Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13](OC(C)(C)C)=O)[CH2:9][CH2:8]2)[N:3]=[CH:2]1.C(O)(C(F)(F)F)=O.ClC1[C:33]([Cl:34])=[CH:32][N:31]=[C:30]([NH2:35])[C:29]=1[N+:36]([O-:38])=[O:37]>C(Cl)Cl>[Cl:34][C:33]1[C:13]([N:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:4]3[N:3]=[CH:2][S:1][CH:5]=3)[CH2:12][CH2:11]2)=[C:29]([N+:36]([O-:38])=[O:37])[C:30]([NH2:35])=[N:31][CH:32]=1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cscn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(Cl)c(N2CCN(Cc3cscn3)CC2)c1[N+](=O)[O-]
Reaction time: 1 h
Yield: 31.3 %

Procedure:
tert-Butyl 4-(thiazol-4-ylmethyl)piperazine-1-carboxylate (0.220 g, 0.79 mmol, 1.1 eq) was dissolved in DCM (2 mL) and the mixture cooled in a ice-water bath before the dropwise addition of TFA (2 mL). Stirring was continued at this temperature for 1 h. The solvents were removed in vacuo and the resulting crude material was azeotroped with toluene and dried. 4-(piperazin-1-ylmethyl)thiazole (supposedly 0.140 g, 0.79 mmol, 1.1 eq) was suspended in iPrOH (0.8 mL) and DIPEA (0.3 mL). To this solution, 4,5-dichloro-3-nitropyridin-2-amine (0.15 g, 0.72 mmol, 1 eq) was added and the mixture was heated and stirred for 17 h at 65° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow powder (0.080 g, 27%); 1H-NMR (500 MHz, DMSO-d6): δ 2.52-2.60 (m, 4H, piperazine N(CH2)2), 3.07 (m, 4H, piperazine N(CH2)2), 3.72 (s, 2H, NCH2), 6.94 (s, 2H, NH2), 7.54 (s, 1H, thiazole 5-H), 8.05 (s, 1H, pyridine 6-H), 9.04 (s, 1H, thiazole 2-H); LC (Method B)-MS (ESI, m/z): Rt=1.71 min—355/357 [(M+H)+, Cl isotopic pattern].
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1.[CH:31]([N:34]([CH2:38][CH2:39]Cl)[CH:35]([CH3:37])[CH3:36])([CH3:33])[CH3:32]>>[Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([O:14][CH2:39][CH2:38][N:34]([CH:35]([CH3:37])[CH3:36])[CH:31]([CH3:33])[CH3:32])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1
Reactant: COc1cc(-c2nc3ccc(O)cc3n2Cc2ccccc2Br)cc(OC)c1OC
Reactant: CC(C)N(CCCl)C(C)C
Product: COc1cc(-c2nc3ccc(OCCN(C(C)C)C(C)C)cc3n2Cc2ccccc2Br)cc(OC)c1OC

Procedure:
The title compound was prepared by reacting the compound of Example 114 with 2-(N,N-diisopropylamino)ethyl chloride essentially as previously described MS 595, 597.
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[O:3][C:2]1=[O:12])[CH2:9]2.C[C:14](=O)[C:15](=[O:17])C.O=O>C(O)(=O)C>[C:15]([C:6]12[CH2:11][CH:1]3[CH2:9][CH:8]([CH2:10][CH:4]([O:3][C:2]3=[O:12])[CH2:5]1)[CH2:7]2)(=[O:17])[CH3:14]
Reactant: CC(=O)C(C)=O
Reactant: O=C1OC2CC3CC(C2)CC1C3
Agent: O=O
Solvent: CC(=O)O
Product: CC(=O)C12CC3CC(C1)OC(=O)C(C3)C2
Temperature: 80 °C
Reaction time: 4 h

