Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:29])[NH:18][C:19]2[CH:28]=[C:27]3[C:22]([CH2:23][CH2:24][NH:25][CH2:26]3)=[CH:21][CH:20]=2)[CH:12]=1)=[O:8].CC(O)=O.[CH:39](=O)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[CH2:39]([N:25]1[CH2:24][CH2:23][C:22]2[C:27](=[CH:28][C:19]([NH:18][C:17]([C:13]3[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=3)[CH2:10][NH:9][C:7](=[O:8])[C:6]3[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:4]([O:3][CH3:2])[CH:5]=3)=[O:29])=[CH:20][CH:21]=2)[CH2:26]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3ccc4c(c3)CNCC4)c2)cc1OC
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3ccc4c(c3)CN(Cc3ccccc3)CC4)c2)cc1OC
Reaction time: 1 h

Procedure:
Suspended 3,4-Dimethoxy-N-[3-(1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzyl]-benzamide hydrochloride (50.0 mg, 0.104 mmol) in 2 mL of THF. To this was added AcOH (0.06 mL, 1.0 mmol) and benzaldehyde (0.016 mL, 0.150 mmol). The mixture stirred for 1 h. To this was added NaBH(OAc)3 (63.3 mg, 0.300 mmol). The mixture stirred for 50 h. LC-MS analysis indicated the desired product. Concentrated the mixture to dryness. Redissolved in CH2Cl2/MeOH and applied to a SiO2 prep plate. Eluted with (10% MeOH/1% NH3/CH2Cl2) to give 40.6 mg of N-[3-(2-Benzyl-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzyl]-3,4-dimethoxy-benzamide. MS, electrospray 536.4 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[CH:4][C:3]=1[C:12]([O:14]C)=O.C(O)(=O)C.[CH:20](=[NH:22])[NH2:21].[H-].[Na+]>O1CCOCC1>[OH:14][C:12]1[C:3]2[CH:4]=[N:5][CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]=2[N:21]=[CH:20][N:22]=1
Reactant: N=CN
Reactant: COC(=O)c1cncc(C(=O)OC)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC(=O)c1cncc2c(O)ncnc12
Temperature: 25 °C
Yield: 56.1 %

Procedure:
To the mixture of dimethyl 4-chloropyridine-3,5-dicarboxylate (0.6 g, 2.6 mmol) and formimidamide acetate (0.82 g, 7.8 mmol) in dioxane (20 mL) was added NaH (0.31 g, 7.8 mmol). The resulting mixture was refluxed for 48 hours, cooled to RT. The precipitate was filtered, and washed with EA to afford the title compound as grey solid (yield 56.1%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:18][CH2:19][CH2:20][CH2:21]I.[Na+].[Cl-]>CN(C)C=O.O>[Cl:18][CH2:19][CH2:20][CH2:21][O:15][C:11]1[CH:10]=[C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:14]=[N:13][CH:12]=1
Reactant: Oc1cncc(OCc2ccccc2)c1
Reactant: ClCCCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCOc1cncc(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, a solution of 5-(phenylmethoxy)pyridine-3-ol (1.52 g, 7.56 mmol) in N,N-dimethylformamide (DMF) (10 mL) was added drop-wise over 5 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.238 g of an 80% dispersion in mineral oil, 7.94 mmol) in DMF (15 mL). The mixture was allowed to stir and warm to ambient temperature over 1 h. Next, 1-chloro-3-iodopropane (1.85 g, 9.07 mmol) was added drop-wise over 5 min. The resulting dark-brown mixture was stirred at ambient temperature for 4 h. Water (25 mL) was added, followed by saturated NaCl solution (25 mL), and the mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give an oil.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=1[NH2:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[C:24](Cl)(Cl)=[S:25]>C(Cl)(Cl)Cl.O>[Si:1]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=1[NH:11][C:24]([NH:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:9]=1)=[S:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: S=C(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1cc([N+](=O)[O-])ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1cc([N+](=O)[O-])ccc1NC(=S)Nc1ccccc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
N-(2-tert-Butyldimethysilyloxy-4-nitrophenyl)-N′-phenyl-thiourea was prepared by treating a biphasic solution of 2-tert-butyldimethysilyloxy-4-nitroaniline (80 mg, 0.308 mmol) and NaHCO3 in CHCl3:H2O (2.5:1, 7 mL) with thiophosgene at 0° C. The solution was allowed to warm to 23° C. and the reaction was continued overnight. The CHCl3 layer was separated and dried over sodium sulfate. The solution was concentrated in vacuo and the residue was dissolved in toluene and treated with aniline (100 uL) at 23° C. for 12 h. The reaction mixture was concentrated and the residue was purified by flash chromatography (10% EtOAc/hexanes) to afford the titled compound as a yellow solid (120.8 mg, 98%) mp: 144-145° C.; 1H NMR (CD3OD/CDCl3): d 8.65 (d, 1H, J=10.0 Hz), 7.58 (d, 1H, J=10.0 Hz), 7.47 (d, 1H, J=1.25 Hz), 7.26 (m, 4H), 7.10(m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:14](O)=[O:15])=[CH:4][CH:3]=1.CN(C)C=O.O=S(Cl)[Cl:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:14]([Cl:26])=[O:15])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccccc1Oc1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)Cc1ccccc1Oc1ccc(Cl)cc1

