Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[NH2:5].O.[NH2:16][NH2:17]>CO>[NH2:5][C@@H:4]([C:3]([NH:16][NH2:17])=[O:2])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1
Reactant: COC(=O)[C@H](N)Cc1ccc(O)cc1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)[C@H](N)Cc1ccc(O)cc1
Yield: 93.3 %

Procedure:
D-Tyrosine methyl ester (30 g, 129 mmol, 99% ee) was dissolved in 150 mL of methanol and stirred until dissolved. Hydrazine hydrate (23 ml, 453 mmol) was then added and solution stirred overnight. Methanol was removed at reduced pressure and saturated NaHCO3 was added (150 ml). The product was precipitated, filtered and dried to yield the title compound as a white powder (23.5 g, 93%). 1H NMR (CD3OD, 400 MHz) δ 7.03 (ad, J=8.8 Hz, 2H), 6.72 (ad, J=8.8 Hz, 2H), 3.44 (t, J=6.8 Hz, 1H), 2.91-2.86 (m, 1H), 2.76-2.71 (m, 1H). ESI-MS (m/z): 196.1 [M+1]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:37])[CH2:18][C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[CH:21]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=4)[CH:21]=3)[CH2:18][C:17](=[O:37])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C(F)(F)F)c3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccnc(C(F)(F)F)c3)c1)=N2

Procedure:
The title compound was prepared from (4-chloro-5-methyl-2-{3-oxo-3-[3-(2-trifluoromethyl-pyridin-4-yl)-phenyl]-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M244) (0.26 g, 0.47 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (200 mg, 98%).
Reaction SMILES: [O:1]=[C:2](Cl)[O:3][C:4](Cl)(Cl)Cl.[NH2:9][C@@H:10]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)CO.CCN(CC)CC.C>C1COCC1>[CH:13]1([C@H:10]2[CH2:4][O:3][C:2](=[O:1])[NH:9]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: N[C@H](CO)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1N[C@@H](C2CCCCC2)CO1
Temperature: 50 °C
Yield: 87.9 %

Procedure:
Diphosgene (0.704 mL, 6.05 mmol) was added dropwise to a stirred suspension of (S)-2-amino-2-cyclohexylethanol (1.02 g, 7.12 mmol), Et3N (6.95 mL, 49.9 mmol) and activated charcoal (40 mg) in THF (20 mL) at 0° C. under N2. The reaction mixture was heated at 50° C. overnight. After cooling, the suspension was filtered through Celite. To the filtrate was added sat. aq. NaHCO3 solution. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by silica gel flash column chromatography (1:1 hexane/EtOAc) to give (S)-4-cyclohexyloxazolidin-2-one (0.900 g, 75%) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]([NH:21][C:22](=[O:24])[CH3:23])([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([O:19][CH3:20])[CH:13]=1)C(OCC)=O)C.[OH-].[K+]>O.C(O)C>[C:22]([NH:21][CH:5]([C:4]([OH:25])=[O:3])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([O:19][CH3:20])[CH:13]=1)(=[O:24])[CH3:23]
Reactant: CCOC(=O)C(Cc1ccc(C)c(OC)c1)(NC(C)=O)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(CC(NC(C)=O)C(=O)O)ccc1C
Temperature: 25 °C
Yield: 106 %

