Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:5])[CH2:4][CH2:3][CH2:2]1.[N+:6]([CH3:9])([O-:8])=[O:7].[O-]CC.[Na+].O>C(O)C>[N+:6]([CH2:9][C:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1)([O-:8])=[O:7]
Reactant: O=C1CCC1
Reactant: C[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])CC1(O)CCC1
Temperature: 25 °C
Reaction time: 144 h
Yield: 45 %

Procedure:
To a solution of cyclobutanone (10.0 g, 143 mmol) and nitromethane (12 mL) in ethanol (10 mL) was added sodium ethoxide in ethanol (2.67 M, 2.7 mL, 7.2 mmol). The mixture was stirred for 6 d at rt. Water was added and the mixture was extracted thrice with ethyl acetate. The organic phases were combined, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The volatiles were removed by distillation under vacuum to provide 1-(nitromethyl)cyclobutanol as a yellow liquid (8.51 g, 45%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](N)=[CH:4][C:3]=1[OH:9].S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:19].[K+]>O1CCCC1.O.[Cu]>[I:19][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([OH:9])[CH:4]=1
Reactant: Cc1ccc(N)cc1O
Reactant: [I-]
Agent: [Cu]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(I)cc1O
Temperature: 25 °C

Procedure:
A solution of 5-amino-O-cresol (10.0 g, 81 mmol) (Aldrich) in a mixture of tetrahydrofuran (100 mL), water (150 mL) and concentrated sulfuric acid (6 mL, 0.11 mmol) was cooled in an ice-water bath. A solution of sodium nitrite (5.6 g, 81 mmol) in water (30 mL) was added dropwise over 30 minutes. Mixture was stirred with cooling for another 30 minutes. (A suspension formed). Powder copper metal (200 mg, 3 mmol) was added followed by a solution of potassium iodide (17.5 g, 0.11 mmol) in water (70 mL). Mixture was allowed to warm to room temperature and stirred for 90 minutes then poured into water (200 mL). Mixture was extracted with ethyl acetate (2×400 mL). Organic layers were washed with water (400 mL) and brine (400 mL), then combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (Biotage 75 L, hexanes-dichloromethane 2:3 as solvent). Pure fractions were combined and material recrystallized from hexanes to give 5-iodo-2-methyl-phenol as white needles in 2 crops. (Yield 10.08 g, 53.0%).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21]>CN(C=O)C.[F-].[Cs+]>[CH2:7]([O:6][C:4](=[O:5])[CH:3]([C:1]#[N:2])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21])[CH3:8]
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CC#N
Agent: [Cs+]
Agent: [F-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C#N)c1ccc(OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
Ethyl cyanoacetate (2.56 mL, 24.0 mmol) was added dropwise to a suspension of 959 mg of NaH (60%, 24.0 mmol) in 10 mL of DMF. The mixture was stirred for 1 h at room temperature. CsF (61 mg, 0.4 mmol) and a solution of 4-chloro-3-nitro-anisole (1.5 g, 8.0 mmol) in 2 mL of DMF were added and the mixture was stirred overnight at 70° C. The reaction mixture was cooled to room temperature and was quenched by the addition of 5 mL of water. Aqueous 1N HCl (5 mL) was added to adjust the pH to 3-4 and the mixture was diluted with dichloromethane. The organic layer was washed with saturated brine, dried over Na2SO4, and dried in vacuo. The crude product was purified on a Biotage (Biotage Inc.) 50 g silica column, eluting with 0-40% EtOAc in heptane over 40 minutes to provide 1.83 g (87%) of cyano-(4-methoxy-2-nitro-phenyl)-acetic acid ethyl ester.
Reaction SMILES: [CH2:1]([S:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[C:2]#[CH:3].[C:10]([C:14]1([CH2:18]O)[CH2:17][O:16][CH2:15]1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]12[CH2:15][O:16][C:7]([CH2:6][CH2:5][S:4][CH2:1][C:2]#[CH:3])([O:9][CH2:18]1)[O:8][CH2:17]2)([CH3:13])([CH3:12])[CH3:11]
Reactant: C#CCSCCC(=O)O
Reactant: CC(C)(C)C1(CO)COC1
Product: C#CCSCCC12OCC(C(C)(C)C)(CO1)CO2

