Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][NH:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=2)[C:14]([CH3:22])=[CH:13]1.[C:23](C1NC=CN=1)(C1NC=CN=1)=[O:24].[CH2:35]([NH2:42])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].C([O-])(O)=O.[Na+]>O1CCCC1.C(O)(=O)C.CCOCC>[CH2:35]([NH:42][C:23](=[O:24])[O:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:12]([NH:11][CH2:10][CH2:9][CH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[F:1])[CH:13]=[C:14]2[CH3:22])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CCCCCCCN
Reactant: Cc1cn(NCCCc2ccncc2F)c2ccc(O)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCNC(=O)Oc1ccc2c(c1)c(C)cn2NCCCc1ccncc1F
Reaction time: 24 h

Procedure:
To a solution consisting of 1-[(3-fluoro-4-pyridinyl)propylamino]-3-methyl-1H-indol-5-ol (2.54 g) and anhydrous tetrahydrofuran (57 ml) was added carbonyl diimidazole (2.75 g) under nitrogen with stirring. The resulting reaction mixture was stirred at room temperature for two days, at which time acetic acid (1.65 ml) was added followed by a solution of heptylamine (1.89 ml) in tetrahydrofuran (5 ml) and acetic acid (0.76 ml). After stirring for 24 hours, an additional equivalent of heptylamine (1.26 ml) in tetrahydrofuran (5 ml) and acetic acid (0.52 ml) was added. After an additional 24 hours the reaction was complete and the reaction mixture was poured into NaHCO3 (aq.) and ether. The layers were separated and the aqueous phase was extracted with ether (3x). The combined organic layers were washed successively with NaHCO3 (aq.) and brine. Drying (Na2SO4), filtration and concentration gave a crude product. Purification via flash column chromatography (silica gel, 30% EtOAc/hexane) afforded 3.38 g of the desired product as an oil. Addition of ether and pentane solidified the product. The solid was filtered and washed with pentane, m.p. 90°-93° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClCC1[O:49][N:48]=[C:47]([C:50]([F:53])([F:52])[F:51])[N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[O:49][N:48]=[C:47]([C:50]([F:53])([F:52])[F:51])[N:46]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: FC(F)(F)c1noc(CCl)n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3nc(C(F)(F)F)no3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-3-(trifluoromethyl)-1,2,4-oxadiazole and isolated as brown gum. MS(m/e): 433.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:13](Cl)=[O:14]>C(Cl)CCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([N:6]=[C:13]=[O:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1c(F)cccc1Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1c(F)cccc1Cl
Yield: 91106.6 %

Procedure:
To a solution of 2-chloro-6-fluorobenzamide (2.0 g, 0.011 mmol) in EDC (10 mL) was added oxalyl chloride (2.18 g, 0.017 mmol). The reaction mass was refluxed for 24 h. Excess of solvent was removed under vacuum to afford 2.0 g of desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][C:10]1[CH:14]=[C:13]([CH3:15])[NH:12][N:11]=1>>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:11]2[C:10]([CH3:9])=[CH:14][C:13]([CH3:15])=[N:12]2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: Cc1cc(C)[nH]n1
Product: Cc1cc(C)n(-c2cncc(Cl)n2)n1

Procedure:
Was prepared according to Example 3 from 2,6-dichloropyrazine and 3,5-dimethylpyrazole.
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:9]#[N:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH3:25]>>[Br-:23].[C:9]([C:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:7][N+:1]([CH2:24][CH3:25])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2)#[N:10]
Reactant: N#CC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Reactant: CCBr
Product: CC[N+]12CCC(C(C#N)(c3ccccc3)c3ccccc3)(CC1)C2
Product: [Br-]
Yield: 29.5 %

