Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[O:2].[C:3]12[CH2:9][C:6]([CH2:7][CH2:8]1)=[CH:5][CH:4]=2.[CH:10]([OH:12])=[O:11]>OS(O)(=O)=O>[CH:10]([OH:12])=[O:11].[CH:10]([OH:12])=[O:11].[OH:2][CH2:1][CH:9]1[CH:6]2[CH2:5][CH:4]3[CH:8]([CH:7]2[OH:11])[CH:3]13
Reactant: C=O
Reactant: C1=C2CCC(=C1)C2
Agent: O=S(=O)(O)O
Solvent: O=CO
Product: OCC1C2CC3C(C2O)C13
Yield: 84 %

Procedure:
To a stirred solution of 39.9 g paraformaldehyde in formic acid (800 ml) and conc. H2SO4 (15 ml) under nitrogen and at 20° C. was added dropwise 132 g norbornadiene while keeping the temperature between 20°-25° C. After 1.5 hr the reaction was quenched by adding to 800 ml of ice-water. Extraction with ether (3×750 ml), washing the organic layer with water (1×250 ml), brine (3×250 ml) and drying (Na2SO4) afforded the crude 3-hydroxymethyl tricyclo [2.2.1.02,6- ]heptan-5-ol bisformate (1') as an oil. Distillation, after a forerum of bp. 40° C./15 mm, gave 235 g pure tricyclenebisformate, bp. 104° C./0.3 mm (84% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](Br)=[CH:4][N:3]=1.[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:16]2[CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=[C:14]([C:13]([F:12])([F:28])[F:27])[CH:15]=2)=[CH:4][N:3]=1
Reactant: Cc1c(Br)cnc(N)c1C#N
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cnc(N)c1C#N

Procedure:
A stirred solution of 1.7 grams (0.008 mole) of 2-amino-5-bromo-3-cyano-4-methylpyridine, 3.2 grams (0.012 mole) of 3,5-di(trifluoromethyl)-phenylboronic acid (commercially available), 4.3 grams (0.031 mole) of potassium carbonate and 0.3 gram of tetrakis(triphenylphosphine)palladium(0) in 150 mL of toluene is heated at 90° C. for about 20 hours. After this time, the reaction mixture is stirred with 100 mL of water, and the organic layer is separated. The organic layer is concentrated under reduced pressure, yielding 2-amino-3-cyano-4-methyl-5-[3,5-di(trifluoromethyl)-phenyl]pyridine.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33](=[O:38])[C:34]([F:37])([F:36])[F:35])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.ClC1C=CC=CC=1C(=O)C(F)(F)F>>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:22]2[O:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33](=[O:38])[C:34]([F:37])([F:35])[F:36])=[CH:25][N:26]=2)=[O:8])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2ccccc2C(=O)C(F)(F)F)o1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: O=C(c1ccccc1Cl)C(F)(F)F
Product: O=C(CCCCCCc1ccccc1)c1ncc(-c2ccccc2C(=O)C(F)(F)F)o1
Yield: 83 %

Procedure:
1-(2-(2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)phenyl)-2,2,2-trifluoroethanone. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (63 mg, 0.095 mmol) and 1-(2-chlorophenyl)-2,2,2-trifluoroethanone following General Procedure B. Flash chromatography (2-10% EtOAc/hexanes) yielded the title compound as a clear oil (43 mg, 83%): 1H NMR (CDCl3, 600 MHz) δ 7.70-7.64 (m, 3H), 7.51-7.48 (m, 1H), 7.26-7.24 (m, 3H), 7.16-7.15 (m, 3H), 4.79 (t, 1H, J=6.0 Hz), 2.58 (t, 2H, J=7.5 Hz), 1.88-1.81 (m, 2H), 1.61-1.60 (m, 2H), 1.35-1.25 (m, 6H), 0.87 (s, 9H), 0.07 (s, 3H), −0.05 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 186.2 (d, J=35 Hz), 167.0, 149.4, 143.7, 133.6, 133.6, 131.1, 129.5, 129.4, 129.3, 129.1, 128.3, 126.4, 125.6, 116.4 (d, J=285 Hz), 69.4, 37.3, 36.8, 32.3, 30.0, 26.5, 26.5, 25.8, 19.0, −4.2, −4.4.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]#[N:8])[N:6]=1.[Br:9]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:9][CH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]#[N:8])[N:6]=1
Reactant: Cc1nc(C#N)cs1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1csc(CBr)n1
Temperature: 95 °C
Reaction time: 15 h
Yield: 94 %

