Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[C:22]([Cl:23])=[CH:21][C:20]([C:24]([OH:26])=[O:25])=[CH:19][N:18]=1)[C:5]([NH:7][CH3:8])=[O:6].C(N1C=CN=C1)(N1C=CN=C1)=O.[H-].[Na+].[C:41]([O:57][CH2:58][CH3:59])(=[O:56])[C:42]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)O.[N-]1C=CN=C1>C1COCC1.O>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[C:22]([Cl:23])=[CH:21][C:20]([C:24]([O:26][C:42]([C:41]([O:57][CH2:58][CH3:59])=[O:56])([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:25])=[CH:19][N:18]=1)[C:5]([NH:7][CH3:8])=[O:6]
Reactant: CNC(=O)C(=NOC)c1ccccc1COc1ncc(C(=O)O)cc1Cl
Reactant: CCOC(=O)C(O)(c1ccccc1)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(OC(=O)c1cnc(OCc2ccccc2C(=NOC)C(=O)NC)c(Cl)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
The product of Example 38 (0.5 g, 1.32 mmol) was dissolved in 15 mL THF to which was added carbonyldiimidazole (0.24 g, 1.48 mmol). The solution was stirred at room temperature for one hour. NaH (60% dispersion in mineral oil, 0.08 g, 3.2mmol) was washed (2×) with hexanes then suspended in THF (10 mL) to which was added ethyl benzilate (0.40 g, 3.2 mmol). After 20 minutes, the imidazolide intermediate was added dropwise to the solution of alcoholic anion and stirring continued at room temperature overnight. The solution was poured into 4-5 volumes of water and extracted with Et2O (2×100 mL). The organics were dried over MgSO4 and concentrate to a yellow oil (0.60 g). Product was chromatographed on medium column using silica gel (230-400 mesh) with isocratic 80/20 petroleum ether/ethyl acetate as the mobile phase. Elution and concentration gave α-(methoxyimino)-N-methyl-2-[[[3-chloro-5-(ethoxycarbonyldiphenylmethoxycarbonyl)-2-pyridinyl]oxy]methyl]-benzeneacetamide (0.50 g) as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][C:8]2[CH:12]=[CH:11][S:10][C:9]=2[CH:13]=O)=[CH:3][CH:2]=1.[CH3:15][O:16][C:17](=[O:30])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[CH:21]=[C:20]1[CH3:29].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl.ClCCCl>[CH3:15][O:16][C:17](=[O:30])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[C:21]([CH2:13][C:9]2[S:10][CH:11]=[CH:12][C:8]=2[S:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[C:20]1[CH3:29]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1sccc1Sc1ccncc1
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cn1c(C)c(Cc2sccc2Sc2ccncc2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.8 %

