Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:11][CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:16][CH2:17]2)=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(OC2CCN(C(=O)OCc3ccccc3)CC2)ccc1[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cc(OC2CCN(C(=O)OCc3ccccc3)CC2)ccc1N
Temperature: 0 °C
Yield: 77.6 %

Procedure:
Phenylmethyl 4-[(3-methyl-4-nitrophenyl)oxy]-1-piperidinecarboxylate (0.798 g, 2.15 mmol) was dissolved in 20 mL of MeOH with stirring. Nickel(II) chloride hexahydrate (0.256 g, 1.08 mmol) was added and the mixture was cooled to 0° C. Sodium borohydride (0.163 g, 4.31 mmol) was added, and the mixture was stirred for 20 min. Additional sodium borohydride (˜20 to 30 mg) was added, and the mixture was stirred for 10 min more. The reaction was quenched by the addition of approximately 15 mL of 2N sodium hydroxide solution. The mixture was poured into EtOAc and H2O, and the layers were separated. The organic layer was washed with brine, and the combined aqueous layers were extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford 0.568 g (78%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.40-7.23 (m, 5H), 6.61-6.43 (m, 3H), 5.04 (s, 2H), 4.37 (s, 2H), 4.27-4.17 (m, 1H), 3.74-3.57 (m, 2H), 3.27-3.12 (m, 2H), 1.97 (s, 3H), 1.86-1.73 (m, 2H), 1.52-1.39 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[CH:8]=[CH:7][CH:6]=[CH:5]2.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[C:16](Cl)=[O:17]>>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:16]([C:10]2[N:9]3[C:4]([CH:5]=[CH:6][CH:7]=[CH:8]3)=[CH:3][C:2]=2[CH3:1])=[O:17])[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23]
Reactant: Cc1cc2ccccn2c1
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Product: COc1cc(C(=O)c2c(C)cc3ccccn23)ccc1[N+](=O)[O-]

Procedure:
This compound is obtained by carrying out the procedure according to the preparation described in Example 1, by benzoylation of 2-methylindolizine, described in Pharmazie; (1980), vol 35(4), pp 203-204, with 3-methoxy-4-nitrobenzoyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[S:11](Cl)(=[O:13])=[O:12].S([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+].S(Cl)(Cl)(=O)=O>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[S:11]([OH:13])=[O:12]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(=O)(Cl)Cl
Product: COc1ccc(S(=O)O)c(OC)c1
Temperature: 0 °C

Procedure:
Next, a mixture containing 35.8 g (0.15 moles) of 2,4-dimethoxy-benzenesulfonyl chloride and 56 g (0.45 moles) of sodium sulfite is shaken for 3 hours with 100 g of ice until complete solution is obtained. The solution is maintained alkaline by adding 5% sodium hydroxide (to prevent formation of sulfur dioxide) and kept cold by adding additional ice (higher temperatures may cause hydrolysis of the sulfonyl chloride). At the end of 3 hours unreacted 2,4-dimethoxy-benzenesulfonyl chloride can be filtered off and the filtrate acidified with cold concentrated hydrochloric acid to yield a white crystalline precipitate of 2,4-dimethoxybenzenesulfinic acid, m.p. 89-91° C. (lit. 92° C.). The 2,4-demethoxybenzene-sulfinic acid is suspended in water and an equimolar quantity of sodium carbonate added in small portions to dissolve the sulfinic acid. The condensation of the sodium salt of the sulfinic acid with ortho-dinitrobenzene can be carried out by refluxing equimolar amounts of the two for 4 hours. Upon cooling the mixture is filtered and the solid residue recovered and crystallized using acetic acid to yield white shiny crystals of 2,4-dimethoxy-2'-nitrobiphenyl sulfone having a melting point of from about 157.5° C. to about 158.5° C.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]3=[O:20])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2].[Cl:21][C:22]1[S:26][CH:25]=[C:24]([CH2:27]O)[CH:23]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:21][C:22]1[S:26][CH:25]=[C:24]([CH2:27][O:19][C:16]2[CH:17]=[CH:18][N:13]([C:10]3[CH:11]=[CH:12][C:5]4[N:4]=[C:3]([CH2:1][CH3:2])[N:7]([CH3:8])[C:6]=4[CH:9]=3)[C:14](=[O:20])[CH:15]=2)[CH:23]=1
Reactant: OCc1csc(Cl)c1
Reactant: CCc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCc1nc2ccc(-n3ccc(OCc4csc(Cl)c4)cc3=O)cc2n1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 48.1 %

