Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]1=[N:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+].[Br:21][CH2:22][CH2:23]Br.O>CN(C)C=O>[CH3:1][O:2][N:3]=[C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]1=[N:13][O:14][CH2:23][CH2:22][Br:21]
Reactant: CON=C1C(=NO)Oc2ccccc21
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CON=C1C(=NOCCBr)Oc2ccccc21
Yield: 70.7 %

Procedure:
1 g (0.0052 mol) of benzofuran-2,3-dione 3-(O-methyloxime) 2-oxime with 1.5 g (0.0141 mol) of sodium carbonate and 3 g (0.016 mol) of 1,2-dibromoethane in 5 ml of dimethylformamide are stirred at 80° C. for 6 hours. The reaction mixture is subsequently poured into water and extracted with diethyl ether. The organic phase is washed with aqueous potassium hydroxide solution and dried over sodium sulphate. The solvent is distilled off under reduced pressure, giving 1.1 g (70.7% of theory) of crude benzofuran-2,3-dione 2-[O-(2-bromoethyl)-oxime] 3-(O-methyloxime) as a mixture of stereoisomers which is reacted further without any purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=1)[CH2:5]O.S(Cl)([Cl:19])=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=1)[CH2:5][Cl:19]
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(Br)ccc1Sc1ccccc1
Solvent: c1ccccc1
Product: ClCc1cc(Br)ccc1Sc1ccccc1
Reaction time: 1.5 h

Procedure:
445 g of 3-bromo-6-(phenylthio)-benzyl alcohol are dissolved in 800 ml of benzene and heated under reflux. 165 ml of thionyl chloride are added dropwise thereto and the mixture is boiled for a further 90 minutes. After evaporation of the solvent, there is obtained 3-bromo-6-(phenylthio)-benzyl chloride as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5](Br)=[CH:6][CH:7]=1.CO.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[C:11]1([C:5]2[N:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Nc1ccc(-c2ccccc2)nc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 86.3 %

Procedure:
To a solution of 3-amino-6-bromopyridine (1.1 g, 6.4 mmol) in THF (7 mL)-MeOH (7 mL) at RT was added phenylboronic acid (1.60 g, 12.8 mmol), PXPd (69 mg, 0.13 mmol), followed by K2CO3 (3.54 g, 25.6 mmol). The reaction mixture was stirred at 70° C. in a preheated oil bath for 16 h. After cooling to RT, the reaction mixture was poured into water (10 mL), and the resultant mixture was extracted with EtOAc (3×40 mL). The combined organic layers were washed with saturated NaCl, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by silica gel (40 g) column chromatography eluting with a gradient of EtOAc (30-100%) in hexane to give the title compound as an off-white solid (940 mg, 86%). LC/MS (method A): retention time=1.28 min, (M+H)+=171.
Reaction SMILES: [F:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:13]([OH:15])=[O:14].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1>CS(C)=O>[CH3:34][O:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][C:29]=1[O:35][CH3:36])[N:26]=[CH:25][CH:24]=[C:23]2[O:12][C:11]1[C:2]([F:1])=[C:3]2[C:8](=[CH:9][CH:10]=1)[C:7]([C:13]([OH:15])=[O:14])=[CH:6][CH:5]=[CH:4]2
Reactant: O=C(O)c1cccc2c(F)c(O)ccc12
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3ccc4c(C(=O)O)cccc4c3F)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-fluoro-6-hydroxy-1-naphthoic acid (1 g, 4.87 mmol) in DMSO (5 mL), Cs2CO3 (4.75 g, 14.61 mmol) was added in one portion. The mixture was stirred at RT 10 min. To the suspension, 4-chloro-6,7-dimethoxyquinoline (1.09 g, 4.87 mmol) was added and the mixture heated to 140° C. O/N. The mixture was allowed to cool to RT, pH adjusted to 7 and the resulting solid filtered and rinsed with water. The title compound was obtained as a tan solid.
Reaction SMILES: [CH2:1]([NH:5][C:6]([C:8]([CH:31]([CH3:33])[CH3:32])=[CH:9][CH:10]1[O:14][C:13]([CH3:16])([CH3:15])[N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]1[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:7])[CH2:2][CH2:3][CH3:4]>C1COCC1.C(Cl)(Cl)Cl.[Rh]>[CH2:1]([NH:5][C:6]([CH:8]([CH:31]([CH3:32])[CH3:33])[CH2:9][CH:10]1[O:14][C:13]([CH3:15])([CH3:16])[N:12]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH:11]1[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)C(=CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1CC1CCCCC1)C(C)C
Agent: [Rh]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCCCNC(=O)C(CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1CC1CCCCC1)C(C)C
Reaction time: 16 h
Yield: 71.8 %

