Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].B.[Na].C(O)(=O)C>O1CCCC1.O.[OH-].[Na+]>[CH3:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: Cc1ccc(-c2ccccc2)cc1C=O
Agent: B
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(-c2ccccc2)cc1CO
Temperature: 17.5 °C
Reaction time: 4 h

Procedure:
123 g (625 mmol) of 2-methyl-5-phenylbenzaldehyde was dissolved in a mixture of 1.1 L of tetrahydrofuran and 110 ml of water, and to the resulted solution was dropped, at 15 to 20° C., a solution prepared by dissolving 7.7 g (203 mmol) of sodium boron hydride in 70 ml of a 0.1 wt % sodium hydroxide aqueous solution. After completion of dropping, the mixture was stirred for 4 hours at 15 to 20° C. To this reaction solution was dropped 10 g of glacial acetic acid at 20° C. or lower, and this was poured into ice water. The reaction solution was extracted with t-butyl methyl ether, the organic layer was washed with water, saturated sodium bicarbonate solution, then, saturated saline, dried over anhydrous magnesium sulfate, then, concentrated to obtain 121 of 2-methyl-5-phenylbenzyl alcohol.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:7]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:23]=[C:24]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)[CH:25]=[CH:26][CH:27]=3)=[CH:16][CH:15]=2)[CH2:8][C:9]([O:11]CC)=[O:10])[S:5][CH:6]=1>CO.C1COCC1.O>[CH3:1][C:2]1[N:3]=[C:4]([CH:7]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]3[CH:23]=[C:24]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:33]=4)[CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:19]=2)[CH2:8][C:9]([OH:11])=[O:10])[S:5][CH:6]=1
Reactant: CCOC(=O)CC(c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1)c1nc(C)cs1
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1csc(C(CC(=O)O)c2ccc(OCc3cccc(-c4ccc(C(F)(F)F)cc4)c3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
Compound 51.3 (50 mg, 0.1 mmol) was dissolved in MeOH/THF/H2O (1:1:1, 3 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to PH=4 and extracted with dichloromethane (3 mL×3). The product was purified on reverse phase HPLC to yield compound 51 (40 mg). MS ESI (pos.) m/e: 498 (M+H). 1H NMR (400 MHz) (DMSO) δ 7.92 (2H, d, J=8.1 Hz); 7.84 (3H, d, J=8.8 Hz); 7.71 (1H, t, J=5.1 Hz); 7.54 (2H, d, J=7 Hz); 7.29 (2H, d, J=8.7 Hz); 7.09 (1H, s); 7.01 (2H, d, J=8.7 Hz); 5.18 (2H, s); 4.66 (1H, m); 3.2 (1H, m); 2.93 (1H, m); 2.33 (3H, s).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].[CH:19]12[CH2:26][CH2:25][CH:22]([CH:23]=[CH:24]1)[CH:21]1[C:27]([O:29][C:30](=O)[CH:20]21)=[O:28]>O>[C:10]([CH:2]([N:1]1[C:27](=[O:28])[CH:21]2[CH:20]([CH:19]3[CH2:26][CH2:25][CH:22]2[CH:23]=[CH:24]3)[C:30]1=[O:29])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([OH:12])=[O:11]
Reactant: O=C1OC(=O)C2C3C=CC(CC3)C12
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)C(Cc1ccccc1)N1C(=O)C2C3C=CC(CC3)C2C1=O
Temperature: 25 °C
Yield: 58 %

