ-valerolactone and 14.52 g (110.0 mmol) of allyl bromide were used instead of β-propiolactone and 10-bromo-1-decene described in Preparation Example 2Z-3, respectively.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:22]([OH:27])[C:23]([F:26])([F:25])[F:24])[C:8]([O:20][CH3:21])=[C:9]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:28][CH:29]1[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1.C(N(CC)C(C)C)(C)C>C(#N)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:22]([OH:27])[C:23]([F:26])([F:24])[F:25])[C:8]([O:20][CH3:21])=[C:9]([NH:11][C:12]([NH:28][CH:29]2[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30]2)=[O:19])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(NC(=O)OCC(Cl)(Cl)Cl)cc(C(C)(C)C)cc1C(O)C(F)(F)F
Reactant: NC1Cc2ccccc2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1c(NC(=O)NC2Cc3ccccc3C2)cc(C(C)(C)C)cc1C(O)C(F)(F)F
Temperature: 110 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
To a solution of 2,2,2-trichloroethyl 5-tert-butyl-2-methoxy-3-(2,2,2-trifluoro-1-hydroxyethyl)phenylcarbamate (0.150 g, 0.331 mmol) and 2-aminoindane (0.053 g, 0.398 mmol) in acetonitrile (1.0 mL), N,N-diisopropylethylamine (0.173 mL, 0.994 mmol) was added, and the mixture was stirred at 110° C. for 18 hours. The reaction mixture was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=0/100-60/40) to obtain 0.133 g of the captioned compound (92% yield).
Reaction SMILES: C(OC([N:8]1[CH2:19][CH:18]2[CH2:20][CH:10]([CH2:11][C:12]3[C:13](=[O:22])[N:14]([CH3:21])[CH:15]=[CH:16][C:17]=32)[CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[CH3:21][N:14]1[C:13](=[O:22])[C:12]2[CH2:11][CH:10]3[CH2:20][CH:18]([CH2:19][NH:8][CH2:9]3)[C:17]=2[CH:16]=[CH:15]1
Reactant: Cn1ccc2c(c1=O)CC1CC2CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cn1ccc2c(c1=O)CC1CNCC2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.9 %

Procedure:
To 5-methyl-6-oxo-5,11-diaza-tricyclo[7.3.1.02,7]trideca-2(7),3-diene-11-carboxylic acid tert-butylester (22 mg, 0.07 mmol) (prepared above) was added anhydrous 3N HCl in ethyl acetate and the solution was stirred at room temperature for 16 h. The reaction mixture was evaporated in vacuo and the resulting white solid was recrystallized from methanol-ether to afford the desired product (9 mg, 64%). 1H NMR (CD3OD, 400 MHz) δ 7.53 (d, 1H, J=7 Hz), 6.25 (d, 1H, J=7 Hz), 3.54 (s, 3H), 3.3 (obsc. M, 4H), 3.08 (br.s, 1H), 2.85 (dd, 1H, J=19 Hz, J=7 Hz), 2.65 (d, 1H, J=19 Hz), 2.55 (br.s, 1H), 2.08 (d, 1H, J=13 Hz), 1.89 (d, 1H, J=13 Hz); APCl MS m/z 205 (M+1)+.
Reaction SMILES: ClC1C=CC(S[CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=CC=1.S(Cl)([Cl:24])(=O)=O>>[Cl:24][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1
Reactant: FC(F)(F)c1cccc(OCSc2ccc(Cl)cc2)c1
Reactant: O=S(=O)(Cl)Cl
Product: FC(F)(F)c1cccc(OCCl)c1
Yield: 89 %

Procedure:
The title compound was prepared as described in Preparation 3 (b) by reaction of 1-(4-chlorophenylthio) methoxy-3-trifluoromethyl-benzene and sulfuryl chloride; yield 89%, b.p. 88°-90° C./15 mmHg. 1H NMR (CDCl3): δ 5.82 (CH2), 7.26 (Ph). MS [70 eV; m/z (% rel.int.)]: 212/210 (10/34,M); 191 (12), 175 (100), 145 (76), 133 (13), 127 (19), 114 (11), 113 (11).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][CH:4]=C.CSC.[C:11]([NH:18][NH2:19])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C(Cl)Cl>[C:11]([NH:18][N:19]=[CH:4][CH2:3][CH2:2][C:1]([OH:7])=[O:6])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)NN
Reactant: C=CCCC(=O)O
Solvent: ClCCl
Solvent: CSC
Product: CC(C)(C)OC(=O)NN=CCCC(=O)O
Temperature: -78 °C
Yield: 63 %