Procedure:
A THF (2.03 mL) solution containing 5-[2-[(butylamino)carbonyl]-3-methyl-1-butenyl]-4-(cyclohexylmethyl)-2,2-dimethyl-3-oxazolidinecarboxylic acid, 1,1-dimethylethyl ester (236 mg, 0.51 mmol) and rhodium on alumina (24 mg, 10% by wt, 5% Rh content) was placed under a hydrogen atmosphere for 16 h. Additional rhodium on alumina (24 mg) in THF (2.03 mL) was added and the reaction continued under H2 atmosphere for 6 h. The mixture was diluted with CHCl3, filtered and concentrated in vacuo. Silica gel chromatography (3:1 to 3:2 hexane:Et2O gradient) of the concentrate afforded the title compound (171 mg, 70%). MS (ESI) m/e 465 (M-H)-MS (ESI) m/e 467 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[S:12][C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:14](OS(C(F)(F)F)(=O)=O)[N:15]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].O>COCCOC>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[C:14]1[N:15]=[C:11]([C:10]2[C:2]([CH3:1])=[N:3][N:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=23)[S:12][C:13]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1sc(-c2c(C)nn3ccccc23)nc1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1sc(-c2c(C)nn3ccccc23)nc1-c1c(F)cccc1F
Temperature: 80 °C
Reaction time: 3 h
Yield: 31.8 %

Procedure:
To a mixture of Methyl 2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-thiazole-5-carboxylate (500 mg, 1.2 mmol) obtained in Example 13-B(ii), 2,6-difluorophenylboronic acid (375 mg, 2.4 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (97 mg, 0.12 mmol) and cesium carbonate (1.2 g, 3.6 mmol) in DME (20 mL), was added water (1 mL) and the mixture was stirred at 80° C. for 3 h. The reaction mixture was allowed to cool to room temperature, and then water (100 mL) was added. The aqueous mixture was extracted with EtOAc (100 mL×2) and the combined organic layer was dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration and the filtrate was concentrated. The residue was purified by silica gel column chromatography (EtOAc) to give the title compound (147 mg, 32%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:3]=1.C([Li])CCC.CCCCCC.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29].Cl>C1COCC1>[CH2:31]([O:30][C:28](=[O:29])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:3]=1)[CH3:32]
Reactant: COCCOCc1cc(Br)ccc1OC
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(OC)c(COCCOC)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 4-bromo-1-methoxy-2-(2-methoxy-ethoxymethyl)-benzene (2.88 g, 10.5 mmol) in absolute THF (30 mL) is added at −70° C. a 1.6N solution of n-butyllithium in hexane (7.20 mL, 11.5 mmol) with stirring. After 40 min, ethyl chloroformate (1.14 g, 10.5 mmol) is added, and the mixture is stirred overnight while gradually warming up to room temperature. The mixture is poured into 2N aqueous HCl, extracted with CH2Cl2, the organic layers are dried (Na2SO4) and concentrated. The crude product is purified by flash chromatography on silica gel (hexane/AcOEt 2:1) to give the title compound as liquid. TLC, Rf (hexane/AcOEt 1:1)=0.13.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[OH-].[Na+].[CH2:9]([C:11]1([CH2:15]OS(C)(=O)=O)[CH2:14][O:13][CH2:12]1)[CH3:10].Cl>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(OCC)(=O)C>[CH2:9]([C:11]1([CH2:15][O:1][CH2:2][CH:3]([OH:4])[CH2:5][OH:6])[CH2:14][O:13][CH2:12]1)[CH3:10]
Reactant: OCC(O)CO
Reactant: CCC1(COS(C)(=O)=O)COC1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: CCC1(COCC(O)CO)COC1
Temperature: 80 °C

