Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.S(=O)(O)[O-].[Na+].[N+:15]([CH2:18][CH3:19])([O-:17])=[O:16].[OH-].[Na+]>O>[N+:15]([CH:18]([CH3:19])[CH:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=1)[OH:8])([O-:17])=[O:16]
Reactant: CC[N+](=O)[O-]
Reactant: Cc1ccc(C=O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(C(O)C(C)[N+](=O)[O-])cc1

Procedure:
The procedure of Example 1 was followed for the reaction of 120 g of p-tolualdehyde and 114 g of sodium bisulfite with 150 g of 1-nitroethane and 80 g of sodium hydroxide. Water was the solvent. The final product was a yellow liquid weighing 103 g: ir (film) 2.85 (m), 3.4 (m), 6.5 (s), 7.2 (m), 7.35 (m), 9.5 (m), 12.15 (m) microns; nmr (CDCl3) 7.12 (4H, s), 5.0 to 4.5 (2H, m), 2.95 (1H, s), 2.3 (3H, s), 1.4 and 1.2 (3H, doublet and doublets) ppm.
Reaction SMILES: [Cl:1][CH:2]([Cl:21])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:20])[CH3:19])=[O:4].[OH:22][CH2:23][C:24]1[N:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[Cl:1][CH:2]([Cl:21])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:27]3[CH:28]=[N:29][C:24]([CH2:23][OH:22])=[CH:25][CH:26]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:20])[CH3:19])=[O:4]
Reactant: OCc1ccc(B(O)O)cn1
Reactant: CC1(C)O[C@H](c2ccc(I)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Product: CC1(C)O[C@H](c2ccc(-c3ccc(CO)nc3)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl

Procedure:
Following the general procedure of Example 1—Step 1 and making non-critical variations but using 2,2-dichloro-1-((4S,5R)-4-(fluoromethyl)-5-(4-iodophenyl)-2,2-dimethyloxazolidin-3-yl)ethanone and (6-(hydroxymethyl)pyridin-3-yl)boronic acid as starting materials the title compound is obtained (800 mg): m/z (CI) M−H 426.1.
Reaction SMILES: [OH:1][CH:2]([CH2:16][OH:17])[CH2:3][N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[N:8]([CH3:15])[C:7]=2[N:6]=[CH:5]1.Cl[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:1][CH:2]([CH2:16][OH:17])[CH2:3][N:4]1[C:12]2[C:11](=[O:13])[N:10]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[C:9](=[O:14])[N:8]([CH3:15])[C:7]=2[N:6]=[CH:5]1
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2CC(O)CO
Reactant: CC(C)(O)CCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCCCC(C)(C)O)c(=O)c2c1ncn2CC(O)CO
Temperature: 110 °C
Reaction time: 18 h

Procedure:
A mixture of 18 g (0.075 mol) of the xanthine compound from stage (a), 12.5 g (0.083mol) of 1-chloro-5-hydroxy-5-methylhexane (Example 1a) and 11.5 g (0.083 mol) of potassium carbonate in 500 ml of dimethylformamide is stirred for 18 hours at 110° C., after which the hot mixture is filtered and the filtrate is concentrated in vacuo. The oily crude product, which gradually crystallizes through, can advantageously be purified by filtration over a silica gel column using a chloroform/methanol (10:1) solvent mixture, followed by a final recrystallization from ethyl acetate with the addition of petroleum ether, at the boil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(N[CH:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH3:51])=[CH:47][CH:48]=3)[CH2:43][CH2:42][CH2:41]2)=NC=1CC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][CH:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH3:51])=[CH:47][CH:48]=3)[CH2:43][CH2:42][CH2:41]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCc1nc(NC2CCCc3cc(OC)ccc32)c(CC)nc1Br
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1NC1CCCc2cc(OC)ccc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-3,6-diethyl-N-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine, ethylene glycol dimethyl ether and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.51, 7.31, 6.81, 6.71, 5.44, 4.63, 3.83, 2.93-2.76, 2.66-2.51, 2.10, 1.91, 1.32-1.14; HRMS (FAB) calcd for C25H27Cl2N3O+H 456.1609, found 456.1624; Anal. Calcd for C25H27Cl2N3O: C, 65.79; H, 5.96; N, 9.21. Found: C, 65.58; H, 5.96; N, 8.99.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1.[H][H]>C(O)(C)C.[Pd]>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])cc1OCCCN1CCN(C)CC1
Agent: [Pd]
Solvent: CC(C)O
Product: COc1ccc(N)cc1OCCCN1CCN(C)CC1

