Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:21]2[C:20]3[C:15](=[CH:16][C:17]([C:22]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[O:23])=[CH:18][CH:19]=3)[NH:14][C:13]=2[C:12]([C:31]([NH2:33])=[O:32])=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH3:65][N:66]([CH3:70])[CH2:67][CH2:68]O>O1CCOCC1.C1COCC1>[CH3:65][N:66]([CH3:70])[CH2:67][CH2:68][O:8][C:7]1[C:2]([F:1])=[C:3]([C:9]2[C:21]3[C:20]4[C:15](=[CH:16][C:17]([C:22]([N:24]5[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]5)=[O:23])=[CH:18][CH:19]=4)[NH:14][C:13]=3[C:12]([C:31]([NH2:33])=[O:32])=[CH:11][CH:10]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(-c4cccc(O)c4F)c23)CC1
Reactant: CN(C)CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CN(C)CCOc1cccc(-c2ccc(C(N)=O)c3[nH]c4cc(C(=O)N5CCN(C)CC5)ccc4c23)c1F
Temperature: 95 °C

Procedure:
A mixture of 4-(2-fluoro-3-hydroxyphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide (Intermediate 84-1, 20 mg, 0.045 mmol) and polymer-supported triphenylphosphine (2.63 mmol/g, 0.358 mmol) in 1,4-dioxane was treated at 0° C. with a solution of diethyl azodicarboxylate (19.5 mg, 0.157 mmol) in THF (0.5 mL), followed after 5 min by a solution of 2-(dimethylamino)ethanol (10 mg, 0.112 mmol) in THF (0.5 mL). The mixture was heated in a sealed tube by microwave irradiation at 90-100° C. for 30 min. The resulting mixture was filtered, the solids were washed with methanol, and the filtrates were concentrated and purified by preparative HPLC to provide 4-(3-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide. Mass spectrum m/z 518.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]2[C:7](=[O:26])[N:8]=[C:9]([C:11]3[N:16]=[C:15]([CH2:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[CH:4]=1.FC(F)(F)C(O)=O>>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]2[C:7](=[O:26])[N:8]=[C:9]([C:11]3[N:16]=[C:15]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(=O)nc(-c3cccc(CCC(=O)OC(C)(C)C)n3)sc2c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(=O)nc(-c3cccc(CCC(=O)O)n3)sc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 3-[6-(7-methoxy-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoate (0.40 g, 1.0 mmol) obtained in Example 173 and trifluoroacetic acid (5.0 ml) was stirred at 0° C. for 2 hrs. The reaction mixture was concentrated under reduced pressure, combined with diisopropyl ether to give the crystals, which were collected by filtration and dried.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([NH:10][C:11](=[O:13])[CH3:12])[CH2:7][CH2:8][CH2:9][C:2]1=2.C(O)(=[O:16])C.C(C(C)=O)C(C)C>O.[Cl-].[Na+]>[O:16]=[C:9]1[C:2]2[S:1][CH:5]=[CH:4][C:3]=2[CH:6]([NH:10][C:11](=[O:13])[CH3:12])[CH2:7][CH2:8]1
Reactant: CC(=O)NC1CCCc2sccc21
Reactant: CC(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CC(=O)NC1CCC(=O)c2sccc21
Reaction time: 0.42 h