Procedure:
Glycerin (138 g (1.5 mol)), benzyltriethylammonium chloride (2.4 g (11 mmol)) and 96% sodium hydroxide (24 g (0.58 mol)) were added to a glass flask of an inner volume of 300 ml equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser, and the mixture was warmed to 80° C. with stirring. Subsequently 3-ethyl-3-methanesulfonyloxymethyloxetane (102 g (0.5 mol)) having a purity of 95% prepared by the same method as in Reference Example 1 was gradually dropwise added while keeping the liquid temperature at 80-85° C. After the completion of the dropwise addition, 96% sodium hydroxide (6 g (0.14 mol)) was newly added, the mixture was further reacted at the same temperature for 2 hours. After the completion of the reaction, hydrochloric acid was added to a reaction solution so that pH was adjusted to 6.5. Ethyl acetate (150 ml) was added, and a liquid separation was performed. After the liquid separation, ethyl acetate (150 ml) was added to a resultant aqueous layer to perform an extraction, and an extract (an ethyl acetate layer) was combined with an organic layer and washed with an aqueous saturated sodium bicarbonate solution (20 ml), then concentrated under reduced pressure. A resultant concentrate was distilled under reduced pressure (147° C., 400-530 Pa) to give, as a colorless liquid, 3-ethyl-3-(2,3-dihydroxypropyl)oxymethyloxetane having a purity of 93% (an analysis value by a gas chromatography) (20 g) (an isolated yield based on 3-ethyl-3-methanesulfonyloxymethyloxetane: 20%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([O:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:12]=[C:13]([CH3:15])[CH:14]=1)C1C=CC=CC=1>[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[C:11]([O:16][S:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:12]=[C:13]([CH3:15])[CH:14]=1
Reactant: Cc1cc(OCc2ccccc2)cc(OS(=O)(=O)c2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2)c1
Yield: 98.4 %

Procedure:
A mixture of benzenesulfonic acid 3-benzyloxy-5-methylphenyl ester (532 mg, 1.5 mmol), as prepared in the preceding step, and 10% palladium on carbon (200 mg) in ethanol (20 mL) was hydrogenated (balloon) overnight. The catalyst was removed by filtering over diatomaceous earth and the filtrate was evaporated in vacuo to give the title compound as a colorless syrup (390 mg, 98%). 1H-NMR (300 MHz, CDCl3 /CD3OD) δ 2.19 (s, 3H), 6.27 (s, 1H), 6.54 (s, 1H), 6.66 (s 1H), 7.43 (m, 1H), 7.55 (t, 1H), 7.70 (t, 1H), 7.85 (m, 2H).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[NH2:15][C:16]1[C:21]2=[C:22]([C:35]#[N:36])[CH:23]=[C:24]([C@@H:25]3[O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@@:26]3([CH3:34])[OH:27])[N:20]2[N:19]=[CH:18][N:17]=1.O>CCO>[NH2:15][C:16]1[C:21]2=[C:22]([C:35](=[S:2])[NH2:36])[CH:23]=[C:24]([C@@H:25]3[O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@@:26]3([CH3:34])[OH:27])[N:20]2[N:19]=[CH:18][N:17]=1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1c1cc(C#N)c2c(N)ncnn12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: CCO
Solvent: O
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1c1cc(C(N)=S)c2c(N)ncnn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
to anhydrous EtOH (30 μl) was added P2S5 (7.30 mg, 0.02 mmol) and the mixture stirred in a sealed vial for 1 h at RT. To the reaction mixture was added a solution of Compound 14 (51 mg, 0.0033 mmol) in anhydrous EtOH. (30 μl). The mixture was heated in a sealed vial at 120° C. for 3 h and then cooled to RT, whereupon water was added and the mixture extracted with DCM. The aqueous layer was concentrated to dryness and the residue purified by column chromatography silica gel (elution gradient ethyl acetate to 17% methanol in ethyl acetate) to afford Compound 21: ESI-MS m/z 340 ([M+H]+).
Reaction SMILES: C1[C:14]2[C:5](=C[C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)C=CC=1.CI.[Mg].C1[C:31]2[C:22](=C[C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)C=CC=1.[Mg].C1C2C(=CC=CC=2)C=C1.CC(CC(C)=O)=O.CC(CC(C)=O)=O.CC(CC(C)=O)=O.[Co:63]>C1COCC1>[CH:22]1([Co:63][CH:5]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:13]=[CH:14]2)[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31]1
Reactant: [Co]
Reactant: c1ccc2cc3ccccc3cc2c1
Agent: C1=Cc2ccccc2C1
Agent: [Mg]
Solvent: CI
Solvent: C1CCOC1
Solvent: CC(=O)CC(C)=O
Product: C1=CC([Co]C2C=Cc3ccccc32)c2ccccc21
Temperature: 23 °C