Procedure:
To a solution of 1-[3-(2-methoxy-5-nitro-phenoxy)-propyl]-4-methyl-piperazine (2.5 g, 8.1 mmol) in 25 mL of iso-propanol was added 10% Pd-C (0.25 g, 10 wt. %). This mixture was shaken under 35-40 psi of hydrogen in a Parr shaker until hydrogen uptake ceased. The reaction mixture was purged with nitrogen and filtered through celite. The resulting solution was concentrated in vacuo to give the crude 4-methoxy-3-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenylamine as a yellow oil which was used directly in the coupling step described below. 1H NMR (300 MHz, CDCl3) δ 6.71 (d, J=8 Hz, 1H), 6.33 (d, J=2.4 Hz, 1H), 6.23 (dd, J=2.4, 8 Hz, 1H), 4.05 (t, J=8 Hz, 2H), 3.80 (s, 3H), 2.53 (m,10H), 2.30 (s, 3H), 2.02 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>ClCCl>[CH3:13][S:14]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:16])=[O:15]
Reactant: C1CCNC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCCC1
Temperature: 25 °C

Procedure:
To a solution of pyrrolidine (8.25 g, 116 mmol) in dichloromethane (120 mL) were added triethylamine (19.0 mL, 139 mmol) followed by addition of methanesulfonyl chloride (9.0 mL, 116 mmol) at 0° C. The reaction was allowed to stir while warming up to rt. overnight, which was transferred to a separatory funnel and washed twice with 1.0N HCl and brine once. Organic phase was dried over magnesium sulfate, filtered and solvent was removed to leave a pure title product as a white solid. Step B: 1-(Pyrrolidin-1-ylsulfonyl)propan-2-one
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][N:7]=1>C(O)C.[Pd]>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: O=[N+]([O-])c1cccnc1C1OCCO1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccnc1C1OCCO1

Procedure:
2-(1,3-Dioxolan-2-yl)-3-nitropyridine (10 g, 51 mmol) was suspended in ethanol (300 mL). To the mixture was added 10% Pd/C (3 g). The reaction mixture was kept at 60 psi pressure using Parr-shaker hydrogenation assembly. After completion of reaction (6 h), the reaction mixture was filtered through Celite™ and the filtrate was concentrated under reduced pressure to give 2-(1,3-dioxolan-2-yl)-3-pyridinamine as an off orange solid: 1H-NMR (CDCl3) δ: 4.4-4.0 (m, 6H), 5.8 (s, 1H), 7.2-6.9 (m, 2H), 8.0 (s, 1H).
Reaction SMILES: Cl[C:2]1(Cl)[CH2:5][C:4](=[O:6])[CH2:3]1.CC(O)=O.O.[CH:13]([OH:16])([CH3:15])[CH3:14].O>[Zn]>[C:4]1(=[O:6])[CH2:3][CH2:2][CH2:5][CH2:15][C:13](=[O:16])[CH2:14]1
Reactant: O=C1CC(Cl)(Cl)C1
Reactant: CC(C)O
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCCCC(=O)C1
Reaction time: 1 h

