Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[O:15][N:14]=[C:13]([CH3:16])[CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:17][C:18]1([CH3:51])[O:22][C@H:21]([C:23]([N:25]2[CH2:30][CH2:29][C:28]([C:31]3[C:36]([F:37])=[CH:35][C:34]([N:38]4[CH2:42][C@H:41]([CH2:43]OS(C)(=O)=O)[O:40][C:39]4=[O:49])=[CH:33][C:32]=3[F:50])=[CH:27][CH2:26]2)=[O:24])[CH2:20][O:19]1.O>CN(C)C=O>[CH3:51][C:18]1([CH3:17])[O:22][C@H:21]([C:23]([N:25]2[CH2:30][CH2:29][C:28]([C:31]3[C:36]([F:37])=[CH:35][C:34]([N:38]4[CH2:42][C@H:41]([CH2:43][N:10]([C:11]5[O:15][N:14]=[C:13]([CH3:16])[CH:12]=5)[C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[O:40][C:39]4=[O:49])=[CH:33][C:32]=3[F:50])=[CH:27][CH2:26]2)=[O:24])[CH2:20][O:19]1
Reactant: CC1(C)OC[C@@H](C(=O)N2CC=C(c3c(F)cc(N4C[C@H](COS(C)(=O)=O)OC4=O)cc3F)CC2)O1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)on1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N(C[C@H]2CN(c3cc(F)c(C4=CCN(C(=O)[C@@H]5COC(C)(C)O5)CC4)c(F)c3)C(=O)O2)C(=O)OC(C)(C)C)on1
Reaction time: 0.17 h
Yield: 68 %

Procedure:
Sodium hydride (60% in oil, 72 mg, 1.8 mM) was suspended in dry N,N-dimethylformamide (3 ml), cooled to 0° under nitrogen, and a solution of 5-(t-butoxycarbonylamino)-3-methylisoxazole (356 mg, 1.8 mM) in N,N-dimethylformamide (3 ml) added. After stirring for 10 minutes, a solution of 3-(4(1-(2,2-dimethyl-1,3-dioxolan-4(S)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-5(R)-methanesulfonyloxymethyloxazolidin-2-one (516 mg, 1.5 mM) in N,N-dimethylformamide (3 ml) was added, and the mixture heated to 40° for 5 hours. After cooling, the mixture was poured into water (50 ml), extracted with dichloromethane (4×20 ml). The organic phase was dried (magnesium sulfate), evaporated and crude product purified by chromatography on a 10 g silica Mega Bond Elut® column, eluting with a gradient from 50% to 75% ethyl acetate in isohexane. Relevant fractions were combined to give the desired product (420 mg).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:34])[C:14]2[O:20][C:19]3[C:21]([Cl:30])=[CH:22][C:23]([NH:25][C:26](=[O:29])[CH2:27]Cl)=[CH:24][C:18]=3[CH2:17][S:16](=[O:32])(=[O:31])[C:15]=2[CH:33]=1)=[O:10]>CN(C=O)C>[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:34])[C:14]2[O:20][C:19]3[C:21]([Cl:30])=[CH:22][C:23]([NH:25][C:26](=[O:29])[CH2:27][NH:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:24][C:18]=3[CH2:17][S:16](=[O:32])(=[O:31])[C:15]=2[CH:33]=1)=[O:10]
Reactant: NC1CCCC1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CCl)cc(Cl)c1O2
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CNC3CCCC3)cc(Cl)c1O2