Procedure:
A mixture of N-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)-acetamide (2.0 g; 10.25 m mole), cobaltous acetate (0.49 g; 2.77 m mole), cobaltous bromide tetrahydrate (0.635 g; 2.18 m mole), water (0.4 ml), acetic acid (5.0 ml) and methyl isobutyl ketone (35.0 ml) in suitable flask fitted with a reflux condenser, a gas dispersion tube and a thermometer is stirred vigorously. Air is introduced through the dispersion tube into the turbid blue solution at room temperature for 45 minutes, and then the mixture is heated. After 25 minutes, the solution turns greenish blue (temperature: 45° C.) and in 15 minutes green (temperature: 55° C.). The reaction is run overnight with periodic additions of methyl isobutyl ketone. The greyish green reaction mixture containing some suspended dark gray solid is then diluted with water (40.0 ml) and saturated with sodium chloride. The upper organic phase is separated and the aqueous phase extracted with chloroform (2×100 ml). The organic phase and the chloroform extracts are combined, washed with brine (50 ml) and water (25 ml), respectively. The water wash is counter-extracted with chloroform (50 ml) and the chloroform extract added to the above organic phase. The combined organic phase is evaporated in vacuo to afford a gum, which contains the desired compound. The latter is hydrolyzed without further purification and the resultant amine hydrochloride is converted to 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea.
Reaction SMILES: Cl[S:2]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])=[O:3].[CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[C:15]=1[OH:23])([CH3:13])[CH3:12]>>[CH:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:11]([CH3:13])[CH3:12])[C:15]=1[O:23][S:2]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])=[O:3])([CH3:22])[CH3:21]
Reactant: CCOC(=O)CS(=O)(=O)Cl
Reactant: CC(C)c1cccc(C(C)C)c1O
Product: CCOC(=O)CS(=O)(=O)Oc1c(C(C)C)cccc1C(C)C

Procedure:
The general procedure of Example I(A) was followed to react ethyl chlorosulfonylacetate with 2,6-diisopropylphenol to give ethyl (2,6-diisopropylphenoxysulfonyl)acetate. The ethyl acetate derivative was hydrolyzed to 2,6-diisopropylphenoxysulfonyl acetic acid. The acetic acid derivative was reacted with dodecylamine and DCC according to Example I(B) to provide 2,6-diisopropylphenyl N-dodecylcarbamoylmethylsulfonate, mp 75°-78° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:7]([O:16]C(OC(C)(C)C)=O)[C:6]([C:24]([F:27])([F:26])[F:25])=[CH:5][CH:4]=1.[Cl:28][C:29]1[N:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[N:34]=[CH:33][C:32]([O:35][CH2:2][C:3]2[C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])=[C:7]([OH:16])[C:6]([C:24]([F:25])([F:26])[F:27])=[CH:5][CH:4]=2)=[CH:31][CH:30]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)c1c(COc2ccc(Cl)nc2)ccc(C(F)(F)F)c1O
Yield: 84 %

Procedure:
According to a method similar to Example (2-3) and Example (33-5), from tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (6.22 g, 13.7 mmol) obtained in Example (28-5) and 6-chloro-3-pyridinol (1.77 g, 13.7 mmol), tert-butyl 6-{[(6-chloro-3-pyridinyl)oxy]methyl}-2-hydroxy-3-(trifluoromethyl)benzoate was obtained (4.61 g, two-step total yield: 84%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([C:12]1[CH:13]=[C:14]([CH:33]=[C:34]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:35]=1[OH:36])[CH:15]=[C:16]1[C:21](=[O:22])[N:20]([CH2:23][C:24]2[NH:28][N:27]=[N:26][N:25]=2)[C:19]2[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=2[S:17]1)([CH3:11])([CH3:10])[CH3:9].Cl>C(N(CC)CC)C>[C:1]([O:36][C:35]1[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:13][C:14]([CH:15]=[C:16]2[C:21](=[O:22])[N:20]([CH2:23][C:24]3[NH:28][N:27]=[N:26][N:25]=3)[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[S:17]2)=[CH:33][C:34]=1[C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=C2Sc3ccccc3N(Cc3nnn[nH]3)C2=O)cc(C(C)(C)C)c1O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1c(C(C)(C)C)cc(C=C2Sc3ccccc3N(Cc3nnn[nH]3)C2=O)cc1C(C)(C)C