Procedure:
In a flask were placed 3-oxatricyclo[4.3.1.14,8]undecan-2-one (16.6 g, 100 mmol), acetylacetonatocobalt [Co(acac)2] (50 mmol), 2,3-butanedione (600 mmol), and acetic acid (100 g). A condenser and an oxygen balloon were attached to the flask, and the mixture in the flask was vigorously stirred at 80° C. for 4 hours. After the completion of the reaction, the reaction mixture was concentrated, followed by addition of toluene and washing with water. The resulting organic layer was concentrated, the concentrate was subjected to silica gel column chromatography and thereby yielded the title compound 6-acetyl-3-oxatricyclo[4.3.1.14,8]undecan-2-one in a yield of 37%.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[CH:10]([OH:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:19])[CH:10]([O:18][N:21]1[C:25](=[O:26])[C:24]2[C:23](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]1=[O:31])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)C(O)Cc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)C(Cc1ccccc1)ON1C(=O)c2ccccc2C1=O
Temperature: -20 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To a mixture of compound from Step 6a (7.00 g, 27.2 mmol), N-hydroxyphthalimide (5.35 g, 32.80 mmol) and PPh3 (9.26 g, 35.30 mmol) in CH2Cl2 (55 mL) was added diisopropyl azodicarboxylate (6.86 mL, 35.38 mmol) during 10 minutes period at −20° C. The resulting mixture was stirred at −20° C. for 2 hours. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (silica gel, CH2Cl2/hexane=1/2) to afford 10.65 g (99%) of the title compound.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[C:6](#[N:9])[CH:7]=[CH2:8]>CO>[CH:1]1([NH:5][CH2:8][CH2:7][C:6]#[N:9])[CH2:4][CH2:3][CH2:2]1
Reactant: C=CC#N
Reactant: NC1CCC1
Solvent: CO
Product: N#CCCNC1CCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At room temperature, cyclobutylamine (5.90 mL, 59.8 mmol) was added dropwise, over 15 mins, to a solution of acrylonitrile (4.76 g, 89.7 mmol) in methanol (7 mL). The mixture was stirred at room temperature for 30 mins and at reflux for 1 hr, cooled to room temperature, concentrated under reduced pressure. The desired product was obtained by distillation under vacuum to provide a clear liquid (7.7 g, 98%). 1H NMR (CDCl3, 300 MHz) δ 3.29-3.21 (m, 1H), 2.88-2.83 (t, 2H, J=6.6 Hz), 2.50-2.46 (t, 2H, J=6.6 Hz), 2.26-2.20 (m, 2H), 1.76-1.63 (m, 4H), 1.30 (br s, 1H).
Reaction SMILES: Cl.C(OC([NH:9][C:10]1([C:23](=[O:36])[NH:24][C@H:25]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH2:26][CH2:27][OH:28])[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1)=O)(C)(C)C>O1CCOCC1.CO>[NH2:9][C:10]1([C:23]([NH:24][C@H:25]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH2:26][CH2:27][OH:28])=[O:36])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCNCC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 107.8 %

Procedure:
Hydrogen chloride 4M in dioxane (11.72 mL, 46.87 mmol) was added to (S)-tert-butyl 4-(tert-butoxycarbonylamino)-4-(1-(4-chlorophenyl)-3-hydroxypropylcarbamoyl)piperidine-1-carboxylate (Intermediate 48) (3 g, 5.86 mmol) in dioxane (30 mL). The resulting solution was stirred at 20° C. for 2 hours. The reaction mixture was dissolved in methanol and purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 3.5N ammonia/MeOH and pure fractions were evaporated to dryness to afford (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)piperidine-4-carboxamide (1.970 g, 108%) as a colourless gum.
Reaction SMILES: [CH2:1]1C2NC(=CC=2)CC2NC(=CC=2)CC2NC(=CC=2)CC2NC1=CC=2.[C:25]([CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])(=[O:27])[CH3:26].Cl>CO>[CH3:1][O:32][C:31](=[O:33])[CH2:30][CH2:29][CH2:28][C:25](=[O:27])[CH3:26]
Reactant: CC(=O)CCCC(=O)O
Reactant: c1cc2[nH]c1Cc1ccc([nH]1)Cc1ccc([nH]1)Cc1ccc([nH]1)C2
Agent: Cl
Solvent: CO
Product: COC(=O)CCCC(C)=O
Yield: 84 %

