Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][C:6]1[N:11](C(OC(C)(C)C)=O)[C:10]2[CH:19]=[CH:20][C:21]([N:23]([S:31]([CH3:34])(=[O:33])=[O:32])C(OC(C)(C)C)=O)=[CH:22][C:9]=2[S:8](=[O:36])(=[O:35])[CH:7]=1)[CH3:2].ClCCl.FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4](=[O:37])[CH2:5][C:6]1[NH:11][C:10]2[CH:19]=[CH:20][C:21]([NH:23][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:22][C:9]=2[S:8](=[O:36])(=[O:35])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)CC1=CS(=O)(=O)c2cc(N(C(=O)OC(C)(C)C)S(C)(=O)=O)ccc2N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC1=CS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Yield: 87 %

Procedure:
A solution of [7-(methanesulfonyl-tert-butyloxycarbonyl-amino)-4-tert-butyloxycarbonyl-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl]-acetic acid ethyl ester (Example 8f, 0.30 g, 0.54 mmol) in 1:1 dichloromethane/trifluoroacetic acid was stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with saturated aqueous sodium bicarbonate solution and brine solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the desired product, (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid ethyl ester (0.17 g, 0.47 mmol, 86% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 1.32 (t, 3H, J=6.9 Hz), 3.03 (s, 3H), 4.02 (s, 2H), 4.21 (q, 2H, J=7.0 Hz), 5.02 (s, 1H), 6.96 (s, 1H), 7.02 (d, 1H, J=8.4 Hz), 7.53 (dd, 1H, J1=8.7 Hz, J2=2.4 Hz), 7.65 (d, 1H, J=2.2 Hz), 10.73 (s, 1H). LC-MS (ESI) calcd for C13H16N2O6S2 [M+H+] 361.04, found 361.18 [M+H+].
Reaction SMILES: C(O)(C(F)(F)F)=O.O[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:27])[N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:12]=1.[SH:28][C:29]1[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=1>>[CH3:34][N:30]1[CH:31]=[CH:32][N:33]=[C:29]1[S:28][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:27])[N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:12]=1
Reactant: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Reactant: Cn1ccnc1S
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)Oc1ccc(CCSc2nccn2C)cc1)c1ccccc1
Yield: 37 %

Procedure:
The title compound was prepared as its TFA salt in 37% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 2-mercapto-1-methylimidazole. NMR (400 MHz; CDCl3): δ 3.01 (t, 2H), 3.40 (br s, 3H), 3.47 (s, 1H), 3.64 (t, 2H), 6.92 (br d, 2H), 6.98 (s, 1H), 7.08 (d, 2H), 7.26-7.43 (m, 6H); HPLC-MS: m/z=368.2 (M+1); Rt=2.30 min.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:5]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)[C:6]2[N:7]([C:9]([CH2:12][CH3:13])=[CH:10][CH:11]=2)[N:8]=1.[C:30](O)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:30]([NH:1][CH2:2][C:3]1[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:5]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)[C:6]2[N:7]([C:9]([CH2:12][CH3:13])=[CH:10][CH:11]=2)[N:8]=1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)CCCCc1c(CN)nn2c(CC)ccc2c1-c1cncc(C)c1
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCc1c(CNC(=O)c2ccccc2)nn2c(CC)ccc2c1-c1cncc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
A mixture of ethyl 5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (75 mg), benzoic acid (27.9 mg), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (54.7 mg) and 1-hydroxybenotriazole (385 mg) in dimethylformamide (2 mL) was stirred at ambient temperature for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1) to give ethyl 5-[2-[(benzoylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate as yellow oil (60 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:18])=O>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:4]=1[C:5]([Cl:18])=[O:6]
Reactant: COc1ccc(C(F)(F)F)cc1C(=O)O
Reactant: O=S(Cl)Cl
Product: COc1ccc(C(F)(F)F)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-methoxy-5-(trifluoromethyl)benzoic acid (0.68 g, 3.1 mmol) in thionyl chloride (10 mL) was warmed to reflux and was allowed to stir for 2 h. The mixture was cooled to ambient temperature, concentrated under reduced pressure and diluted with 10 mL of toluene. This material was again concentrated under reduced pressure and was again diluted with 10 mL of toluene. This concentration and dilution was repeated for an additional time and the crude acid chloride was carried on to the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].Cl.[CH:18](=O)[CH3:19]>CO>[CH2:18]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)[CH3:19]
Reactant: CC=O
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNc1ccc(C(=O)OCC)cc1