Procedure:
[2-(4-chloro-phenoxy)-phenyl]-acetic acid (IX) (47.3 grams; 180 mmol) was suspended in toluene (140 ml) at 48° C. To this suspension dimethyl-formamide (4.0 ml) and SOCl2 (19.8 ml; 271 mmol; 1.5 eq) in toluene (18 ml) were added. After 10 min the reaction mixture was concentrated under vacuo and stripped twice with toluene, to yield a brownish oil of [2-(4-chloro-phenoxy)-phenyl]-acetyl chloride. The oil was suspended in toluene (75 ml). To the suspension was added at 5° C. a solution of sarcosine methylester (30.3 grams 217 mmol) and triethylamine (57 ml) in a mixture of dimethyl-formamide (236 ml) and toluene (47 ml). The brownish suspension was stirred for 2 hours at room temperature. To the reaction mixture water (750 ml) was added and the mixture was extracted twice with ethyl acetate (500 ml). The organic phase was washed with saturated brine (700 ml) and dried on magnesium sulphate. The solvent was removed in vacuum to yield methyl-N-[2-(4-chloro-2-phenoxyphenyl)-1-oxethyl]-N-methylglycinate (X) (61.3 grams, 202 mmol) as a brownish oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][CH2:4][C@@H:3]1[CH2:7][OH:8].C(N(CC)CC)C.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH2:16]([N:5]1[CH2:6][C@H:2]([OH:1])[C@@H:3]([CH2:7][OH:8])[CH2:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: OC[C@H]1CNC[C@@H]1O
Solvent: CCN(CC)CC
Solvent: CCO
Product: OC[C@H]1CN(Cc2ccccc2)C[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3R,4R)-(4-Hydroxypyrrolidin-3-yl)methanol (1.18 g) was dissolved in ethanol (25 mL). To this solution, triethylamine (1.40 mL) was added and while the mixture was chilled in a salt/ice water bath, benzyl bromide (1.10 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour and was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: ethyl acetate: methanol=20:1) to give (3R,4R)-(1-benzyl-4-hydroxypyrrolidin-3-yl)methanol as a milky white syrup (1.02 g).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]3[N:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][N:14]=3)[CH:8]=2)[C:3]=1[OH:26].[CH2:27]([CH:30]1[O:32][CH:31]1[CH2:33]O)[CH2:28][CH3:29]>>[F:1][C:2]1[C:3]([O:26][CH2:33][CH:31]2[CH:30]([CH2:27][CH2:28][CH3:29])[O:32]2)=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH:8]=[C:7]([C:13]1[N:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][N:18]=1)[CH:6]=[CH:5]2
Reactant: CCCC1OC1CO
Reactant: CCCCCCOc1cnc(-c2ccc3c(O)c(F)c(F)cc3c2)nc1
Product: CCCCCCOc1cnc(-c2ccc3c(OCC4OC4CCC)c(F)c(F)cc3c2)nc1