Procedure:
Cyclopentyl amine (0.27 ml, 2.7 mmol) was added to a solution of Example 133 (0.4 g, 0.9 mmol) in DMF (10 mL). The reaction mixture was processed as described in the synthesis of Example 139k to obtain the title compound. Yield: 0.37 g, (83%); 1H NMR (CDCl3): δ 1.38 (m, 2H, CH2), 1.72 (m, 4H, 2CH2), 1.87 (m, 2H, CH2), 2.7 (s, 3H, CH3), 2.96 (s, 1H, NH), 3.15 (m, 1H, CH), 3.38 (s, 2H, CH2), 3.92 (s, 3H, OCH3), 4.7 (s, 2H, CH2), 7.57 (s, 1H, Ar), 7.83 (s, 1H, Ar), 8.1 (s, 1H, Ar), 8.45 (s, 1H, Ar), 9.64 (s, 1H, NH); MS: m/e (ES+) 493 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:21]3[CH:20]=[CH:19][C:18]4[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=4[C:16]=3[N:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]2[CH:29]=[CH:28][CH:27]=[CH:26][C:13]=23)[CH:5]=[CH:6][CH:7]=1.[C:30]1(B(O)O)[C:43]2[C:44]3=[C:45]4[C:40](=[CH:41][CH:42]=2)[CH:39]=[CH:38][CH:37]=[C:36]4[CH:35]=[CH:34][C:33]3=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(O)C>[C:30]1([C:2]2[CH:3]=[C:4]([C:8]3[C:21]4[CH:20]=[CH:19][C:18]5[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=5[C:16]=4[N:15]=[C:14]4[C:9]=3[CH:10]=[CH:11][C:12]3[CH:29]=[CH:28][CH:27]=[CH:26][C:13]=34)[CH:5]=[CH:6][CH:7]=2)[C:43]2[C:44]3=[C:45]4[C:40](=[CH:41][CH:42]=2)[CH:39]=[CH:38][CH:37]=[C:36]4[CH:35]=[CH:34][C:33]3=[CH:32][CH:31]=1
Reactant: Brc1cccc(-c2c3ccc4ccccc4c3nc3c2ccc2ccccc23)c1
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1cc(-c2c3ccc4ccccc4c3nc3c2ccc2ccccc23)cc(-c2ccc3ccc4cccc5ccc2c3c45)c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
10 (700 mg, 1.61 mmol), pyren-1-ylboronic acid (434 mg, 1.76 mmol), Palladium tetrakis triphenylphoshine (186 mg, 0.16 mmol) and potassium carbonate (1.34 g, 9.66 mmol) were introduced in a flask together with 17 mL toluene, 8.8 mL ethanol and 2.6 mL distilled water. This mixture is stirred at 80° C. during 24 hours before being filtered. The solid is then washed with hexane, water and some mL of chloroform before being dried.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[O:11])[N:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:14][CH:13]=3)[C:8](=[S:24])[NH:7][C:6]=2[N:25]=1.[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>[Cu]I.O.CN(C)C=O>[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[O:11])[N:9]([C:12]4[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:14][CH:13]=4)[C:8](=[S:24])[NH:7][C:6]=3[N:25]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=c1c2ccc(Cl)nc2[nH]c(=S)n1-c1ccc(OCC(F)(F)F)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ccc3c(=O)n(-c4ccc(OCC(F)(F)F)cc4)c(=S)[nH]c3n2)cc1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
A mixture of 7-chloro-2-thioxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidin-4(3H)-one (200 mg), 4-methoxybenzylamine (181 μl), copper(I) iodide (57 mg), potassium carbonate (166 mg) and N,N-dimethylformamide (3 ml) was stirred at 130° C. for 2 hr. To the reaction mixture were added saturated aqueous ammonium chloride solution and water, and the precipitate was collected by filtration, and dissolved in tetrahydrofuran. The solution was filtered through celite, and concentrated under reduced pressure. The residue was dissolved in a mixed solvent of ethyl acetate/tetrahydrofuran, and the solution was washed with aqueous ammonia solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the white title compound (108 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:6]=[CH:5]2.O.O.O.O.O.O.O.S([O-])([O-])=O.[Na+:27].[Na+].C(=O)(O)[O-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([O-:14])=[O:13])[CH:6]=[CH:5]2.[Na+:27]
Reactant: O=S(=O)(Cl)c1ccc2cc(Br)ccc2c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=S([O-])c1ccc2cc(Br)ccc2c1
Temperature: 70 °C
Yield: 89.5 %