Procedure:
To a mixture of 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (126 mg), (5-chloro-3-thienyl)methanol (139 mg) and tributylphosphine (0.347 ml) in THF (8 ml) was added 1,1′-(azodicarbonyl)dipiperidine (354 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried MgSO4, and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc to MeOH/EtOAc). The resulting solid was recrystallized from EtOH/hexane to give the title compound (90 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]#[CH:11])=[CH:6][C:5]([NH:12][C:13](=O)[CH:14]=[N:15][O:16][CH3:17])=[C:4]([F:19])[CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>C1C=CC=CC=1.ClCCl>[CH3:17][O:16][N:15]=[CH:14][C:13](=[N:12][C:5]1[CH:6]=[C:7]([O:8][CH2:9][C:10]#[CH:11])[C:2]([Cl:1])=[CH:3][C:4]=1[F:19])[N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C#CCOc1cc(NC(=O)C=NOC)c(F)cc1Cl
Reactant: C1CCNC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccccc1
Product: C#CCOc1cc(N=C(C=NOC)N2CCCC2)c(F)cc1Cl
Yield: 64.2 %

Procedure:
0.42 g of the obtained N-(4-chloro-2-fluoro-5-propargyloxyphenyl)-2-(methoxyimino)acetamide was dissolved in 30 ml of benzene and after the addition of 0.36 g of phosphorus pentachloride, the resulting solution was refluxed for 4 hours. The concentrate obtained by concentrating the resulting reaction solution under reduced pressure was dissolved in 20 ml of dichloromethane and 0.32 g of pyrrolidine was added dropwise thereto at room temperature and the resultant solution was stirred at room temperature for 1 hour. The concentrate obtained by evaporating solvents from the resulting reaction solution under reduced pressure was purified by silica gel column chromatography to obtain 0.32 g of 2-(4-chloro-2-fluoro-5-propargyloxyphenylimino)-2-(pyrrolidine-1-yl)acetaldehyde O-methyloxime (1-5) (yield 64%). m.p. 73-75° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1.[S:24]1[CH2:28][C:27](=[O:29])[NH:26][C:25]1=[O:30]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][CH:28]2[S:24][C:25](=[O:30])[NH:26][C:27]2=[O:29])=[CH:5][C:4]=1[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1
Reactant: COc1ccc(C=O)cc1COCc1ccc(C(F)(F)F)cc1
Reactant: O=C1CSC(=O)N1
Product: COc1ccc(CC2SC(=O)NC2=O)cc1COCc1ccc(C(F)(F)F)cc1

Procedure:
Using 4-methoxy-3-({[-4-(trifluoromethyl)benzyl]oxy}methyl)benzaldehyde and 2,4-thiazolidinedione, 5-[4-methoxy-3-([4-(trifluoromethyl)benzyl]oxymethyl)benzyl]-1,3-thiazolane-2,4-dione was obtained in the same method as in Production Example 27c) and then in Example 29).
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2].[CH2:18]([NH2:20])[CH3:19]>O>[N+:1]([CH:4]=[C:5]([NH:20][CH2:18][CH3:19])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1nccs1
Reactant: CCN
Solvent: O
Product: CCNC(=C[N+](=O)[O-])NCCSCc1nccs1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-(2-thiazolylmethylthio)ethylamino]ethylene (see Example 55(i)) with ethylamine by the procedure of Example 8(ii) gives the title product, m.p. 115°-116° (from water).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)Cl>[Br:12][C:10]1[C:5]2[C:6](=[N:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:8]([CH3:11])[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1ccc2ccc(F)nc21
Solvent: ClCCl
Product: Cn1cc(Br)c2ccc(F)nc21
Yield: 99.4 %

Procedure:
To a solution of 6-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine (257.3 g, 1.71 mol) in DCM (3.86 L) is added N-bromosuccinimide (320.3 g; 1.80 mol) in five portions over 30 minutes. The mixture is stirred without heating or cooling overnight, then filtered and concentrated to about 1 L. This is purified by column chromatography on silica, eluting with 0 to 30% EtOAc in isohexane. The appropriate fractions are evaporated to give the product as an off white solid (391.3 g, 1.7 mol). 1H-NMR (400 MHz, CDCl3): δ 7.91-7.87 (m, 1H), 7.15 (s, 1H), 6.77 (d, 1H), 3.81 (s, 3H).
Reaction SMILES: [Na].[N+](CCC)([O-])=[O:3].Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1>C(O)C>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]=[O:3])=[CH:11][C:12]=1[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCC[N+](=O)[O-]
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Agent: [Na]
Solvent: CCO
Product: O=Cc1ccc(F)c(Oc2ccccc2)c1
Reaction time: 3.5 h