Procedure:
Dichlorocyclobutanone 3 (128 g, 0.48 mol) was dissolved in 520 mL of 1:1 isopropanol-water in a 2 L, 3-neck flask with an overhead stirrer. Zinc granules (126 g, 1.9 mol, −30+100 mesh) were added in one portion. After 60 min at room temperature, 130 mL of AcOH plus 260 mL of water were added dropwise via addition funnel (ca. 4 mL are added initially, followed by a 10 min hold to check for exotherms; 20 ml were then added, followed by another 10 min hold; once any exotherm has abated, the remaining acid solution was added dropwise; the entire addition takes 1.5-2 h). After 16 h, the mixture was transferred to a separatory funnel, decanting away from most of the zinc (several small isopropanol rinses were used). The isopropanol-AcOH-water mixture was then extracted with 5 portions of toluene (250 mL each), which are combined and concentrated to provide 51.7 g of product as a dark, orange-brown oil (85% crude mass balance, ca. 85% pure by 1H nmr). This material is suitable for subsequent reactions, or can be purified by distillation, which provided 29.4 g (0.23 mol, 49% yield) of product as a clear, colorless oil (b.p. 65-75° C. at 1.2 mm). It's spectral properties (1H nmr, GC/MS) were identical to samples prepared by the oxymercurafion route of Chandrasekaran (Synthetic Communications 1984, 14, 339-345).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[C:13]([C:17]2[O:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=2)[CH:14]=[CH:15][CH:16]=1.C(OC1C=CC=CC=1C(=O)C)C1C=CC=CC=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:65][CH2:66][C:67]([N:69]1[CH2:74][CH2:73][CH:72]([O:75][C:76]2[CH:81]=[CH:80][CH:79]=[C:78]([C:82]([F:85])([F:84])[F:83])[CH:77]=2)[CH2:71][CH2:70]1)=[O:68]>CN(C=O)C.O>[O:68]=[C:67]([N:69]1[CH2:70][CH2:71][CH:72]([O:75][C:76]2[CH:81]=[CH:80][CH:79]=[C:78]([C:82]([F:85])([F:83])[F:84])[CH:77]=2)[CH2:73][CH2:74]1)[CH2:66][NH:65][C:22]([C:19]1[CH:18]=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([OH:10])[CH:12]=2)[O:21][N:20]=1)=[O:24]
Reactant: O=C(O)c1cc(-c2cccc(O)c2)on1
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Agent: CC(=O)c1ccccc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cc(-c2cccc(O)c2)on1
Reaction time: 8 h
Yield: 37.5 %

Procedure:
DIPEA (133 mg, 1.03 mmol) was added to a stirred solution of 5-(3-hydroxy-phenyl)-isoxazole-3-carboxylic acid (61 mg, 0.294 mmol)) (prepared by the method used for the synthesis of Intermediate 25, starting from 2′-benzyloxyacetophenone) in DMF (2 mL) followed by HOBt (41.7 mg, 0.308 mmol) and EDCI.HCl (59 mg, 0.308 mmol). After 2 minutes 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (99 mg, 0.294 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure The residue was purified by washing with ethylacetate to afford 54 mg (37.7% Yield) of 5-(3-hydroxy-phenyl)-isoxazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 490, 94.4%. 1H NMR (300 MHz, DMSO-d6): δ9.9 (s, 1H), 8.65 (t, 1H), 7.5 (t, 1H), 7.3 (m, 7H), 6.95 (m, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 3.9 (s, 1H), 3.7 (m, 1H), 3.4 (m, 2H), 2.0 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [BH4-].[Na+].[Br:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)=[O:7].Cl>CO>[Br:3][CH2:4][CH2:5][CH:6]([C:8]1[CH:9]=[CH:10][C:11]([Br:14])=[CH:12][CH:13]=1)[OH:7]
Reactant: O=C(CCBr)c1ccc(Br)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(CCBr)c1ccc(Br)cc1
Reaction time: 1 h
Yield: 94.4 %