Procedure:
From 2,3-difluoro-6-(5-hexyloxypyrimidin-2-yl)naphthalen-1-ol and (3-propyloxiranyl)methanol by means of the Mitsunobu reaction.
Reaction SMILES: COC(=O)[CH:4]([C:17]#[N:18])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6].[Cl-].[Na+].O>CS(C)=O.[Cl-].[Na+].O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]([CH3:6])([CH3:7])[CH2:4][C:17]#[N:18])=[C:9]([O:15][CH3:16])[CH:10]=1
Reactant: COC(=O)C(C#N)C(C)(C)c1ccc(F)cc1OC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(F)ccc1C(C)(C)CC#N
Reaction time: 4 h
Yield: 80.9 %

Procedure:
A mixture of 4.2 g (15.03 mmol) of 2-cyano-3-(4-fluoro-2-methoxyphenyl)-3-methylbutyric acid methyl ester and 2.5 g (42.77 mmol) of sodium chloride in 40 mL of DMSO with 2 mL of water was warmed to reflux. Gas evolution was clearly evident early in the reaction. After 4 hours, the reaction was cooled and diluted with 100 mL of brine and extracted with four 75 mL portions of EtOAc. The combined organic layers were washed with six 50 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated to afford an oil which solidified under vacuum. The tan solid was triturated with hexanes and collected by filtration to afford 2.52 g (81%) of 3-(4-fluoro-2-methoxyphenyl)-3-methylbutyronitrile, m.p. 80° C.-83° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:30]([C:32]2[S:36][C:35]3[CH:37]=[CH:38][CH:39]=[C:40]([F:41])[C:34]=3[C:33]=2[Cl:42])=[O:31])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:19]=[CH:18][C:17]=2[O:28][CH3:29])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:19]=[CH:18][C:17]=2[O:28][CH3:29])[C:30]([C:32]2[S:36][C:35]3[CH:37]=[CH:38][CH:39]=[C:40]([F:41])[C:34]=3[C:33]=2[Cl:42])=[O:31])[CH2:10][CH2:9]1
Reactant: COc1ccc(-c2cccnc2)cc1CN(C(=O)c1sc2cccc(F)c2c1Cl)C1CCC(NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2cccnc2)cc1CN(C(=O)c1sc2cccc(F)c2c1Cl)C1CCC(N)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48 %

Procedure:
410 is prepared according to a method similar to Method G. {4-[(3-Chloro-4-fluoro-benzo-[b]thiophene-2-carbonyl)-(2-methoxy-5-pyridin-3-yl-benzyl)-amino]-cyclohexyl}-carbamic acid tert-butyl ester (N3) (0.93 g, 1.48 mmol) is dissolved in 10 mL methylene chloride. Trifluoroacetic acid is added (0.35 mL) and the mixture is stirred at room temperature for 20 minutes. The reaction mixture is evaporated and pumped dry. The residue is partitioned between 5% methanol/methylene chloride and half-saturated aqueous sodium bicarbonate. The aqueous layer is extracted with 5% methanol/methylene chloride, and the combined organic extracts are dried (MgSO4), filtered and evaporated to yield an ivory solid (0.375 g, 0.717 mmol; 48% yield) that was pure by LCMS analysis.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=1[O:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CCOC(C)=O>[CH:1]1([N:6]2[C:10]3=[N:11][C:23]([C:22]4[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[C:20]([O:27][CH2:28][CH2:29][N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[CH:21]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C=O)cc1OCCN1CCOCC1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Solvent: CCOC(C)=O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc(OC)c(OCCN4CCOCC4)c3)nc(=O)c1-2
Temperature: 160 °C

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.25 g, 5.63 mmol), 4-methoxy-3-[2-(4-morpholinyl)ethoxy]benzaldehyde (1.64 g), and xylenes (12 ml) was heated at 160° C. overnight. Additional aldehyde (0.5 g) was added and the mixture was refluxed until complete, then cooled to room temperature. The solvent was stripped, the residue was slurried with EtOAc and the product was collected by filtration and combined with the product from a similar experimental run. The combined product was recrystallized from CH3CN to afford 1-cyclopentyl-3-ethyl-6-[4-methoxy-3-[2-(4-morpholinyl)ethoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-one, m.p. 205°-206° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[CH3:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=O>>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][CH:17]1[C:12]2([CH3:11])[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CC1CCCCC1=O
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Product: CC12CCCCC1Nc1ccc(Br)cc12
Yield: 63 %