Procedure:
Following the general procedure outlined in Example 24, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)acetonitrile (0.044 g, 0.152 mmol) and bromoethane (0.020 mL, 0.268 mmol) in 2CH3CN/3CHCl3 (3.5 mL) were reacted to give the desired product (0.0178 g, 29.7%). EI-MS m/z 317 (M+) Rt (1.53 rain).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1.O>CN(C)C=O>[N+:20]([C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][S:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH2:1])([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: Nc1cccc(S)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cccc(SCc2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of 3-aminobenzenethiol (0.51 mL, 4.8 mmol) and sodium methoxide (0.31 g, 5.8 mmol) in N,N-dimethylformamide (5.3 mL) was stirred at 25° C. for 10 minutes (min). The reaction mixture was treated with a solution of 1-(bromomethyl)-3-nitro-benzene (1.0 g, 4.8 mmol) in N,N-dimethylformamide (4.5 mL) dropwise and stirred at 25° C. for 1 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was separated and washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude brown oil. This material was purified by flash column chromatography to give the desired product (1.2 g, 95%) as a tan oil. LCMS for C13H13N2O2S (M+H)+: m/z=261.0.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[S:14][C:13]([C:15]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:18][NH:17][N:16]=2)=[CH:12][CH:11]=1.C(OCC)(=O)C>CN(C)C=O>[Br:1][C:18]1[NH:17][N:16]=[C:15]([C:13]2[S:14][C:10]([Cl:9])=[CH:11][CH:12]=2)[C:19]=1[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1
Reactant: Clc1ccc(-c2n[nH]cc2-c2ccncc2)s1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1ccc(-c2n[nH]c(Br)c2-c2ccncc2)s1
Temperature: 80 °C
Reaction time: 2 h
Yield: 123.6 %

Procedure:
N-Bromosuccinimide (1 eq, 0.38 mmol) was added to a solution of 4-[3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (1 eq, 0.38 mmol) in 2 mL of N,N-dimethylformamide. The mixture was then stirred at 80° C. for 2 h. Further N-Bromosuccinimide (0.3 eq, 0.12 mmol) was added and the mixture was stirred for one more hour. After cooling to room temperature, ethyl acetate was added and the organic layer was washed with water, dried over MgSO4, filtered and evaporated. The residue was suspended in diisopropylether and dichloropethane, filtered and dried in a vacuum oven at 50° C. to afford 0.16 g of 4-[5-bromo-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16]>C(O)(=O)C.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([OH:11])[CH:5]=[C:14]2[C:15]([OH:17])=[O:16]
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: O=C(O)CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)c1cc(O)nc2ccc(F)cc12
Yield: 54 %

Procedure:
A stirred suspension of 5-fluoroisatin, also known as 5-fluoro-2,3-indoledione, available from Sigma-Aldrich (10.00 g, 61 mmol) and malonic acid (18.91 g, 182 mmol) in acetic acid (400 ml) was refluxed for 16 h. Acetic acid was removed under reduced pressure, the residue was suspended in water (400 ml), filtered and washed with water (300 ml) to give a brown solid. The solid was stirred in NaHCO3 saturated aqueous solution (800 ml) and the insoluble material was filtered off. The filtrate was acidified to pH 1-2 with concentrated HCl and the resulting precipitate was filtered, washed with water (300 ml) and dried. The resulting pale yellow solid (10 g, Yield 54%) was used directly for synthesis of preparation 4 without further purification. The mixture was analysed by 1H NMR and LCMS: 1H NMR (500 MHz; d6-DMSO) δ 2.08 (s, 1.5 H), 7.01 (s, 1H), 7.35-7.37 (m, 0.5 H)*, 7.48-7.49 (m, 2H), 7.64-7.68 (m, 0.9H)*, 8.01-8.04 (m, 1H), 12.29 (brs, 1H), 13.38 (brs, 0.7H)* ppm.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[NH2:26].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O.C(Cl)Cl>[F:23][C:2]([F:24])([F:1])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:26][NH:25][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: NNc1ccccn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNc1ccccn1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
A 500-mL, 3-necked, round-bottomed flask was charged with a suspension of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (10 g, 1.0 eq.) in 1:1 CH2Cl2:AcOEt (200 mL). 2-Hydrazinopyridine (3.11 g) was added at −40° C. T3P (50% in ethylacetate) (21.75 g) was added dropwise followed by DIPEA (7.36 g) and the reaction mixture was stirred for 30 min at −40° C. before being concentrated under reduced pressure (35° C., 20 mm Hg) to afford a crude brown oil that was purified by column chromatography (the compound eluted with 1.3% MeOH in CH2Cl2). Fractions containing desired compound were combined to afford 6.0 g (yield: 48%) (Z)-3-(3-(3,5-bis-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(pyridin-2-yl)acrylohydrazide. 1H NMR (400 MHz, DMSO-d6) δ, 10.41 (s, 1H), 9.66 (s, 1H), 8.59 (s, 1H), 8.53 (s, 2H), 8.28 (s, 1H), 8.06-8.08 (d, J=5.2 Hz, 1H), 7.48-7.53 (m, 1H), 7.49-7.52 (d, J=10.4, 1H), 6.71-6.75 (m, 1H), 6.66-6.68 (d, J=8.4 Hz, 1H), 6.07-6.09 (d, J=10.4, 1H). LCMS for C18H12F6N6O [M+H]+ predicted: 443.33. found: 443.44 (RT 2.45 min, purity: 100%).
Reaction SMILES: [CH3:1][C:2]([CH3:29])=[CH:3][CH2:4][C:5]1[C:6]([OH:28])=[CH:7][C:8]2[O:27][C:15]3[CH:16]=[C:17]([OH:26])[C:18]([OH:25])=[C:19]([CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[C:14]=3[C:12](=[O:13])[C:9]=2[C:10]=1[OH:11].[C-:30]#N.[Na+]>CS(C)=O>[CH3:1][C:2]([CH3:29])=[CH:3][CH2:4][C:5]1[C:10]([OH:11])=[C:9]2[C:12]([C:14]3[C:15]([O:27][C:8]2=[CH:7][C:6]=1[OH:28])=[CH:16][C:17]([OH:26])=[C:18]([O:25][CH3:30])[C:19]=3[CH2:20][CH:21]=[C:22]([CH3:23])[CH3:24])=[O:13]
Reactant: [C-]#N
Reactant: CC(C)=CCc1c(O)cc2oc3cc(O)c(O)c(CC=C(C)C)c3c(=O)c2c1O
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1c(O)cc2oc3cc(O)c(CC=C(C)C)c(O)c3c(=O)c2c1CC=C(C)C
Temperature: 195 °C
Reaction time: 6 h
Yield: 64 %