Procedure:
NaBH4 (1.5 g, 39.7 mmol) was added by portions to a solution of 3-bromo-1-(4-bromophenyl)propan-1-one (11.7 g, 40 mmol) (Preparation 5) in MeOH while keeping the temperature below 10° C. After 1 h at RT, 1N aqueous hydrochloric acid was added at 5° C. to pH=1 and the mixture was concentrated in vacuum. The residue was dissolved in water and extracted three times with DCM. The organic layer was dried over Na2SO4 and concentrated to yield 3-bromo-1-(4-bromophenyl)propan-1-ol as a yellow oil (11.1 g). 1H NMR (CDCl3): 7.47 (2H, d, J=8.3 Hz), 7.22 (2H, d, J=8.3 Hz), 4.87 (1H, br s), 3.50–3.62 (1H, m), 3.31–3.42 (1H, m), 2.35 (1H, OH, br s), 2–2.31 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Br)cc1
Product: O=C(Cl)c1ccc(Br)cc1
Yield: 100 %

Procedure:
1.5 g (0.00745 mol) of 4-bromobenzoic acid were dissolved in 25 ml of thionyl chloride under argon and boiled under reflux for 2 hrs. The excess thionyl chloride was distilled off and the residue was taken up twice with 50 ml of toluene and concentrated each time. 1.63 g (100%) of 4-bromobenzoyl chloride were obtained as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18]C)[C:12]=2[C:11]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[N:10]1.[I-].[Na+].Cl[Si](C)(C)C.C(=O)([O-])O.[Na+]>C(#N)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][NH:14][C:13](=[O:18])[C:12]=2[C:11]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[N:10]1
Reactant: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2-c1c(F)cccc1F
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(-c2nn(-c3c(F)cccc3F)c3cc[nH]c(=O)c23)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
To a solution of 4-(1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (46.0 mg) in acetonitrile (4 mL) were added sodium iodide (41.4 mg) and chloro(trimethyl)silane (0.140 mL), and the mixture was stirred at 50° C. for 30 min. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate to ethyl acetate/methanol) to give the title compound (28.5 mg).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[N:21]1[CH:26]=[C:25](B(O)O)[CH:24]=[N:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][C@@H:14]1[CH2:15][CH2:16][CH2:17][N:13]1[C@H:11]1[CH2:12][C@H:9]([C:7]2[S:8][C:4]3[CH:3]=[C:2]([C:25]4[CH:26]=[N:21][CH:22]=[N:23][CH:24]=4)[CH:20]=[CH:19][C:5]=3[N:6]=2)[CH2:10]1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(-c4cncnc4)cc3s2)C1

Procedure:
A solution of the product of Example 1E (40 mg, 0.114 mmole), pyrimidine-5-boronic acid (CAS # 109299-78-7) (21 mg, 0.169 mmole), dichlorobis(triphenylphosphine)palladium(II) (8 mg, 0.01 mmole) and potassium carbonate (47 mg, 0.34 mmole) in 1 ml isopropanol was heated at 85° C. overnight with stirring. The reaction was then quenched with water and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (eluted by 0.35% ammonium hydroxide and 3.5% methanol in dichloromethane) to give 33 mg (82%/o yield) of title compound. 1H NMR (400 MHz, CDCl3) δ ppm 9.23 (s, 1H), 9.02 (s, 2H), 8.12 (d, J=8.59 Hz, 1H), 8.06 (d, J=1.84 Hz, 1H), 7.67 (dd, J=8.44, 1.99 Hz, 1H), 3.83-3.94 (m, 1H), 3.46-3.62 (m, 1H), 2.99-3.14 (m, 1H), 2.64-2.85 (m, 3H), 2.43-2.64 (m, 2H), 2.23-2.40 (m, 1H), 1.89-2.03 (m, 1H), 1.78-1.91 (m, 1H), 1.67-1.78 (m, 1H), 1.42-1.56 (m, 1H), 1.14 (d, J=4.91 Hz, 3H). MS: (M+H)+=351.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=[O:20])[CH2:10][C:11]1[NH:15][C:14]2[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=2[N:12]=1.C[O-].[Na+].[C:24](OC)(=[O:27])[C:25]#[CH:26]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([C:10]1[CH:26]=[CH:25][C:24](=[O:27])[N:15]2[C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[NH:12][C:11]=12)=[O:20]
Reactant: C#CC(=O)OC
Reactant: O=C(Cc1nc2c([nH]1)CCCC2)c1cc(F)ccc1F
Agent: C[O-]
Agent: [Na+]
Product: O=C(c1cc(F)ccc1F)c1ccc(=O)n2c3c([nH]c12)CCCC3

