Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([CH2:17]O)=[C:11]3[N:10]=[CH:9]2)=[CH:5][CH:4]=1.O=S(Cl)[Cl:23]>ClCCl>[Cl:23][CH2:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:9]=[N:10][C:11]=12
Reactant: COc1ccc(Cn2cnc3c(CO)ccnc32)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(Cn2cnc3c(CCl)ccnc32)cc1
Reaction time: 1.5 h

Procedure:
[3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methanol x183 (0.5 g, 1.86 mmol) is dissolved in dichloromethane (20 ml). SOCl2 (2 ml) is added dropwise. The reaction mixture is refluxed for 1 h. The volatiles are distilled off in the vacuum of a rotary evaporator. Then 50 ml of chloroform is distilled off additionally from the residue. The residual chloroform solution is added dropwise at 0° C. to a vigorously stirred saturated aqueous solution of NaHCO3. The organic phase is separated, dried with anhydrous sodium sulfate, and evaporated. The residue is kept under 1 mmHg for 1.5 h at 40° C. to afford 7-(chloromethyl)-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine x185 sufficiently pure for the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[OH:15].ClC1C=CC=C(C(OO)=[O:24])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9]([CH2:10][C:11]([F:14])([F:13])[F:12])=[O:24])=[CH:4][C:3]=1[OH:15]
Reactant: Cc1cc(C)c(SCC(F)(F)F)cc1O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c(S(=O)CC(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
In 30 ml of chloroform was dissolved 2.60 g (11.0 mmol) of 2,4-dimethyl-5-(2,2,2-trifluoroethylthio)phenol. Thereto was added 3.25 g (13.18 mmol) of 3-chloroperbenzoic acid (purity: about 70%) under ice cooling, and the mixture was stirred for 30 minutes at room temperature. Then, saturated aqueous solution of sodium thiosulfate was added to the reaction mixture to decompose excess peroxide. Thereafter, the solvent was distilled off under reduced pressure, and phase separation was conducted by adding ethyl acetate and water. The organic phase obtained was washed by aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, to obtain 2.13 g (yield: 77%) of an intended product.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][C:12](Cl)=[N:13][OH:14])=[CH:7][CH:6]=1.O1CCCC1.[C:25]([C:27]1[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][C:12]2[CH:26]=[C:25]([C:27]3[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=3)[O:14][N:13]=2)=[CH:7][CH:6]=1
Reactant: C#Cc1ccc(N)nc1
Reactant: ON=C(Cl)Cc1ccc(Oc2ccccc2F)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(-c2cc(Cc3ccc(Oc4ccccc4F)nc3)no2)cn1
Temperature: 50 °C
Reaction time: 5 h
Yield: 16.7 %

Procedure:
To a mixture of (6-(2-fluoro-phenoxy)-pyridin-3-yl)-acetohydroximoyl chloride (28 mg) described in Manufacturing Example 74-1-4 and tetrahydrofuran (1 mL) were added 5-ethynyl-pyridin-2-ylamine (9.0 mg, 0.076 mmol) described in Manufacturing Example 28-1-3 and triethylamine (21 μL, 0.15 mmol), which was stirred for 5 hours at 50° C. The reaction mixture was allowed to room temperature, water was added at the same temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (4.6 mg, 17%).
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[CH:3]=1.[CH3:13]O>>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([O:8][CH3:13])=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1cc(F)c(Br)cc1F
Product: COC(=O)c1cc(F)c(Br)cc1F