Procedure:
4-Pentenoic acid (10.00 g, 99.88 mmol) was dissolved in methylene chloride (150 mL), and the mixture was cooled to −78° C. under N2(g). Ozone was bubbled through the reaction mixture, and the course of the reaction was monitored by TLC. After TLC showed disappearance of the starting material (ca. 2.5 h), methyl sulfide (15.0 mL, 205.23 mmol) was added and the reaction mixture was allowed to warm to room temperature. Subsequently, solvent was removed under reduced pressure, and the residue was dissolved in THF (200 mL). BocNHNH2 (13.2 g, 99.88 mmol) was then added, and the reaction mixture was refluxed overnight under Ar(g). Solvent was removed under reduced pressure, and the residue was purified by flash chromatography (silica gel, 6% v/v methanol in methylene chloride) to give BocNHN═CHCH2CH2CO2H as a white solid (13.60 g, 63%). HRMS (ESI) [M−H]− calcd for C9H15N2O4, 215.1032; found, 215.1035; 1H NMR (300 MHz, d6-DMSO) δ 12.16 (s, 1H), 10.45 (s, 1H), 7.30 (app bs, 1H), 2.45-2.30 (m, 4H), 1.41 (s, 9H); 13C NMR (100 MHz, d6-DMSO) δ 173.5, 152.4, 145.6, 78.9, 30.4, 28.1, 27.2.
Reaction SMILES: [F:1][C:2]1[C:15]([F:16])=[C:14](F)[C:13]([F:18])=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH3:19][N:20]([CH2:22][CH:23]1[O:28][CH2:27][CH2:26][NH:25][CH2:24]1)[CH3:21].C(=O)([O-])O.[Na+]>C(#N)C>[CH3:19][N:20]([CH2:22][CH:23]1[CH2:24][N:25]([C:14]2[C:13]([F:18])=[CH:12][C:3]([C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])=[C:2]([F:1])[C:15]=2[F:16])[CH2:26][CH2:27][O:28]1)[CH3:21]
Reactant: CN(C)CC1CNCCO1
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1cc(F)c(N2CCOC(CN(C)C)C2)c(F)c1F
Yield: 77 %

Procedure:
A suspension of 26.4 g of ethyl 2,3,4,5-tetrafluorobenzoylacetate, 18.7 g of 2-(dimethylaminomethyl)morpholine and 8.4 g sodium hydrogencarbonate in 130 ml of acetonitrile is refluxed for 7 hours. The reaction mixture is concentrated under reduced pressure, to the obtained residue is added 100 ml of chloroform and the solution is washed with water. After drying over anhydrous magnesium sulfate, the chloroform is distilled off under reduced pressure and the residue is purified by chromatography on silica gel to give 29.9 g of ethyl 4-[2-(dimethylaminomethyl)morpholino]-2,3,5-trifluorobenzoylacetate in 77% yield as an oily substance.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([CH2:6][CH2:7][C:8]([OH:10])=O)[CH2:3]1.[C:11]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1)([CH3:14])([CH3:13])[CH3:12].N1C=CC=CC=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>O1CCOCC1.CCOC(C)=O>[C:11]([C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:8](=[O:10])[CH2:7][CH2:6][CH:4]2[CH2:3][C:2](=[O:1])[CH2:5]2)=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(O)CCC1CC(=O)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(NC(=O)CCC2CC(=O)C2)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 7 h
Yield: 84.7 %