Procedure:
The compound is prepared as described in example 20 with 500 mg (1.81 mmol) of 1-(2,5-Difluorophenyl)-2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone (example XXXXII), 195.5 mg (3.62 mmol) of sodium methylate and 152.2 mg (1.81 mmol) methyl propiolate.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]3[CH2:15][NH:16][CH2:17][CH2:18][C:19]=3[C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:8]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:4][CH3:5])[CH3:2].[C:35]1([N:41]=[C:42]=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[CH2:4]([N:3]([CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]3[CH2:15][N:16]([C:42](=[O:43])[NH:41][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:17][CH2:18][C:19]=3[C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:8]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:1][CH3:2])[CH3:5]
Reactant: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCNC3
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCN(C(=O)Nc1ccccc1)C3
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
A mixture of the compound obtained in Example 5A (1.0 g), phenyl isocyanate (0.27 g) and tetrahydrofuran (20 ml) was stirred at room temperature for 3 hours, after which it was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane-methanol (20:20:1, v/v) to yield ethyl 2-(N,N-diethylaminomethyl)-4-(3,4-dimethoxyphenyl)-7-phenylcarbamoyl-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']dipyridine-3-carboxylate (for structural formula, see below) (1.10 g, 88%), which was then recrystallized from ethyl acetate-hexane to yield colorless prismatic crystals having a melting point of 154 to 155° C. ##STR52##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][CH3:24])[CH:11]=2)[C:6]1=[O:25].[Na].Cl.CCOC(C)=O.[CH2:35](O)[CH2:36][CH2:37]C>>[CH2:1]([O:2][C:3]([C:4]1[N:5]=[C:6]([OH:25])[C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][C:10]([O:15][C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:23][CH3:24])=[CH:9][CH:8]=2)=[O:26])[CH2:35][CH2:36][CH3:37]
Reactant: CCCCO
Reactant: CCc1cccc(C)c1Oc1ccc2c(c1)C(=O)N(CC(=O)OC)C2=O
Agent: Cl
Agent: [Na]
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1nc(O)c2ccc(Oc3c(C)cccc3CC)cc2c1O
Reaction time: 3 h

Procedure:
To a solution of [5-(2-Ethyl-6-methyl-phenoxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-acetic acid methyl ester (22 mmol, 7.77 g) in anhydrous n-butanol (150 mL) was added a 1 N solution of sodium in n-butanol (45 mmol, 45 mL) at 95° C. in one portion with stirring. Stirring was continued at 95° C. for 3 h before the mixture was concentrated in vacuo. To the residue was added 2 N hydrochloric acid (60 mmol, 30 mL) and EtOAc (150 mL) and the mixture was stirred vigorously for 45 min. Subsequently, the solid component was sucked off, washed with water and dried in vacuo to give the title compound as a tan solid (623 mg); MS-(+)-ion: M+1=396.5.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]([CH3:27])([O:24]CC)[C:6]([CH2:12][S:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1)([PH2:10]=[O:11])[CH:7]([CH3:9])[CH3:8])C.[OH-].[Na+].CO>C1COCC1>[OH:24][C:5]([CH3:27])([C:6]([CH2:12][S:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1)([PH2:10]=[O:11])[CH:7]([CH3:9])[CH3:8])[C:4]([OH:28])=[O:3]
Reactant: CCOC(=O)C(C)(OCC)C(CSc1ccc2ccccc2n1)([PH2]=O)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C(CSc1ccc2ccccc2n1)([PH2]=O)C(C)(O)C(=O)O
Yield: 97.3 %