Procedure:
4-t-Butyl-1-[2-(prop-2-ynylthio)ethyl]-2,6,7-trioxabicyclo[2.2.2]octane was prepared from 3-(prop-2-ynylthio)propionic acid and 3-t-butyl-3- hydroxymethyloxetane using methodology described in Example I.
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][C:6]([N+:16]([O-:18])=[O:17])=[C:7]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][Cl:15])[CH:8]=1.[Na].[N+](C1C=CC=CC=1O)([O-])=O.COC1C=CC([N+]([O-])=O)=C(O)C=1>>[N+:16]([C:6]1[CH:5]=[CH:4][CH:3]=[CH:8][C:7]=1[O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][Cl:15])([O-:18])=[O:17]
Reactant: COc1ccc([N+](=O)[O-])c(OCCOCCCl)c1
Agent: COc1ccc([N+](=O)[O-])c(O)c1
Agent: O=[N+]([O-])c1ccccc1O
Agent: [Na]
Product: O=[N+]([O-])c1ccccc1OCCOCCCl

Procedure:
This compound was prepared in a manner analogous to the preparation of 5-methoxy-2-nitro-[2-(2-chloroethoxy)ethoxy]benzene for crown ether XIX, except that the sodium salt of o-nitrophenol was used instead of the sodium salt of 5-methoxy-2-nitrophenol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[C:5]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)=[N:4][N:3]=1.[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>CN1CCCCC1=O>[Cl:24][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[O:22][CH3:23])[CH2:15][NH:14][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=2)[C:2]([N:29]2[CH2:30][CH2:31][CH:26]([OH:25])[CH2:27][CH2:28]2)=[N:3][N:4]=1
Reactant: COc1ccc(CNc2nnc(Cl)c3ccc(C#N)cc23)cc1Cl
Reactant: OC1CCNCC1
Agent: CN1CCCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2nnc(N3CCC(O)CC3)c3ccc(C#N)cc23)cc1Cl
Temperature: 170 °C
Yield: 85.6 %

Procedure:
1H-NMR(400 MHz, CDCl3) δ: 3.87(3H, s), 4.78(2H, d, J=5.0 Hz), 5.75(1H, t, J=5.0 Hz), 6.87(1H, d, J=8.5 Hz), 7.31(1H, dd, J=8.5, 2.0 Hz), 7.43(1H, d, J=2.0 Hz), 8.05(1H, dd, J=8.5, 1.5 Hz), 8.24(1H, dd, J=1.5, 1.0 Hz), 8.29(1H, dd, J=8.5, 0.5 Hz). 10.0 g of 1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine was dissolved in 50 ml of N-methyl-2-piperidone. After adding 43.32 g of 4-hydroxypiperidine and 10 ml of diisopropylethylamine, the resulting mixture was heated at 170° C. for 8 hours. Then ethyl acetate wag added thereto and the resulting mixture was successively washed for three times with water and once with brine and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (methylene chloride:methanol=30:1) to give 10.1 g of 4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(4-hydroxypiperidino)phthalazine as yellow crystals. M.p.: 172.0-173.5° C., Mass 424(MH+),
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:12][CH:11]([S:13][C:14]3[C@H:15]([CH3:45])[C@@H:16]4[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]4[C:18]=3[C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])[CH2:10]2)[S:7][CH:8]=1)([OH:3])=O.Cl.[N+:47]([C:50]1[CH:64]=[CH:63][C:53]([CH2:54][O:55][C:56](=[O:62])[C@H:57]([CH:59]([CH3:61])[CH3:60])[NH2:58])=[CH:52][CH:51]=1)([O-:49])=[O:48].C(P(C#N)(CC)=O)C.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:60][CH:59]([CH3:61])[C@H:57]([NH:58][C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:12][CH:11]([S:13][C:14]3[C@H:15]([CH3:45])[C@@H:16]4[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:38])[CH3:39])[CH3:35])[C:32](=[O:44])[N:17]4[C:18]=3[C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])[CH2:10]2)[S:7][CH:8]=1)=[O:3])[C:56]([O:55][CH2:54][C:53]1[CH:63]=[CH:64][C:50]([N+:47]([O-:49])=[O:48])=[CH:51][CH:52]=1)=[O:62]
Reactant: CC(C)[C@H](N)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)O)cs4)C3)[C@H](C)[C@H]12
Agent: CCP(=O)(C#N)CC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]4[C@H]3C)C2)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
To a solution of p-nitrobenzyl (1R,5S,6S)-2-[1-(4-carboxy-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylate (1.00 g, 1.48 mmol) (obtained as described in Reference Example 41(7)) and L-valine p-nitrobenzyl ester hydrochloride (514 mg, 1.78 mmol) (obtained as described in Reference Example 46(2)) in dimethylformamide (50 ml) were added diethylphosphoryl cyanide (275 μl, 1.78 mmol) and diisopropylethylamine (620 μl, 3.56 mmol) in an ice bath under an atmosphere of nitrogen. The mixture was stirred at room temperature for 2 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:1) as the eluant to afford p-nitrobenzyl(1R,5S,6S)-2-{1-[4-((1S)-2-methyl-1-(p-nitrobenzyloxycarbonyl)-propylcarbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylate (1.15 g, yield 86%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].[CH3:26][C:27]1[CH:28]=[C:29]([OH:36])[CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34].O>CN(C)C=O>[CH3:26][C:27]1[CH:28]=[C:29]([O:36][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOc1ccc([N+](=O)[O-])c(C)c1
Temperature: 110 °C
Reaction time: 60 h
Yield: 112.9 %