Procedure:
Calix[4]pyrrole meso-monoester 3. 4-Acetylbutyric acid (3.8 g, 29 mmol) was dissolved in methanol (50 mL) in a 100 mL round bottomed flask with magnetic stirring. Concentrated hydrochloric acid (1 mL, 37%) was added and the mixture heated at reflux for 12 hr. The solvent was then removed in vacuo and the residue redissolved in dichloromethane (50 mL). The solution was then washed with saturated NaHCO3 (aq) solution (2×50 mL) and then brine (1×100 mL). The organic layer was separated and then dried over MgSO4 and reduced in vacuo to give the methyl ester, methyl-4-acetylbutyrate, as a yellow oil (3.5 g, 24.3 mmol) corresponding to a yield of 84%. 1H NMR (CDCl3) 3.64 (s, 3, OCH3), 2.49 (t, J=7.2 Hz, 2, CH2), 2.32 (t, J =7.2 Hz, 2, CH2), 2.12 (s, 3, CH3), 1.86 (m, 2, CH2). 13C NMR (CDCl3) 207.0, 172.8, 50.7, 41.7, 32.3, 29.1, 18.25. CI MS m/z @ 145 (MH+)
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.CON(C)[C:16]([C:18]1[CH:26]=[C:25]2[C:21]([C:22]([CH:28]([C:42]3[CH:50]=[CH:49][C:45]4[O:46][CH2:47][O:48][C:44]=4[CH:43]=3)[C:29]([NH:31][S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])=[O:30])=[CH:23][N:24]2[CH3:27])=[CH:20][CH:19]=1)=[O:17]>O1CCCC1>[O:46]1[C:45]2[CH:49]=[CH:50][C:42]([CH:28]([C:22]3[C:21]4[C:25](=[CH:26][C:18]([C:16]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=5)=[O:17])=[CH:19][CH:20]=4)[N:24]([CH3:27])[CH:23]=3)[C:29]([NH:31][S:32]([C:35]3[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=3)(=[O:34])=[O:33])=[O:30])=[CH:43][C:44]=2[O:48][CH2:47]1
Reactant: Brc1ccccn1
Reactant: CON(C)C(=O)c1ccc2c(C(C(=O)NS(=O)(=O)c3ccc(C)cc3)c3ccc4c(c3)OCO4)cn(C)c2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(C(=O)c4ccccn4)ccc23)cc1
Temperature: -70 °C
Reaction time: 4 h

Procedure:
n-Butyllithium (0.32 ml of 2.5M solution in hexane) was added to a stirred solution of 2-bromopyridine (0.08 ml, 0.8 mmol) in anhydrous tetrahydrofuran (5 ml) at −70° C. under a nitrogen atmosphere. After 30 minutes a solution of N6-methoxy-N6,1-dimethyl-3-{1-(1,3-benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-1H-6-indolecarboxamide (the compound of Example 103, 200 mg, 0.36 mmol) in anhydrous tetrahydrofuran (2 ml) was added to the mixture at −70° C. The mixture was stirred at −70° C. for an additional 4 hours before being warmed to 0° C., and then quenched with the addition of water (5 ml). The mixture was acidified with acetic acid, and extracted with ethyl acetate (100 ml). The organic phase was separated and washed with brine, dried (magnesium sulphate) and the solvent was removed in vacuo. The residue was flash chromatographed using a gradient elution of a mixture of 90% hexane and 10% ethyl acetate, through to 100% ethyl acetate, to give the title compound (42 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.Cl.[NH2:32][CH2:33][C:34]([NH2:36])=[O:35].C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([NH:32][CH2:33][C:34]([NH2:36])=[O:35])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: NCC(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)CNC(=O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
N-benzyloxycarbonylglycine (3 g, 14.4 mmole) were dissolved in 200 mL of dichloromethane and 4.5 g (21.6 mmole) of DCC were added. The mixture was stirred at room temperature for 2 hours, the insoluble materials were removed and 3.2 g (28.8 mmole) of glycinamide hydrochloride and 2.93 g (28.8 mmole) of TEA (triethylamine) were added to the filtrate. The reaction was stirred for 24 hours at room temperature, the insoluble materials were filtered and the filtrate was evaporated to dryness in vacuum. The residue was recrystallized from distilled water to get a pure product 1.9 g (7.2 mmole), yield of 50%.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].[SH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[SH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])=[O:24]
Reactant: O=C(O)CCCCCCCCCCS
Reactant: O=[N+]([O-])c1ccccc1CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(CCCCCCCCCCS)OCc1ccccc1[N+](=O)[O-]