Procedure:
Acetic anhydride (5.8 ml) and triethylamine (2.1 ml) were added to 2-(3,5-di-tert.-butyl-4-hydroxybenzylidene)-3,4-dihydro-3-oxo-4-(1H-tetrazol-5-ylmethyl)-2H-1,4-benzothiazine (compound No. 2-1, 0.32 g) and the mixture was refluxed overnight. To the mixture, dilute hydrochloric acid was added and the whole was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue was purified by silica gel column chromatography to give the titled compound.
Reaction SMILES: [OH-].[Y+3:2].[OH-].[OH-].[N+:5]([O-:8])([OH:7])=[O:6]>O>[N+:5]([O-:8])([O-:7])=[O:6].[Y+3:2].[N+:5]([O-:8])([O-:7])=[O:6].[N+:5]([O-:8])([O-:7])=[O:6]
Reactant: O=[N+]([O-])O
Agent: [OH-]
Agent: [Y+3]
Solvent: O
Product: O=[N+]([O-])[O-]

Procedure:
An approximately 1M solution of yttrium nitrate was prepared by stirring 28 g of yttrium hydroxide in 200 ml water and adding concentrated nitric acid dropwise until the solid yttrium hydroxide just dissolved.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[OH:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.[OH-].[K+].Cl>CS(C)=O>[N+:14]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:21]1[CH:22]=[CH:23][C:18](=[O:17])[CH:19]=[CH:20]1)[NH:9][C:8](=[O:12])[C:7](=[O:13])[NH:6]2)([O-:16])=[O:15]
Reactant: Oc1ccncc1
Reactant: O=c1[nH]c2cc(F)c([N+](=O)[O-])cc2[nH]c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=c1ccn(-c2cc3[nH]c(=O)c(=O)[nH]c3cc2[N+](=O)[O-])cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 62.9 %

Procedure:
First, 9.007 g of 7-fluoro-6-nitro-1,4-dihydroquinoxaline-2,3-dione, 7.611 g of 4-hydroxypyridine, and 5.219 g of powdered potassium hydroxide were added to 120 ml of dry dimethylsulfoxide. The mixture was stirred at 130° C. for 2 hours in a nitrogen atmosphere. Then, 50 ml of ice water and 30 ml of 4N hydrochloric acid were added to the reaction mixture so as to make it weakly acidic (pH 3 to 4). The resultant yellow precipitate was filtered and washed with water. The precipitate was dissolved by heating in a mixture containing 560 ml of water and 56 ml of conc. aqueous ammonia. One gram of activated carbon was added to the resultant mixture, stirred, and filtered. The filtrate was neutralized with conc. hydrochloric acid and ice-cooled. The precipitated crystals were then filtered and washed with water, methanol, and ethanol, successively. The resultant crystals were dried to give 7.56 g of 6-nitro-7-(4-oxo-4H-pyridin-1-yl)-1,4-dihydroquinoxaline-2,3-dione (hereinafter, abbreviated as Ia).
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@@H:17]([C:29]#[N:30])[C@:18]5([OH:28])[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C([C@@H]1C2[C@](C)(CCC(=[O:51])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[OH:28][C@:18]12[CH2:19][C:20](=[O:51])[CH2:21][CH2:22][C@:23]1([CH3:24])[C@@H:25]1[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]1)([CH3:5])[C:3](=[O:12])[CH2:8][CH2:7]3)[CH2:16][C@H:17]2[C:29]#[N:30]
Reactant: C[C@]12CC[C@H]3[C@@H](C[C@@H](C#N)[C@@]4(O)CCCC[C@]34C)[C@@H]1CC13OCCOC12OCCO3
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C[C@]12CC[C@H]3[C@@H](C[C@@H](C#N)[C@@]4(O)CC(=O)CC[C@]34C)[C@@H]1CCC2=O
Yield: 82 %

Procedure:
The title compound II-ai was prepared in 82% yield from 3,3:17,17-bis(ethylendioxy)-5α-hydroxy-6β-cyanoandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The crude product was purified by flash chromatography (SiO2, n-hexane/CH2Cl2/acetone 60/20/20) to give the title compound II-ae. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 4.27 (s, 1H), 3.21 (d, 1H), 2.92 (m, 1H), 2.62-1.24 (m, 18H), 1.50 (s, 3H), 0.93 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:3][C:4]([OH:6])=O.[CH3:18][CH2:19]OCC.C([Li])C.Cl>C1C=CC=CC=1>[CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:3][C:4](=[O:6])[CH2:18][CH3:19]
Reactant: CCOCC
Reactant: CC(C)=CCCC(C)CC=CC(C)=CC(=O)O
Agent: Cl
Agent: [Li]CC
Solvent: c1ccccc1
Product: CCC(=O)C=C(C)C=CCC(C)CCC=C(C)C
Reaction time: 3 h