Procedure:
γ-Mangostin from 3,6,7-trimethyl-γ-mangostin: To a solution of 3,6,7-trimethyl-γ-mangostin (0.5 g, 1.14 mmol) in DMSO (LR, 20 mL) was added sodium cyanide (1.0 g, 20.5 mmol) at RT and the mixture was stirred at 190-200° C. for 6 h. The reaction mixture was allowed to ambient temperature and poured into ice cold water and extracted with a mixture of ethyl acetate and THF (1:1, 5×100 mL). The combined organic layer was washed with aqueous potassium permanganate (10%), water, brine and dried over sodium sulfate. The solution was filtered and the solvent evaporated under vacuum and the residue was chromatographed over silica gel column using chloroform-methanol mixture (95:5) as eluents to give α-mangostin (300 mg, 64%). The α-mangostin was then converted to γ-mangostin using the inventive demethylation procedure as described in example 12.
Reaction SMILES: [C:1]([C:3]1[O:7][N:6]=[CH:5][CH:4]=1)#[N:2].[NH2:8][C:9]1[S:10][C:11]([N+:19]([O-:21])=[O:20])=[CH:12][C:13]=1[C:14](OCC)=O.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:14]1[C:13]2[CH:12]=[C:11]([N+:19]([O-:21])=[O:20])[S:10][C:9]=2[N:8]=[C:1]([C:3]2[O:7][N:6]=[CH:5][CH:4]=2)[N:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1ccno1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])sc1N
Product: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 477, the reaction of 5-cyanoisoxazole and 2-amino-5-nitro-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(isoxazol-5-yl)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.C[S+](C)C1C=CC(O[C:21](=[O:35])[C@H:22]([CH3:34])[NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=CC=1.[NH2:37][C@H:38]([C:42]([OH:44])=[O:43])[CH:39]([CH3:41])[CH3:40].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:27]([O:26][C:24]([NH:23][C@H:22]([C:21]([NH:37][C@H:38]([C:42]([OH:44])=[O:43])[CH:39]([CH3:41])[CH3:40])=[O:35])[CH3:34])=[O:25])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([S+](C)C)cc1
Reactant: CC(C)[C@H](N)C(=O)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
In 50 ml of chloroform was dissolved 4.14 g of benzyloxycarbonylalanine p-dimethylsulfoniophenyl ester p-toluenesulfonate, and 20 ml of an aqueous solution of 0.91 g of valine and 1.1 ml of triethylamine was added dropwise thereto while under stirring at room temperature. The reaction mixture was stirred for 8 hours at room temperature and then separated. The chloroform layer was washed with water, dried, and concentrated under reduced pressure, and ether was added to the residue to afford white crystals.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:12]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10]2[C:5](=[CH:6][C:7]([NH2:23])=[C:8]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:9]=2)[N:4]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(O)(=O)C>[ClH:1].[CH3:2][C:3]1[CH:12]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10]2[C:5](=[CH:6][C:7]([NH:23][C:24](=[O:26])[CH3:25])=[C:8]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:9]=2)[N:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(N2CCCC2)c2cc(N3CCCC3)c(N)cc2n1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)Nc1cc2nc(C)cc(N3CCCC3)c2cc1N1CCCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 58 %