Procedure:
One equivalent of 2-nitrobenzyl alcohol (2.17 g, 14.15 mmol) was combined with one equivalent of 11-mercaptoundecanoic acid (3.09 g, 14.15 mmol), 0.1 equivalents DMAP (0.173 g, 1.42 mmol) and dissolved in 50 mL CH2Cl2. To this mixture a solution of DCC (2.92 g, 14.15 mmol) in 30 mL CH2Cl2 was slowly added while stirring. Upon addition a white precipitate formed after a few minutes. The mixture was stirred at room temperature overnight. Vacuum filtration removed the white precipitate and the filtrate was concentrated by rotovap. Silica gel column chromatography was employed for purification using C1H2Cl2/MeOH (v/v 50:1) as the eluent. The product was dried over Na2SO4, the solvent removed by rotovap, and dried under vacuum thus producing a yellow solid. Yield: 3.57 g (71.4%). 1H-NMR (CDCl3) δ (ppm): 8.1 (d, 1H, Ar), 7.6 (t, 1H, Ar), 7.5 (d, 1H, Ar), 7.4 (t, 1H, Ar), 5.5 (s, 2H, O—CH2), 2.6 (t, 1H, SH) 2.5 (q, 2H, CH2—SH), 2.4 (t, 2H, CH2—C═O), 1.6 (m, 4H, CH2), 1.2 (m, 12H, CH2). 13C-NMR (CDCl3) δ (ppm): 173.5, 147.0, 134.1, 132.7, 129.5, 129.2, 125.5, 63.2, 34.6, 34.4, 29.8, 29.7, 29.6, 29.5, 29.4, 28.8, 25.3, 25.1. MS (ESI): (M+Na)+=376.19 (calc. 376.47).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[CH2:11]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:11]([CH:19]1[CH2:20][CH2:21][N:22]([C:2]2[N:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=2)[CH2:23][CH2:24]1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc(CCC2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: Nc1ccc(N2CCC(CCc3ccccc3)CC2)nc1

Procedure:
Intermediate B-22 was prepared by the general procedure for intermediate B-2, by using 2-chloro-5-nitropyridine and 4-phenethylpiperidine as starting materials. MS (M+1): 312.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH:10]=O>CO.[Pd].O>[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH:5][CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1]
Reactant: CC(C)CCN
Reactant: COC(C=O)OC
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COC(CNCCC(C)C)OC
Reaction time: 3 h

Procedure:
A solution of 3-methylbutan-1-amine (1.33 mL) and 2,2-dimethoxyacetaldehyde (1.73 mL) in MeOH (10 mL) was added to palladium on carbon (0.366 g) in water (0.5 mL) at 25° C. The mixture of was hydrogenated under 5 bar at 25° C. for 3 h. The reaction mixture was filtered and concentrated in vacuo to afford N-(2,2-dimethoxyethyl)-3-methylbutan-1-amine (1.8 g) as a liquid. 1H NMR (300 MHz, CDCl3) δ 4.47 (t, J=5.5 Hz, 1H), 3.39 (s, 6H), 2.74 (d, J=5.6 Hz, 2H), 2.65-2.59 (m, 2H), 1.62 (septet, J=6.7 Hz, 1H), 1.44-1.33 (m, 2H), 0.90 (d, J=6.7 Hz, 6H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH3:19][NH:20][CH3:21].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:20]([CH3:21])[CH3:19])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CNC
Reactant: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(Cl)Cl
Product: COc1cc(N2CCC(N(C)C)CC2)ccc1[N+](=O)[O-]
Reaction time: 0.75 h
Yield: 91 %

Procedure:
1-(3-Methoxy-4-nitro-phenyl)-piperidine-4-one (300 mg, 1.20 mmol) in dichloroethane (6 mL) was treated with 2 M Dimethylamine in THF (3 mL, 6 mmol) followed by sodium triacetoxyborohydride (420 mg, 2 mmol) at rt. After 16 h the mixture was treated with saturated aqueous NaHCO3, stirred 45 minutes. The layers were then separated, and the organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give 305 mg (91%) of desired [1-(3-Methoxy-4-nitro-phenyl)-piperidine-4-yl]dimethyl-amine, which was used without further manipulation. LC/MS (E/I+) 280.12 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8](Br)[CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:12].[N+:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]>>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:13]([O-:15])=[O:14])[CH:21]=3)[CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:12]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Cn1c(=O)[nH]c2ccc(Br)cc21
Product: Cn1c(=O)[nH]c2ccc(-c3cccc([N+](=O)[O-])c3)cc21