Procedure:
6-Bromonaphth-2-ylsulphonyl chloride (9.4 g) was added in small portions over 3 hours to a stirred mixture of sodium sulphite heptahydrate (14.46 g), sodium bicarbonate (5.08 g) and water (100 ml) which had been heated to 70° C. The resultant mixture was allowed to cool slowly to ambient temperature. The crystalline precipitate was isolated giving sodium 6-bromonaphth-2-ylsulphinate (8.07 g) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C@@:8]2([CH3:15])[NH:13][C:12](=[S:14])[CH2:11][O:10][CH2:9]2)[CH:7]=1.[Cl:17][C:18]1[C:19]([CH:26]=O)=[N:20][N:21]([CH:23]([F:25])[F:24])[CH:22]=1.[B][B][B][B][B][B][B][B][B][B]>CO>[Cl:17][C:18]1[C:19]([CH2:26][NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C@@:8]3([CH3:15])[NH:13][C:12](=[S:14])[CH2:11][O:10][CH2:9]3)[CH:7]=2)=[N:20][N:21]([CH:23]([F:25])[F:24])[CH:22]=1
Reactant: C[C@@]1(c2cc(N)ccc2F)COCC(=S)N1
Reactant: O=Cc1nn(C(F)F)cc1Cl
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: C[C@@]1(c2cc(NCc3nn(C(F)F)cc3Cl)ccc2F)COCC(=S)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 5 ml-reaction tube under an inert atmosphere a mixture of (R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholine-3-thione (48 mg, 0.2 mmol) and 4-chloro-1-difluoromethyl-1H-pyrazole-3-carbaldehyde (20 mg, 0.11 mmol) in methanol (0.3 ml) was stirred at room temperature for 1 hour. Then decaborane (24 mg, 0.2 mmol) was added in one portion and the mixture warmed to 45° C. for 15 hours. For the workup, the light yellow solution was quenched with sodium carbonate (10% solution), the methanol removed at reduced pressure and then the residue extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulphate, then evaporated at reduced pressure. The crude product was purified by preparative HPLC using a gradient of water (+0.1% triethylamine) and acetonitrile (90:10 to 10:90). The (R)-5-{5-[(4-chloro-1-difluoromethyl-1H-pyrazol-3-ylmethyl)-amino]-2-fluoro-phenyl}-5-methyl-morpholine-3-thione was obtained as a colourless foam (49 mg, 60%); (calculated) C16H16ClF3N4OS [404.84]; (found) [M+H]+=405.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]([CH3:13])[C:10](=[O:14])[CH:9]=[CH:8][C:7]=2[C:6]([CH:15]=O)=[CH:5][CH:4]=1.[C:17]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].N1CCCCC1.Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:15]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17]([O:25][CH2:26][CH3:27])=[O:24])=[C:7]2[C:12]=1[N:11]([CH3:13])[C:10](=[O:14])[CH:9]=[CH:8]2
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1ccc(C=O)c2ccc(=O)n(C)c12
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CCOC(=O)C(=Cc1ccc(OC)c2c1ccc(=O)n2C)C(=O)OCC
Temperature: 95 °C
Reaction time: 6 h
Yield: 53 %

Procedure:
8-Methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-5-carboxaldehyde (18.9 g), diethyl malonate (26.5 ml) and piperidine (2.7 ml) were added to pyridine (90 ml), and the resulting mixture was stirred at 90 to 100° C. for 6 hours. After cooling to room temperature, the reaction mixture was added to cold concentrated hydrochloric acid, and the precipitated solid was collected by filtration, washed with water and dried to thereby obtain 16.62 g (yield: 53%) of diethyl 2-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-ylmethylene)malonate as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[S:11](Cl)(=O)=O.S(=O)(=O)(O)O>ClCCl.[Zn]>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[SH:11]
Reactant: COc1ccc(S(=O)(=O)Cl)c(Cl)c1Cl
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: ClCCl
Product: COc1ccc(S)c(Cl)c1Cl
Temperature: 0 °C
Yield: 77.4 %

Procedure:
A mixture of 9.37 g of 2,3 dichloro-4-methoxybenzenesulfonyl chloride, 72 g of crushed ice, 24 g of conc. sulfuric acid and 12 g of zinc dust is stirred under reflux for 16 hours. The mixture is diluted with dichloromethane, cooled and stirred at room temperature for 2 hours. Filtration removes the unreacted zinc and the organic extracts are washed with water, sodium bicarbonate solution and dried over anhydrous magnesium sulfate. Removal of solvent in vacuo leaves a white solid which is recrystallized from ether-pentane to give 5.5 g of 2,3-dichloro-4-methoxy-thiophenol as colorless needles, mp 81.5°-83°.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH:11]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1>O1CCOCC1>[CH:11]1([C:16]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(Cl)C1CCCC1
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: C1COCCO1
Product: O=C(O)c1ccc(NC(=O)C2CCCC2)cc1