Procedure:
To a solution of 5 g of ethyl 4-aminobenzoate in 100 ml of methanol, 0.74 ml of acetaldehyde, 1.89 g of sodium cyanoborohydride and 2.1 ml of hydrochloric acid 23% were added.
Reaction SMILES: F.[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][C:17]=3[N+:23]([O-:25])=[O:24])[CH:12]=[CH:13][CH:14]=2)=[CH:5][N:4]=1.[O:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1>>[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:28]4[CH:29]=[CH:30][O:26][CH:27]=4)=[CH:18][C:17]=3[N+:23]([O-:25])=[O:24])[CH:12]=[CH:13][CH:14]=2)=[CH:5][N:4]=1
Reactant: OB(O)c1ccoc1
Reactant: Nc1ncc(-c2cccc(Nc3ccc(I)cc3[N+](=O)[O-])c2)cn1
Agent: F
Product: Nc1ncc(-c2cccc(Nc3ccc(-c4ccoc4)cc3[N+](=O)[O-])c2)cn1

Procedure:
N-(3-(2-Aminopyrimid-5-yl)phenyl)-4-(3-furanyl)-2-nitroaniline (71) was prepared analogously from 6l (Example 10) and 3-furanylboronic acid in quantitative yield. Mp 185-186° C.
Reaction SMILES: O[CH2:2][CH:3]([CH2:5]O)O.[N+](C1C=CC=CC=1)([O-])=O.S(=O)(=O)(O)O.[NH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.[OH-].[Na+]>O>[N:21]1[C:22]2[C:23](=[CH:24][N:25]=[CH:26][CH:27]=2)[CH:5]=[CH:3][CH:2]=1
Reactant: OCC(O)CO
Reactant: Nc1ccncc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: c1cnc2ccncc2c1
Temperature: 0 °C
Yield: 18 %

Procedure:
Glycerol (138.15 g, 1.5 mol) was added dropwise to an ice-cold mixture of "sulfo-mix" (a mixture of nitrobenzene and fuming sulfuric acid, see: Utermohlen, W. P., J. Org. Chem, 1943 8, 544). Addition of 4-aminopyridine (56.46 g, 0.6 mol) was followed by a rapid dropwise addition of water (225 ml), which caused a rise in temperature to 80°; the reaction mixture was allowed to stir until it became homogeneous, and was subsequently heated to 135° for 48 hours. It was then allowed to cool, poured into 1 l ice water, and the pH was adjusted to 13 by the addition of sodium hydroxide pellets. The resulting thick precipitate was removed by filtration, and the filtrate was extracted with methylene chloride (2×2 l). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to yield a crude product, which was purified by column chromatography (98:2 methylene chloride:methanol). The title product was obtained as an amber oil which crystallized upon standing (13.7 g, 0.11 mol, 18% yield).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[CH2:5][NH:6][CH2:7][CH:8]1[O:12][CH2:11][CH2:10][O:9]1)[CH3:2].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:29](=[O:34])[CH:30]([Cl:33])[CH2:31][CH3:32]>O>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[CH2:5][N:6]([CH2:7][CH:8]1[O:12][CH2:11][CH2:10][O:9]1)[C:29](=[O:34])[CH:30]([Cl:33])[CH2:31][CH3:32])[CH3:2]
Reactant: CCC(Cl)C(=O)Cl
Reactant: CCOC(CNCC1OCCO1)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(CN(CC1OCCO1)C(=O)C(Cl)CC)OCC

Procedure:
N-(2,2-Diethoxyethyl)-N-(1,3-dioxolan-2-ylmethyl)amine (0.05 mole), benzene (100 ml), water (100 ml) and sodium carbonate (2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of from 5° to 10° C and α-chlorobutanoyl chloride (0.05 mole) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture has reached room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,2-diethoxyethyl)-N-(1,3-dioxolan-2-ylmethyl)-α-chlorobutanamide as the residue.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:11])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:3]=[C:4]([CH3:11])[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1cc(Br)cn2ccnc12
Product: Cc1cc(-c2ccc(Cl)cc2)cn2ccnc12
Yield: 75.2 %

