Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C1COCC1.[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)[CH:20]=1)[C:14]([O:16]C)=[O:15])[CH3:9].Cl>CO>[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)[CH:20]=1)[C:14]([OH:16])=[O:15])[CH3:9]
Reactant: CCOc1cc(C(=O)OC)cc(-c2nnn[nH]2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cc(C(=O)O)cc(-c2nnn[nH]2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Aqueous 5 N sodium hydroxide solution (0.46 mL, 2.23 mmol) was added to a THF (2.0 mL)-methanol (2.0 mL) solution of methyl 3-ethoxy-5-(tetrazol-5-yl)benzoate (190 mg, 0.77 mmol), and stirred at room temperature for 18 hours. 5 N hydrochloric acid (0.46 mL, 2.23 mmol) was added to the reaction mixture, and concentrated under reduced pressure. 20% methanol/chloroform was added to the residue, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound as a colorless solid.
Reaction SMILES: [H-].[Na+].[C:3]1([C@H:9]([N:11]2[C@H:15]3[CH2:16][O:17][C:18](=[O:19])[C@H:14]3[NH:13][C:12]2=[O:20])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1.C(O)(=O)C>CN(C)C=O>[C:3]1([C@H:9]([N:11]2[C@H:15]3[CH2:16][O:17][C:18](=[O:19])[C@H:14]3[N:13]([CH2:27][C:26]3[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[C:12]2=[O:20])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc(CCl)cc1
Reactant: C[C@H](c1ccccc1)N1C(=O)N[C@@H]2C(=O)OC[C@@H]21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)N([C@H](C)c3ccccc3)[C@H]3COC(=O)[C@H]32)cc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
9.75 g (0.22 mol) of sodium hydride (55 percent in oil) was added in 10 portions in 2 hours at -10° C. under argon to a solution of 50.0 g (0.2 mol) of (3aS,6aR)-1-[(R)-(1-phenylethyl)]-dihydro-1H-furo[3,4-d]imidazol-2,4(3H,3aH)-dione and 39.8 g (0.25 mol) of 4-methoxybenzyl chloride in 500 ml of dried N,N-dimethylformamide. The reaction mixture was stirred at 5° C. for 2 hours and then at room temperature for another 2 hours. Then 8 ml of acetic acid was added. Then the mixture was evaporated to dryness. Then the residue was taken up in 100 ml of water and 200 ml of dichloromethane, the phases were separated and the aqueous phase was extracted twice with 100 ml of dichloromethane. The organic phases were dried over magnesium sulfate and concentrated. After suspension in ethanol with refluxing, cooling and filtering, 53.5 g (72 percent) of the title product was obtained in the form of white needles. Concerning the product: Melting point: 146.1°-146.4° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[O:11]1[C:16]2[CH:17]=[CH:18][C:19]([N:21]3[CH2:25][C@@H:24]([CH2:26][OH:27])[O:23][C:22]3=[O:28])=[CH:20][C:15]=2[O:14][CH2:13][CH2:12]1>C(Cl)Cl>[O:11]1[C:16]2[CH:17]=[CH:18][C:19]([N:21]3[CH2:25][C@@H:24]([CH:26]=[O:27])[O:23][C:22]3=[O:28])=[CH:20][C:15]=2[O:14][CH2:13][CH2:12]1
Reactant: O=C1O[C@H](CO)CN1c1ccc2c(c1)OCCO2
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C[C@@H]1CN(c2ccc3c(c2)OCCO3)C(=O)O1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of oxalyl chloride (0.229 mL, 2.71 mmol) in DCM (5 mL) was cooled to −78° C. and DMSO (0.395 mL, 5.572 mmol) was added dropwise. The mixture was stirred for 10 min at that temperature and a suspension of (S)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-hydroxymethyl-oxazolidin-2-one (400 mg, 1.59 mmol) in DCM (6 mL) was then added dropwise within 1 min. Stirring was continued for 20 min. TEA (0.665 mL, 4.78 mmol) was added and the mixture was stirred for 5 min, and then allowed to warm to 0° C. The mixture was filtered through Celite and concentrated with a bath temperature below 30° C. The residue was partitioned between water and EA and the org. layer was washed with brine, dried over Na2SO4 and concentrated with a bath temperature below 30° C. The highly unstable intermediate was used immediately in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[C:9]([S:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:8]2[CH2:22][C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:39][C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[N:45][CH:46]=2)[N:41]=1>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:39][C:40]4[CH:49]=[CH:48][C:47]5[C:42](=[CH:43][CH:44]=[N:45][CH:46]=5)[N:41]=4)=[CH:13][CH:14]=3)[C:9]([S:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[C:8]2[CH2:22][C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25])=[CH:30][CH:31]=1