Procedure:
1-Bromooctadecane (43.54 g, 0.131 mol) and potassium carbonate (54.15 g, 0.392 mol) were added to a solution of 3-methyl-4-nitrophenol (20 g, 0.131 mol) in dimethylformamide (120 mL) The reaction mixture was heated to 110° C. and stirred at this temperature for 60 hours. The reaction mixture was cooled and poured into water (2 L), stirred for 0.5 hour and extracted with methylene chloride (1 L). The organic extract was washed with 5% aqueous solution sodium bicarbonate (0.5 L), water (2×0.6 L), dried over sodium sulfate and concentrated to give (60 g) of crude product. This product was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:4][C:3]=1I.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[CH2:17]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:4][C:3]=1/[CH:17]=[CH:16]/[C:15]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: C=CC(=O)OCC
Reactant: Cc1cc(-n2cnnn2)cc(I)c1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cc(-n2cnnn2)cc(C)c1N

Procedure:
To a solution of 1-(4-amino-3-iodo-5-methylphenyl)tetrazole (5 g) in acetronitrile (80 cm3) was added ethyl acrylate (2 g), triethylamine (2 g) and palladium acetate (0.1 g). The mixture was heated under reflux for 11/2 hours, cooled and then partitioned between water (100 cm3) and dichloromethane (100 cm3). The aqueous phase was re-extracted with more dichloromethane (100 cm3) and the combined organic phases were dried (MgSO4), filtered and evaporated in vacuo. The residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with dichloromethane: methanol, 20:1. Combination and evaporation of appropriate fractions gave a solid which on recrystallisation from ethyl acetate/methanol afforded yellow needles of trans-ethyl 3-(2-amino-3-methyl-5-[tetrazol-1-yl]phenyl)prop-2-enoate, m.p. 210°-211°, (3.45 g).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25](NC3CCCC3)=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19].[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([NH:39][CH2:38][C:37]3[CH:40]=[CH:41][C:34]([Cl:33])=[CH:35][CH:36]=3)=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19]
Reactant: NCc1ccc(Cl)cc1
Reactant: Nc1nc(-n2cc(C(=O)NC3CCCC3)cn2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: Nc1nc(-n2cc(C(=O)NCc3ccc(Cl)cc3)cn2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
Compound 22 was prepared in a manner similar to that of compound 21 using 4-chlorobenzylamine instead of cyclopentylamine, MS 501.19 (M+1).
Reaction SMILES: [CH2:1](O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.S(Cl)([Cl:15])=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH2:1][Cl:15]
Reactant: COc1ccc(CO)cc1OC
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CCl)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a solution of 235 g of veratryl alcohol in 1.4 liters of dry methylene chloride, 200 g of thionyl chloride was added dropwise while cooling with ice, and the mixture was stirred at room temperature overnight. The resulting dark brown reaction solution was poured into one liter of ice water. The pH of the solution was adjusted to 7.0 with sodium bicarbonate. The methylene chloride layer was separated, washed with water, dehydrated, and concentrated to dryness under vacuum to obtain 220 g of 3,4-dimethoxybenzyl chloride having a melting point of 50° to 51° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24].[CH2:25]([NH2:33])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:33][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24]
Reactant: NCCc1ccccc1
Reactant: CN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Solvent: CCOC(C)=O
Product: CN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(NCCc3ccccc3)nc21
Temperature: 180 °C
Yield: 31.4 %