Procedure:
A mixture of 3-(pyridin-4-ylsulfanyl)thiophene-2-carbaldehyde (1.3 g), (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (1.3 g) and 1,2-dichloroethane (30 mL) at −10° C. was treated with a mixture of triethylsilane (5.8 mL), trifluoroacetic acid (2.4 mL) and 1,2-dichloroethane (20 mL), and the resulting mixture was stirred at room temperature for 48 hours. The mixture was diluted with dichloromethane, washed with aqueous sodium bicarbonate solution and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate to afford the title compound as yellow foam (2.4 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][OH:15].O[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>ClCCl.CCCCCC>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21]
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Reactant: O=Cc1cccc(O)c1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1oc(-c2ccccc2)nc1CCOc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
2-(5-methyl-2-phenyloxazol-4-yl)ethanol (1.02 g), 3-hydroxybenzaldehyde (0.73 g) and triphenylphosphine (1.57 g) were dissolved in dichloromethane (10 ml) and thereto was added 1, 1′-(azodicarbonyl)dipiperidine (1.74 g) at 0° C. and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added hexane and the solid was filtered off. The filtrate was concentrated. The residue was purified by column chromatography on silica gel (methanol:chloroform=1:100) to give the title compound (1.30 g) having the following physical data.
Reaction SMILES: O.[OH-].[K+].[C:4]1([CH:10]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[NH:11][C:12]([C@H:14]2[CH2:19][CH2:18][C@H:17]3[C@H:20]4[C@H:30]([CH2:31][CH2:32][C@:15]23[CH3:16])[C@:28]2([CH3:29])[C:23]([CH:24]=[C:25]([C:33]([O:35]C)=[O:34])[CH2:26][CH2:27]2)=[CH:22][CH2:21]4)=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[C:4]1([CH:10]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:11][C:12]([C@H:14]2[CH2:19][CH2:18][C@H:17]3[C@H:20]4[C@H:30]([CH2:31][CH2:32][C@:15]23[CH3:16])[C@:28]2([CH3:29])[C:23]([CH:24]=[C:25]([C:33]([OH:35])=[O:34])[CH2:26][CH2:27]2)=[CH:22][CH2:21]4)=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)C1=CC2=CC[C@H]3[C@@H]4CC[C@H](C(=O)NC(c5ccccc5)c5ccccc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C(=O)O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccccc1)c1ccccc1

Procedure:
10 ml of water and 1 g of potassium hydroxide were added to a solution of 25 ml of methanol containing 214 mg of methyl 17β-(N-diphenylmethylcarbamoyl)androsta-3,5-diene-3-carboxylate (prepared as described in Example 27). The reaction mixture was then heated under reflux for 4 hours. At the end of this time, methanol from the reaction mixture was removed by distillation under reduced pressure. The mixture was then made acidic by the addition of 1N aqueous hydrochloric acid and extracted with methylene chloride three times. The combined organic extracts were washed with water and with a saturated aqueous solution of sodium chloride, in that order, dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 20 g of silica gel and using a gradient elution method, with mixtures of acetone and methylene chloride in ratios ranging from 2:98 to 50:50 by volume as the eluent, to give 110 mg of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[N:18]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[N:17]=[N:16][N:15]=1.O.Cl.[CH2:30]([C:32]1[CH:41]=[C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=2)[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1)[CH3:31]>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.C1(C)C=CC=CC=1.CO>[CH2:30]([C:32]1[CH:41]=[C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:14]3[N:18]([C:19]4[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=4)[N:17]=[N:16][N:15]=3)=[CH:46][CH:45]=2)[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1)[CH3:31]
Reactant: O=[N+]([O-])c1ccc(-n2nnnc2-c2ccccc2Br)cc1
Reactant: CCc1cc(OCc2ccc(B(O)O)cc2)c2ccccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CCc1cc(OCc2ccc(-c3ccccc3-c3nnnn3-c3ccc([N+](=O)[O-])cc3)cc2)c2ccccc2n1
Temperature: 60 °C
Yield: 65 %