Procedure:
To a suspension of L-phenylalanine (502 mg, 3.0 mmol) in H2O (15 mL) was added a solution of K2CO3 (252 mg, 1.8 mmol) in H2O (3 mL) and the mixture was stirred until a homogeneous solution was obtained. Bicyclo[2.2.2]oct-5-en-2,3-dicarboxylic anhydride (452 mg, 2.5 mmol) was added and the mixture was heated to reflux temperature and allowed to react for 19 hrs. After cooling to room temperature, the reaction mixture was washed with EtOAc and acidified with conc. HCl until the pH reached 1. The aqueous phase was extracted with EtOAc and the organic phase washed with 5% HCl followed by brine and then dried over Na2SO4. Removal of the solvent gave a colorless solid which was recrystallized from EtOAc/hexane to yield the pure product as colorless crystals: 475 mg (58% yield), mp=161° C.
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][C:7]1[CH:12]=[C:11](Br)[CH:10]=[C:9]([CH3:14])[C:8]=1[O:15][CH3:16].I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C1COCC1.[Cl-].[Zn+2].[Cl-]>[CH3:6][C:7]1[CH:12]=[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=[C:9]([CH3:14])[C:8]=1[O:15][CH3:16]
Reactant: Ic1ccccc1
Reactant: COc1c(C)cc(Br)cc1C
Agent: Cl
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1c(C)cc(-c2ccccc2)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
T-butyllithium (1.3M in pentane, 17.9 ml, 23.2 mmol) was added slowly to a solution of 2,6-dimethyl-4-bromo-methoxybenzene (2.5 g, 11.6 mmol) in anhydrous THF (50 ml) at −78° C. under an atmosphere of argon, then after 1 hour a solution of anhydrous zinc chloride (1.6 g, 11.7 mmol) in THF (40 ml) was added by cannula and the clear solution allowed to warm to room temperature and stir for 1 hr. This solution was then added by cannula to iodobenzene (2.37 g, 11.6 mmol) and bis(triphenylphosphine)palladium (II)chloride (81 mg, 116 μmol) in THF (40 ml) and allowed to stir overnight. The reaction was added to 1N HCl (150 ml) and extracted into dichloromethane (2×300 ml). The organic phase was washed with water (150 ml), brine (150 ml) and dried (Na2SO4). The crude product was concentrated and purified by chromatography on silica gel (100 g), eluent 10% dichloromethanelhexanes to give 2,6-dimethyl-4-phenyl-methoxybenzene (2.11 g, 9.9 mmol) in 86% yield. 1H nmr (CDCl3): δ=7.6-7.2 (m, 7H); 3.78 (s, 3H) and 2.37 (s, 6H). Boron tribromide (4.72 g, 19 mmol) was added dropwise to a solution of 2,6-dimethyl-4-phenyl-methoxybenzene (2.35 g, 11.1 mmol) in dichloromethane (45 ml) at −78° C. under argon, then the solution was allowed to warm to room temperature overnight. Ice/water (75 g) was added to quench the reaction, then the reaction was extracted with dichloromethane (2×200 ml). The organic layer was washed with water (50 ml), brine (50 ml) and dried (Na2SO4). Removal of the solvent gave 2,6-dimethyl-4-phenyl-phenol (2.15 g, 10.8 mmol) in 98% yield as a white solid, a single component by TLC Rf (0.13) eluent 4:1 dichloromethane/hexanes and 1H nmr. 1H nmr (CDCl3): δ=7.6-7.2 (m, 7H); 4.70 (s, 1H) and 2.37 (m, 6H).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:17])[C:6]2[C:14](=[CH:15][CH:16]=1)[C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH:7]=2)(=[O:3])[CH3:2].[Se](=O)=[O:19]>O1CCOCC1>[C:5]1(=[O:17])[C:6]2[C:14]([C:13]3[C:8]([CH:7]=2)=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:15][CH:16]=[C:4]1[C:1](=[O:3])[CH:2]=[O:19]
Reactant: O=[Se]=O
Reactant: CC(=O)C1=CC=C2C(=Cc3ccccc32)C1=O
Solvent: C1COCCO1
Product: O=CC(=O)C1=CC=C2C(=Cc3ccccc32)C1=O

Procedure:
The thus-isolated 2-acetylfluorenon is oxidized by selenium dioxide in dioxane medium at 98°-100° C during 22 hours to obtain 2-fluorenonyl-glyoxal isolated as semiacetal, the yield being equal to 31.2 weight percent. The thus-obtained intermediate product is subjected to treatment with sodium bisulfite in 60-percent ethanol to obtain the final product crystallizable with a molecule of water. The yield of the final product amounts to 57 weight percent when calculated for the semiacetal of 2-fluorenonyl-glyoxal and to 55 weight percent when calculated for the parent fluorene (of.Sintez organicheskikh preparatov/synthesis of organic preparations/, v.4, P.77, 1953 /in Russian/; Zhurnal organicheskoy khimii /Journal of organic chemistry/, 33, 3053, 1963 (in Russian).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[C:4](F)[CH:3]=1.[C-:15]#[N:16].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[C:4]([C:15]#[N:16])[CH:3]=1
Reactant: [C-]#N
Reactant: CN(C)S(=O)(=O)c1ccc(Br)cc1F
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)c1ccc(Br)cc1C#N
Yield: 7.1 %