Procedure:
2-(Ethoxy) (quinolin-2-ylthiomethyl)-phosphinoyl-methyl-4-methylpentanoic acid ethyl ester (4.5 g) was dissolved in 100 mL THF and 12.5 mL of 2N NaOH was added together with enough methanol to make the solution homogeneous. After 18 hours the THF was removed by evaporation, the residue diluted with 50 mL H2O and washed with 50 mL ethyl acetate. The aqueous phase was then acidified to pH 4, and the product extracted with 50 mL ethyl acetate (2×). The ethyl acetate was washed with 20 mL brine, dried with MgSO4 and evaporated to yield 3.8 g of 2-(hydroxy) (quinolin-2-ylthiomethyl)-phosphinoyl-methyl-4-methylpentanoic acid as a yellow oil, MS: 368 (MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:21]=[C:22]([CH2:24][O:25][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[N:23]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[OH-:36].[Na+].OO.Cl>CCO.CS(C)=O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:21]=[C:22]([CH2:24][O:25][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[N:23]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([NH2:20])=[O:36])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)cn1
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)cn1
Temperature: 60 °C

Procedure:
To a solution of compound 54a (60 mg, 0.13 mmol) in EtOH (4 mL) and DMSO (1 mL) was added a 3N aqueous NaOH (0.06 mL, 0.18 mmol) and 30% hydrogen peroxide (0.3 mL). The reaction mixture was refluxed at 60° C. for 12 h. The reaction mixture was allowed to cool to rt and acidified with 2N HCl to pH˜2 and extracted with DCM (2×30 mL). The combined DCM layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (0-10% MeOH/DCM) to give the title compound 84. 1H-NMR (400 MHz, MeOH) δ (ppm): 3.83-3.87 (m, 4H), 4.27-4.32 (m, 4H), 5.62 (s, 2H), 6.90 (d, J=8.8 Hz, 1H), 7.32-7.38 (m, 2H), 7.59 (ddd, J=8.4, 7.0, 1.5 Hz, 1H), 7.65-7.72 (m, 1H), 7.74-7.81 (m, 2H), 7.97 (d, J=8.8 Hz, 1H), 8.03 (dd, J=8.1, 2.2 Hz, 1H), 8.25 (d, J=8.1 Hz, 1H), 8.73 (d, J=1.5 Hz, 1H). (LCMS, ESI pos.) Calcd. for C26H23N7O3: 482.2 [M+H]. found 482.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([NH:11][CH:12]=[O:13])[C:6](O)([CH3:9])[CH:7]=[CH2:8])[CH3:2].S(Br)(Br)=O.[P:19]([O:26]CC)([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([NH:11][CH:12]=[O:13])/[C:6](/[CH3:9])=[CH:7]/[CH2:8][P:19]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:26])[CH3:2]
Reactant: CCOP(OCC)OCC
Reactant: C=CC(C)(O)C(NC=O)C(=O)OCC
Agent: O=S(Br)Br
Product: CCOC(=O)C(NC=O)/C(C)=C/CP(=O)(OCC)OCC

Procedure:
The starting material is manufactured as follows: 5-Methyl-5-vinyl-2-oxazoline-4-carboxylic acid ethyl ester, b.p. 65°-75° (13 Pa) is obtained by reaction of isocyanoacetic acid ethyl ester with methyl vinyl ketone in a manner analogous to that described in Example 30. By hydrolysis of the 5-methyl-5-vinyl-2-oxazoline-4-carboxylic acid ethyl ester in a manner analogous to that described in Example 1, 2-formylamino-3-hydroxy-3-methyl-4-pentenoic acid ethyl ester is obtained. Reaction of the 2-formylamino-3-hydroxy-3 methyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with triethyl phosphite in a manner analogous to that described in Example 1 yields E-2-formylamino-3-methyl-5-diethylphosphono-3-pentenoic acid ethyl ester in the form of a colourless liquid.