Procedure:
1.1 g (6.2 mMoles) of anthracene, 350 ml of THF and 0.1 ml of methyliodide are added to 14.4 g (600 mMoles) of magnesium powder (particle size <0.15 mm) in an inert gas atmosphere. A yellow-brown solution is formed while stirring at 23° C., orange-colored magnesium anthracene precipitating therefrom after 100 minutes. The reaction mixture is treated for about 3 hours in an ultrasonic bath (continuous peak HF output 240 watts, 35 kHz) and subsequently heated with stirring to 60° C. After the addition of 34.8 g (300 mMoles) of indene, the heat source is removed and 35.6 g (100 mMoles) of solid cobalt-(III)acetylacetonate are added over a period of 40 minutes. The reaction mixture changes color to dark brown with an increase in temperature to 68° C. After cooling to 23° C., the reaction mixture is filtered off from excess magnesium through a G-3-glass frit and the clear brown red filtrate is concentrated by evaporation to dryness (max. bath temperature 30° C.) in a high vacuum (10-3Torr). The residue is taken up in 500 ml of pentane and any insoluble fractions are isolated by filtration through a G-3-glass frit. The filter cake is washed several times with a total of 500 ml of pentane until the filtrate is substantially colorless. The clear red-brown filtrate is concentrated to approximately 200 ml and the complex left to crystallize out at -80° C. The supernatant mother liquor is removed under pressure and washed 2 to 3 times with approximately 50 ml of pentane cooled to -80° C. Drying in vacuo (0.1 Torr) gives 10.3 g (35 mMoles=35.5% of the theoretical) of bis-(indenyl)-cobalt in the form of glittering black crystals.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([NH:14][C@H:15]2[C@@H:19]3[O:20]C(C)(C)[O:22][C@@H:18]3[C@@H:17]([O:25][CH2:26][CH2:27][OH:28])[CH2:16]2)=[N:5][C:6]([S:10][CH2:11][CH2:12][CH3:13])=[N:7][C:8]=1[Cl:9].[N:29]([O-])=O.[Na+]>O>[Cl:9][C:8]1[C:3]2[N:2]=[N:29][N:14]([C@@H:15]3[CH2:16][C@H:17]([O:25][CH2:26][CH2:27][OH:28])[C@@H:18]([OH:22])[C@H:19]3[OH:20])[C:4]=2[N:5]=[C:6]([S:10][CH2:11][CH2:12][CH3:13])[N:7]=1
Reactant: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCCO)[C@H]3OC(C)(C)O[C@H]32)n1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCSc1nc(Cl)c2nnn([C@@H]3C[C@H](OCCO)[C@@H](O)[C@H]3O)c2n1
Yield: 80 %