Procedure:
Prepared from 6-bromo-8-methyl-imidazo[1,2-a]pyridine (example C.20 step 1) (7.0 g, 33 mmol) and commercially available 4-chlorophenylboronic acid (6.005 g, 36 mmol) as described in example C.20 step 2. Obtained the title compound as a white solid (6.02 g, 75%). MS (ISP) 243.2 [(M+H)+], 245.1 [(M+2+H)+].
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH2:10]([O:12][P:13]([O:27][CH2:28][CH3:29])([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]([OH:26])=O)=[CH:18][CH:17]=1)=[O:14])[CH3:11].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:54][CH2:55][C@@H:56]1[O:60][C:59](=[O:61])[N:58]([C:62]2[CH:67]=[CH:66][C:65]([C:68]3[S:69][CH2:70][C:71](=[O:74])[NH:72][N:73]=3)=[C:64]([F:75])[CH:63]=2)[CH2:57]1>CN(C=O)C>[F:75][C:64]1[CH:63]=[C:62]([N:58]2[CH2:57][CH:56]([CH2:55][NH:54][C:24]([CH:23]=[CH:22][C:19]3[CH:18]=[CH:17][C:16]([O:15][P:13](=[O:14])([O:12][CH2:10][CH3:11])[O:27][CH2:28][CH3:29])=[CH:21][CH:20]=3)=[O:26])[O:60][C:59]2=[O:61])[CH:67]=[CH:66][C:65]=1[C:68]1[S:69][CH2:70][C:71](=[O:74])[NH:72][N:73]=1
Reactant: NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Reactant: CCOP(=O)(OCC)Oc1ccc(C=CC(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[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: CCOP(=O)(OCC)Oc1ccc(C=CC(=O)NCC2CN(c3ccc(C4=NNC(=O)CS4)c(F)c3)C(=O)O2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 539.4 %

Procedure:
N,N-Diisopropylethylamine (0.507 ml, 2.91 mmol) was added to 3-[4-(diethoxy-phosphoryloxy)phenyl]acrylic acid (0.065 g, 0.217 mmol) [prepared according to the procedure described in Tetrahedron Lett 1996, 37, 3635] and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.124 g 0.326 mmol) in DMF (3 ml) and stirred for 20 minutes at room temperature. 2-[4-(5(S)-aminomethyl-2-oxo-oxazolidin-3-yl)-2-fluorophenyl]-4H-[1,3,4]thiadiazin-5-one (0.084 g, 0.259 mmol) was added and stirring continued at room temperature overnight. The reaction mixture was partially evaporated under vacuum, diluted with water (5 ml), and extracted with ethyl acetate (50 ml). The extract was washed with brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (5% MeOH/DCM) to give pure product as a white solid (0.71 g, 54%); MS (m/z): [M+H]+=607.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]1[NH:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>CN(C=O)C.O>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:8][C:9]3[NH:10][C:11]4[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N2CCN(Cc3nc4ccccc4[nH]3)CC2)cc1
Reaction time: 8 h

Procedure:
Potassium carbonate (2.76 g, 20 mmol) and 2-(chloromethyl)benzimidazole (1.70 g, 10 mmol) were added to a solution of 1-(4-methoxyphenyl)piperazine (1.92 g, 10 mmol) in DMF (20 ml) under a nitrogen atmosphere and the mixture was stirred overnight. The mixture was diluted with water (200 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with water (100 ml) and brine (100 ml), dried (MgSO4) and evaporated in vacuo to give a solid which was recrystallised from toluene to give the title compound as a buff solid (731 mg, 23%). mp 214°-216° C.; (Found: C, 70.80; H, 6.82; N, 17.28. C19H22N4O requires C, 70.78; H, 6.88; N, 17.38%); δH (DMSO-d6) 2.59-2.62 (4H, m, 2×piperazinyl CH2), 3.03-3.05 (4H, m, 2×piperazinyl CH2), 3.67 (3H, s, OCH3), 3.77 (2H, s, CH2N), 6.79-6.82 (2H, m, ArH), 6.85-6.89 (2H, m, ArH), 7.10-7.17 (2H, m, ArH), 7.43 (1H, d, J 6.9 Hz, ArH), 7.55 (1H, d, J 6.9 Hz, ArH), and 12.30 (1H, brs, NH); m/z (CI+, NH3) 323 (M+1)+.
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][C:13]#[N:14].[Cl:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1>C1COCC1>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH:12]([C:18]1[CH:19]=[CH:20][N:21]=[C:16]([Cl:15])[N:17]=1)[C:13]#[N:14]
Reactant: Clc1ccnc(Cl)n1
Reactant: N#CCc1nc2ccccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(c1ccnc(Cl)n1)c1nc2ccccc2s1
Temperature: 25 °C
Yield: 65.1 %