Procedure:
4-Bromo-2-fluoro-N,N-dimethylbenzenesulfonamide (1.0 g, 3.5 mmol) and sodium cyanide (350 mg, 7.1 mmol) were dissolved in DMF (3 mL) and irradiated in the microwave at 150° C. for 20 minutes. DMF was removed in vacuo and the residue was redissolved in dichloromethane (5 mL). The organics were washed with 5 mL of each 1N aqueous HCl, saturated aqueous NaHCO3, and brine. Organics were dried over Na2SO4 and evaporated to dryness. Crude product was purified by chromatography on silica gel (eluting with 0-50% ethyl acetate in hexanes) to afford 4-bromo-2-cyano-N,N-dimethylbenzenesulfonamide (72 mg, 7%). ESI-MS m/z calc. 288.0. found 288.9 (M+1)+; retention time 1.44 minutes.
Reaction SMILES: OC1C(C2C=CC=CC=2)=CC(C(CC(C)(C)C)(C)C)=CC=1N=NC1C=CC(C2C=CC=CC=2)=CC=1[N+]([O-])=O.[OH-].[Na+].S([O-])(O)(=O)=O.[C:46]1([C:52]2[CH:57]=[CH:56][C:55]([N+:58]#[N:59])=[C:54]([N+:60]([O-:62])=[O:61])[CH:53]=2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[C:63]([C:72]1[CH:77]=[C:76]([C:78]([CH2:81][C:82]([CH3:85])([CH3:84])[CH3:83])([CH3:80])[CH3:79])[CH:75]=[CH:74][C:73]=1[OH:86])([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)([CH3:65])[CH3:64]>CO>[OH:86][C:73]1[C:72]([C:63]([C:66]2[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=2)([CH3:65])[CH3:64])=[CH:77][C:76]([C:78]([CH2:81][C:82]([CH3:85])([CH3:84])[CH3:83])([CH3:80])[CH3:79])=[CH:75][C:74]=1[N:59]=[N:58][C:55]1[CH:56]=[CH:57][C:52]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[CH:53][C:54]=1[N+:60]([O-:62])=[O:61]
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(C(C)(C)c2ccccc2)c1
Reactant: N#[N+]c1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Agent: CC(C)(C)CC(C)(C)c1cc(N=Nc2ccc(-c3ccccc3)cc2[N+](=O)[O-])c(O)c(-c2ccccc2)c1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)CC(C)(C)c1cc(N=Nc2ccc(-c3ccccc3)cc2[N+](=O)[O-])c(O)c(C(C)(C)c2ccccc2)c1

Procedure:
The procedure of Example 1 (D) is followed using sodium hydroxide (4 g, 0.1 mol), methanol (100 mL), 4-phenyl-2-nitrobenzenediazonium hydrogen sulfate (16 g, 0.034 mol) and 2-α-cumyl-4-tert-octylphenol (8.1 g, 0.028 mol) to give the title compound as a dark red solid melting at 176–179° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:31])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:22][CH2:21][CH2:20][C:19]3[N:18](S(C(F)(F)F)(=O)=O)[N:17]=[CH:16][C:15]2=3)[C:10]1=[O:30].ClC1C=C(OS(C(F)(F)F)(=O)=O)C=C(Cl)C=1C[C@@H]1CCN(C2CCCC3C2=CN(S(C(F)(F)F)(=O)=O)N=3)C1=O.[F:79][C:80]1[CH:85]=[CH:84][C:83](B(O)O)=[CH:82][CH:81]=1.C(=O)([O-])[O-].[Na+].[Na+].[Li+].[OH-]>C1COCC1.O.C(OCC)(=O)C.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>[Cl:1][C:2]1[CH:3]=[C:4]([C:83]2[CH:84]=[CH:85][C:80]([F:79])=[CH:81][CH:82]=2)[CH:5]=[C:6]([Cl:31])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:22][CH2:21][CH2:20][C:19]3[NH:18][N:17]=[CH:16][C:15]2=3)[C:10]1=[O:30]
Reactant: O=C1[C@H](Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCCc2c1cnn2S(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccc(F)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: O=C1[C@H](Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCCc2nn(S(=O)(=O)C(F)(F)F)cc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1[C@H](Cc2c(Cl)cc(-c3ccc(F)cc3)cc2Cl)CCN1C1CCCc2[nH]ncc21
Temperature: 80 °C