Procedure:
A mixture of 2-acetylamino-2-(3-methoxy-4-methylbenzyl)-malonic acid diethyl ester (10.0 g), potassium hydroxide solution (1.88 g) in water (25 ml) and ethanol (25 ml) were stirred under reflux for 1 hour. Another potassium hydroxide solution (1.88 g) in water (10 ml) was added to the mixture and the whole was stirred under reflux for 2 hours. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Water (50 ml) and ethyl acetate (50 ml) were added to the resulting aqueous solution. The aqueous layer was separated and was adjusted to pH 1.5 with 6N hydrochloric acid. The solution was extracted with ethyl acetate, washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give N-acetyl-3-methoxy-4-methyl-DL-phenylalanine (7.58 g) as a viscous oil.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([S:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)(=[O:15])=[O:14])[CH:10]=[CH:9][C:8]=2[NH:22][C:23]([C:25]2[N:26](COCC[Si](C)(C)C)[CH:27]=[C:28]([C:30]#[N:31])[N:29]=2)=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[C:1]1([C:7]2[CH:12]=[C:11]([S:13]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)(=[O:14])=[O:15])[CH:10]=[CH:9][C:8]=2[NH:22][C:23]([C:25]2[NH:26][CH:27]=[C:28]([C:30]#[N:31])[N:29]=2)=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(S(=O)(=O)N2CCOCC2)cc1C1=CCCCC1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(S(=O)(=O)N3CCOCC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
A solution of 15.0 mg (0.0262 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(morpholine-4-sulfonyl)-phenyl]-amide (as prepared in the previous step) in CH2Cl2 (5 mL) was treated with MeOH (1 drop) and TFA (1 mL). The mixture was stirred at RT for 2 h, and the solvents were evaporated in vacuo. Purification of the residue by RP-HPLC (C18) with 10-80% CH3CN in 0.1% TFA/H2O over 30 min afforded 3.4 mg (29%) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 8.62 (d, 1H, J=8.8 Hz), 8.07 (s, 1H), 7.72 (dd, 1H, J=8.8, 2.0 Hz), 7.57 (d, 1H, J=2.0 Hz), 6.01-5.96 (m, 1H), 3.77-3.70 (m, 4H), 3.02-2.95 (m, 4H), 2.40-2.30 (m, 4H), 1.97-1.82 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C21H23N5O4S, 442.2 (M+H), found 441.9.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[CH2:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19]>>[C:1]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:7]
Reactant: O=C(O)CCCCC(=O)O
Reactant: CC(C)CCCCCCCO
Product: CC(C)CCCCCCCOC(=O)CCCCC(=O)OCCCCCCCC(C)C
Temperature: 220 °C

Procedure:
A standard 2-liter esterification apparatus was charged with 292 g adipic acid and 727 g isodecyl alcohol. The mixture was heated to reflux, removing water as formed. After 30 minutes of reflux the temperature was 215° C. and 40 ml of water was collected, at which time 0.9 g of catalyst compound ATC-I was added to the flask. The pressure was reduced as needed to maintain the reflux temperature at 220° C. After an additional 45 minutes the water of reaction was collected and the acid number of the residue was measured to be 0.01 mg KOH/g. Heating was discontinued and excess alcohol removed as the pressure was reduced to 20 torr. The reaction mixture was cooled to 170° C., the catalyst was hydrolyzed and the remaining alcohol removed by steam distillation using 100 ml water during 2 hours at 100 torr. The residue was filtered with a No. 1 Whatman paper coated with diatomaceous earth to yield a clear residue product diisodecyl adipate (DIDA) (nD25 =1.4502) having an acid number of 0.05 mg KOH/g and color of 15 APHA. The product remained clear after storage for six months at ambient temperature.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]2[C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:24][N:25]=[C:11]2[CH:10]=1)(C)(C)C.[C:33](Cl)(=[O:35])[CH3:34].N1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH2:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]2[C:23]([N:26]3[CH2:27][CH2:28][N:29]([C:33](=[O:35])[CH3:34])[CH2:30][CH2:31]3)=[CH:24][N:25]=[C:11]2[CH:10]=1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCc1cc2ncc(N3CCNCC3)n2cc1-c1ccc(Cl)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCN(c2cnc3cc(CN)c(-c4ccc(Cl)cc4Cl)cn23)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 56.7 %