Procedure:
After dissolving sodium metal (0.41 g, 17.8 g-atom) in ethanol (25 ml), nitropropane (1.65 g) and 4-(bromomethyl)-1-fluoro-2-phenoxybenzene (5.00 g) are added and the mixture stirred for 3.5 h. The reaction was filtered and concentrated in vacuo. The residue is taken up in ether and washed with water (10 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel eluting with ether:hexane (10:90) to afford the title compound as a colorless liquid which is characterized by 1HNMR spectral analyses.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: FC(F)(F)c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Product: FC(F)(F)c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-trifluoromethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-trifluoromethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][N:2](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH:4]([C:6]1[N:7](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:8]=[CH:9][N:10]=1)[OH:5].[ClH:49]>CC(C)=O.O1CCOCC1>[ClH:49].[ClH:49].[NH:7]1[CH:8]=[CH:9][N:10]=[C:6]1[CH:4]([OH:5])[CH2:3][NH:2][CH3:1]
Reactant: CN(CC(O)c1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1)C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: CNCC(O)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2-[methyl(trityl)amino]-1-(1-trityl-1H-imidazol-2-yl)ethanol (3.4 g, 5.43 mmol) in 70 mL of acetone was treated with a solution of 4N HCl in dioxane (5 mL) and stirred for 4 h at room temperature. The solvent was removed by evaporation in vacuum and the residue was suspended in EtOAc. The solid was collected by filtration and washed with hot EtOAc. A white solid, 0.92 g (79%) was obtained after drying under vacuum. mp 176.4-177.3° C.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:12][P:13]([N:22]([CH2:26][CH:27]=[CH2:28])[CH2:23][CH:24]=[CH2:25])([N:15]([CH2:19][CH:20]=[CH2:21])[CH2:16][CH:17]=[CH2:18])=[S:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=O>C(O)C>[CH2:26]([N:22]([P:13]([CH2:12][NH:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])([N:15]([CH2:19][CH:20]=[CH2:21])[CH2:16][CH:17]=[CH2:18])=[S:14])[CH2:23][CH:24]=[CH2:25])[CH:27]=[CH2:28]
Reactant: C=CCN(CC=C)P(=S)(CN(CC(=O)OCC)C(=O)C(F)(F)F)N(CC=C)CC=C
Solvent: CCO
Product: C=CCN(CC=C)P(=S)(CNCC(=O)OCC)N(CC=C)CC=C
Yield: 18.9 %

Procedure:
N-trifluoroacetyl-N-[bis(diallylamino)phosphinothioylmethyl]glycine, ethyl ester (2 g, 4.2 mm), was dissolved in ethanol (40 ml). The solution was stirred and sodium tetrahydrido boron (162 mg, 4.2 mm) was added portionwise over a ten minute period. The solution was stirred for an additional 30 minutes. The solvent was removed by evaporation under vacuum and the residue was washed with water. The water washings were saturated with sodium chloride and the aqueous layer and insoluble residue were simultaneously extracted with ethyl acetate three times. The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was then chromatographed on silica gel employing dichloromethane and then ether to yield N-[bis(diallylamino)phosphinothioylmethyl]glycine, ethyl ester (300 mg), as a yellow solid, m.p. 80°-82° C. and having the following analysis: Calculated: C, 54.97; H, 8.14; N, 11.31. Found: C, 54.74; H, 8.13; N, 11.25.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[O:8][CH2:9][C:10]([OH:12])=[O:11])([OH:3])=[O:2].[Cl:17][S:18](O)(=[O:20])=[O:19]>>[C:10]([CH2:9][O:8][C:7]1[CH:13]=[C:14]([S:18]([Cl:17])(=[O:20])=[O:19])[CH:15]=[CH:16][C:6]=1[O:5][CH2:4][C:1]([OH:3])=[O:2])([OH:12])=[O:11]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)COc1ccccc1OCC(=O)O
Product: O=C(O)COc1ccc(S(=O)(=O)Cl)cc1OCC(=O)O
Temperature: 25 °C