Procedure:
To a mixture of 2-methyl-thiazole-4-carbonitrile (3.0 g, 24.1 mmol), N-bromosuccinimide (4.3 g, 24.1 mmol) in CCl4 (50 mL) was added benzoyl peroxide (0.583 g, 0.10 mmol). The resulting mixture was stirred at 95° C. for 15 h, concentrated under reduced pressure, diluted with EtOAc (100 mL) and washed with saturated Na2S2O3 (50 mL), NaHCO3 (50 mL) and brine (20 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude residue was purified via silica gel column chromatography using EtOAc/n-hexane as eluent to afford the title compound (4.6 g, 83%) as yellow oil. Rf0.39 (silica gel,EtOAc/hexane,3/7).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([OH:11])[C:5]=1[N+:12]([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O1CCCC1.O.C(OCC)(=O)C.Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([OH:11])[C:5]=1[NH2:12]
Reactant: COC(=O)c1ccc(Br)c(O)c1[N+](=O)[O-]
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Br)c(O)c1N
Temperature: 60 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To a solution of 4-bromo-3-hydroxy-2-nitro-benzoic acid methyl ester (Example 6.2) (3.13 g) in tetrahydrofuran (40 ml) was added a solution of sodium dithionite (10.23 g) in water (40 ml). The reaction mixture was stirred at 60° C. for 2 hours. Then the reaction was diluted with ethyl acetate (80 ml) and aqueous hydrochloric acid (1M) (30 ml) and the mixture vigorously shaken. The phases were separated and the aqueous phase was extracted with ethyl acetate (60 ml). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated to give 2-amino-4-bromo-3-hydroxy-benzoic acid methyl ester (2.46 g). 1H-NMR (400 MHz, CDCl3): 7.35 (d, 1H), 6.72 (d, 1H), 6.05 (s, 1H), 5.47 (s, 1H), 3.87 (s, 3H) ppm.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:10][CH:9]2[C@@H:7]([O:8]2)[CH2:6][C@H:5]1[OH:11])=[N+:2]=[N-:3].[NH3:12]>C(O)C>[NH2:12][C@@H:7]1[CH2:6][C@@H:5]([OH:11])[C@H:4]([N:1]=[N+:2]=[N-:3])[CH2:10][C@H:9]1[OH:8]
Reactant: [N-]=[N+]=N[C@@H]1CC2O[C@H]2C[C@H]1O
Reactant: N
Solvent: CCO
Product: [N-]=[N+]=N[C@@H]1C[C@@H](O)[C@H](N)C[C@H]1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(1S,3R,4R)-4-Azido-7-oxabicyclo[4.1.0]heptan-3-ol 3d (600 mg, 3.87 mmol) was dissolved in 20 mL ethanol followed by the addition of 10 mL of aqueous ammonia. The resulting solution was heated to reflux for 4 hours, then cooled down to room temperature and stirred for another 12 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound (1R,2R,4R,5R)-2-amino-5-azido-cyclohexane-1,4-diol 3e (665 mg, as a yellow oil), which was used in the next step without further furification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:11][C:10]=1[N+:23]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6](=[O:26])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:11][C:10]=1[NH2:23])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNc1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Solvent: CO
Product: CC(C)(C)OC(=O)CNc1ccc(NC(=O)OC(C)(C)C)cc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(4-tert-Butoxycarbonylamino-2-nitro-phenylamino)-acetic acid tert-butyl ester (10.8 g, 29.4 mmol) was dissolved in MeOH (70 mL) and purged with N2. Palladium on activated carbon (2.2 g, 10% by weight) was added, and the reaction mixture was charged with a balloon of H2. The reaction mixture was stirred for 3 h at room temperature, and then filtered through a pad of celite. The celite was washed with MeOH, and the filtrate was concentrated to afford 2.1 g (22%—two steps) of the sub-title compound. MS calculated for C17H27N3O4+H: 338, observed: 338.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9](CC3C=CC(Cl)=CC=3)[C:8]3[CH:19]([CH2:22][C:23]([OH:25])=[O:24])[CH2:20][CH2:21][C:7]=3[C:6]=2[CH:5]=[C:4]([F:26])[CH:3]=1.N1C=CC=CC=1.BrBr.C(O)(=O)C>ClCCl.[Zn]>[Br:1][C:2]1[C:10]2[NH:9][C:8]3[CH:19]([CH2:22][C:23]([OH:25])=[O:24])[CH2:20][CH2:21][C:7]=3[C:6]=2[CH:5]=[C:4]([F:26])[CH:3]=1
Reactant: O=C(O)CC1CCc2c1n(Cc1ccc(Cl)cc1)c1c(Br)cc(F)cc21
Agent: BrBr
Agent: [Zn]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: O=C(O)CC1CCc2c1[nH]c1c(Br)cc(F)cc21
Reaction time: 0.08 h