Procedure:
A mixture of trifluoro-methanesulfonic acid 3,5-dichloro-4-[(R)-2-oxo-1-(1-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)-pyrrolidin-3-ylmethyl]-phenyl ester and trifluoro-methanesulfonic acid 3,5-dichloro-4-[(R)-2-oxo-1-(2-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-2H-indazol-4-yl)-pyrrolidin-3-ylmethyl]-phenyl ester, Preparation 73, (0.49 g, 0.76 mmol), 4-fluorophenylboronic acid (0.13 g, 0.91 mmol), sodium carbonate (0.24 g, 2.28 mmol) in THF (20 mL) and water (6 mL) is brought to 60° C. To the mixture at 60° C., add Pd(PPh3)4 (0.044 g, 0.038 mmol). Raise the reaction temperature to 80° C. and stir the reaction for 1 hour. Cool the reaction, dilute with ethyl acetate and wash with water and brine. Dry the organic layer (Na2SO4) and remove the solvent in vacuo to afford crude product (0.45 g). Dissolve in THF (5 mL) and LiOH (2 N, 5 mL) and stir at room temperature for 1 hour. Quench the reaction with HCl (1N, 8 mL) and dilute with ethyl acetate and washed with water. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify on silica gel column with 50% ethyl acetate in hexanes to 100% ethyl acetate to afford 0.25 g of the title product. MS (m/z): 458 (M+). Separate the two component mixture into individual enantiomers via preparative chiral chromatography (Chiralpak AD, 5×15 cm, 60/40 ethanol/heptane/0.2% DMEA, flow=40 mL/min, 260 nm). The analytical conditions are as follows: Chiralpak AD-H, 4.6×150 mm, 60/40 ethanol/heptane/0.2% DMEA, flow=0.6 mL/min, 260 nm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].Br[C:17]1[CH:18]=[C:19]([CH2:23][OH:24])[CH:20]=[N:21][CH:22]=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.C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:17]2[CH:22]=[N:21][CH:20]=[C:19]([CH:18]=2)[CH2:23][OH:24])=[CH:4][CH:3]=1
Reactant: OCc1cncc(Br)c1
Reactant: OB(O)c1ccc(F)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: Cc1ccccc1
Solvent: O
Product: OCc1cncc(-c2ccc(F)cc2)c1
Reaction time: 2 h

Procedure:
13.2 g of 4-fluorobenzeneboronic acid and 10.8 g of sodium hydrogen-carbonate are initially introduced, and a mixture of 16.1 g of 5-bromo-3-hydroxymethylpyridine, 30 ml of water and 60 ml of toluene is added with stirring and under a protective gas. A further 14 ml of water, 28 ml of toluene and 0.5 g of tetrakis(triphenylphosphine)palladium(0) are subsequently added. The reaction mixture is heated to reflux and held at this temperature for 2 hours. After cooling, the mixture is subjected to conventional work-up, giving 5-(4-fluorophenyl)nicotinyl alcohol. The alcohol is subsequently oxidized by conventional methods to give 5-(4-fluorophenyl)nicotinic acid.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].[C:7]([CH2:9][OH:10])#[N:8].C(N(CC)CC)C>C(COC)OC>[C:7]([CH2:9][O:10][C:3](=[O:4])[CH:2]([Br:1])[CH3:6])#[N:8]
Reactant: N#CCO
Reactant: CC(Br)C(=O)Br
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CC(Br)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.7 %