Procedure:
A flask was charged with water (20 mL) and concentrated hydrochloric acid (35%, 1.5 mL). To this, 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol (5 g) was added and the mixture was stirred for clear solution. To this mixture, aqueous sodium nitrite solution (0.86 g in 5 mL) was slowly added at room temperature over a period of 15 minutes and mixture was stirred for about 30 minutes and completion of reaction was monitored by TLC. The solid obtained is isolated by filtration and washed with water (5 mL) and dried under vacuum to afford the title compound in about 80% yield.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4][C:3]=1[O:18]C.Br.[O-]S([O-])(=O)=O.[Na+].[Na+]>C(O)(=O)C>[OH:18][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[OH:1]
Reactant: COc1cc(CCCCC(=O)O)cc([N+](=O)[O-])c1O
Agent: Br
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)CCCCc1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
The above product obtained in Example 23 was dissolved in a mixture containing 500 ml of acetic acid and 500 ml of 48% hydrobromic acid and refluxed for 4 h. 1 l of saturated Na2SO4 -solution was added to the reaction mixture and the solution was allowed to stand over night at 5° C. The product crystallized was filtered and washed with 50% acetic acid. This product was recrystallized from ethyl acetate. Yield 32 g (16%), m.p. 135°-138° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][S:9][C:10]2[S:11][CH:12]=[C:13]([C:15]([OH:17])=[O:16])[N:14]=2)[C@@H:5](/[CH:18]=[CH:19]/[CH2:20][C:21](O)([CH3:29])[CH2:22][CH2:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH2:4][O:3]1.C(N(CC)CC)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.C1(C)C=CC=CC=1>O1CCCC1>[CH3:29][C@:21]1([CH2:22][CH2:23][CH2:24][C:25]([F:27])([F:26])[F:28])[O:16][C:15](=[O:17])[C:13]2[N:14]=[C:10]([S:11][CH:12]=2)[S:9][CH2:8][CH2:7][N:6]2[C@H:5]([CH2:4][O:3][C:2]2=[O:1])[CH:18]=[CH:19][CH2:20]1
Reactant: CC(O)(C/C=C/[C@H]1COC(=O)N1CCSc1nc(C(=O)O)cs1)CCCC(F)(F)F
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@]1(CCCC(F)(F)F)CC=C[C@H]2COC(=O)N2CCSc2nc(cs2)C(=O)O1

Procedure:
To a solution of the compound 45-4 (208 mg) in anhydrous tetrahydrofuran (5.0 mL) were added triethylamine (0.08 mL), 2,4,6-trichlorobenzoylchloride (0.08 mL) at 0° C. The solution was stirred for 1 Hour and then 30 minutes at room temperature. Anhydrous toluene (45.0 mL) was added to the reaction solution, which was filtrated. The obtain filtrate was added to a solution of 4-(dimethylamino)pyridine (272 mg) in anhydrous toluene (45.0 ml) with heating to reflux and the solution was allowed to return to room temperature. 1N hydrochloric acid was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (Fuji-silysia, FL60D, 75 cc, hexane:ethyl acetate=4:1) to give the title compound (less polar:83.9 mg, more polar:75.0 mg) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:11]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[N:30]=[C:31]([C@@H:34]5[CH2:38][CH2:37][CH2:36][N:35]5[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:32][CH:33]=4)=[CH:25][CH:24]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:46]([O:50][C:51]([N:53]1[CH2:57][CH2:56][CH2:55][C@H:54]1[C:58](O)=[O:59])=[O:52])([CH3:49])([CH3:48])[CH3:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[C:42]([O:41][C:39]([N:35]1[CH2:36][CH2:37][CH2:38][C@H:34]1[C:31]1[NH:32][CH:33]=[C:29]([C:26]2[CH:27]=[CH:28][C:23]([CH:11]3[N:12]([C:13]4[CH:18]=[CH:17][C:16]([C:19]([CH3:21])([CH3:22])[CH3:20])=[CH:15][CH:14]=4)[CH:8]([C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:58]([C@H:54]5[CH2:55][CH2:56][CH2:57][N:53]5[C:51]([O:50][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:52])=[O:59])=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)=[CH:24][CH:25]=2)[N:30]=1)=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(C3CCC(c4ccc(N)cc4)N3c3ccc(C(C)(C)C)cc3)cc2)c[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)Nc1ccc(C2CCC(c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)OC(C)(C)C)n4)cc3)N2c2ccc(C(C)(C)C)cc2)cc1
Yield: 58.6 %