Procedure:
Prepared from 1-methyl-6-bromo-1,3-dihydro-benzoimidazol-2-one and 3-nitro-phenyl boronic acid in the same fashion as that of Example 5. White solid: mp 264-265° C.; 1H-NMR (DMSO-d6) δ11.0 (s, 1H), 8.47 (t, 1H, J=1.5 Hz), 8.19-8.15 (m, 2H), 7.75 (t, 1H, J=8.25 Hz), 7.58 (d, 1H, J=1.5 Hz), 7.43 (dd, 1H, J=8.25, 1.5 Hz), 7.1 (d, 1H, J=8.25 Hz), 3.37 (s, 3H); MS (ES) m/z 268([M−H]−, 50%); Anal. Calc. For C14H11N3O3: C, 62.45; H, 4.12; N, 15.61. Found: C, 61.48; H, 4.36; N, 14.75.
Reaction SMILES: [CH:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][C:9]2[CH:21]=[CH:20][C:12]([C:13]([CH:15]=[CH:16][C:17]([OH:19])=[O:18])=[O:14])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:24][C:25]1C=CC(OC2C=CC(C(C=CC(O)=O)=O)=CC=2)=CC=1>>[CH:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][C:9]2[CH:21]=[CH:20][C:12]([C:13]([CH:15]=[CH:16][C:17]([O:19][CH2:24][CH3:25])=[O:18])=[O:14])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(Oc2ccc(C(=O)C=CC(=O)O)cc2)cc1
Reactant: CC(C)c1ccc(Oc2ccc(C(=O)C=CC(=O)O)cc2)cc1
Product: CCOC(=O)C=CC(=O)c1ccc(Oc2ccc(C(C)C)cc2)cc1

Procedure:
The procedure in Example 17(1) was followed, except that 6.20 g of 3-[4-(4-isopropylphenoxy)benzoyl]acrylic acid were used in place of 3-[4-(4-methylphenoxy)benzoyl]acrylic acid, to give 4.91 g of ethyl 3-[4-(4-isopropylphenoxy)-benzoyl]acrylate in the form of an oil.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[C:6](=[O:13])[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1.O.O1CCC[CH2:20]1>>[CH3:1][CH:2]1[CH:7]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[C:6]([CH3:20])([OH:13])[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: CC1Oc2ccccc2C(=O)C1n1ccnc1
Reactant: C1CCOC1
Solvent: O
Product: CC1Oc2ccccc2C(C)(O)C1n1ccnc1
Reaction time: 1 h