Procedure:
A slurry of the DCHA salt from Step 1 above in dichloromethane (0.241 M solution) was cooled to −20 to −15° C. Pyridine (2 eq.) was added in one shot and to the slurry was added dropwise bromine (2.5 eq.) over 30 to 45 minutes maintaining the temperature between −20° C. and −15° C. (At about ⅓ addition of bromine, the reaction mixture was thick and an efficient stirring was needed. Eventually, at about ½ addition of bromine, the mixture became “loose” again.) After completion of the addition, the reaction mixture was aged for one additional hour at −15° C. Acetic acid (3.04 eq.) was then added over 5 minutes and zinc dust (3.04 eq.) was added portion wise. (A portion of zinc was added at −15° C. and the mixture was aged for about 5 minutes to ensure that the exotherm was going (about −15° C. to −10° C.)). This operation was repeated with about 5 shots of zinc over about 30 min. When no more exotherm was observed, the remaining zinc was added faster. The whole operation takes around 30 to 45 minutes.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[C:12](=[O:18])[N:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[C:12](=[O:18])[N:13]([O:17][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccn(O)c1=O)OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cccn(OCc2ccccc2)c1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of (1-hydroxy-2-oxo-1,2-dihydro-pyridin-3-yl)-carbamic acid benzyl ester (1.5 g, 5.76 mmol) from Step C and K2CO3 (1.59 g, 11.5 mmol) in dry DMF (15 mL) was added benzyl bromide (0.82 mL, 6.91 mmol). The reaction mixture was stirred at room temperature for 2 h and diluted with water. The usual work-up (EtOAc extraction) and purification by chromatography (silica gel, 25% EtOAc/hexanes) gave the desired product. MS 351 (M+H)+.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COCCOc1ccc2ncnc(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COCCOc1ccc2ncnc(Cl)c2c1
Yield: 71 %