Procedure:
4-bromo-2,5-difluorobenzoic acid (4.82 g, 20.3 mmol) and methanol (100 ml, saturated with gaseous HCl) was heated at 65° C. for 3 h. The volatiles were evaporated, MeOH was added and once again it was evaporated. This procedure was repeated three times. Purification by flash column chromatography (isooctane/EtOAc 4:1) gave the title compound (4.2 g). MS m/z (rel. intensity, 70 eV) 252 (M+, 33), 250 (M+, 34), 221 (95), 219 (bp), 193 (20), 191 (21), 112 (32).
Reaction SMILES: [N:1]1[C:2]([C:10]([O:12]CC)=[O:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[OH-].[Li+].Cl>C1COCC1.O>[N:1]1[C:2]([C:10]([OH:12])=[O:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCOC(=O)c1cn2ccccc2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cn2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a flask containing a mixture of ethyl imidazo[1,2-a]pyridine-2-carboxylate (1 g, 5.26 mmol), THF (5 ml) and water (5 ml), lithium hydroxide (0.378 g, 15.77 mmol) was added and stirred overnight at RT. The pH of the reaction mixture was adjusted to 2 with 2 M HCl and THF was evaporated. The remaining water phase was extracted with ethyl acetate and the combined ethyl acetate phases were dried. The product had precipitated into the water phase. Water was evaporated, and the remaining solid recrystallized from methanol. The product was used as a salt in the next step. 1H-NMR (400 MHz; DMSO-d6): δ 7.23-7.26 (m, 1H), 7.63-7.70 (m, 1H), 7.76 (dd, 1H), 8.72 (s, 1H), 8.73-8.77 (m, 1H).
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:22][F:23])[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6]2[CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=[CH:18][C:5]=2[O:4]1>C(O)C>[NH2:19][C:16]1[CH:17]=[CH:18][C:5]2[O:4][C:3]([CH2:2][F:1])([CH2:22][F:23])[CH:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[C:6]=2[CH:15]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccn1)=CC(CF)(CF)O2
Solvent: CCO
Product: Nc1ccc2c(c1)C(c1ccccn1)=CC(CF)(CF)O2
Yield: 85.5 %

Procedure:
A mixture of 6.2 g of 2,2-bisfluoromethyl-6-nitro-4-(2-pyridyl)-2H-1-benzopyran, 11.7 g of stannous chloride and 80 ml of ethanol was refluxed with heating for 3 hours. The solvent was distilled off and sodium hydroxide solution was added to form an alkaline solution. The solution was extracted with methylene chloride and the organic layer was extracted with 2N hydrochloric acid. To the aqueous layer was added 2N sodium hydroxide to form a strongly alkaline solution, which was then extracted with methylene chloride. The organic layer was washed with water and dried and the solvent was distilled off to obtain 4.8 g of 6-amino-2,2-bisfluoromethyl-4-(2-pyridyl)-2H-1-benzopyran. To a mixture of 4.8 g of the above-obtained 6-amino-2,2-bisfluoromethyl-4-(2-pyridyl)-2H-1-benzopyran, 1.0 ml of concentrated sulfuric acid and 80 ml of water was added 1.20 g of sodium nitrite dissolved in 10 ml of water with stirring under ice-cooling. After the mixture was stirred for 20 minutes, 3.31 g of potassium iodide dissolved in 10 ml of water was added. After addition of 100 ml of methylene chloride, the mixture was stirred at room temperature for 2 hours. Water was added thereto and the mixture was extracted with methylene chloride. The organic layer was washed with sodium hydroxide solution and dried. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 4.50 g of oily 2,2-bisfluoromethyl-6-iodo-4-(2-pyridyl)-2H-1-benzopyran represented by the following formula.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12](O)=[O:13])[C:6]=2[CH2:5][CH2:4][N:3]1[CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18].Cl.[NH2:23][C@@H:24]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C@H:25]([OH:41])[CH2:26][NH:27][C:28]1([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)[CH2:30][CH2:29]1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>ClCCl.O>[CH2:42]([C@H:24]([NH:23][C:12]([C:7]1[C:6]2[CH2:5][CH2:4][N:3]([CH:15]([CH2:16][CH2:17][CH3:18])[CH2:19][CH2:20][CH3:21])[C:2](=[O:1])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:13])[C@H:25]([OH:41])[CH2:26][NH:27][C:28]1([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=2)[CH2:29][CH2:30]1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)CNC1(c2cccc(C(F)(F)F)c2)CC1
Reactant: CCCC(CCC)N1CCc2c(C(=O)O)cccc2C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(CCC)N1CCc2c(C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CNC3(c4cccc(C(F)(F)F)c4)CC3)cccc2C1=O
Reaction time: 24 h
Yield: 129.8 %