Procedure:
To a solution of [6-(2,4-dichloro-phenyl)-3-piperazin-1-yl-imidazo[1,2-a]pyridin-7-ylmethyl]-carbamic acid tert-butyl ester (30 mg, 0.06 mmol) in DCM (0.5 mL) were added successively acetyl chloride (6 mg, 0.07 mmol), pyridine (0.015 mL, 0.19 mmol) and DMAP (1 mg, 0.006 mmol). The reaction mixture was stirred at RT for 14 h then evaporated to dryness. The resulting residue was dissolved in DCM (2 mL) then TFA (1 mL) was added and the mixture was stirred at RT for 30 min. The reaction mixture was concentrated to dryness and the remaining residue purified by reverse phase prep-HPLC (Waters system) to give the title compound (2TFA salt, 22 mg, 0.034 mmol, 57% for 2 steps) as a white solid. MS: 419 [M+1]+; HPLC: AtRet=1.00.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1)[C:20](=O)[CH2:21][CH3:22])C.O1CCOCC1.C([O-])(=O)C.[Na+]>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:29][CH:30]=1)=[C:20]([CH2:21][CH3:22])[NH:13]2
Reactant: CCOC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(=O)CC
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1[nH]c2c(Cl)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-chlorophenoxy)acetic acid methyl ester (0.54 g), 2-(4-methanesulfonylbenzyl)-3-oxopentanoic acid ethyl ester (0.78 g), polyphosphoric acid (2.5 mL) and dioxane (10 mL) was heated at 130° C. for 17 hours. The mixture was diluted with water (100 mL) and the pH of this solution adjusted to 4 by the addition of sodium acetate. The mixture was extracted with ethyl acetate and the combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound as a honey coloured solid, 1.2 g.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:3]=1[NH:4][C:5](=[O:9])[O:6][CH2:7][CH3:8].[H][H]>[C].[Pd].C(O)C>[NH2:14][C:11]1[CH:12]=[CH:13][C:2]([F:1])=[C:3]([CH:10]=1)[NH:4][C:5](=[O:9])[O:6][CH2:7][CH3:8]
Reactant: CCOC(=O)Nc1cc([N+](=O)[O-])ccc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Nc1cc(N)ccc1F
Yield: 80.5 %

Procedure:
100.3 mg (10 wt %) of 5% palladium carbon (containing water) was added to a mixture of 1.00 g (4.39 mmol) of ethyl 2-fluoro-5-nitrocarbanilate and 20 ml of ethanol, and the resultant mixture was stirred until 309 ml of hydrogen was absorbed. The reaction mixture was filtered to remove the catalyst, and the solvent was then distilled off under a reduced pressure. Thus, 700 mg of the objective product (yield: 81%) was obtained in the form of light brown crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1Br.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([O:9][CH3:10])[C:3]=1[O:2][CH3:1]
Reactant: COc1cccc(B(O)O)c1OC
Reactant: Fc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cccc(-c2ccccc2F)c1OC
Temperature: 25 °C
Yield: 84.8 %

Procedure:
In the atmosphere of argon, 18.2 g of 2,3-dimethoxyphenylboronic acid, 17.5 g of 2-fluorobromobenzene, 2.31 g of tetrakistriphenylphosphine palladium (0), 300 mL of 1,2-dimethoxyethane and 150 mL of an aqueous 2M sodium carbonate solution were placed in a flask. The resulting mixture was stirred with heating under reflux for 8 hours. After cooling to room temperature, an aqueous phase was removed, and an organic phase was washed with saturated saline. The organic phase was dried with magnesium sulfate and then concentrated. Residues were purified by silica gel column chromatography, whereby 19.7 g of (yield 85%) of 2′-fluoro-2,3-dimethoxybiphenyl was obtained.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:17][C:18]([C:20]1[O:21][C:22]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:23]=2[CH:24]=1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1[O:21][C:22]2[CH:28]=[CH:27][C:26]([NH:29][C:12]([C:10]3[O:11][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)=[O:14])=[CH:25][C:23]=2[CH:24]=1)=[O:19])[CH3:16]
Reactant: O=C(O)c1ccc(-c2ccccc2)o1
Reactant: CCOC(=O)c1cc2cc(N)ccc2o1
Product: CCOC(=O)c1cc2cc(NC(=O)c3ccc(-c4ccccc4)o3)ccc2o1