Procedure:
To a stirred solution of 2.4 g. of 3,7,11-trimethyldodeca-2,4,10-trienoic acid in 20 ml. of dry ether is added slowly, at 0°, 23 ml. of a one molar solution of ethyl lithium in benzene. After about 3 hours at 20°, the mixture is poured into iced 1N hydrochloric acid (100 ml.) with vigorous stirring. The ether layer is separated, combined with ethereal washings of the aqueous phase, washed with water, saturated potassium bicarbonate and then saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to yield 5,9,13-trimethyltetradeca-4,6,12-trien-3-one, which can be purified by chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]([O:8][CH3:9])([CH3:7])[CH:4]([OH:6])[CH3:5]>CC(=O)CC>[CH3:1][O:2][C:3]([O:8][CH3:9])([CH3:7])[C:4](=[O:6])[CH3:5]
Reactant: COC(C)(OC)C(C)O
Solvent: CCC(C)=O
Product: COC(C)(OC)C(C)=O

Procedure:
Advantageous starting materials of the formula II are also compounds in which X is 2 alkoxy groups. These can be obtained very advantageously, even industrially, by the electrochemical process described in EP 460 451 B1. Thus, for example, 3,3-dimethoxy-2-butanol, which is particularly suitable for the preparation of diacetyl, is obtained by this process from 2-butanone (methyl ethyl ketone) in a selectivity of 70% of theory (cf. Example 1A). From this, the novel process can be used to obtain 3,3-dimethoxy-2-butanone in yields above 90% (cf. Example 1B), which can be converted into diacetyl by alkaline or, preferably, acidic hydrolysis in a manner known per se in virtually quantitative yield. This is therefore a very advantageous overall process for the preparation of diacetyl from the readily available methyl ethyl ketone.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][C:19]([C:22]4[CH:23]=[C:24]([CH:39]=[CH:40][CH:41]=4)[CH2:25][N:26]([CH3:38])[C:27](=[O:37])[CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[N:4][CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1>ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[C:3]([N:10]2[CH2:11][CH2:12][N:13]([C:16]3[N:17]=[CH:18][C:19]([C:22]4[CH:23]=[C:24]([CH:39]=[CH:40][CH:41]=4)[CH2:25][N:26]([CH3:38])[C:27](=[O:37])[CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[CH:20][N:21]=3)[CH2:14][CH2:15]2)=[N:4][CH:5]=[C:6]([CH:8]=[O:9])[CH:7]=1
Reactant: CN(Cc1cccc(-c2cnc(N3CCN(c4ncc(CO)cc4Cl)CC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CN(Cc1cccc(-c2cnc(N3CCN(c4ncc(C=O)cc4Cl)CC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.9 %

Procedure:
tert-Butyl (2-{[3-(2-{4-[3-chloro-5-(hydroxymethyl)pyridin-2-yl]piperazin-1-yl}pyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (288 mg) was dissolved in dichloromethane (8 ml), and manganese dioxide (1.16 g) was added thereto, followed by stirring at room temperature for 1.5 hours. Manganese dioxide (220 mg) was added thereto, followed by additionally stirring at room temperature for 1 hour. The reaction mixture was filtered using Celite as a filtration assistant, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH=100/0 to 96/4) to obtain tert-butyl {2-[(3-{2-[4-(3-chloro-5-formylpyridin-2-yl)piperazin-1-yl]pyrimidin-5-yl}benzyl)(methyl)amino]-2-oxoethyl}carbamate (235 mg).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH:11]([N:13]([CH2:15][CH2:16][CH2:17][P:18](=[O:21])([OH:20])[OH:19])[OH:14])=[O:12].[OH-].[Na+]>CC(C)=O.O>[C:1]([O:14][N:13]([CH2:15][CH2:16][CH2:17][P:18](=[O:20])([OH:19])[OH:21])[CH:11]=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CN(O)CCCP(=O)(O)O
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=CN(CCCP(=O)(O)O)OC(=O)c1ccccc1
Reaction time: 0.17 h
Yield: 48.2 %