Procedure:
Poured into a suspension of 125 mg of 1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid, 170 mg of (2R,3S)-3-amino-4-phenyl-1-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)butan-2-ol hydrochloride (2:1), 9 mg of hydroxybenzotriazole and 104 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 15 cm3 of dichloromethane is 0.444 cm3 of N,N-diisopropylethylamine at a temperature close to 20° C. The solution is kept stirring for 24 h. 15 cm3 of dichloromethane and 15 cm3 of water are added to the reaction medium. The aqueous phase is extracted with 15 cm3 of dichloromethane. The organic phases are combined, washed with 10 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The 350 mg of oil obtained are purified by flash chromatography over silica (column: 50 g; particle size: 120-40 μm, spherical; eluent: 100% ethyl acetate). After concentrating the fractions under reduced pressure, 79 mg of N-[(1S,2R)-1-benzyl-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 100 °C
Yield: 86.4 %

Procedure:
Combine [2-(4-Hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (1.0 g, 4.2 mmol), 4-fluoronitrobenzene (0.6 g, 4.2 mmol), cesium carbonate (2.7 g, 8.4 mmol), and N,N-dimethylformamide (35 mL), stir and heat at 100° C. for 18 hours. Cool to room temperature and evaporate on a rotary evaporator to yield the crude product (9.5 g). The crude product is purified by flash column chromatography on silica gel eluting with (10% conc. ammonium hydroxide in ethanol) and chloroform to yield {2-[4-(4-nitro-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1.3 g): 1H NMR (CDCl3, 300.00 MHz): 8.23 (d, 2H, J=9.2 Hz), 7.32-7.25 (m, 2H), 7.10-7.00 (m, 4H), 4.63 (s, 1H), 3.43 (m, 2H), 2.86 (t, 2H, J=7.0 Hz), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11](Cl)=[O:12].[CH:15]([OH:18])([CH3:17])[CH3:16]>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:18][CH:15]([CH3:17])[CH3:16])=[O:12]
Reactant: CC(C)O
Reactant: COC(=O)/C=C/[C@H]1[C@@H](C(=O)Cl)C1(C)C
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)/C=C/[C@H]1[C@@H](C(=O)OC(C)C)C1(C)C

Procedure:
Using the procedure of Example 3, 1.51 g of (1R,cis) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane -1-carboxylic acid chloride in benzene and 0.61 ml of isopropanol were reacted to obtain 0.820 g of isopropyl (1R,cis) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =-28°±1.5°(c=1% in chloroform).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]3)=[N:19][CH:20]=1)=[N:11][C:10](Cl)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([Cl:52])[C:38]=1[OH:53]>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]3)=[N:19][CH:20]=1)=[N:11][C:10]([C:41]1[CH:40]=[C:39]([Cl:52])[C:38]([OH:53])=[C:37]([Cl:36])[CH:42]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 84.2 %