Procedure:
2-Carboxymethoxyphenoxyacetic acid (15.3 g, 0.0675 mol) was added in portions over 30 min to stirred chlorosulfonic acid (59.0 g, 0.506 mol) that was cooled in an ice/methanol bath. The mixture was allowed to warm to room temperature over 2.5 hr and was then poured slowly into stirred ice water. The resulting solid was collected by filtration, washed with water, and dried at high vacuum over sodium hydroxide. The product, title compound, weighed 6.54 g (30%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([C:16]1[N:20]([CH3:21])[C:19]2[CH:22]=[CH:23][C:24]([N:26]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=3)[CH3:27])=[CH:25][C:18]=2[N:17]=1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][S:37]([CH2:40][C:41]1[CH:42]=[C:43]([NH2:47])[CH:44]=[CH:45][CH:46]=1)(=[O:39])=[O:38]>>[C:1]([O:5][C:6](=[O:35])[N:7]([C:16]1[N:20]([CH3:21])[C:19]2[CH:22]=[CH:23][C:24]([N:26]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:47][C:43]4[CH:44]=[CH:45][CH:46]=[C:41]([CH2:40][S:37]([CH3:36])(=[O:39])=[O:38])[CH:42]=4)[N:29]=3)[CH3:27])=[CH:25][C:18]=2[N:17]=1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(N(C(=O)OC(C)(C)C)c2nc3cc(N(C)c4ccnc(Cl)n4)ccc3n2C)cc1
Reactant: CS(=O)(=O)Cc1cccc(N)c1
Product: COc1ccc(N(C(=O)OC(C)(C)C)c2nc3cc(N(C)c4ccnc(Nc5cccc(CS(C)(=O)=O)c5)n4)ccc3n2C)cc1

Procedure:
The title compound was prepared following the procedure of example 78 using {5-[(2-Chloro-pyrimidin-4-yl)-methyl-amino]-1-methyl-1H-benzoimidazol-2-yl}-(4-methoxy-phenyl)-carbamic acid tert-butyl ester (100 mg, 0.20 mmol) and 3-methanesulfonylmethyl-phenylamine (37 mg, 0.20 mmol) to give the desired product as a white solid. 1H NMR (300 MHz, d6-DMSO) δ 9.44 (s, 1H), 7.80-7.82 (m, 2H), 7.63-7.70 (M, 2H), 7.56 (d, J=1.5 Hz, 1H), 7.34 (d, J=8.7 Hz, 2H), 7.25 (dd, J=8.6 and 1.2 Hz, 1H), 7.18 (t, J=7.5 Hz, 1H), 6.94 (d, J=9.0 Hz, 2H), 5.75 (d, J=6.0 Hz, 1H), 4.34 (s, 2H), 3.79 (s, 3H), 3.74 (s, 3H), 3.47 (s, 3H), 2.89 (s, 3H), 1.41 (s, 9H). MS (ESI) m/z=644 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][NH:9][C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21](O)[CH3:22].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[CH2:21]([O:12][C:11](=[O:13])[C@H:10]([NH:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:22]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)CN[C@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)[C@@H](Cc1ccccc1)NCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 44.5 %