Procedure:
To a stirred suspension of NaH (60% in oil, 9.2 g, 0.23 mol) in dry THF (200 ml) was added drop wise under inert atmosphere a solution of 1,3-benzothiazol-2-yl-acetonitrile (20 g, 0.15 mol) in dry THF (200 ml). After 1 h30 stirring at r.t., a solution of 2,4-dichloropyrimidine (17.1 g, 0.15 mol) in dry THF (200 ml) was added dropwise. The reaction mixture was allowed to stir under inert atmosphere at r.t. until complete disappearance of the starting material. The reaction was quenched by addition of water and the THF was evaporated. Water was added and the suspension was slightly acidified with aqueous HCl 1M. The precipitate obtained was filtered off and washed thoroughly with water until neutral then with hexane to remove the oil. The crude solid was dried under vacuum at 40° C., affording 28 g (84%) of the title compound as a light brown powder: mp 246° C. dec.; MS: 286.8 (M+1); HPLC (Conditions a, 268 nm) 97%, rt.5.66 min; 1HNMR (DMSO-d6) δ 13.25 (br s, 1H, exchangeable), 8.09 (d, J=4.14 Hz, 1H), 7.90 (d, J=7.53 Hz, 1H), 7.61 (d, J=7.92 Hz, 1H), 7.39-7.34 (m, 1H), 7.20-7.15 (m, 1H), 6.96 (br d, 1H). CHN analysis: C13H7ClN4S: Calculated: C, 54.19%; H, 2.48%, N, 19.45%; Found: C, 53.35%; H, 2.77%; N, 17.62%.
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([O:7][C:8](=[O:14])[C:9](OCC)=[O:10])[CH3:6].[CH2:15]([O:17][C:18](=[O:29])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[CH3:16].Cl>C(OCC)C>[CH2:15]([O:17][C:18](=[O:29])[CH:19]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[C:9](=[O:10])[C:8]([O:7][CH2:5][CH3:6])=[O:14])[CH3:16]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)COc1cccc(OC)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(=O)C(Oc1cccc(OC)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium ethoxide (32.5 g, 454 mmol) is covered with 1 l of dry diethyl ether. Oxalic acid diethyl ester (55.2 ml, 416 mmol) is added drop wise within 20 min. After 30 min stirring at room temperature, the mixture is heated to reflux. A solution of (3-methoxy-phenoxy)-acetic acid ethyl ester (22) (79.5 g, 378 mmol) in 80 ml of dry diethyl ether is added drop wise within 30 min and the mixture is allowed to reflux for 1 hour. After cooling down to room temperature, the reaction mixture is poured on 2M HCl (400 ml)/ice (400 g) and extracted with diethyl ether. The organic layers are dried over sodium sulfate, filtrated and evaporated.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([CH2:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][CH:24]=[CH:23][N:19]3[C:20](=[O:22])[CH:21]=2)[CH2:3][CH2:2]1.[I:26]N1C(=O)CCC1=O>C(#N)C.O>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([CH2:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][CH:24]=[CH:23][N:19]3[C:20](=[O:22])[C:21]=2[I:26])[CH2:2][CH2:3]1
Reactant: CCc1cccc(/C=C/c2cc(=O)n3ccsc3n2)c1OCC1CC1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: O
Product: CCc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of Step 3 intermediate (3.89 g, 10.72 mmol) was added N-iodosuccinimide (2.69 g, 11.79 mmol) in acetonitrile at room temperature. The reaction temperature was then raised to 60° C. and stirred for 4 h. The reaction mixture was then cooled to room temperature, diluted with water and stirred for 20 min. The filtered solid was washed with water and dried to afford 5.19 g of the desired compound; 1H NMR (300 MHz, CDCl3) δ 0.32-0.33 (m, 2H), 0.54-0.56 (d, J=7.2 Hz, 2H), 1.22 (br s, 1H), 3.77-3.81 (m, 5H), 7.06-7.14 (m, 2H), 7.27-7.29 (d, J=7.2 Hz, 1H), 7.49-7.52 (m, 1H), 7.57 (s, 1H), 7.96 (d, J=3.9 Hz, 1H), 8.18 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 481.45 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]([CH3:17])([CH3:16])[CH:6](Cl)[CH2:7][C:8]([Cl:14])(Cl)[C:9]([F:12])([F:11])[F:10].[Na].[CH2:20](O)C>>[CH2:1]([O:2][C:3]([CH:4]1[CH:6]([CH:7]=[C:8]([Cl:14])[C:9]([F:10])([F:11])[F:12])[C:5]1([CH3:17])[CH3:16])=[O:18])[CH3:20]
Reactant: COC(=O)CC(C)(C)C(Cl)CC(Cl)(Cl)C(F)(F)F
Reactant: CCO
Agent: [Na]
Product: CCOC(=O)C1C(C=C(Cl)C(F)(F)F)C1(C)C
Temperature: 45 °C