Procedure:
4-hydroxy-6-(2-methoxyethoxy)quinazoline (870 mg, 3.9 mmol) was reacted with POCl3 as described in Example 4A Step 2 to give 4-chloro-6-(2-methoxyethoxy)quinazoline (662 mg, 2.8 mmol, 71%). LC-MS (ESI) m/z 239 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([CH3:17])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:4].[CH2:18]([SH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([S:25][CH2:2][C:3]([C:5]1[C:6]([CH3:17])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:4])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: SCc1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CBr
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CSCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 120, Step 1, using 2-bromo-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanone and benzyl mercaptan.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]2=[N:4][CH:3]=1.CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.[Cl:41][C:42]1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:43]=1[C:44](Cl)=[O:45]>ClCCl>[Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:44]([C:43]3[CH:47]=[CH:48][C:49]([Cl:51])=[CH:50][C:42]=3[Cl:41])=[O:45])[CH2:10][C:5]2=[N:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Clc1cnc2n1CCNC2
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1Cl)N1CCn2c(Cl)cnc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Chloro-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (I20) (450 mg, 2.86 mmol) and diethylaminomethyl polystyrene (2855 mg, 9.14 mmol) were slurried in dichloromethane (DCM) (10 mL) and treated with 2,4-dichlorobenzoyl chloride (0.439 mL, 3.14 mmol). The slurry was stirred at RT for 24 h, whereupon the resin was filtered and washed with dichloromethane (20 mL). The filtrate was concentrated in vacuo to afford crude product. The product was purified by flash chromatography (Isolera, 10 g, 0-100% ethyl acetate/iso-hexane) to afford product then by MDAP (High pH method) to afford clean desired product in 350 mg.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:7]([O:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5][NH:4][CH2:3]1.C1C=CC(C(O[C@@H](C(O)=O)[C@@H](OC(C2C=CC=CC=2)=O)C(O)=O)=O)=CC=1>CCOC(C)=O>[CH3:1][C@@H:2]1[C@@H:7]([O:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: C[C@@H]1CNCC[C@H]1OC(=O)C(C)(C)C
Agent: O=C(O[C@@H](C(=O)O)[C@@H](OC(=O)c1ccccc1)C(=O)O)c1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H]1CNCC[C@@H]1OC(=O)C(C)(C)C

Procedure:
Racemic 19 (62.7 g, 314.4 mmol) is dissolved in EtOAc (300 ml) and a solution of L-(−)-0,0′-Dibenzoyl tartaric acid (56.3 g, 157.2 mmol) in EtOAc (450 ml) is added. The formed solid is filtered off, washed with cold EtOAc and dried. It is then re-crystallized from hot methanol (400 ml). The crystals are collected and the free base is liberated by treatment with 1N-NaOH and extraction with ether.
Reaction SMILES: [NH2:1][CH:2]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:12]=2)[CH2:7]1)[C:3](O)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C(OCC)(=O)C>[NH2:1][CH:2]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:12]=2)[CH2:7]1)[CH2:3][OH:4]
Reactant: CCCCCCCCc1ccc2c(c1)CCC(C(N)C(=O)O)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CCCCCCCCc1ccc2c(c1)CCC(C(N)CO)C2
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
The amino acid 8 prepared in Example 9 was added to a refluxing solution of lithium aluminum hydride (62 mg, 1.63 mmol) in TI-IF (10 ml). The reaction mixture was heated at reflux for 12 hours, subsequently cooled to 0° C. and 10 M NaOH was added and stirred for 20 minutes. Ethyl acetate (20 ml) was added and the mixture was filtered through Celite and magnesium sulfate. The filtrate was concentrated under vacuum and purified by column chromatography (Silica gel, 50% MeOH in CH2Cl2) to provide 41 mg of the product, VPC104059 (21%, two steps).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][C:6]([CH3:8])=[N:5][CH2:4][NH:3]1.[Na]>CO>[CH3:1][C:2]1([CH3:9])[CH2:7][CH:6]([CH3:8])[N:5]=[CH:4][NH:3]1
Reactant: CC1=NCNC(C)(C)C1
Agent: [Na]
Solvent: CO
Product: CC1CC(C)(C)NC=N1
Reaction time: 17 h