Procedure:
Following general procedure II, (R)-tert-butyl 1-(5-(3-acetyl-6-chloro-1,5-naphthyridin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (200 mg, 0.40 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (170 mg, 0.60 mmol) to afford the desired product (210 mg, 85%) as a orange solid. ESI MS m/z 623 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:24][Mg]Br.C(Cl)Cl.C([O-])(O)=O.[Na+]>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)([OH:12])[CH3:24])=[CH:9][N:10]=2)[N:7]=1
Reactant: C[Mg]Br
Reactant: O=C(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(O)(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-(7-fluoro-quinolin-6-yl)-methanone (Stage 174.2, 294 mg, 0.9 mmol) was dissolved in anhydrous THF (70 mL) at 40° C. and methylmagnesium bromide in Et2O (3 M, 0.36 mL) was slowly added and the RM was then allowed to cool down to rt and stirred for 2 h. More methylmagnesium bromide in Et2O (3 M, 0.5 mL) was added and the RM was stirred for 1 h more. It was then taken into DCM and 10% aqueous NaHCO3 solution and extracted. The organic phase was dried on MgSO4. After evaporation of the solvent the crude was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, EtOAc/MeOH=100:0->90:10) to afford the title compound (tR 3.74 min (conditions 3), MH+=343, 1H-NMR in DMSO-d6: 8.87 (dd, 1H); 8.50 (d, 1H); 8.49 (d, 1H); 8.18 (d, 1H); 7.85 (s, 1H); 7.59 (d, 1H); 7.51 (dd, 1H); 7.23 (d, 1H); 6.33 (s, 1H); 2.13 (s, 3H))
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6](\[Br:11])/[C:7](=[O:10])[O:8][CH3:9])[C@H:3]1[C:12]([OH:14])=[O:13].[C:16]([C@@H:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)#[N:17]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6](\[Br:11])/[C:7](=[O:10])[O:8][CH3:9])[C@H:3]1[C:12]([O:14][C@H:18]([C:16]#[N:17])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:20]=1)=[O:13]
Reactant: COC(=O)/C(Br)=C/[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: ClC(Cl)Cl
Product: COC(=O)/C(Br)=C/[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Example 1, the product of Step C and (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(Z)-[2-bromo-3-oxo-3-methoxy-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+29.5°±2.5° (c=0.5% in chloroform).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[N:8][C:7]([Sn:10]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:6][N:5]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C1COCC1>[CH3:23][S:24]([NH:3][C:4]1[CH:9]=[N:8][C:7]([Sn:10]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:6][N:5]=1)(=[O:26])=[O:25]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(N)cn1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(NS(C)(=O)=O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.3 %

Procedure:
NaH (60%, 20 mg) was added into a solution of 2-amino-5-(tri-n-butylstannyl)pyrazine (0.2 g) in THF (30 mL) at room temperature. After the mixture stirred at room temperature for 30 minutes, to it was added methylsulfonyl chloride (63 mg). The reaction mixture was stirred at room temperature over 8 hours. The reaction was quenched with aqueous ammonium chloride solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic extract was dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to afford 2-methylsulfonylamino-5-(tri-n-butylstannyl)pyrazine (20 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15](=[O:25])[C@H:16]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH2:17].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(N(CC)CC)C>[CH3:13][O:14][C:15](=[O:25])[CH:16]([NH:17][C:10](=[O:11])[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Cc1ccccc1)NC(=O)CCc1ccc(O)cc1
Reaction time: 0.17 h
Yield: 91.6 %

Procedure:
3-(4-hydroxyphenyl)propionic acid (1.0 g, 6.0 mmol), phenylalanine methyl ester (1.2 g, 6.7 mmol) and 1-hydroxybenzotriazole hydrate (1.0 g, 7.4 mmol) were dissolved in dimethylformamide (25 mL). The resulting solution was then placed in a water bath at 0° C. and treated with triethylamine (3.5 mL), followed by stirring for 10 minutes. To the resulting mixture, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.4 g, 7.4 mmol) was added. After removing the water bath, the mixture was stirred for 18 hours at room temperature. The reaction was diluted in water (60 mL), extracted with ethylacetate (EtOAc) (200 mL), dried over magnesium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (column size: 25 mm×150 mm, silica gel 70-230 mesh, eluent: hexane/EtOAc (1/1)) to obtain 1.8 g of the title compound. The yield was 91%. The results of analyses of the compound are as follows:
Reaction SMILES: Cl.[F:2][C:3]([F:36])([F:35])[C:4]1[CH:34]=[CH:33][C:7]([CH2:8][NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][N:20]=[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[N:18]=3)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[CH2:46]([O:48][C:49](=[O:53])[C:50](Cl)=[O:51])[CH3:47]>C(Cl)Cl>[O:51]=[C:50]([N:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:3]([F:2])([F:35])[F:36])=[CH:34][CH:33]=1)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[O:21][N:20]=[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[N:18]=2)=[CH:15][CH:16]=1)[C:49]([O:48][CH2:46][CH3:47])=[O:53]
Reactant: CCCCCCCCCCCc1noc(-c2ccc(CNCc3ccc(C(F)(F)F)cc3)cc2)n1
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCc1noc(-c2ccc(CN(Cc3ccc(C(F)(F)F)cc3)C(=O)C(=O)OCC)cc2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 71.8 %