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Reactant: ClCc1ccc2cnccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccc4cnccc4n3)ccc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-hydroxyindol-2-yl]-2,2-dimethylpropanoate (EP 419,049, Mar. 27, 1991, Example 1, Step C) (350 mg) in acetonitrile (5 mL) were added Cs2CO3 (489 mg) and 80% pure halide (180 mg) from Step 1. The mixture was stirred at room temperature for 18 hr. then the mixture was poured into 25% aq. NH4OAc (50 mL), extracted with ethyl acetate (2×50 mL), washed with brine (50 mL), dried (MgSO4), and evaporated to dryness. Chromatography of the residue on flash silica gel using ethyl acetate:toluene (2:3) as eluant gave the title compound as a white solid; m.p. 152°-155° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:28])[CH2:13][NH:14][C:15](=[O:27])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[CH2:26][CH2:25][NH:24][CH2:23]2)[CH:17]=1.C=O.[BH3-][C:32]#N.[Na+].CC(O)=O>CO>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:28])[CH2:13][NH:14][C:15](=[O:27])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[CH2:26][CH2:25][N:24]([CH3:32])[CH2:23]2)[CH:17]=1
Reactant: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(C2CCNC2)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCC(c2cccc(C(=O)NCC(O)CN3CCc4ccccc4C3)c2)C1
Yield: 14.2 %

Procedure:
To a solution of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(pyrrolidin-3-yl)benzamide (200 mg, 0.53 mmol) in MeOH (4 ml) was added HCHO (31.9 mg, 1.05 mmol) and NaBH3CN (66.1 mg, 1.05 mmol) at 29° C. The mixture was then added AcOH (0.5 ml) at 29° C. and stirred for 16 h. The mixture was purified by prep-HPLC to give the title compound (29.6 mg, Yield 14.3%). 1H NMR (CD3OD, 400 MHz): δ 8.52 (brs, 2H), 7.88 (s, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.53-7.60 (m, 1H), 7.43-7.52 (m, 1H), 7.22-7.33 (m, 3H), 7.15-7.21 (m, 1H), 4.36 (s, 3H), 3.78 (brs, 2H), 3.46-3.67 (m, 6H), 3.41 (brs, 1H), 3.07-3.19 (m, 3H), 3.01 (s, 3H), 2.50-2.64 (m, 1H), 2.19-2.34 (m, 1H). LCMS (m/z): 394.2 (M+1).
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]3[S:12][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:9]=3[C:8]=2[C:20](OC(C)(C)C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(=O)C)(=O)C.[C:34]1(=O)[CH2:39][CH2:38]C[CH2:36][CH2:35]1.P(=O)(O)(O)O.C([SiH](CC)CC)C>C(O)(=O)C>[CH:20]1([C:8]2[C:9]3[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:12][C:10]=3[NH:11][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:38][CH2:39][CH2:34][CH2:35][CH2:36]1
Reactant: O=C1CCCCC1
Reactant: CCOC(=O)c1cc2c(C(=O)OC(C)(C)C)c(-c3ccccc3)[nH]c2s1
Agent: CC[SiH](CC)CC
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc2c(C3CCCCC3)c(-c3ccccc3)[nH]c2s1
Temperature: 80 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A solution (0.2 M) of 4-tert-butyl 2-ethyl 5-phenyl-6H-thieno[2,3-b]pyrrole-2,4-dicarboxylate in acetic acid was treated with acetic anhydride (2.5 eq.), cyclohexanone (10 eq.) and 85% phosphoric acid (2.3 eq.). The mixture was heated at 80° C. overnight, then it was poured into ice cold ammonium hydroxide. The product was extracted with AcOEt and the combined organic layers were washed sequentially with aqueous HCl (1 N), aqueous NaHCO3 (saturated solution) and brine then dried and concentrated. The crude was dissolved in TFA and cooled to 0° C. The resulting solution (0.1 M) was treated with triethylsilane (2 eq.) and stirred at 0° C. for 1 h then solvent was evaporated to give a residue that was purified by flash chromatography on silica gel (1:9 AcOEt/petroleum ether) to afford the title compound (58%) as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C@H:4]([C:5](O[C@@H](C2C=CC=C(OC3C=CC=CC=3)C=2)C#N)=[O:6])[C@@H:3]1/[CH:24]=[C:25](\[Cl:30])/[C:26]([F:29])([F:28])[F:27].[Cl:32]/C(/C(F)(F)F)=C\[C@@H]1[C@H](C(O)=O)C1(C)C>>[Cl:30]/[C:25](/[C:26]([F:29])([F:28])[F:27])=[CH:24]\[C@@H:3]1[C@H:4]([C:5]([Cl:32])=[O:6])[C:2]1([CH3:31])[CH3:1]