Procedure:
To a sample of 126 grams of 4,4,6-trimethyl-2,3,4,5-tetrahydropyrimidine in 300 cc. of methanol was added with stirring and cooling over a 2 hr. period 20.8 grams of sodium boronhydride. The mixture was allowed to stand for 17 hrs. The reaction mixture was extracted with chloroform and the chloroform removed under diminished pressure. The remaining product was distilled and the fraction b25 76.5°-77° C. was collected as 108 grams of 4,4,6-trimethyl hexahydropyrimidine. Anal. Calc.ed for C7H16N2 : N, 21.85. Found: N, 21.6 Nuclear magnetic resonance spectrum, solvent CDCl3, δ in ppm; 3.82 s, 2H; 2.87 m, 1H; 1.42 & 1.65, 2d's, 2H; 1.02 d, 3H; 1.08 & 1.13 2s's, 6H; 1.67 s, 2H exchangeable with D2O. A sample of 12.8 grams of 4,4,6-trimethylhexahydropyrimidine and 0.5 grams of 60% nickel catalyst on kieselguhr was heated for 8 hrs. at 185°-187° C. During this time the theoretial amount of hydrogen gas was evolved.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]/[CH:51]=[CH:52]\[CH2:53]/[CH:54]=[CH:55]\[CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[CH:22]([OH:41])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.[CH3:62][N:63]([CH3:70])[CH2:64][CH2:65][CH2:66][C:67](O)=[O:68].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:62][N:63]([CH3:70])[CH2:64][CH2:65][CH2:66][C:67]([O:41][CH:22]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:21]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]/[CH:51]=[CH:52]\[CH2:53]/[CH:54]=[CH:55]\[CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:68]
Reactant: CN(C)CCCC(=O)O
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOCC(OCCCCCCCC/C=C\C/C=C\CCCCC)C(O)CCCCCCCC/C=C\C/C=C\CCCCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC/C=C\C/C=C\CCCCCCCCOCC(OCCCCCCCC/C=C\C/C=C\CCCCC)C(CCCCCCCC/C=C\C/C=C\CCCCC)OC(=O)CCCN(C)C
Temperature: 25 °C
Yield: 46 %

Procedure:
To a solution of (12Z,15Z)-1,2-bis((9Z,12Z)-octadeca-9,12-dienyloxy)henicosa-12,15-dien-3-ol (450 mg, 0.54 mmol), 4-(dimethylamino)butanoic acid hydrochloride (135 mg, 0.8 mmol), EDCI hydrochloride (153 mg, 0.8 mmol), DIPEA (260 μL, 1.6 mmol) in anhydrous dichloromethane (10 mL) was added DMAP (5 mg). The solution was refluxed for 3 hours, cooled to room temperature and concentrated in vacuo to dryness. The reaction mixture was purified by column chromatography on silica gel 60 (eluted with a gradient of 100% hexanes to 1:1 hexanes/ethyl acetate) to afford (12Z,15Z)-1,2-bis((9Z,12Z)-octadeca-9,12-dienyloxy)henicosa-12,15-dien-3-yl 4-(dimethylamino)butanoate as a colorless oil (236 mg). 5.43-5.29 (m, 2H), 5.05-4.98 (m, 1H), 3.68-3.64 (m, 1H), 3.52-3.46 (m, 1H), 3.40 (t, 2H, J=6.7 Hz), 2.78 (t, 6H, J=6.4 Hz), 2.46-2.35 (m, 4H), 2.32 (s, 6H), 2.09-2.02 (m, 12H), 1.91-1.81 (m, 2H), 1.70-1.48 (m, 6H), 1.41-1.23 (m, 50H), 0.90 (t, 9H, J=6.7 Hz).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[CH:11]=3)[CH:7]=[CH:6][C:5]=12.C1C(=O)N([Br:25])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[O:14][C:13]([CH3:15])([CH3:16])[C:12](=[O:17])[C:11]=3[Br:25])[CH:7]=[CH:6][C:5]=12
Reactant: CC1(C)OC(c2ccc3nonc3c2)=CC1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(c2ccc3nonc3c2)=C(Br)C1=O
Reaction time: 3 h
Yield: 59.6 %