Procedure:
The product from Example 40D (1.3 g, 2.146 mmol), (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.386 g, 6.44 mmol), HATU (1.305 g, 3.43 mmol) and Hunig's base (1.124 mL, 6.44 mmol) in DMSO (20 mL) was reacted according to the procedure in Example 39H to provide the title compound (1.01 g, 59%) as a mixture of stereoisomers.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[P:16](Cl)(Cl)[Cl:17].[Cl-].[Cl-].[Cl-].[Al+3].CC1C=CC2OC3C(=CC(C)=CC=3)PC=2C=1C(O)=O.P(Cl)(Cl)(Cl)=O>>[Cl:17][P:16]1[C:5]2[CH:6]=[C:1]([CH3:15])[CH:2]=[CH:3][C:4]=2[O:7][C:8]2[C:13]1=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2
Reactant: Cc1ccc(Oc2ccc(C)cc2)cc1
Reactant: ClP(Cl)Cl
Agent: Cc1ccc2c(c1)Pc1c(ccc(C)c1C(=O)O)O2
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc2c(c1)P(Cl)c1cc(C)ccc1O2
Yield: 59.6 %

Procedure:
From the literature, processes are already known for the production of 10-chloro-phenoxaphosphines. Freedman et al describes in J. Organ. Chem. 1961, Vol 26, 284 the conversion of p-tolyl ether with phosphorus trichloride and aluminum trichloride. After the aqueous processing, the reaction product was identified as 2,8-dimethyl-phenoxaphosphinic acid. The 2,8-dimethyl-phenoxaphosphinc acid can be converted analogously to the teaching of Hellwinkel and Krapp in Chem. Ber. 1978, Vol 111, 13 for dibenzophosphoric acid by reaction with phosphorus oxychloride at 200° C. and subsequent reaction with red phosphorus at 180° C. to form 10-chloro-2,8-dimethylphenoxaphosphine. The synthesis from ether is thus a three-stage synthesis and the total yield is 59.6% over all stages. Thus, an economical production of the compound is not possible.
Reaction SMILES: [O:1]([CH2:8][C:9]#[N:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COCCO[AlH2-]OCCOC.[Na+].C[Si]([C:27]#[N:28])(C)C>C1(C)C=CC=CC=1>[NH2:10][CH:9]([CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:27]#[N:28]
Reactant: N#CCOc1ccccc1
Reactant: C[Si](C)(C)C#N
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CC(N)COc1ccccc1
Temperature: 0 °C
Yield: 20 %

Procedure:
10 millimoles (1.33 g) of phenoxyacetonitrile are dissolved in 10 ml of anhydrous toluene at 0° C., under an argon atmosphere. A solution of vitride (NaH2Al[O-CH2 -CH2OCH3 ]2) at 70% in toluene (1,4 ml viz 0.5 eq) in 3 ml of anhydrous toluene is added, dropwise, at this temperature. The stirring is maintained for 1 hour at 0° C., then 2 ml (1.5 eq) of trimethylsilyl cyanide are added. The reaction mixture is maintained at room temperature for 3 hours, while stirring, then hydrolyzed by usual way. After purification by acid base extraction, there are obtained 0.300 g of -2-amino-3-phenoxy propionitrile with a yield of 20%.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:14](=O)[C:15](Cl)=[O:16])=[CH:9][N:10]2[CH3:13])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].Cl.C([O:23][C:24](=[NH:38])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][C:31]([O:35][CH3:36])=[CH:32][CH:33]=2)[N:28]([CH3:37])[CH:27]=1)(C)C>>[N:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:14]3[C:15](=[O:16])[NH:38][C:24](=[O:23])[C:25]=3[C:26]3[C:34]4[C:29](=[CH:30][C:31]([O:35][CH3:36])=[CH:32][CH:33]=4)[N:28]([CH3:37])[CH:27]=3)=[CH:9][N:10]2[CH3:13])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: Cn1cc(C(=O)C(=O)Cl)c2ccc(N=[N+]=[N-])cc21
Reactant: COc1ccc2c(CC(=N)OC(C)C)cn(C)c2c1
Agent: Cl
Product: COc1ccc2c(C3=C(c4cn(C)c5cc(N=[N+]=[N-])ccc45)C(=O)NC3=O)cn(C)c2c1

Procedure:
3-(6-Azido-1-methyl-1H-indol-3-yl)-4-(6-methoxy-1-methyl-1H-indol-3-yl)-pyrrole-2,5,-dione was prepared from (6-azido-1-methyl-1H-indol-3-yl)-oxo-acetyl chloride and 2-(6-methoxy-1-methyl-1H-indol-3-yl)-acetimidic acid isopropyl ester hydrochloride.