Procedure:
In a 1 liter 2-neck roundbottom flask, 40 grams of 4-aminobenzoic acid was dissolved in about 400 mL of dioxane. Then, 19.35 g of cyclopentanecarbonyl chloride was added dropwise to the solution. The reaction intermediate, 4-(cyclopentanecarbonyl-amino)-benzoic acid, formed as a white solid in the step and was collected by filtration. After washing the product with about 200 mL dioxane and then with about 1 liter of boiling water, the reaction intermediate was dried in an oven at 110° C. The yield at this step was about 27.7 g (81%).
Reaction SMILES: CO[C:3]([C:5]1[CH2:10][CH:9]([CH2:11][CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH2:7][CH:6]=1)=O.CC(C[AlH]CC(C)C)C.N1C=CC=CC=1.S(=O)(=O)=O>C1COCC1>[CH3:3][C:5]1[CH2:10][CH:9]([CH2:11][CH2:12][O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:8][CH2:7][CH:6]=1
Reactant: COC(=O)C1=CCCC(CCOCc2ccccc2)C1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC1=CCCC(CCOCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
5-(2-Benzyloxy-ethyl)-cyclohex-1-enecarboxylic acid methyl ester (Intermediate R3 obtained above in Example R1 in accordance with Method R) was reduced with DIBAL. The resulting alcohol (Intermediate R7, 1.18 g, 4.81 mmol) in THF (20 mL) at 0° C. was treated with sulfur trioxide-pyridine. (1.15 g, 7.21 mmol) for 3 h. LIAR (15 mL, 15 mmol) was injected into the mixture at 0° C. The solution was allowed to warm to rt for 18 h. The mixture was subjected to an aqueous work-up and purified by chromatography to give [2-(3-methyl-cyclohex-3-enyl)-ethoxymethyl]-benzene (Intermediate R8, 0.90 g, 82%). Deprotection with Na/NH3 and subsequent “Swern” oxidation produced (3-methyl-cyclohex-3-enyl)-acetaldehyde (Intermediate R9). (3-methyl-cyclohex-3-enyl)-acetaldehyde (Intermediate R9) was subjected to the applicable steps combined from Method A and Method P to yield 4-(3-methyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazol-2-one (Compound 57).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[C:12]([O:16][C:17]([NH:19][C@:20]12[CH2:28][N:27]([C@@H](C3C=CC=CC=3)C)[CH2:26][C@@H:25]1[CH2:24][CH:23]=[CH:22][CH2:21]2)=[O:18])([CH3:15])([CH3:14])[CH3:13]>ClCCl>[CH2:5]([O:4][C:2]([N:27]1[CH2:28][C@@:20]2([NH:19][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[C@@H:25]([CH2:24][CH:23]=[CH:22][CH2:21]2)[CH2:26]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[C@H](c1ccccc1)N1C[C@@H]2CC=CC[C@@]2(NC(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@]12CC=CC[C@H]1CN(C(=O)OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 17 h
Yield: 76.9 %

Procedure:
Benzyl chloroformate (0.600 mL, 4.20 mmol) was added to a solution of (1S,6S)-1-tert-butoxycarbonylamino-8-[(1R)-1-phenylethyl]-8-azabicyclo[4.3.0]non-3-ene (479 mg, 1.40 mmol) in dichloromethane (4.66 mL) in a nitrogen atmosphere, and the mixture was stirred at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→90:10→75:25→66:34) to give 401 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[C:7]1([SH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1.CN(C)C=O>[C:7]1([S:13][CH2:12][CH2:7][CH2:8][CH2:9][CH2:1][C:2]([OH:4])([CH3:5])[CH3:3])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Sc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(O)CCCCCSc1ccccc1