Procedure:
A mixture of 100 mg (0.26 mmol) of 3-(2,6-dichlorophenyl)-3,4-dihydro-7-methanesulfonyl-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 400 μl (3.4 mmol) of phenethylamine was heated at 180° C. for 4 hours and then cooled to room temperature. The mixture was dissolved in 10 ml of ethyl acetate and washed in sequence with 10 ml of 2M hydrochloric acid and 10 ml of saturated aqueous sodium bicarbonate solution. The ethyl acetate phase was separated, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash column chromatography on silica gel using 5% methanol/dichloromethane for the elution. Product-containing fractions were combined and evaporated to give 35 mg of 3-(2,6-dichlorophenyl)-3,4-dihydro-1-methyl-7-(2-phenylethylamino)pyrimido[4,5-d]pyrimidin-2(1H)-one as a pale yellow solid of melting point 148-151° C.
Reaction SMILES: O=[N:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[N:14]#[C:15][NH2:16]>>[NH2:16][C:15]1[NH:2][CH:3]=[C:4]([C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[N:14]=1
Reactant: N#CN
Reactant: O=NCCc1c[nH]c2ccccc12
Product: Nc1nc(-c2c[nH]c3ccccc23)c[nH]1

Procedure:
In another embodiment of the invention, a method of synthesizing N,N-didesmethylgrossularine-1 2 is described comprising: condensing oxotryptamine 3 and cyanamide in the absence of air to produce 2-amino-4-(3-indolyl)imidazole 6; exposing 2-amino-4-(3-indolyl)imidazole 6 to an ammonia saturated methanol solution in air to produce imine 10; and exposing imine 10 to hydrolosis conditions to produce N,N-didesmethylgrossularine-1 2.
Reaction SMILES: CO[C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3([CH3:19])[O:18]CCO3)[CH:12]=2)[N:7]([CH3:20])[C:6]1=[O:21])=[O:4].[NH2:22][C:23]1[CH:24]=[C:25]([CH:36]=[CH:37][CH:38]=1)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)=[O:27]>>[Br:35][C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:26]([C:25]2[CH:24]=[C:23]([NH:22][C:3]([CH:5]3[C:13]4[C:8](=[CH:9][CH:10]=[C:11]([C:14](=[O:18])[CH3:19])[CH:12]=4)[N:7]([CH3:20])[C:6]3=[O:21])=[O:4])[CH:38]=[CH:37][CH:36]=2)=[O:27])=[CH:30][CH:31]=1
Reactant: COC(=O)C1C(=O)N(C)c2ccc(C3(C)OCCO3)cc21
Reactant: Nc1cccc(C(=O)Nc2ccc(Br)cc2)c1
Product: CC(=O)c1ccc2c(c1)C(C(=O)Nc1cccc(C(=O)Nc3ccc(Br)cc3)c1)C(=O)N2C

Procedure:
Prepared as in Example 1 from 1-methyl-5-(2-methyl-[1,3]dioxolan-2-yl)-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid methyl ester and 3-amino-N-(4-bromo-phenyl)-benzamide. Purified by flash-chromatography (hexanes/acetone, 1:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.C(O)(=O)C.[Br:16]Br>O>[NH2:1][C:2]1[C:7]([Br:16])=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Nc1ncc(C(F)(F)F)cc1Br
Temperature: 0 °C
Yield: 78.5 %

Procedure:
In a 100 ml four necked flask equipped with the same equipments as those used in Example 3 were placed 3 g of 2-amino-5-trifluoromethylpyridine and 30 ml of acetic acid to provide a homogeneous solution. 4.4 g of bromine was dropwise added thereto while cooling the flask with ice water at 10° to 20° C., and after completion of the dropwise addition, the mixture was reacted for 1 hour. The reaction product was poured into 200 ml of water, washed with an aqueous solution of sodium thiosulfate and extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate, and the solvent was evaporated off. The solid thus obtained was washed with n-hexane to obtain 3.5 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:16]([F:19])([F:18])[F:17])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](C(O)=O)=[CH:8][CH:7]=[CH:6]2.C[N:21](C)C=O>S(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[C:4]([C:16]([F:19])([F:18])[F:17])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([NH2:21])=[CH:8][CH:7]=[CH:6]2
Reactant: CN(C)C=O
Reactant: COc1ccc2c(C(=O)O)cccc2c1C(F)(F)F
Solvent: O=S(Cl)Cl
Product: COc1ccc2c(N)cccc2c1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
6-Methoxy-5-(trifluoromethyl)-1-naphthalenecarboxylic acid (30.0 g, 1.11×10-1M) was stirred in thionyl chloride (120 mL) at 20° C. under nitrogen. Dimethylformamide (0.75 mL, anhydrous) was added, and the mixture was refluxed for 4 hours. The solvent and excess of thionyl chloride were evaporated under reduced pressure. Toluene (200 mL) was added, the solvent re-evaporated and the residual solid was dried (20° C./0.1 mm). The white solid was dissolved in acetone (300 mL), cooled to 0° C. and a solution of sodium azide (7.8 g, 1.19×10-1M) in water (25 mL) was added dropwise (precipitate formation). The mixture was stirred at 0° C. for 30 minutes, diluted to 600 mL volume with water, stirred for 1 hour at 0° C., filtered, and the filtered solid was washed with water (2×200 mL). The damp solid (Any azides are generally unsafe to handle.) was dissolved in toluene (400 mL), and the filtrate concentrated to 280 mL under reduced pressure, refluxed for 1 hour, then cooled to 20° C. Potassium hydroxide (40% aq, 200 mL) was added. The resultant mixture was refluxed for 1 hour, cooled to 30° C., and filtered. The filtered solid (This solid is an unwanted side product. Care should be taken to avoid precipitation of the desired product from toluene during filtration.) was washed with water (200 mL), and toluene (200 mL). The filtrate and washings were combined. The organic layer was separated, washed with water (200 mL), dried (MgSO4), filtered, and solvent evaporated to furnish the product (19.0 g, 84%) m.p. 120° C. as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[C:7]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:19](N1C=CN=C1)(N1C=CN=C1)=[O:20]>C1COCC1>[C:1]([O:5][C:6](=[O:18])[C:7]([CH3:9])([N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:19]1=[O:20])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Nc1ccccc1N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)n1c(=O)[nH]c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.7 %