Procedure:
To a cold (0° C.) solution of N-[4-(trifluoromethyl)benzyl]-N-[4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzyl]amine hydrochloride (45 mg, 0.09 mmol) and DIEA (24 mg, 0.19 mmol) in anhydrous DCM (1 mL) was added dropwise the chloro-oxo-acetic acid ethyl ester (24 mg, 0.19 mmol). The reaction mixture was stirred at 0° C. for 3 h. Evaporation of the solvents under vacuum gave an orange oil. This crude product was purified by column chromatography over silica gel (AcOEt/c-Hex 1/9) to give the title compound as a colorless oil (38 mg, 75%). 1H NMR (CDCl3, 300 MHz) δ 8.10 (d, J=8.3 Hz, 1H), 8.02 (d, J=8.3 Hz, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.39-7.21 (m, 4H), 4.50 (s, 2H), 4.37 (s, 2H), 4.29 (dq, J1=7.1 Hz, J2=2.3 Hz, 2H), 2.72 (t, J=7.4 Hz, 2H), 1.85-1.65 (m, 2H), 1.41-1.05 (m, 19H), 0.89 (t, J=7.0 Hz, 3H). HPLC (Condition A), Rt: 7.5 min (HPLC purity: 88.8%).
Reaction SMILES: Cl.[CH3:2]COCC.ICI.[CH3:10][C:11]1[CH2:32][CH2:31][CH2:30][C:13]2([O:17][C@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:14]2)[CH:12]=1>[Zn].[Cu].[Zn].II.CO>[CH3:10][C@@:11]12[CH2:2][C@@H:12]1[C:13]1([O:17][C@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:14]1)[CH2:30][CH2:31][CH2:32]2
Reactant: CC1=CC2(CCC1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2
Reactant: CCOCC
Agent: [Cu]
Agent: Cl
Agent: II
Solvent: CO
Solvent: ICI
Product: C[C@]12CCCC3(O[C@H](c4ccccc4)[C@@H](c4ccccc4)O3)[C@H]1C2
Temperature: 25 °C
Yield: 61 %

Procedure:
Zinc/copper couple was freshly prepared by quickly washing zinc dust with 1N HCl (4×100 mL) in a flask and decanting the supernatant. The solid was then washed in the same manner with distilled water (4×120 mL), 2 mol % CuSO4 solution (2×200 mL), distilled water (4×120 mL), EtOH (4×120 mL) and Et2O (5×100 mL). The Et2O washes were poured onto a funnel and dried by vacuum filtration. The resulting solid was added to a 3 L flask and dried under vacuum at 50° C. for 30 min, then cooled to RT. The flask was fitted with an addition funnel and reflux condenser, then purged with nitrogen and kept under N2 throughout the reaction. Next, 650 mL of Et2O was added followed by I2 (0.886 g, 3.49 mmol), and the solution was stirred and heated to reflux. Once at reflux, heating was stopped and diiodomethane (150 mL, 1865 mmol) was slowly added making sure to not allow the reaction to reflux out of control. (2R,3R)-7-methyl-2,3-diphenyl-1,4-dioxaspiro[4.5]dec-6-ene (214 g, 698 mmol in 600 mL Et2O) was then added to the reaction mixture, followed by an additional 0.5 eq of diiodomethane. The reaction was heated to reflux, and the reaction was monitored by LCMS. After 1.5 h the reaction was cooled to RT and quenched with saturated aq Na2CO3 (170 g in 800 mL water). The mixture was stirred for 30 min, then filtered through celite. The inorganics were washed with Et2O (2 L), then the combined organics were washed with saturated NH4Cl (1 L), saturated NaHCO3 (1 L), brine (1 L), then dried over MgSO4, filtered and concentrated to afford the crude product. Methanol (350 mL) was added to the residue and the suspension was heated to 50° C. The resultant solution was cooled with stirring to RT to crystallize the product. The slurry was stirred overnight at RT, then cooled to 0° C., and stirred for an additional 1 h. The slurry was filtered, washed with a minimal amount of MeOH and dried under reduced pressure to afford the desired product as a white solid (137 g, 61% yield).