Procedure:
Carboxylic acid (56) (60 mg, 0.32 mmol) was coupled to 5-amino-benzofuran-2-carboxylic acid ethyl ester (65 mg, 0.32 mmol) using Method C to give the title compound.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].ClCCl.P(Cl)(Cl)(Cl)=O.[CH4:23]>C(OCC)C.CN(C)C=O>[CH3:23][C:6]([NH:5][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])([CH3:11])[CH3:7]
Reactant: C
Reactant: O=[N+]([O-])c1cnc2ccccc2c1O
Solvent: ClCCl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)Nc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A solution of 19 g (0.10 mole) of 4-hydroxy-3-nitroquinoline, 200 mL of dichloromethane, 10 mL of N,N-dimethylformamide and 10 mL of phosphorus oxychloride was stirred at about 20° C. for 30 minutes and then heated at its reflux temperature for 30 minutes. The solution was cooled to about 20° C. and diluted with 300 mL of diethyl ether. This solution was stirred for 30 minutes at 20° C., treated with decolorizing charcoal and filtered through celite. The filtrate was washed repeatedly with 200 mL portions of cold sodium bicarbonate solution until foaming stopped and the washings were basic. The solution containing 4-chloro-3-nitroquinoline was dried over magnesium sulfate and filtered and evaporated in vacuo. To the solid was added a mixture of 20 g of tertiary-butylamine and 100 mL of N,N-dimethylformamide and the mixture was heated on a steam bath for about one hour. To this mixture was added about 200 mL of water and the product was isolated by filtration and recrystallized from hexane to provide N-(1,1-dimethylethyl)-3-nitro-4-quinolinamine, m.p. 106°-108° C. Analysis: Calculated for C13H15N3O2 : %C, 63.7; %H, 6.2; %N, 17.1; Found: %C, 64.0; %H, 6.3; %N, 17.1.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.Cl[C:12]1[C:13]([NH2:20])=[N:14][C:15]([Cl:19])=[C:16]([Cl:18])[N:17]=1.Cl>COCOC.O>[Cl:18][C:16]1[N:17]=[C:12]([O:10][CH2:9][C:5]2[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=2)[C:13]([NH2:20])=[N:14][C:15]=1[Cl:19]
Reactant: Nc1nc(Cl)c(Cl)nc1Cl
Reactant: OCc1cccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCOC
Product: Nc1nc(Cl)c(Cl)nc1OCc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.7 %

Procedure:
To a stirred suspension of sodium hydride (1.20 g of a 60% dispersion in oil) in dry dimethoxymethane (40 mL) was added pyridine-3-methanol (2.18 g) in 1,2-dimethoxymethane (10 mL). The resulting suspension was stirred at room temperature for 0.5 h and then 3,5,6-trichloro-2-aminopyrazine (1.2 g) was added and the mixture stirred at 70° C. for 4 h. The reaction mixture was cooled and cautiously added to water (100 mL) and neutralised with 2M hydrochloric acid. The mixture was extracted with ethyl acetate (2×50 mL), dried (MgSO4), filtered and concentrated. The residue was purified by chromatography on silical gel eluting with ethyl acetate to afford the sub-titled compound as a white solid (0.29 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]([O:15][C:16]3[CH:17]=[C:18]([CH:21]=[C:22]([CH3:24])[CH:23]=3)[CH:19]=O)=[C:13]([CH:25]([CH3:27])[CH3:26])[C:12](=[O:28])[NH:11][C:10]2=[O:29])[CH:5]=[C:4]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[N:3]=1.[C:40]([CH2:42]P(=O)(OCC)OCC)#[N:41].CC(C)([O-])C.[K+]>C1COCC1.CC(=O)OCC>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]([O:15][C:16]3[CH:17]=[C:18]([CH:19]=[CH:42][C:40]#[N:41])[CH:21]=[C:22]([CH3:24])[CH:23]=3)=[C:13]([CH:25]([CH3:27])[CH3:26])[C:12](=[O:28])[NH:11][C:10]2=[O:29])[CH:5]=[C:4]([NH:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[N:3]=1
Reactant: COc1ccc(CNc2cc(Cn3c(Oc4cc(C)cc(C=O)c4)c(C(C)C)c(=O)[nH]c3=O)cc(Cl)n2)cc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CNc2cc(Cn3c(Oc4cc(C)cc(C=CC#N)c4)c(C(C)C)c(=O)[nH]c3=O)cc(Cl)n2)cc1
Reaction time: 1 h
Yield: 69.5 %