Procedure:
A mixture of potassium carbonate (5.8 g), 5-(2-bromophenyl)-1-(4-nitrophenyl)-1H-tetrazole (5.81 g) (Compound B), water (43 ml), toluene (43 ml), and methanol (43 ml) was heated to 60° C. to give a clear solution. 4-[(2-Ethylquinolin-4-yloxy)methyl]phenylboronic acid hydrochloride (4.3 g) and tetrakis(triphenylphosphine)palladium (0.032 g) were added and the reaction mixture heated at reflux for 4 hours. The mixture was allowed to cool and further toluene (50 ml) added. The organic phase was separated and the aqueous phase extracted with toluene (2×50 ml). The combined organic phases were evaporated and the resultant solid recrystallised from toluene to give 2-ethyl-4-[(2'-(1-(4-nitrophenyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline as a solid (4.3 g); NMR (CDCl3): 1.42(3H,t), 3.0(2H,q), 5.23(2H,s), 6.67(2H,d), 6.75(1H,s), 6.85(2H,d), 7.25 (2H,d), 7.43(1H,d), 7.55(1H,t), 7.70(3H,m), 7.90(3H,d), 8.05(1H,d), 8.20(1H,d).
Reaction SMILES: [CH3:1][C:2](OC(C)=O)=[O:3].CCCCCC.CCOC(C)=O.[CH3:20][CH:21]([C:23]([C@@:25]12[C@@:35]([CH2:37][CH2:38][CH:39]=[C:40]([CH3:42])[CH3:41])([CH3:36])[C@@H:34]([CH2:43][CH:44]=[C:45]([CH3:47])[CH3:46])[CH2:33][C@@:30]([CH2:48][CH:49]=[C:50]([CH3:52])[CH3:51])([C:31]1=[O:32])[C:29]([OH:53])=[C:28]([CH2:54][CH:55]=[C:56]([CH3:58])[CH3:57])[C:26]2=[O:27])=[O:24])[CH3:22].C([O-])(=O)C>O>[CH3:22][CH:21]([C:23]([C@:25]12[C@@:35]([CH2:37][CH2:38][CH:39]=[C:40]([CH3:41])[CH3:42])([CH3:36])[C@@H:34]([CH2:43][CH:44]=[C:45]([CH3:46])[CH3:47])[CH2:33][C@@:30]([CH2:48][CH:49]=[C:50]([CH3:52])[CH3:51])([C:31]1=[O:32])[C:29]([O:53][C:2]([CH3:1])=[O:3])=[C:28]([CH2:54][CH:55]=[C:56]([CH3:58])[CH3:57])[C:26]2=[O:27])=[O:24])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)=CCC[C@]1(C)[C@@H](CC=C(C)C)C[C@@]2(CC=C(C)C)C(=O)[C@]1(C(=O)C(C)C)C(=O)C(CC=C(C)C)=C2O
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)OC1=C(CC=C(C)C)C(=O)[C@]2(C(=O)C(C)C)C(=O)[C@]1(CC=C(C)C)C[C@H](CC=C(C)C)[C@@]2(C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 0.28 %

Procedure:
A solution of 12 g of the plant extract obtained in Example 1 in 48 mL of pyridine was added to 9.8 mL of Ac2O and stirred at room temperature. The reaction was monitored by thin layer chromatography (TLC) (hexane-EtOAc 95:5; hyperforin Rf: 0.24; acetate Rf: 0.49). After 24 hours, the reaction mixture was diluted with water and extracted with a 3:1 hexane-ether mixture. The organic phase was washed with dilute HCl, saturated NaHCO3, and saline solution. After drying (Na2SO4) and evaporation, the residue was purified by chromatography on a silica gel column (ca 30 g), eluted first with petroleum ether to remove fats, then using hexane-EtOAc 95:5 as soon as the title compound started to elute. Hyperforin acetate (3.34 g, 0.28%) was obtained as a colorless paste with the following properties:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:10]([CH3:11])[C:9](=[O:12])[N:8]2[C:4](=[N:5][C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=32)[NH:3]1.[C:18](Cl)(=[O:20])[CH3:19].Cl.C([NH+](CC)CC)C.[NH4+].[OH-]>CO.C(Cl)(Cl)Cl.C(N(CC)CC)C.CC(C)=O>[C:18]([N:5]1[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[N:8]2[C:9](=[O:12])[N:10]([CH3:11])[C:2]([CH3:17])([CH3:1])[N:3]=[C:4]12)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: CN1C(=O)n2c(nc3ccccc32)NC1(C)C
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: [NH4+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)N1C2=NC(C)(C)N(C)C(=O)N2c2ccccc21
Yield: 52 %