Procedure:
To a solution of 7-bromo-2-methyl-2-trimethylsilyloxyheptane (10) (14.0 g) in methanol (55 ml) at room temperature was added ethanolic hydrogen chloride (ca. 1M, 0.2 ml). After 10 minutes the solution was concentrated in vacuo (at room temperature) to constant weight. The residue was taken up in chloroform and reconcentrated to constant weight to give 7-bromo-2-methyl-2-heptanol (H, n=4, R1 =R2 =Me) as a chromatographically homogenous oil. The product was dissolved in THF (10 ml) and added to a premixed, stirred solution of potassium tert-butoxide (6.7 g) and thiophenol (3.6 ml) in N,N-dimethylformamide (50 ml) at room temperature. After a few minutes a precipitate started forming, and after 30 minutes the mixture was partitioned between ethyl acetate (300 ml) and water (200 ml). The organic layer was washed consecutively with 2N sodium hydroxide solution, water and brine. Drying and concentration in vacuo gave 6-hydroxy-6-methylheptyl phenyl sulphide as a chromatographically homogenous oil. This was dissolved in methanol (60 ml), and to the stirred solution was added sodium hydrogen carbonate (4.7 g), aqueous sodium tungstate solution (2%, 5 ml) and hydrogen peroxide (100 vol, 11.8 ml). The initial exothermic reaction which ensued was checked by momentary ice-cooling. The reaction mixture was then stirred at 50° C. for 1 hour. After cooling, the mixture was partitioned between dichloromethane (200 ml) and water. The aqueous layer was extracted with more dichloromethane, and the combined dichloromethane layers were washed with water, brine, and dried. Concentration in vacuo gave a crude product which was purified by chromatography (150 g silica gel; ether as eluant) to give the sulphone (13) as a viscous oil, δ (300 MHz) 1.18 (6H, s), 1.4 (7H, m), 1.75 (2H, m), 3.09 (2H, m), 7.5-7.75 (3H, m), 7.90 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][CH:17]=1.[O:25]=[S:26]1(=[O:40])[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:28][CH2:27]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[O:40]=[S:26]1(=[O:25])[CH2:27][CH2:28][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:22]([C:19]3[CH:18]=[CH:17][C:16]([C:3]4[C:2]([CH3:1])=[CH:7][CH:6]=[C:5]([NH:8][C:9]([C:11]5[S:12][CH:13]=[CH:14][CH:15]=5)=[O:10])[CH:4]=4)=[CH:21][CH:20]=3)=[O:23])=[CH:35][CH:34]=2)[CH2:30][CH2:31]1
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cc1
Reactant: Cc1ccc(NC(=O)c2cccs2)cc1-c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: Cc1ccc(NC(=O)c2cccs2)cc1-c1ccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1