Procedure:
215.9 g (1 mole) of α-bromopropionyl bromide are dissolved in 500 ml of dimethoxy ethane and to the resulting solution are slowly added 62.8 g (1.1 moles) of cyanomethanol at 10° C. Then 111.3 g (1.1 moles) of triethylamine are added dropwise at 10°-20° C. The reaction mixture is stirred for 10 minutes at room temperature and filtered over hyflo. The filtrate is concentrated and the residue is distilled in a water jet vacuum, yielding as main fraction 107 g (55.7%) of α-bromopropionic acid cyanomethyl ester with a boiling point of 109° C./17 torr and having the formula ##STR6##
Reaction SMILES: C(O[CH:4]=[N:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[F:13])C.Cl[C:15]1[CH:28]=[C:27]([Cl:29])[C:26]([F:30])=[CH:25][C:16]=1[C:17]([CH2:19][C:20]([O:22]CC)=[O:21])=[O:18].[O-2].[Mg+2].Cl>C(OCCO)CCC.O.C(O)C>[F:13][C:7]1[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=1[N:5]1[C:15]2[C:16](=[CH:25][C:26]([F:30])=[C:27]([Cl:29])[CH:28]=2)[C:17](=[O:18])[C:19]([C:20]([OH:22])=[O:21])=[CH:4]1
Reactant: CCOC(=O)CC(=O)c1cc(F)c(Cl)cc1Cl
Reactant: CCOC=Nc1ccc(F)cc1F
Agent: Cl
Agent: [Mg+2]
Agent: [O-2]
Solvent: CCO
Solvent: O
Solvent: CCCCOCCO
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(Cl)c(F)cc2c1=O
Temperature: 110 °C
Yield: 78.1 %

Procedure:
60 ml of ethylene glycol monobutyl ether, 37 g of N-(2,4-difluorophenyl)-formimino ethyl ether and 50 g of ethyl 2,4-dichloro-5-fluoro-benzoylacetate were heated at 60° to 65° C. for 5 hours. Ethanol and a little solvent were stripped off under 20 mbar. The mixture was then diluted with 150 ml of ethylene glycol monobutyl ether, 12 g of magnesium oxide were added and the mixture was heated at 110° C. for 10 hours. For working up, the reaction mixture was poured into a mixture of 150 ml of water and 50 ml of 37% strength aqueous hydrochloric acid, heated at the boiling point for 5 hours and diluted with water and the precipitate was filtered off with suction and washed with water and 2-propanol to give 49.5 g of 99% pure N-(2,4-difluorophenyl)-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid. This corresponds to 70% of theory, based on the formimino ether employed.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.C(Cl)(=O)C(Cl)=O.[CH3:17][C@H:18]1[CH2:23][N:22]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][CH3:32])=[CH:27][C:26]=2C)[CH2:21][CH2:20][N:19]1[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C(N(CC)CC)C>ClCCl.O.CN(C)C=O>[CH3:17][C@H:18]1[CH2:23][N:22]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]([CH3:32])[C:8]([CH:5]3[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]3)=[O:10])=[CH:27][CH:26]=2)[CH2:21][CH2:20][N:19]1[C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35]
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)c(C)c1
Reactant: O=C1CCC(C(=O)O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)C3CCC(=O)CC3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
4-Oxocyclohexanecarboxylic acid (90 mg, 0.633 mmol) was dissolved in dichloromethane (5 mL), and oxalyl chloride (265 μL, 3.16 mmol) and a catalytic amount of dimethylformamide were added thereto at 0° C., and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 30 minutes. The residue obtained by distilling off the solvent in the reaction solution under reduced pressure was dissolved in dichloromethane (15 mL), and tert-butyl (2S)-2-methyl-4-[2-methyl-4-(methylamino)benzyl]piperazine-1-carboxylate (100 mg, 0.313 mmol), which is a known compound, and triethylamine (130 μL, 0.939 mmol) were added thereto at 0° C., and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. To the reaction solution, water was added at room temperature, and the organic matter was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. The obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 0:100 (v/v)), whereby the target compound was obtained as a white solid substance (44.5 mg, yield: 32%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[C:11]2[CH3:28])=[CH:4][CH:3]=1.[CH2:29]([CH:31]([CH2:35][CH3:36])[C:32](O)=[O:33])[CH3:30].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)C(C)C)C>C(Cl)Cl.O>[CH2:29]([CH:31]([CH2:35][CH3:36])[C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:12]=[C:11]2[CH3:28])=[CH:6][CH:7]=1)=[O:33])[CH3:30]
Reactant: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CCc1ccc(N)cc1
Reactant: CCC(CC)C(=O)O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCC(CC)C(=O)Nc1ccc(CCN2C(=O)C(c3ccccc3)(c3ccccc3)N=C2C)cc1
Temperature: 50 °C
Yield: 35.6 %