Procedure:
A 250-ml, round-bottomed flask containing a magnetic stirring bar was charged with 2.45 g (0.0106 mole) of 1,2-dihydro-2,2,3-trimethyl-1,3,5-triazino[1,2-a]benzimidazol-4-(3H)-one, 150 ml of acetone and 1.53 ml of triethylamine. Acetyl chloride (0.86 g, 0.0110 mole) was added rapidly via syringe to the resulting solution. The mixture was stirred for two hours at room temperature after which time a white precipitate of triethylammonium hydrochloride was visible. Examination of the reaction mixture by TLC (silica, 80:2:1, CHCl3 : CH3OH: NH4OH) showed that only a trace of starting material remained. The mixture was concentrated in vacuo and the resulting solid was taken up in methylene chloride. The resulting solution was washed with water (3 times) brine, dried (MgSO4) and concentrated under reduced pressure to afford 1.5 g (52% yield) of a white solid which was analytically pure, mp 159°-62° C.
Reaction SMILES: [I-].C[S+](C)(C)=O.[C:7](O[K])(C)(C)[CH3:8].[CH3:13][C@@H:14]1[CH2:19][C:18](=[O:20])[CH2:17][CH2:16][N:15]1[C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22].O>CC(O)(C)C>[CH3:13][C@H:14]1[N:15]([C@@H:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH3:22])[CH2:16][CH2:17][C@:18]2([O:20][CH2:8][CH2:7]2)[CH2:19]1
Reactant: C[C@@H]1CC(=O)CCN1[C@H](C)c1ccccc1
Reactant: CC(C)(C)O[K]
Agent: C[S+](C)(C)=O
Agent: [I-]
Solvent: CC(C)(C)O
Solvent: O
Product: C[C@@H]1C[C@]2(CCO2)CCN1[C@H](C)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To a solution of trimethylsulfoxonium iodide (10.1 g, 46.0 mmol) in t-BuOH (anhydrous, 10 mL) was added tBuOK (1M in t-BuOH, 36.8 mL, 36.8 mmol) and the resulting mixture was stirred at 60° C. for 1 h. Then a solution of (R)-2-methyl-1-((R)-1-phenylethyl)piperidin-4-one (2 g, 9.20 mmol) in t-BuOH (6 mL) was added slowly. The reaction mixture was heated at 60° C. for 72 h, then cooled to room temperature and poured into water. The aqueous phase was extracted with EtOAc (2×). The organic phases were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (0-30% EtOAc/heptanes) to provide the desired isomer (4S,6R)-6-methyl-7-((R)-1-phenylethyl)-1-oxa-7-azaspiro[3.5]nonane as a colorless oil (0.67 g, 30%). 1H NMR (400 MHz, CD2Cl2) δ ppm 7.48 (d, J=7.83 Hz, 2H), 7.34 (t, J=7.58 Hz, 2H), 7.24 (t, J=6.82 Hz, 1H), 4.39-4.51 (m, 2H), 4.25 (q, J=6.74 Hz, 1H), 2.78-3.01 (m, 1H), 2.30-2.45 (m, 3H), 2.21-2.30 (m, 1H), 2.13 (td, J=2.56, 13.07 Hz, 1H), 1.85-1.95 (m, 1H), 1.44-1.62 (m, 2H), 1.28 (d, J=6.82 Hz, 3H), 1.20 (d, J=6.32 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:16]([CH2:22][OH:23])[CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1C=C2C(C=C(C[C@H](N)C(O)=O)C=C2)=CC=1.[CH3:40][O:41][C:42]([NH:44][CH:45]([CH2:49][C:50]1[CH:59]=[CH:58][C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:51]=1)[C:46](O)=[O:47])=[O:43].C1C=C2C=CC=C(C[C@H](N)C(O)=O)C2=CC=1>>[CH3:40][O:41][C:42](=[O:43])[NH:44][C@H:45]([C:46](=[O:47])[NH:21][CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]([N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:22][OH:23])[CH2:49][C:50]1[CH:59]=[CH:58][C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:51]=1
Reactant: COC(=O)NC(Cc1ccc2ccccc2c1)C(=O)O
Reactant: CC(C)CN([C@H](CO)CCCCN)S(=O)(=O)c1ccc(N)cc1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: N[C@@H](Cc1cccc2ccccc12)C(=O)O
Product: COC(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)NCCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (1S)-4-amino-N-(5-amino-1-hydroxymethyl-pentyl)-N-isobutyl-benzenesulfonamide (XII) (example 28, step D) as described in general procedure B using L-2-naphthylalanine. The L-2-naphthylalanine was initially transformed into its 2-methoxycarbonylamino-3-naphthalen-2-yl-propionic acid derivative following the procedure used for L-1-naphthylalanine (example 28, step E). The final product was obtained in 41% yield (165 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[C:17](=[C:18]([C:22]([OH:24])=O)[CH:19]=[CH:20][CH:21]=3)[N:13]2[CH2:12][CH2:11][CH2:10]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[OH:48][CH:49]1[CH2:52][NH:51][CH2:50]1>CN(C)C=O.C(=O)([O-])O.[Na+].C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([N:51]4[CH2:52][CH:49]([OH:48])[CH2:50]4)=[O:24])[C:17]=3[N:13]2[CH2:12][CH2:11][CH2:10]1
Reactant: OC1CNC1
Reactant: O=C(O)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)N1CC(O)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 47.7 %