Procedure:
To a stirred solution of (16) (335 mg, 0.611 mmol) and diethyl cyanomethylphosphonate (104 μl, 0.64 mmol) in THF (10 ml) at 0° C. (ice bath) under nitrogen atmosphere, was added potassium t-butoxide (151 mg, 1.34 mmol). After stirring for 1 hr., the mixture was stirred for overnight at room temperature. The mixture was then diluted with EA, washed with aqueous saturated ammonium chloride solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:2)) to afford 243 mg (70%) of a white foam; 1H NMR (200 MHz, CDCl3) δ 1.10 (6H, d, J=6.8 Hz), 2.32 (3H, s), 2.68 (1H, m), 3.78 (3H, s), 4.30 (2H, d, J=5.2 Hz), 4.68 (2H, s), 5.23 (1H, t, J=5.2 Hz), 5.82 (1H, d, J=16.6 Hz), 6.05 (1H, s), 6.21 (1H, s), 6.62 (2H, s), 6.84-6.90 (2H, m), 6.97 (1H, s), 7.18-7.27 (3H, m), 9.63 (1H, s).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([CH2:19][CH2:20]OS(C)(=O)=O)[CH:13]=[CH:12]3)[CH:6]=[N:7][CH:8]=1)#[N:2].[CH3:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:20][CH2:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:5]1[CH:6]=[N:7][CH:8]=[C:3]([CH:4]=1)[C:1]#[N:2])[CH:18]=[CH:17]2
Reactant: CS(=O)(=O)OCCc1ccc2cc(-c3cncc(C#N)c3)ccc2c1
Reactant: C[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCc1ccc2cc(-c3cncc(C#N)c3)ccc2c1
Yield: 57.4 %

Procedure:
Methanesulfonic acid 2-[6-(5-cyano-pyridin-3-yl)-naphthalen-2-yl]-ethyl ester (Example 81B, 190 mg, 0.54 mmol), (2R)-2-methylpyrrolidine (138 mg, 1.62 mmol, 3.0 equiv.), and cesium carbonate (176 mg, 0.54 mmol) in anhydrous acetonitrile (6 mL) were stirred in a sealed tube at 50° C. for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous Na2CO3. The organic layer was washed with brine, then dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (98:2:trace dichloromethane/methanol/NH4OH). Fractions containing product were combined and concentrated under reduced pressure to provide the free base of the title compound as a white solid (105.9 mg, 57% yield). This free base was dissolved in methanol and treated with excess dioxane-HCl. Ether was added to induce crystallization of the dihydrochloride salt of the title compound. 1H NMR (CD3OD, 300 MHz) δ 9.26 (br s, 1H), 8.97 (br s, 1H), 8.68 (s, 1H), 8.29 (s, 1H), 8.05 (s, 1H), 8.02 (s, 1H), 7.90 (br s, 1H), 7.88 (dd, J=2, 9 Hz, 1H), 7.56 (d, J=8 Hz, 1H), 3.84-3.49 (m, 7H), 2.45-2.30 (m, 1H), 2.27-1.99 (m, 2H), 1.84-1.69 (m, 1H), 1.50 (d, J=6 Hz, 3H). MS (DCl-NH3) [M+H]+ at 342.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[CH2:3].[CH2:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O>>[CH2:5]=[C:6]([CH2:10][C:11]([O:13][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:12])[C:7]([O:9][C:2]([CH3:4])([CH3:1])[CH3:3])=[O:8]
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Product: C=C(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 22 h