Procedure:
3-(3-Oxocyclobutyl)propanoic acid (10) (1.610 g, 11.3 mmol) and 4-tert-butyl-2-nitroaniline (11) (2.000 g, 10.3 mmol) were dissolved in 1,4-dioxane (20 ml) and pyridine (2.6 ml, 30.9 mmol) and T3P (50% solution in EtOAc) (9.1 ml, 15.5 mmol) was added at r.t. The reaction was heated to 100° C. and left for 7 hrs. The reaction was cooled to r.t., diluted with EtOAc (20 ml) and washed with 2M NaOH (2×20 ml), 2M HCl (20 ml), brine (20 ml), dried over MgSO4 and concentrated in vacuo to give the crude product. The product was purified by silica flash column chromatography using between 100% heptanes to 40% EtOAc:60% heptanes as eluent to give 12 as a yellow oil (2.776 g, 85%): MS (ESI+) for C17H22N2O4 m/z 319.25 [M+H]+, 341.00 [M+Na]+; LC purity 99% (UV) (ret. time, 2.11 min); 1H NMR (500 MHz, CDCl3) δ 10.28 (s, 1H), 8.66 (d, J=8.9 Hz, 1H), 8.20 (d, J=2.3 Hz, 1H), 7.70 (dd, J=8.9, 2.3 Hz, 1H), 3.30-3.12 (m, 2H), 2.86-2.69 (m, 2H), 2.50 (ddd, J=30.3, 14.9, 7.6 Hz, 3H), 2.07 (q, J=7.6 Hz, 2H), 1.34 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][CH2:13][N:14]=[C:15]=[S:16])[CH:5]=[C:6]([F:10])[C:7]=1[O:8][CH3:9].[N-:17]=[N+:18]=[N-:19].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][CH2:13][N:14]2[C:15]([SH:16])=[N:19][N:18]=[N:17]2)[CH:5]=[C:6]([F:10])[C:7]=1[O:8][CH3:9]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1c(F)cc(CCCN=C=S)cc1F
Agent: [Na+]
Product: COc1c(F)cc(CCCn2nnnc2S)cc1F
Yield: 38.8 %

Procedure:
3-(3,5-Difluoro-4-methoxyphenyl)propylisothiocyanate (0.036 mol) and sodium azide (0.054 mol) were reacted substantially as described in Example 7H above to give 4 g (39%) white crystals: mp 64°-65°.
Reaction SMILES: S(Cl)(Cl)(=O)=[O:2].[Cl:6][C:7]1[CH:8]=[C:9]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]3[NH:28][C:27](=[O:29])[O:26][C:25]([CH3:31])([CH3:30])[C:24]=3[CH:32]=2)[CH:10]=[CH:11][C:12]=1[Cl:13]>C(Cl)Cl>[Cl:6][C:7]1[CH:8]=[C:9]([S:14]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]3[NH:28][C:27](=[O:29])[O:26][C:25]([CH3:30])([CH3:31])[C:24]=3[CH:32]=2)=[O:2])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc21
Solvent: ClCCl
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 1 gm (0.0085 mol) of sulfurylchloride in 5 ml of methylene chloride is added dropwise, at -70° C., to a solution of 3.2 gm (0.0075 mol) of 6-[4-(3,4-dichloro-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one in 50 ml of methylene chloride, under stirring, and after it has all been added, stirring is continued at -70° C. for 15 hours. After heating to ambient temperature, aqueous soda solution is added, under vigorous stirring, and the organic phase is separated from the aqueous phase, washed with water, and dried with sodium sulfate. The residue remaining after the methylene chloride has been distilled off is recrystallized from isopropanol/diisopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:21][O:22][C:23](=[O:44])[C@H:24]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:43])[C:35]2[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:42])=[CH:29][CH:28]=1)[NH2:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O>[CH3:21][O:22][C:23](=[O:44])[C@H:24]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([NH:33][C:34]([C:35]2[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:42])=[O:43])=[CH:31][CH:32]=1)[NH:25][C:4]([C:3]1[CH:7]=[CH:8][C:9]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])=[CH:10][C:2]=1[Cl:1])=[O:6]
Reactant: O=C(Nc1cccc(O)c1)c1ccc(C(=O)O)c(Cl)c1
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1ccc(C(=O)Nc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 40.3 %

Procedure:
In an argon atmosphere, to a stirred solution of 2-chloro-4-[[(3-hydroxyphenyl)amino]carbonyl]benzoic acid (45 mg; 0.1472 mmol), 4-(2,6-dichlorobenzoylamino)-L-phenylalanine methyl ester (60 mg; 0.1488 mmol) and HBTU (59 mg; 0.16 mmol) in dimethylformamide (3 mL) was added DIPEA (0.102 mL; 0.585 mmol). The reaction mixture was stirred for 17 hr at room temperature, then was concentrated to dryness in vacuo and the residue was partitioned between dichloromethane (25 mL) and 0.5 N HCl (10 mL). The organic layer was washed with water and the aqueous layers were backwashed in turn with dichloromethane. The combined dichloromethane extracts were dried (Na2SO4) and evaporated to give 80 mg of crude material that was crystallized from methanol-ethyl acetate to provide 38 mg of N-[[2-chloro-4-[[(3-hydroxyphenyl)amino]carbonyl]phenyl]carbonyl]-4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester. mp 230-232° C. FAB HRMS: (C32H26Cl3N3O6) Obs. Mass 654.0952 Calcd. Mass 654.0965 (M+H).