Reactant: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)O
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C(\Cl)C(F)(F)F
Product: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)Cl

Procedure:
In order to produce gamma-cyhalothrin on an industrial scale it is desirable to find methods of making the final product that avoid the use of expensive reagents and have as few chemical stages as possible. The present invention provides a direct process to meet these requirements. There is therefore provided a process for the preparation of gamma-cyhalothrin (IV) comprising a) chlorinating 1R cis-Z 3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethyl cyclopropanecarboxylic acid (I) to give 1R cis-Z 3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethyl cyclopropanecarboxylic acid chloride (II) and b) esterifying 1R cis-Z 3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethyl cyclopropanecarboxylic acid chloride (II) with the (S)-cyanohydrin of 3-phenoxy benzaldehyde (III).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[CH:29][C:30]([CH3:40])=[C:31]([S:33]([NH:36][CH2:37][CH2:38][OH:39])(=[O:35])=[O:34])[CH:32]=1>>[OH:39][CH2:38][CH2:37][NH:36][S:33]([C:31]1[CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:28]=[CH:29][C:30]=1[CH3:40])(=[O:35])=[O:34]
Reactant: Cc1ccc(Br)cc1S(=O)(=O)NCCO
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1S(=O)(=O)NCCO

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (150 mg, 0.9 mmol) and 5-Bromo-N-(2-hydroxy-ethyl)-2-methyl-benzenesulfonamide (example B.17) (129 mg, 1.0 mmol) according to general procedure II. Obtained as an orange solid (59 mg, 25%). MS (ISP) 569.2 [(M+H)+]; mp 174-175° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[NH:13][CH:12]=2)=[CH:7][CH:6]=1.[H-].[Na+].[Br:22][CH2:23][CH2:24][CH2:25]Br>O>[Br:22][CH2:23][CH2:24][CH2:25][N:13]1[C:14]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[C:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][CH:9]=2)=[CH:12]1
Reactant: BrCCCBr
Reactant: COCOc1ccc(-c2c[nH]c3cccnc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COCOc1ccc(-c2cn(CCCBr)c3cccnc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-[4-(methoxymethoxy)phenyl]-1H-pyrrolo[3,2-b]pyridine (650 mg) was added NaH (60% in oil, 153 mg) at 0° C. After stirring at room temperature for 1 h, the mixture was added dropwise to 1,3-dibromopropane (0.778 mL). The mixture was stirred at room temperature for 2 h. The mixture was added to water and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (486 mg).
Reaction SMILES: [CH3:1][C:2]1([N:13]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[C@H:20]1([NH2:27])[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]1[NH2:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl>[NH2:26][C@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@@H:20]1[NH:27][CH:16]1[CH2:17][CH2:18][N:13]([C:2]2([CH3:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH2:14][CH2:15]1
Reactant: CCOC(=O)N1CCC(C)(N2CCC(=O)CC2)CC1
Reactant: N[C@H]1CCCC[C@@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)N1CCC(C)(N2CCC(N[C@H]3CCCC[C@@H]3N)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.5 %

Procedure:
To a solution ethyl 4-methyl-4-(4-oxo-1-piperidyl)piperidine-1-carboxylate (336 mg, 1.25 mmol) and (1S,2S)-cyclohexane-1,2-diamine (286 mg, 0.5 mmol) in dichloromethane (10 mL) was added sodium triacetoxyborohydride (398 mg, 1.88 mmol) and stirred at room temperature for 12 h. Saturated NaHCO3 (5 mL) was added, the phases were separated and the aqueous phase was extracted with dichloromethane (2×10 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by passing through a short silica gel pad (5-10% MeOH in dichloromethane) to afford the title compound (87 mg, 19%). MS (M+1): 367.31.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][N:12]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:13]/[CH:14]=[CH:15]/[CH2:16][N:17]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[CH:45](I)([CH3:47])[CH3:46]>CN(C=O)C>[CH:45]([N:21]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:20][CH2:19][CH2:18][N:17]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:16]/[CH:15]=[CH:14]/[CH2:13][N:12]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])([CH3:47])[CH3:46]