Procedure:
A mixture of 2-(2-amino-phenylamino)-2-methyl-propionic acid tert-butyl ester (570 mg, 2.3 mmol) in THF (25 mL) was added 1,1′-carbonyldiimidazole (560 mg, 3.5 mmol). The solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated. The resulting residue was purified by CombiFlash with 50% EtOAc in Hexane as the eluent to afford the desired 2-methyl-2-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid tert-butyl ester (462 mg, 72%).
Reaction SMILES: [S:1]([CH2:11][N+:12]#[C-:13])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH3:14][S:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.[C-]#N.[Na+]>>[CH3:14][S:15][C:16]1[CH:23]=[CH:22][C:19]([C@@H:20]2[O:21][CH:13]=[N:12][C@@H:11]2[S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])=[CH:18][CH:17]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [C-]#N
Agent: [Na+]
Product: CSc1ccc([C@@H]2OC=N[C@@H]2S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
In a manner analogous to Preparation 1, tosylmethylisocyanide (0.23 g, 1.20 mmol), 4-(methylthio)benzaldehyde (0.19 g, 1.26 mmol), and NaCN (5.9 mg, 0.12 mmol) gave the desired compound as a tan solid. MS(ES+) m/z 348.4 (M+H+).
Reaction SMILES: [C:1]([C:3]1[C:19]([O:20][CH2:21][C@@H:22]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:18][C:6]2[N:7]([CH3:17])[C:8](=[O:16])[C:9]3[C:14]([C:5]=2[CH:4]=1)=[CH:13][CH:12]=[N:11][C:10]=3[CH3:15])#[N:2].[H-].[Na+].[CH3:37]I>CN(C=O)C>[C:1]([C:3]1[C:19]([O:20][CH2:21][C@@H:22]([N:27]([CH3:37])[C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:18][C:6]2[N:7]([CH3:17])[C:8](=[O:16])[C:9]3[C:14]([C:5]=2[CH:4]=1)=[CH:13][CH:12]=[N:11][C:10]=3[CH3:15])#[N:2]
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(C#N)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)N(C)C(=O)OC(C)(C)C)c(C#N)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98.4 %

Procedure:
(S)-tert-Butyl (1-((9-cyano-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (60 mg, 0.129 mmol), prepared as described in Example 64, Part B, was taken in DMF (3 mL) and cooled to 0° C. The reaction mixture was treated with NaH (10.33 mg, 0.258 mmol) followed by MeI (0.016 mL, 0.258 mmol). After stirring at 0° C. for 10 min, the reaction mixture was warmed to room temperature and stirred overnight. The mixture was then quenched with ice-cold water and extracted with ethyl acetate (2×3 mL). The combined organic layers were dried with sodium sulfate and concentrated under reduced pressure to afford (S)-tert-butyl (1-((9-cyano-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)(methyl)carbamate (70 mg, 0.127 mmol, 99% crude yield) as an off-white solid. The material was carried forward without further purification. LC/MS (ESI) m/e 479.2 [(M+H)+, calcd for C27H35N4O4 479.3]; LC/MS retention time (method C): tR=2.16 min.