Procedure:
A solution 0.1 g (0.27 mmol of 2-methyl-4,6-di-pyrrolidin-1-yl-quinolin-7-ylamine hydrochloride (×1.58 HCl), product of example 70 in acetic acid (0.22 ml) was treated with 0.1 ml (1.08 mmol) of acetic anhydride and then stirred at RT for 19 h. The reaction mixture was concentrated in vacuo, brought to pH 9 with conc. ammonia and then twice extacted with CH2CL2. The organic phase was washed with water saturated with brine and dried over magnesium sulfate. The solvent was removed in vacuo, the residue triturated with ether (10 ml) and treated tropwise with 0.3 ml of 3 N HCL in MeOH. The brown crystalline solid obtained was filtered off by suction and dried in a high vacuum to give 58.7 mg (89%) of N-(2-methyl-4,6-di-pyrrolidin-1-yl-quinolin-7-yl)-acetamide hydrochloride as a brown solid. ISP mass spectrum, m/e: 339.3 (M+1 calculated for C20H27N4O: 339).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][OH:12])[CH2:6]1)=[O:4].[F:15][C:16]1[CH:30]=[CH:29][C:19]([O:20][C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=2)=[CH:18][CH:17]=1>>[F:14][C:2]([F:1])([F:13])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][O:12][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][C:19]3[CH:29]=[CH:30][C:16]([F:15])=[CH:17][CH:18]=3)=[CH:22][CH:23]=2)[CH2:6]1)=[O:4]
Reactant: O=C(N1CCCC(CO)C1)C(F)(F)F
Reactant: Fc1ccc(Oc2ccc(CCl)cc2)cc1
Product: O=C(N1CCCC(COCc2ccc(Oc3ccc(F)cc3)cc2)C1)C(F)(F)F
Yield: 13.4 %

Procedure:
Using 1-trifluoroacetylpiperidin-3-yl methanol (422 mg, 2.00 mmol) and 4-(4-fluorophenoxy)benzylchloride (473 mg, 2.00 mmol), the same procedure was followed as in Step 5a of Example 5 to give 110 mg (13%) of the desired compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:10])[CH3:9])=[CH:4][N:3]=1.[CH3:11][S:12][C:13](SC)=[CH:14][N+:15]([O-:17])=[O:16]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:13]([S:12][CH3:11])=[CH:14][N+:15]([O-:17])=[O:16])[CH3:9])=[CH:4][N:3]=1
Reactant: CC(N)c1ccc(Cl)nc1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: CSC(=C[N+](=O)[O-])NC(C)c1ccc(Cl)nc1
Yield: 40.2 %

Procedure:
A mixture of 1-(2-chloro-5-pyridyl)ethylamine (4.7 g), 1,1-bis-methylthio-2-nitroethylene (5.0 g) and ethanol (50 ml) was refluxed under heating until the generation of mercaptan ceased. Then, the ethanol was distilled off from the mixture under reduced pressure and the resulting residue was purified on a chromatographic column (the eluent mixture=ethanol+chloroform) to obtain the desired 1-{1-(2-chloro-5-pyridyl)ethylamino}-1-methylthio-2-nitroethylene (3.3 g) having a melting point in the range of from 136° to 140° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1)(=[O:3])[CH3:2].Br[CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:15]=O.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([O:4][CH2:5][C:6]1[C:7]2[N:8]([C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][N:12]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: O=CC(Br)c1ccccc1
Reactant: CC(=O)OCc1cccnc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)OCc1cccn2c(-c3ccccc3)cnc12
Yield: 59.2 %