Procedure:
A solution of benzoyl chloride (700 mg) in dry acetone (6 ml) was added dropwise to a solution of sodium salt of 3-(N-formyl-N-hydroxyamino)propylphosphonic acid (820 mg) in a mixture of water (15 ml) and acetone (15 ml) under ice-cooling, while stirring. During this period, pH of the mixture was kept at around 7.5-7.7 with 1 N aqueous sodium hydroxide solution. The stirring was continued at the same temperature for 10 minutes and then acetone was evaporated under reduced pressure. The resulting aqueous solution was adjusted to pH 3.5 with 1N hydrochloric acid and ether (40 ml) was added thereto. After removal of the precipitated impurities, the aqueous layer was adjusted to pH 1.6 with 1N hydrochloric acid and extracted three times with ethyl acetate (50 ml, 20 ml×2). The combined ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness to give crystals, which were washed with ether to give crystalline 3-(N-benzoyloxy-N-formylamino)propylphosphonic acid (620 mg). Mp 149°-153° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[C:6]=2[CH:17]=1.[C:18]1([CH3:32])[CH:23]=[CH:22][C:21]([N:24]2[C:28](B(O)O)=[CH:27][CH:26]=[N:25]2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[C:13]1([CH3:16])[CH:14]=[CH:15][C:10]([N:7]2[C:6]3[CH:17]=[C:2]([C:28]4[N:24]([C:21]5[CH:22]=[CH:23][C:18]([CH3:32])=[CH:19][CH:20]=5)[N:25]=[CH:26][CH:27]=4)[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(-n2cnc3ccc(Br)cc32)cc1
Reactant: Cc1ccc(-n2nccc2B(O)O)cc1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-n2nccc2-c2ccc3ncn(-c4ccc(C)cc4)c3c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.4 %

Procedure:
To a mixture of 6-bromo-1-p-tolyl-1H-benzo[d]imidazole (intermediate F) (100 mg, 348 μmol) and 1-p-tolyl-1H-pyrazol-5-ylboronic acid (intermediate B) (91.5 mg, 453 μmol) in 1,2-dimethoxyethane (3 ml) was added 2M sodium carbonate solution (696 μl, 1.39 mmol) and the reaction mixture was purged with argon for 10 min in an ultrasonic bath. To the stirred mixture tetrakis(triphenylphosphine)palladium(0) (80.5 mg, 69.6 μmol) was added at room temperature and the reaction mixture was allowed to stir under reflux conditions for 15 h. The reaction mixture was cooled to room temperature, poured into water (20 ml) and extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with brine (1×20 ml), dried (MgSO4) and evaporated. The crude material (200 mg) was purified by flash chromatography on silica gel (heptane/ethyl acetate 1:1) and trituration from diethyl ether/heptane to yield the title compound as a off-white solid (55 mg, 43%), MS (ISP) m/z=365.2 [(M+H)+], mp 165° C.
Reaction SMILES: C(OC([C@:6]1([CH:21]([CH3:23])[CH3:22])[C:19](=[O:20])[N:9]2[C@@H:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:11][CH2:12][C@@H:8]2[CH2:7]1)=O)C.[OH-].[Na+].C1(C)C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH:21]([C@H:6]1[C:19](=[O:20])[N:9]2[C@@H:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:11][CH2:12][C@@H:8]2[CH2:7]1)([CH3:23])[CH3:22]
Reactant: CCOC(=O)[C@@]1(C(C)C)C[C@H]2CO[C@H](c3ccccc3)N2C1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)[C@@H]1C[C@H]2CO[C@H](c3ccccc3)N2C1=O
Temperature: 70 °C