Reactant: CC(C)I
Reactant: CC(C)(C)OC(=O)NCCCN(C/C=C/CN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(CCCN(C/C=C/CN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
To a solution of 1.5 g (2.5 mmol) of (E)-1,5,10,14-tetra-BOC-1,5,10,14-tetraazatetradec7-ene in 20 ml of DMF there are added, with stirring, 0.4 g (10 mmol) of sodium hydride dispersion (approx. 60%) and, after 15 min., 1 ml (10 mmol) of isopropyl iodide. The reaction mixture is stirred for 16 h at room temperature; a further 0.4 g (10 mmol) of sodium hydride dispersion (approx. 60%) and 1 ml (10 mmol) of isopropyl iodide are added, and the mixture is stirred for a further 24 h at 20° C. and for 24 h at 50° C. and is then concentrated by evaporation in vacuo. Working up analogously to Example 1a), using ethyl acetate-hexane (1:3) and ethyl acetate-hexane (1:2) in the flash chromatography, yields the title compound, Rf value=0.37 (silica gel/ethyl acetate:hexane (2:3)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([NH:20][C:21](=O)[C:22](F)(F)F)[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ICC[CH2:36][S:37]([N:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1)(=[O:39])=[O:38]>CN(C)C=O.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([NH:20][CH2:21][CH2:22][CH2:36][S:37]([N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)(=[O:39])=[O:38])[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(CCCI)N1CCCC1
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCCS(=O)(=O)N1CCCC1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of ethyl 5-[(4-fluorophenyl)methyl]-3-[(trifluoroacetyl)amino]-2-pyridinecarboxylate (206 mg, 0.556 mmol) in N,N-dimethylformamide (2 mL) was added cesium carbonate (362 mg, 1.11 mmol) and 1-[(3-iodopropyl)sulfonyl]pyrrolidine (253 mg, 0.834 mmol), respectively. The reaction mixture was stirred at 80° C. for 5 hours, after which additional cesium carbonate (362 mg, 1.11 mmol) and 1-[(3-iodopropyl)sulfonyl]pyrrolidine (253 mg, 0.834 mmol) were added. The reaction mixture was stirred at 80° C. for an additional 7 hours. The reaction mixture was cooled and diluted with toluene. The resulting mixture was washed with water and brine, then dried over sodium sulfate. Filtration and concentration, followed by flash chromatography (0 to 5% gradient, methanol in dichloromethane) provided ethyl 5-[(4-fluorophenyl)methyl]-3-{[3-(1-pyrrolidinylsulfonyl)propyl]amino}-2-pyridinecarboxylate as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=1.3 Hz, 1 H), 7.79 (t, J=5.7 Hz, 1 H), 7.13 (dd, J=8.5, 5.4 Hz, 2 H), 6.97 (t, J=8.7 Hz, 2 H), 6.86 (s, 1 H), 4.41 (q, J=7.2 Hz, 2 H), 4.26 (t, J=6.2 Hz, 2 H), 3.91 (s, 2 H), 3.37-3.31 (m, 4 H), 3.03 (m, 2 H), 2.19-2.09 (m, 2 H), 1.95-1.89 (m, 4 H), 1.42 (t, J=6.9 Hz, 3 H); MS m/z 450 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C@H:14]([C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])[CH3:15].C([BH3-])#N.[Na+]>CO.O>[C:9]([CH:8]([NH:13][C@H:14]([C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])[CH3:15])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:11])=[O:10]
Reactant: O=C(O)C(=O)Cc1ccccc1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@H](NC(Cc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
A mixture of phenylpyruvic acid (753 mg) and L-alanyl-L-proline (171 mg) in methanol-water are adjusted to pH 6.8 and treated with sodium cyanoborohydride (173 mg) at room temperature until reaction is complete. The product is absorbed on strong cation exchange resin and eluted with 2% pyridine in water to give 294 mg of crude diastereomeric product, N-(1-carboxy-2-phenylethyl)-L-alanyl-L-proline. A portion is purified by gel filtration (LH-20) for spectrographic analysis. The nmr spectrum shows a broad singlet at 7.2, complex absorption from 3.0 to 4.6, a multiplet at 2.1 and a pair of doublets at 1.5 ppm.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])=[C:8]2[C:12]([O-:14])=[O:13])[CH3:3].[Na+].[C:23]([O:29][CH2:30]I)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25].C(OCC)(=O)C>CN(C)C=O>[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])=[C:8]2[C:12]([O:14][CH2:30][O:29][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:13])[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3ccccc3O)C[C@H]12