Procedure:
3-[2-(4-Amino-phenyl)-ethyl]-2-methyl-5,5-diphenyl-3,5-dihydro-imidazol-4-one (56 mg, 0.15 mmol) is dissolved in 10 mL methylene chloride and 2-ethyl-butyric acid (18 mg, 0.15 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (113 mg, 0.24 mmol) and ethyl diisopropyl amine (42 uL, 0.24 mmol) are added. The mixture is stirred and heated to 50° C. for 5 hours. Subsequently water and methylene chloride are added the organic phase is separated, dried and evaporated. The residue is purified by preparative HPLC (Method 1) to yield 2-ethyl-N-{4-[2-(2-methyl-5-oxo-4,4-diphenyl-4,5-dihydro-imidazol-1-yl)-ethyl]-phenyl}-butyramide (25 mg, 35%). LC/MS at 254 nm; [M+H] 468; Rt 3.351.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][P:9](=[O:12])([OH:11])[OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][CH:16]([CH2:19]O)[CH2:17]O>>[CH3:15][CH:16]1[CH2:19][O:11][P:9](=[O:10])([CH2:8][C:7]2[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[O:12][CH2:17]1
Reactant: O=[N+]([O-])c1ccc(CP(=O)(O)O)cc1
Reactant: CC(CO)CO
Product: CC1COP(=O)(Cc2ccc([N+](=O)[O-])cc2)OC1

Procedure:
4-Nitrobenzylphosphonic acid and 2-methyl-1,3-propanediol were treated in the same manner as in Reference Example 20 to yield 5-methyl-2-(4-nitrobenzyl)-1,3,2-dioxaphosphorinan-2-oxide, which was then recrystallized from ethanol-hexane to yield colorless prisms having a melting point of 170°-171° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:29][O:30][CH3:31])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][N:20]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([NH2:17])=O)=[CH:11]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>O1CCCC1>[CH3:1][O:2][CH2:3][CH:4]([CH2:29][O:30][CH3:31])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][N:20]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15](=[S:41])[NH2:17])=[CH:11]2
Reactant: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(N)=O)[nH]c12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(N)=S)[nH]c12
Temperature: 50 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a solution of 7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxamide (1.66 g) in tetrahydrofuran (40 mL) was added Lawesson's reagent (1.5 g), and the mixture was stirred at 50° C. for 2 h. Lawesson's reagent (0.5 g) was added to the mixture again. After stirring at 50° C. for 1 h, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the mixture was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by basic silica gel column chromatography (methanol/ethyl acetate/hexane=0/10/90 to 10/90/0, volume ratio) to give the title compound (1.69 g, 98%) as a yellow amorphous solid. MS 466 (MH+).
Reaction SMILES: [H-].C[O:3][C:4]([C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)=O.C(OCC)(=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(OCC)C>[NH:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:6]([CH2:4][OH:3])[C:7]=2[CH:8]=[CH:9]1
Reactant: COC(=O)c1cccc2[nH]ccc12
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: OCc1cccc2[nH]ccc12
Temperature: -70 °C
Reaction time: 1 h
Yield: 101.5 %

Procedure:
biisobutylaluminum hydride (1M in toluene; 1.3 mL, 1.3 mmol) was added to a solution of 1H-indole-4-carboxylic acid methyl ester (Example 1; 85 mg, 0.49 mmol) in diethyl ether (1.6 mL) at −70° C. The solution was allowed to stir at −70° C. for 1 h, then at room temperature for 1 h. Ethyl acetate (20 mL) was added and the solution was stirred with an aqueous solution of potassium sodium tartrate (30% w/v; 20 mL) for 30 min. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried (MgSO4), filtered, evaporated and dried under high vacuum to give 1H-indole-4-methanol (73.2 mg, quantitative yield) which was used in the next step without further purification.