Procedure:
A solution of 2-methyl-3-(1-imidazolyl)-2,3-dihydro-4H-1-benzopyran-4-one (0.53 g) in anhydrous tetrahydrofurane (20 ml) was added to the reaction mixture, which was refluxed moderately for 30 minutes and then for 1 hour on a water bath. The mixture was cooled, poured into a mixture of crushed ice and water (100 ml) and extracted with CHCl3 (100 ml). The organic layer, dried on anhydrous Na2SO4 and evaporated to dryness under vacuum, afforded 2-methyl-3-(1-imidazolyl)-2,3-dihydro-4-methyl-benzopyran-4-ol (0.3 g);
Reaction SMILES: C([O:4][C@@H:5]1[O:18][C@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:7]([O:8][C:9](=[O:11])[CH3:10])[C@H:6]1[N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])(=O)C.[C:35]1([SH:41])[CH:40]=[CH:39][CH:38]=CC=1.[Sn](Cl)(Cl)(Cl)Cl>ClCCl>[S:41]1[CH:35]=[CH:40][CH:39]=[C:38]1[C@:5]1([O:18][C@H:17]([CH2:12][O:13][C:14](=[O:16])[CH3:15])[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:7]([O:8][C:9](=[O:11])[CH3:10])[C@H:6]1[N:24]1[C:25](=[O:34])[C:26]2=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]2[C:28]1=[O:29])[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Sc1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@](O)(c2cccs2)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
The product compound [2] (0.31-8.02 g, 0.68-17.7 mmol) is dissolved in 3.2-100 ml of dry dichloromethane, and thiophenol (0.15-3.9 g, 1.36-35.4 mmol) and tin tetrachloride (0.35-9.22 g, 1.36-35.4 mmol) are added and the mixture is stirred until reaction is complete. The reaction mixture is diluted and then washed with saturated sodium bicarbonate solution. Concentration results in the crude product compound [3]. Purification takes place by chromatography on silica gel with an ethyl acetate/isohexane gradient (0.27-71.4 g, 0.54-14.2 mmol, about 80%). FAB-MS: M+H+ =504. NMR data consistent with Nicolaou et al., J. Am. Chem. Soc. 112:3695 (1990) and T. J. Caulfield, Ph.D. Dissertation, the University of Pennsylvania (1991).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2OC)[N:3]=1.[NH2:30][C:31]1[C:36]2[C:37](=[O:41])[N:38]([CH3:40])[CH2:39][C:35]=2[CH:34]=[CH:33][N+:32]=1[O-:42]>>[CH3:40][N:38]1[CH2:39][C:35]2[CH:34]=[CH:33][N+:32]([O-:42])=[C:31]([NH:30][C:2]3[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:14]=[CH:15][C:16]([CH2:17][P:18](=[O:25])([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])=[CH:26][CH:27]=4)[N:3]=3)[C:36]=2[C:37]1=[O:41]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CN1Cc2cc[n+]([O-])c(N)c2C1=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3c4c(cc[n+]3[O-])CN(C)C4=O)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (204 mg, 0.381 mmol) and 4-amino-2-methyl-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one 5-oxide (Compound 310A, 68.3 mg, 0.381 mmol). The reaction mixture was concentrated under reduced pressure to yield a dark yellow oil which was purified by silica gel chromatography on the combi-flash Rf system using DCM/MeOH (100:0→90:10). The fractions containing product were combined and concentrated under reduced pressure to yield a white solid (38.4 mg, 17%). 1H NMR (DMSO-d6, 400 MHz): δ=8.99 (br. s., 1H), 8.47-8.55 (m, 3H), 7.47 (d, J=6.57 Hz, 1H), 7.24 (d, J=7.58 Hz, 1H), 6.85 (s, 1H), 6.56 (d, J=8.08 Hz, 1H), 4.45 (s, 2H), 3.90-3.99 (m, 4H), 3.70 (s, 3H), 3.12-3.21 (m, 2H), 2.86-2.89 (m, 3H), 1.17 (t, J=7.07 Hz, 6H). MS (ES+): m/z 597.10 [MH+] (TOF, polar).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][Si:6]([O:11][CH3:12])([O:9][CH3:10])[O:7][CH3:8].[CH:13]([N:16]=[C:17]=[N:18][CH:19]([CH3:21])[CH3:20])([CH3:15])[CH3:14]>>[CH:13]([N:16]=[C:17]([NH:18][CH:19]([CH3:21])[CH3:20])[N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][Si:6]([O:11][CH3:12])([O:7][CH3:8])[O:9][CH3:10])([CH3:15])[CH3:14]
Reactant: CNCCC[Si](OC)(OC)OC
Reactant: CC(C)N=C=NC(C)C
Product: CO[Si](CCCN(C)C(=NC(C)C)NC(C)C)(OC)OC
Reaction time: 2 h

Procedure:
A mixture of 60.5 g of N-methyl-(3-(trimethoxysilyl)propyl)amine (0.313 mol) and of 47.6 g of diisopropylcarbodiimide (0.376 mol, 20% excess) was heated for 3 h 30 min at 100° C. (amine conversion of greater than 99%). The final colorless mixture was devolatilized at 100° C. under 2 mbar for 2 h to give 99.5 g of a colorless, low-viscosity liquid corresponding to the expected guanidine.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:22]#[N:23])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:9]=2)=[O:4].OC(C(F)(F)F)=O.[NH2:31][CH2:32][C:33]([CH3:38])([CH3:37])[C:34]([OH:36])=[O:35].C[O-].[Na+]>CCO>[C:22]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:31][CH2:32][C:33]([CH3:38])([CH3:37])[C:34]([OH:36])=[O:35])=[O:4])[N:6]=1)#[N:23]
Reactant: COC(=O)c1nc(C#N)c2cc(-c3ccccc3)ccc2c1O
Reactant: CC(C)(CN)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(-c3ccccc3)ccc2c1O)C(=O)O
Temperature: 150 °C
Yield: 61.6 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenyl-isoquinoline-3-carboxylic acid methyl ester (47 mg, 0.15 mmol), 3-amino-2,2-dimethyl-propionic acid TFA salt (143 mg, 0.62 mmol) and NaOMe (67 mg, 1.24 mmol) in EtOH (3 mL) was heated at 150° C. in a microwave reactor for 2 h. The solvent was evaporated, and the residue was partitioned between water (30 mL) and EtOAc (30 mL). 1 M HCl was added with vigorous stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-25% EtOAc/hexanes+2% AcOH) to give 36 mg of the title compound as a light brown solid. MS: (−) m/z 388.13 (M−1).