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3ccccc3O)C[C@H]12
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
A solution of sodium (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(hydroxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (106 mg) in dry dimethylformamide (4.5 ml) was cooled with ice, and thereto pivaloyloxymethyl iodide (123 mg) was added. The mixture was stirred for 1 hour at the same temperature. Ethyl acetate and ice water were added to the reaction solution, and the mixture was separated with a separating funnel. After the organic layer was washed with a cold saturated aqueous sodium chloride solution (4 times), it was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and then the residue was purified by silica gel column chromatography (chloroform/methanol) to give [(2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(hydroxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (36 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][NH:11][CH:12]=2)[N:5]2[CH:13]=[CH:14][N:15]=[C:4]2[CH:3]=1.[CH:16]1([CH:19]=[CH:20][C:21]#[N:22])[CH2:18][CH2:17]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:12]=[N:11][N:10]([CH:19]([CH:16]3[CH2:18][CH2:17]3)[CH2:20][C:21]#[N:22])[CH:9]=2)[N:5]2[CH:13]=[CH:14][N:15]=[C:4]2[CH:3]=1
Reactant: N#CC=CC1CC1
Reactant: Clc1cc2nccn2c(-c2cn[nH]c2)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: N#CCC(C1CC1)n1cc(-c2nc(Cl)cc3nccn23)cn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
To a solution of 7-chloro-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (0.107 g, 0.4872 mmol) and 3-cyclopropylacrylonitrile (Preparation B; 0.3403 g, 3.654 mmol) in 2 mL of acetonitrile was added DBU (0.1457 mL, 0.9744 mmol). The reaction mixture was sealed and heated to 50° C. and stirred overnight. To the reaction mixture was added more 3-cyclopropylacrylonitrile (0.100 g, 0.107 mmol) and DBU (0.072 mL, 0.448 mmol) and the reaction mixture was sealed and heated to 60° C. for 4 hours. The reaction mixture was loaded onto directly onto a column of silica gel and eluted with a gradient of 50-75% ethyl acetate in hexanes with 0.5% ammonium hydroxide to afford the title compound (0.119 g, 0.3729 mmol, 76.54% yield). MS (apci) m/z=313.1 (M+H).
Reaction SMILES: [CH2:1]1[O:15][C:14]2[C:3](=[CH:4][C:5]3[O:10][CH2:9][CH:8]([CH2:11][NH2:12])[O:7][C:6]=3[CH:13]=2)[O:2]1.Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][CH:27]=[N:28]2)=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN(C=O)C>[N:28]1[C:29]2[C:24](=[CH:23][CH:22]=[C:21]([O:20][CH2:19][CH2:18][CH2:17][NH:12][CH2:11][CH:8]3[O:7][C:6]4[CH:13]=[C:14]5[O:15][CH2:1][O:2][C:3]5=[CH:4][C:5]=4[O:10][CH2:9]3)[CH:30]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: NCC1COc2cc3c(cc2O1)OCO3
Reactant: BrCCCOc1ccc2cccnc2c1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: c1cnc2cc(OCCCNCC3COc4cc5c(cc4O3)OCO5)ccc2c1
Temperature: 80 °C
Yield: 57.6 %

Procedure:
2,3-Dihydro-6,7-methylenedioxy-1,4-benzodioxin-2-methanamine (1.3 g, 6.2 mmole), 7-(3-bromopropoxy)quinoline (1.53 g, 5.5 mmole), diisopropylethylamine 2.6 g, 20 mmole) and sodium iodide (5.5 g, 37 mmole) were combined in 200 ml of DMF and heated at 80° C. for 15 hours under a nitrogen atmosphere. The solvent was then removed in vacuum and replaced with 500 ml of dichloromethane. The mixture was washed with 250 ml each of saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was column chromatographed on 250 g of silica gel using 3% methanol/dichloromethane as eluant. The product-containing fractions were combined and concentrated in vacuum and the residue (2.25 g) recrystallized from ethanol with the addition of 6 ml of 4N isopropanolic HCl to give 1.25 g of the title compound as a yellow solid dihydrochloride salt, m.p. 224°-226° C.