Procedure:
To a suspension of 1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylic acid (430 mg, 1.18 mmol) in N,N-dimethylformamide (8.0 mL) were added 1-hydroxy-1H-benzotriazole (235 mg, 1.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (249 mg, 1.30 mmol), 3-hydroxyazetidine hydrochloride (258 mg, 2.36 mmol), and triethylamine (0.50 mL). The mixture was stirred at room temperature for 15 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 75-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was washed with ethyl acetate to give the title compound as a colorless powder (235 mg, 0.563 mmol, 48%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].S([O-])([O-])(=O)=O.[K+].[K+].C[O-].[Ca+2:16].C[O-]>>[CH2:3]([C:4]([O-:6])=[O:5])[CH2:2][NH2:1].[CH2:3]([C:4]([O-:6])=[O:5])[CH2:2][NH2:1].[Ca+2:16]
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Product: NCCC(=O)[O-]

Procedure:
reacting the beta-alanine and potassium sulfate mixture with calcium methoxide to form calcium beta alanate;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.Br[CH2:25][CH2:26][CH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]=1[C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:25][CH2:26][CH2:27][O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)=[CH:21][CH:22]=1
Reactant: BrCCCOC1CCCCO1
Reactant: COC(=O)c1cc(-c2ccc(O)cc2)c(-c2ccccc2Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1cc(-c2ccc(OCCCOC3CCCCO3)cc2)c(-c2ccccc2Cl)s1
Temperature: 60 °C
Yield: 95.4 %

Procedure:
2.3 g of the compound obtained in stage 23E), 1.95 g of 2-(3-bromopropoxy)tetrahydro-2H-pyran and 1.2 g of potassium carbonate are added to 15 ml of DMF and then the mixture is heated at 60° C. for 7 hours. It is poured onto ice-cold water, extraction is carried out with ether and the extract is dried and concentrated to dryness. After purifying by chromatography on silica (heptane and then heptane/AcOEt 80/20), 3.1 g of the expected compound are obtained.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[O:12][C:13]([CH2:16][NH:17][CH3:18])=[CH:14][CH:15]=1)([O-:3])=[O:2].[CH2:21]([NH2:24])[C:22]#[CH:23]>C(#N)C>[N+:1]([CH:4]=[C:5]([NH:24][CH2:21][C:22]#[CH:23])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[O:12][C:13]([CH2:16][NH:17][CH3:18])=[CH:14][CH:15]=1)([O-:3])=[O:2]
Reactant: CNCc1ccc(CSCCNC(=C[N+](=O)[O-])SC)o1
Reactant: C#CCN
Solvent: CC#N
Product: C#CCNC(=C[N+](=O)[O-])NCCSCc1ccc(CNC)o1