Procedure:
135 g of 3,3-dimethyl-4,6,6-trichloro-7,7,7-trifluoroenanthic acid methyl ester were added dropwise to a solution of 20.7 g of sodium in 300 ml of ethanol at room temperature in the course of 3 hours, while stirring. The mixture was subsequently stirred at room temperature for 1 hour and then heated to 45° C. for 7 hours. After cooling, sodium chloride which had separated out was filtered off, the filtrate was concentrated somewhat in vacuo, the residue was added to 500 ml of water and the mixture was rendered neutral. Extraction with methylene chloride and fractional distillation gave 90 g of 2,2-dimethyl-3-(2'-chloro-3',3',3'-trifluoropropenyl)-cyclopropanecarboxylic acid ethyl ester (isomer mixture) of boiling point: 55°-57° C./0.2 mm Hg.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1)[CH2:10]O>C1COCC1>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1)[CH2:10][Br:2]
Reactant: BrP(Br)Br
Reactant: COc1cc(CO)cc(OC)c1
Solvent: C1CCOC1
Product: COc1cc(CBr)cc(OC)c1
Reaction time: 0.38 h
Yield: 92 %

Procedure:
Phosphorus tribromide (0.4 eq) was added to the alcohol 304 (25 g, 0.13 mol) in THF (100 mL) very slowly at −10° C. and the mixture which resulted was stirred for 15-30 min at the same temperature. By this time all the starting material had disappeared (TLC). The reaction mixture was quenched by addition of ice-cold H2O (100 mL) and then filtered through a Buchner funnel. The filtrate was diluted with brine (100 mL) and extracted with EtOAc (3×300 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The crude oil was purified by FCC (20% ethylacetate in hexane) to afford the bromide 305 as a white solid (92%)a: 1H NMR (500 MHz, CDCl3) δ 6.61 (2H, d, J=2.3 Hz), 6.46 (1H, t, J=2.3 Hz), 4.5 (2H, s), 3.85 (6H, s). 13C NMR (125 MHz, CDCl3): δ 161.3, 140.2, 107.4, 101.0, 55.8, 34.1. The spectral data for 305 were in excellent accord with data previously reported on it (Seidel et al., 1990)1. This material was employed directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[C:12]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25]O)[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][O:11][C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2cc([N+](=O)[O-])ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-chloro-5-nitro phenol (10 g, 63.497 mmol), N-boc-4-piperidine methanol (13.67 g, 63.49 mmol), and PPh3 (16.63 g, 63.49 mmol) in 130 mL THF, cooled at −20° C. was added dropwise over 1.5 h a 50 mL THF solution containing DIAD (12.75 ml, 64.76 mmol). The mixture turned a deep red. The reaction was warmed gradually to RT and stirred for 18 h. The mixture was concentrated in vacuo, dissolved in Et2O, washed once with water, then NaHCO3 (sat). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was treated with a mixture of hexanes and EtOAc (1:1) and the solid was filtered. The filtrate was evaporated and the residue was purified by silica gel column chromatography to yield the title compound as a yellow solid. MS (MH+)=NA; Calc'd 370.13 for C17H23ClN2O5.
Reaction SMILES: [CH3:1][C:2]([CH3:50])([CH3:49])[C@H:3]([NH:7][C:8](=[O:48])[C@@H:9]([CH2:17][C@@H:18]([O:40][Si](C(C)(C)C)(C)C)[CH2:19][S:20][C:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:4](C)=[O:5].[F-].[CH2:52]([N+:56](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOCC>[CH3:50][C:2]([CH3:1])([CH3:49])[C@H:3]([NH:7][C:8](=[O:48])[C@@H:9]([CH2:17][C@@H:18]([OH:40])[CH2:19][S:20][C:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:4](=[O:5])[NH:56][CH3:52]
Reactant: CCCCCCC[C@H](C[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)O[Si](C)(C)C(C)(C)C)C(=O)N[C@H](C(C)=O)C(C)(C)C
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCC[C@H](C[C@@H](O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@H](C(=O)NC)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
To a solution of 5.13 g (7.027 mmol) of the product of Example 29 dissolved in 75 mL of THF was added 17.6 mL (0.01 8 mmol) of a 1.0M solution of tetrabutylammonium fluoride in THF. The reaction mixture was stirred at room temperature for 4 h and then diluted with ether. The resulting solution was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc/Hexanes (gradient: 1:3-1:1) to provide 2.78 g (64%) of the desired product as a colorless oil. Electrospray Mass Spec: 617.5 (M+H)+.