Procedure:
A mixture of 4.4 g (26 mmole) of 3-(acetoxymethyl)-2-pyridinamine and 6.0 g (30 mmole) of 2-bromo-2-phenylacetaldehyde was heated at 65°. The mixture was dissolved in water, made basic with aqueous potassium carbonate, and extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with diethyl ether to yield 4.1 g of 8-(acetoxymethyl)-3-phenylimidazo[1,2-a]pyridine as confirmed by the nmr and infrared spectra and by elemental analysis. [Calcd. for C16H14N2O2 : C, 72.17; H, 5.30; N, 10.52. Found: C, 71.90; H, 5.25; N, 10.43.] The title compound (1.5 g) was prepared by the method described in Example 26 using 1.3 g (5 mmole) of 8-(acetoxymethyl)-3-phenylimidazo[1,2-a]pyridine instead of 8-hydroxymethyl-2-phenylimidazo[1,2-a]pyridine. Structure assignment was supported by the nmr and infrared spectra and by elemental analysis.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)OC(C)C)#[N:2].[N+]([O-])(O)=O.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([CH:28]([O:31][N+:32]([O-:34])=[O:33])[CH2:29][NH2:30])=[CH:24][CH:23]=1)([O-:21])=[O:20].C[O-].[Na+]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[N:30][CH2:29][CH:28]([C:25]1[CH:26]=[CH:27][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=1)[O:31][N+:32]([O-:34])=[O:33])#[N:2]
Reactant: CC(C)OC(=NC#N)c1ccncc1
Reactant: NCC(O[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: CO
Product: N#CNC(=NCC(O[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1)c1ccncc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.3 %

Procedure:
Isopropyl N-cyano-4-pyridinecarboximidate (0.22 g, 1.2 mmol) was dissolved in methanol (10 ml), and 2-(4-nitrophenyl)-2-nitroxyethylamine nitrate (0.40 g, 1.4 mmol) and sodium methoxide (0.14 g, 2.6 mmol) were added. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was extracted with chloroform (50 ml×3). The chloroform layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual concentrate thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with chloroform-methanol (50:1). The eluted fractions were concentrated under reduced pressure and crystallized from methanol-diethyl ether to give the title compound (0.13 g, 0.4 mmol, yield: 31%) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([CH2:8][O:9][C:10]([C:12]2[CH:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N+:30]([O-:32])=[O:31])[C:14]([C:20]([O:22]C)=O)=C(C)[NH:16][C:17]=2[CH3:18])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]>C(O)C>[CH3:8][O:9][C:10]([CH2:12][C:20](/[CH:14]=[CH:13]/[C:24]1[C:25]([N+:30]([O-:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:22])=[O:11].[N+:1]([C:4]1[CH:34]=[CH:33][C:7]([CH2:8][O:9][C:10](=[O:11])/[CH:12]=[C:17](\[NH2:16])/[CH3:18])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1c1ccccc1[N+](=O)[O-]
Solvent: CCO
Product: C/C(N)=C/C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: COC(=O)CC(=O)/C=C/c1ccccc1[N+](=O)[O-]

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 2'-nitrobenzylideneacetoacetic acid methyl ester and 75 mmols of β-aminocrotonic acid 4-nitrobenzyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-methoxycarbonyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 4-nitrobenzyl ester of melting point 156° C (from ethanol).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11](O)=[O:12])=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([NH:37][CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:33][CH:34]([CH3:36])[CH3:35].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH3:20][C:2]([CH3:21])([CH3:1])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11]([N:37]([CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:32][CH2:33][CH:34]([CH3:35])[CH3:36])=[O:12])=[O:4]
Reactant: CC(C)CCNCCC(C)C
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)O)c2c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)N(CCC(C)C)CCC(C)C)c2c1
Temperature: 40 °C

Procedure:
Dissolve a mixture of 17 mg [2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid from the Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 18.0 μL di-iso-amylamine followed by 23.0 mg EDC and 35 μL DIEA. This solution was heated at 40° C. for 2 hours. It was purified directly on RP-HPLC using 70-100% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. LC-MS: 4.67 min. (m/Z=430.4, 346.2, 452.2).