Procedure:
(2R)-2-((tert-Butoxycarbonyl)methylamino)-3-phenylpropionic acid (4.0 g, 14.27 mmol) was dissolved in dichloromethane (5 ml) and ethanol (0.95 ml, 16.27 mmol). 4-Dimethylaminopyridine (0.19 g, 1.57 mmol) was added. The solution was cooled to 0° C. and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.98 g, 15.55 mmol) was added. The reaction mixture was stirred for 2 h at 0° C. for 16 h at room temp. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate/water (30 ml/30 ml). The phases were separated. The organic phase was washed with a saturated solution of sodium hydrogencarbonate and water and dried over magnesium sulfate. The crude product was purified by flash chromatography on silica (180 g) with ethyl acetate/heptane 1:2 to give 1.95 g of (2R)-2-((tert-butoxycarbonyl)methylamino)-3-phenylpropionic acid ethylester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C@@H:8]([OH:10])[CH3:9])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:33]1[C:34]([N+:39]([O-:41])=[O:40])=[N:35][CH:36]=[CH:37][CH:38]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(=O)=O.C1(C)C=CC=CC=1.C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C@H:8]([O:10][C:33]2[C:34]([N+:39]([O-:41])=[O:40])=[N:35][CH:36]=[CH:37][CH:38]=2)[CH3:9])[CH:7]=1
Reactant: O=[N+]([O-])c1ncccc1O
Reactant: COc1ccc(F)cc1[C@H](C)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc(F)cc1[C@@H](C)Oc1cccnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
To an ice cooled solution (0° C.) of (S)-1-(5-fluoro-2-methoxy-phenyl)-ethanol (see H. C. Brown, Tet. Letts., 35 (14), 2141-4, 1994. Optical purity of alcohol: >99.5% e.e. (based on SFC on a chiral column: Chiralpak IA (250*4.6 mm i.d.), eluent 5% methanol alcohol in carbon dioxide, Flow rate 4 mL/min, temp. 40° C., back pressure 150 bar, Rt=2.16 min (opposite enantiomer Rt=2.35 min))) (2.00 g, 11.7 mmol), triphenylphosphine (3.54 g, 13.5 mmol, 1.15 eq.) and 3-hydroxy-2-nitro-pyridine (1.81 g, 12.9 mmol, 1.1 eq) in toluene (100 mL) was added a solution of diisopropyl azodicarboxylate (2.73 g, 13.5 mmol, 1.15 eq.) in toluene (20 mL) at such a rate as to maintain the temperature below 10° C. The resulting mixture was stirred at room temperature for 18 hr. The crude reaction mixture was extracted with aqueous potassium hydroxide solution (2M, 2×50 mL). The organic phase was washed with brine and dried over magnesium sulphate before filtering. The filtrate was evaporated under reduced pressure to give an orange semi solid material. This material was suspended in diethyl ether and heptane (80:20 by volume) and filtered. This filtrate was evaporated under reduced pressure. The residue was purified by chromatography on silica gel eluting with a gradient of diethyl ether in heptane (50:50 to 80:20 by volume) to produce the title compound as a pale yellow oil (3.48 g, 86%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=1.Cl[C:19]1[CH:20]=[C:21]2[N:28]([CH3:29])[C:27]([CH3:31])([CH3:30])[CH2:26][N:22]2[C:23](=[O:25])[N:24]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=1)[CH2:16][O:17][C:19]1[CH:20]=[C:21]2[N:28]([CH3:29])[C:27]([CH3:31])([CH3:30])[CH2:26][N:22]2[C:23](=[O:25])[N:24]=1
Reactant: OCc1ccc(Oc2ccnc(F)c2)c(F)c1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CN1c2cc(OCc3ccc(Oc4ccnc(F)c4)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-((2-fluoropyridin-4-yl)oxy)phenyl)methanol and 7-chloro-1,2,2-trimeth-yl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([O:16][C:17](=[O:23])[C:18](OCC)=[O:19])[CH2:14]C.CC[O-].[Na+].Cl>CCO>[CH2:13]([O:16][C:17](=[O:23])[C:18](=[O:19])[CH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[CH3:14]
Reactant: CCCOC(=O)C(=O)OCC
Reactant: Cc1ccc(C#N)cc1[N+](=O)[O-]
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
Treat a suspension of 4-methyl-3-nitro-benzonitrile (2.11 g, 12.5 mmol) and oxalic acid ethyl ester propyl ester (2.99 g, 18.7 mmol) in EtOH (80 mL) with NaOEt (21% w/w, 18.2 mL). Stir the mixture at 40° C. overnight. Quench the reaction with water and acidify with 1 M HCl solution. Concentrate to a residue and partition between EtOAc and water. Concentrate the organic layer and purify by silica gel chromatography to give the desired product 3-(4-cyano-2-nitro-phenyl)-2-oxo-propionic acid ethyl ester (3:1 keto/enol mixture) as a solid in 37% yield (1.21 g, 4.62 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][N:3]=1.C([Li])CCC.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][Cl:18]>O1CCCC1.CCOCC>[Cl:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:5]1[S:4][N:3]=[C:2]([CH3:1])[CH:6]=1
Reactant: Cc1ccsn1
Reactant: ClCCCCCBr
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(CCCCCCl)sn1
Reaction time: 0.25 h
Yield: 49.4 %

Procedure:
To a solution of 6.4 g 3-methylisothiazole in 100 ml dry tetrahydrofuran at -78° C. under nitrogen was slowly added 7.6 ml n-butyllithium (9.5 m). After 15 min. at -78° C., a solution of 12.0 g 1-bromo-5-chloropentane in 10 ml dry ether was added. The reaction mixture was allowed to reach room temperature where it was stirred for 90 min., then diluted with ether, washed with water and sodium chloride solution, and dried over sodium sulfate. Concentration and flash filtration (silica gel, 4:1 hexane/ethyl acetate) gave 6.5 g of 5-(5-chloropentyl)-3-methylisothiazole as a red oil, sufficiently pure (NMR) for use in the subsequent reaction.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[C:5]=1[C:6]([NH2:8])=[NH:7].O=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]1>>[ClH:1].[NH2:7][C:6]1[C:5]2[C:4](=[CH:12][C:11]([F:13])=[CH:10][C:9]=2[F:14])[NH:3][C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]2)[N:8]=1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: N=C(N)c1c(N)cc(F)cc1F
Agent: Cl
Product: CCOC(=O)N1CCC2(CC1)N=C(N)c1c(F)cc(F)cc1N2

Procedure:
This was prepared by the method of Example 173 using 2-anino-4,6-difluorobenzamidine dihydrochloride (Example H) and ethyl 4-oxopiperidine-1-carboxylate to give the title compound, m.p. 245°-246° C.