Procedure:
A mixture of 1-nitro-2-methylthio-2-{2-[(5-methylaminomethyl-2-furyl)methylthio]ethylamino}ethylene [prepared according to the procedure described in Belgian Pat. No. 857,388] and propargylamine in acetonitrile is stirred and heated under a positive pressure of nitrogen to give, after workup and chromatography, the title compound.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:9][C:10]([Cl:13])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.CCCCC.CN([CH:27]=[O:28])C>>[C:1]([NH:5][C:6]([C:8]1[S:9][C:10]([Cl:13])=[CH:11][C:12]=1[CH:27]=[O:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(C)(C)NC(=O)c1ccc(Cl)s1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Product: CC(C)(C)NC(=O)c1sc(Cl)cc1C=O
Temperature: -75 °C
Reaction time: 1.5 h
Yield: 102.8 %

Procedure:
A 1 L three-neck flask was charged with N-tert-butyl-5-chlorothiophene-2-carboxamide (10.0 g, 45.9 mmol) and thoroughly flushed with nitrogen gas. The flask was charged with THF (400 ml) by cannulation, then cooled to −75° C. Tert-butyllithium, 1.7 m solution in pentane (68.4 ml, 116 mmol) was added by syringe pump over 45 min, keeping the temperature less than −70° C. After stirring at −75° C. for 90 min, the reaction was gradually warmed to −60° C. and stirred for 1 hr. The mixture was again cooled to −75° C. and DMF (14.2 ml, 184 mmol) was added dropwise, ensuring the temperature remained below −70° C. The mixture was stirred at −75° C. for 1 hr. The reaction was quenched with 200 ml sat. aq. NH4Cl, then allowed to warm to RT. Water was added to the solution to dissolve solids and the mixture was extracted with EtOAc (3×). The combined organics were dried over Na2SO4, filtered and concentrated to give the title compound as a tan solid (11.6 g.). MS (ESI, pos. ion) m/z: 246 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.CCN(CC)CC.[S:19](Cl)([CH3:22])(=[O:21])=[O:20]>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][O:9][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 102.3 %

Procedure:
2-(4-Bromo-phenoxy)-ethanol (125 g, 0.576 mol) was dissolved in CH2Cl2 (650 mL), and the sol. was cooled to 0° C. Et3N (110 mL, 0.864 mol), then mesyl chloride (67.1 mL, 0.864 mol) were dropped at such a speed that the temperature did not raise above 10° C. (about 60 min). The mixture was stirred at 0° C. for 1 h, then at rt overnight. The mixture was diluted with CH2Cl2, and washed with brine (2×). The aq. phase was extracted back with CH2Cl2. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded the crude title compound (174 g, quantitative yield) that was used further without purification. LC-MS: tR=0.92 min.
Reaction SMILES: [CH2:1]([C:4]1([O:17][CH2:18][CH:19]=[CH2:20])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)C=C>C1C=CC=CC=1>[O:17]1[C:4]2([CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:8][CH2:9]2)[CH2:1][CH:20]=[CH:19][CH2:18]1
Reactant: C=CCOC1(CC=C)CCN(C(=O)OC(C)(C)C)CC1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CC=CCO2)CC1
Reaction time: 18 h

Procedure:
A solution of Example 518B (0.79 g, 2.81 mmol) in degassed benzene (100 mL) at room temperature was treated with bis-tricyclohexylphosphine benzylidene ruthenium (IV) dichloride (150 mg), stirred for 18 hours, and concentrated The concentrate was purified by flash column chromatography on silica gel with 10%-25% ethyl acetate/heptane to provide the desired product. MS (DCI(+)) m/e 254 (M+H)+.