Procedure:
A solution of 960 g of (3R,6R,7aS)-6-isopropyl-5-oxo-3-phenyl-tetrahydro-pyrrolo[1,2-c]oxazole-6-carboxylic acid ethyl ester in 8 L of tetrahydrofuran is treated with 3.33 L of a 2.0 M solution of sodium hydroxide at room temperature. The reaction mixture is stirred for 24 hours toluene (5.15 L) is added and the reaction pH adjusted to between 2-4 with a 10% solution of citric acid. The layers are separated and the aqueous layer saturated with sodium chloride. The aqueous layer is washed with 4 L of toluene and the organic layers combined and dried. The toluene solution is heated to reflux for 48 hours. Finally the solution is cooled to 70° C. and the toluene removed under a slight negative pressure to give (3R,6S,7aS)-6-isopropyl-3-phenyltetrahydro-pyrrolo[1,2-c]oxazol-5-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29](O)=[O:30])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].C(N1C=CN=C1)([N:35]1C=CN=C1)=O.[OH-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3](=[O:32])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29](=[O:30])[NH2:35])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2C(=O)O)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2C(N)=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(2,6-dichlorobenzoyl)-4-(2-carboxyphenyl)-L-phenylalanine methyl ester (52.6 mg) was dissolved in anhydrous THF (1 mL), carbonyldiimidazole (36.1 mg) was added and the mixture was stirred at room temperature under N2 for 2 h. Ammonium hydroxide (29% aqueous solution, 135 μL) was added and the mixture was stirred for an additional 22 h. The mixture was then extracted with EtOAc. The extract was washed with 1N HCl, sat. NaHCO3 and brine, dried (MgSO4) and evaporated. The residue was purified through a silica gel column using toluene/EtOAc (1:1) as an eluent to give N-(2,6-dichlorobenzoyl)-4-(2-carbamoylphenyl)-L-phenylalanine methyl ester (48.1 mg. ESMS: m/z 471 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([O:20][CH3:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22]>CCOC(C)=O>[ClH:22].[CH3:21][O:20][C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: COC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC1(c2ccccc2)CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the ester from step (b) above (8.6g) and saturated solution of hydrogen chloride in EtOAc (100 mL) was stirred at room temperature for 1 h. The solvent was removed in vacuo and the residue was washed with EtOAc, and dried in vacuo to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 192 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]1[CH2:19][S:16](=[O:18])(=[O:17])[O:15][CH2:14]1>CC(C)=O>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:14][CH2:13][CH2:19][S:16]([OH:18])(=[O:17])=[O:15])[CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S1(=O)CCCO1
Reactant: C1=C(c2ccccc2)CCNC1
Solvent: CC(C)=O
Product: O=S(=O)(O)CCCN1CC=C(c2ccccc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-phenyl-1,2,3,6-tetrahydropyridine (1.95 g, 12.2 mmol) in acetone (20 mL) was added 1,3-propane sultone (1.66 g, 13.5 mmol). The mixture was stirred at reflux for 2 h. The resulting suspension was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. The product was suspended in 50% MeOH/acetone (75 mL). The suspension was stirred at reflux for 5 min. The solid material was filtered and washed with acetone (2×25 μL). This allowed the isolation of compound O, 1.74 g (51%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:12])=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C(O)C>[CH2:10]([O:9][C:7]([C:6]1[CH:5]=[C:4]([CH3:12])[S:3][C:2]=1[NH:1][CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:8])[CH3:11]
Reactant: CCOC(=O)c1cc(C)sc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=CNc1sc(C)cc1C(=O)OCC)C(=O)OCC
Temperature: 110 °C

Procedure:
A mixture of 3.7 parts of ethyl 2-amino-5-methylthiophene-3-carboxylate and 4.4 parts of diethyl ethoxymethylenemalonate is heated at 110° C for 1.5 hour. After cooling ethanol is added and the crystals are collected by filtration, whereby diethyl (3-ethoxycarbonyl-5-methylthienyl)aminomethylenemalonate is obtained as crystals. Recrystallization from ethanol gives pale yellow needles melting at 67°-68° C