Procedure:
2-Methylprop-1-ene (50.3 mL) was added to 2-methylenesuccinic acid (10.0 g) at −78 C, then sulfuric acid (0.819 mL) was added dropwise at −78 C, and then, the obtained mixture was stirred at room temperature at 4.5 to 3.5 atm for 22 hours in a sealed tube. After removal of 2-methylprop-1-ene at room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and added to a saturated aqueous solution of sodium bicarbonate (100 mL) at 0 C, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (12.8 g).
Reaction SMILES: B(Br)(Br)Br.[C:5]12([C:15]([C:17]3[C:22]([O:23]C)=[CH:21][C:20]([O:25]C)=[CH:19][C:18]=3[Cl:27])=[O:16])[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2.O>C(Cl)Cl>[C:5]12([C:15]([C:17]3[C:22]([OH:23])=[CH:21][C:20]([OH:25])=[CH:19][C:18]=3[Cl:27])=[O:16])[CH2:6][CH:7]3[CH2:8][CH:9]([CH2:10][CH:11]([CH2:13]3)[CH2:12]1)[CH2:14]2
Reactant: COc1cc(Cl)c(C(=O)C23CC4CC(CC(C4)C2)C3)c(OC)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(c1c(O)cc(O)cc1Cl)C12CC3CC(CC(C3)C1)C2
Yield: 29.5 %

Procedure:
Boron tribromide 1M in CH2Cl2 was added to a solution of 1-adamantyl-(2-chloro-4,6-dimethoxyphenyl)methanone (7 g, 21.0 mmoles) and CH2Cl2 (30 ml). The mixture was warmed overnight and then poured into water, extracted with ethyl acetate, dried over Na2SO4 and concentrated under vacuum to give the expected product (1.9 g, 30%).
Reaction SMILES: [CH2:1]([S:3][CH:4]=[CH:5][N:6]1[CH2:10][CH2:9][NH:8][C:7]1=[N:11][N+:12]([O-:14])=[O:13])[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Cl)=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:8]2[CH2:9][CH2:10][N:6]([CH:5]=[CH:4][S:3][CH2:1][CH3:2])[C:7]2=[N:11][N+:12]([O-:14])=[O:13])=[CH:18][N:17]=1
Reactant: CCSC=CN1CCNC1=N[N+](=O)[O-]
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCSC=CN1CCN(Cc2ccc(Cl)nc2)C1=N[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A mixture comprising 8.0 g of 1-(2-ethylthiovinyl)-2-nitroiminoimidazolidine, 7.2 g of 2-chloro-5-chloromethylpyridine, 20.0 g of potassium carbonate .and 30 ml of dimethylsulfoxide was stirred at 60° C. for 30 minutes. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried (with anhydrous MgSO) and concentrated to give an oily residue. This was purified by column chromatography silica gel, eluent: ethyl acetate/hexane 4/1) to give 8.3 g of 1-(2-chloropyridin-5-ylmethyl)-2-nitroimino-3-(2-ethylthiovinyl)imidazolidine.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[S:14][CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CCO>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][C:13]2[S:14][CH:15]=[CH:16][C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: CCOC(=O)c1ccsc1N
Solvent: CCO
Product: CCOC(=O)c1ccsc1Nc1ccc(F)cc1[N+](=O)[O-]

Procedure:
2,5-Difluoro-nitrobenzene and ethyl 2-amino-thiophene-3-carboxylate, m.p. 125° C. (EtOH).