Procedure:
To a stirred solution of 5-(benzo[c][1,2,5]oxadiazol-5-yl)-2,2-dimethylfuran-3(2H)-one (0.25 g, 1.086 mmol) in CHCl3 (15 mL), NBS (0.29 g, 1.630 mmol) was added portionwise at RT. The reaction mixture was then stirred for 3 h and diluted with DCM (10 mL). The organic layer was then washed with water (5 mL) and brine (10 mL), dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(benzo[c][1,2,5]oxadiazol-5-yl)-4-bromo-2,2-dimethylfuran-3(2H)-one (0.2 g, 60%) as a yellow solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][N:10]([CH3:14])[C:11](=[O:13])[CH3:12].[F:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C@H:22]([CH:26]([CH3:28])[CH3:27])[C:21](=[O:29])[CH2:20][CH2:19]2>O1CCCC1>[CH3:9][N:10]([CH3:14])[C:11](=[O:13])[CH2:12][C@@:21]1([OH:29])[CH2:20][CH2:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]([F:15])[CH:17]=2)[C@@H:22]1[CH:26]([CH3:27])[CH3:28]
Reactant: CC(C)[C@@H]1C(=O)CCc2cc(F)ccc21
Reactant: CC(=O)N(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)[C@H]1c2ccc(F)cc2CC[C@]1(O)CC(=O)N(C)C
Temperature: -55 °C

Procedure:
Lithium diisopropylamide, 1.3 mL of 0.84 molar solution in tetrahydrofuran, was added to a solution of 0.11 mL N,N-dimethylacetamide in 1 mL tetrahydrofuran at -78° C. The mixture was stirred for fifteen minutes, then allowed to warm to -55° C. A solution of 220 mg (S)-6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one in 1 mL tetrahydrofuran was added at that temperature, then allowed to warm to 0-5° C. with stirring, and stirred for 2.5 hours. The reaction mixture was quenched with 3 mL saturated aqueous ammonium chloride, and extracted three times with 3 mL portions of diethyl ether. The ether extracts were combined, dried with magnesium sulfate, and stripped to give 290 mg (1S,2S)-N,N-dimethyl-(6-fluoro-2-hydroxy-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-yl)acetamide as a pale yellow oil.
Reaction SMILES: C(N(CC)[CH2:4][CH2:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)C.COC1C=C(CCCC(=O)C=C)C=CC=1.[CH:36]([CH:39]1[C:43](=[O:44])[CH2:42][CH2:41][C:40]1=[O:45])([CH3:38])[CH3:37]>>[CH:36]([C:39]1([CH2:4][CH2:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:43](=[O:44])[CH2:42][CH2:41][C:40]1=[O:45])([CH3:38])[CH3:37]
Reactant: CC(C)C1C(=O)CCC1=O
Reactant: CCN(CC)CCC(=O)CCCc1cccc(OC)c1
Agent: C=CC(=O)CCCc1cccc(OC)c1
Product: COc1cccc(CCCC(=O)CCC2(C(C)C)C(=O)CCC2=O)c1
Yield: 97.7 %

Procedure:
Condense a mixture (6 g) of 1-diethylamino-6-(m-methoxyphenyl)hexan-3-one and 6-(m-methoxyphenyl)hex-1-en-3-one with 2-isopropylcyclopentane-1,3-dione (3 g) using a procedure similar to that described for the condensation of the 2-ethyl compound. Obtain the corresponding triketone, 2-isopropyl-2-(6-m-methoxyphenyl-3-oxohexyl)cyclopentane-1,3-dione (7.2 g) as an uncrystallizable gum.
Reaction SMILES: [C:1]1([C:7]2[N:8]([N:12]3C(=O)C4C(=CC=CC=4)C3=O)[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NN>C(O)C>[C:1]1([C:7]2[N:8]([NH2:12])[CH:9]=[CH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1n1cccc1-c1ccccc1
Agent: NN
Solvent: CCO
Product: Nn1cccc1-c1ccccc1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
To a stirred suspension consisting of 2-(2-phenyl-1H-pyrrol-1-yl)-1H-isoindol-1,3(2H)dione (7.2 g) in abs. ethanol (150 ml) was added hydrazine (3.9 ml) at room temperature. The reaction mixture was warmed to reflux for 2 hours and allowed to cool to room temperature overnight. The solid by-product was filtered and washed with ether. The combined filtrates were concentrated in vacuo to give an oil which solidified on standing. Recrystallization from ether afforded 3.9 g of the product as a solid, m.p. 80°-82° C.