Procedure:
2′-Methyl-5′-[(thiophene-2-carbonyl)-amino]-biphenyl-4-carboxylic acid (45 mg), 4-(1,1-dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-phenylamine (32 mg), EDAC (25 mg), HOBT (18 mg) and N-methylmorpholine (27 mg) in dry DMF (0.5 ml) was stirred at 20 C for 18 h. The mixture was then diluted with water (6 ml) and the resulting colourless solid collected by filtration and dried (62 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1[C:8]([CH2:9][CH3:10])=[CH:7][C:6]([PH:11](=O)[C:12]2[CH:17]=[C:16]([CH2:18][CH3:19])[C:15]([N:20]([CH3:22])[CH3:21])=[C:14]([CH2:23][CH3:24])[CH:13]=2)=[CH:5][C:4]=1[CH2:26][CH3:27].[BH3:29].O1CCCC1>C1(C)C=CC=CC=1>[CH3:28][N:2]([CH3:1])[C:3]1[C:8]([CH2:9][CH3:10])=[CH:7][C:6]([PH:11][C:12]2[CH:17]=[C:16]([CH2:18][CH3:19])[C:15]([N:20]([CH3:21])[CH3:22])=[C:14]([CH2:23][CH3:24])[CH:13]=2)=[CH:5][C:4]=1[CH2:26][CH3:27].[BH3:29]
Reactant: CCc1cc([PH](=O)c2cc(CC)c(N(C)C)c(CC)c2)cc(CC)c1N(C)C
Agent: B
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCc1cc(Pc2cc(CC)c(N(C)C)c(CC)c2)cc(CC)c1N(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
Under an argon atmosphere, to a solution of bis(4-dimethylamino-3,5-diethylphenyl)phosphine oxide (8.12 g, 20 mmoL) synthesized in Example 4 in toluene (48 mL) was added borane-tetrahydrofuran solution (68 mL, 3.5 equivalents) at 25° C. to 30° C. over 2 hr. Then, silica gel (8.3 g, 7.0 equivalents) was added to the mixture, and the mixture was stirred at room temperature for 1 hr. The silica gel was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 50 g, toluene) to give the title compound (5.1 g, colorless oil). yield 64%.
Reaction SMILES: [CH3:1][C:2]1([C:8]([O:10]C)=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.O.[OH-].[Li+]>O1CCOCC1.O.CO>[CH3:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: COC(=O)C1(C)CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CC1(C(=O)O)CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
A solution of methyl 4-methyltetrahydro-2H-pyran-4-carboxylate (5.00 g, 31.6 mmol) in 1:1:1 dioxane/water/MeOH (60 mL) was treated with lithium hydroxide hydrate (5.31 g, 126 mmol) and stirred at RT overnight. The mixture was partially concentrated, diluted with water and EtOAc and acidified to pH=1 with 6M HCl. The layers were separated, the aqueous layer extracted with additional EtOAc (50 mL) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford 4-methyltetrahydro-2H-pyran-4-carboxylic acid (4.61 g, 100%). 1H NMR (400 MHz, DMSO-d6): δ 12.29 (s, 1H), 3.65 (dt, J=11.8, 4.3 Hz, 2H), 3.33-3.32 (m, 2H), 1.87-1.86 (m, 2H), 1.35 (ddd, J=13.5, 9.9, 4.1 Hz, 2H), 1.13 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:25])[C:5]([C:8](=[N:23][OH:24])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])=[N:6][CH:7]=1.[C:26](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([Cl:25])[C:5]([C:8](=[N:23][O:24][CH3:26])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:19])([F:21])[F:20])=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NCC(=NO)c1ncc(Br)cc1Cl)c1ccccc1C(F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 23 h
Yield: 69.3 %

Procedure:
To a suspension of 200 mg of N-[2-(5-bromo-3-chloropyridin-2-yl)-2-(hydroxyimino)ethyl]-2-(trifluoromethyl)benzamide and 189 mg of potassium carbonate in 1 ml of N,N-dimethylformamide, 97 mg of iodomethane was added, and the mixture was stirred at room temperature for 23 hours. After completion of the reaction, the reaction mixture was mixed with 10 ml of water and extracted with ethyl acetate (20 ml×2), the resulting organic layers were combined, washed with water (10 ml×2) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 50:50) as the eluent to obtain 143 mg of the desired product as a pale yellow resinous substance.
Reaction SMILES: Cl.C(O[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])C.C([O-])(=O)C.[NH4+:18].O.[OH-].[NH4+]>C(N(CC)CC)C.C(OCC)(=O)C>[N+:11]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:5]=1[NH2:18])([O-:13])=[O:12]
Reactant: CCOc1ccncc1[N+](=O)[O-]
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ccncc1[N+](=O)[O-]
Temperature: 4 °C
Yield: 86.6 %

Procedure:
A 500 ml 3-neck round bottom flask equipped with a condenser, thermometer and mechanical stirrer was charged with 78.4 g (0.383 mol) of 4-ethoxy-3-nitropyridine hydrochloride, 118.1 g (1.53 mol) of ammonium acetate and 183 ml of water. The stirred reaction mixture was refluxed for 71/2 hours and the progress of the reaction was followed by thin layer chromatography employing a 10:1 ethyl acetate:triethylamine solvent system. The reaction flask was chilled to approximately 4° C. after the pH of the mixture was adjusted from 5.2 to 8.1 with 60 ml of concentrated ammonium hydroxide. The yellow precipitate was collected by filtration, washed twice with chilled water and dried under vacuum at 50° C. for 10 hours. A total dry weight of 46.15 g (86.6% yield) of 3-nitro-4-aminopyridine was obtained. The product was verified by NMR and compared to an authentic sample.