Procedure:
This compound was prepared by the procedure of Example 1 using 4-bromo-phenyl hydrazine hydrochloride (2.0 g, 8.95 mmol) and 2-methylcyclohexanone (1.0 g, 8.95 mmol). The subtitled compound (1.5 g, 65%) was obtained as a yellow oil: 1H NMR (CDCl3) δ1.26 (s, 3H), 1.38-1.46 (m, 4H), 1.56-1.68 (m, 4H), 3.4 (t, J=4.4 Hz, 1H), 3.6 (br s, 1H), 6.53 (d, J=8 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 7.09 (dd, J=8.0, 2.0 Hz, 1H); 13C-NMR (CDCl3) δ21.45, 21.87 (t), 23.96 (q), 27.92, 35.32 (t), 43.56 (s), 66.65 (d), 110.73 (s), 111.88, 125.25, 129.99 (d), 142.17, 149.03 (s); MS (EI) m/z 268, 270 (M+H)+.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2.[C:16]1([CH:22]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[C:31]1([CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH2:15][CH:2]([OH:1])[CH2:3][O:4][C:5]3[CH:14]=[CH:13][CH:12]=[C:11]4[C:6]=3[CH:7]=[CH:8][CH:9]=[N:10]4)[CH2:29][CH2:30]2)=[O:24])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(C(c1ccccc1)c1ccccc1)N1CCNCC1
Reactant: c1cc(OCC2CO2)c2cccnc2c1
Solvent: CCO
Product: O=C(C(c1ccccc1)c1ccccc1)N1CCN(CC(O)COc2cccc3ncccc23)CC1
Yield: 62.6 %

Procedure:
71 g of the above-mentioned 5-(2,3-epoxypropoxy) quinoline and 94 g of N-(2,2-diphenylacetyl)piperazine were dissolved in 1.5 l of ethanol and then the resulting solution was refluxed with heating for 3 hours. After the reaction, ethanol was evaporated and the residue was purified by chromatography. The elution was carried out with a solvent miture of chloroform:methanol=50:1 (volume ratio) and the targeted fraction was concentrated under reduced pressure to obtain 101 g of 5-[3-{4-(2,2diphenylacetyl)piperazin-1-yl}-2- hydroxypropoxy]quinoline (compound No. 1).
Reaction SMILES: [C:1]1(=[O:10])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][NH:2]1.C(N(CC)CC)C.[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>O1CCCC1.CN(C)C1C=CN=CC=1>[C:22]([O:21][C:19]([N:2]1[CH2:3][CH:4]2[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[C:1]1=[O:10])=[O:18])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=C1NCC2CCCCC12
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2CCCCC2C1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 3 (835 mg, 6 mmol) in suspension in tetrahydrofuran (7 mL) was successively added, under an argon atmosphere, 4-dimethylaminopyridine (18.3 mg; 0.15 mmol), triethylamine (0.84 mL; 6 mmol) and BOC2O (2.62 g; 12 mmol). The reaction mixture was stirred at room temperature for 3 days. The solvent was removed under vacuum. The residue was diluted with diethyl ether (20 mL) and washed with water (2×10 mL). The phases were separated, and the organic phase was dried over MgSO4 and concentrated. The crude oil was purified over silica gel chromatography (ether/heptane 1:1) to give 4 (986 mg; 4.1 mmol; 70%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:24])[C:7](=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)[C:27](O)=[O:28]>C1(C)C=CC=CC=1.[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>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:6]2[O:24][C:27](=[O:28])[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=3)[C:7]=2[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccc(C=C2C=C(C(C)(C)C)C=C(C(C)(C)C)C2=O)cc1C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc1C
Temperature: 80 °C
Yield: 66 %

Procedure:
A solution of 645 mg (2.0 mmol) of a mixture of 2,4-di-tert-butyl-6-(3,4-dimethyl-benzylidene)-cyclohexa-2,4-dieone (compound (301), Table 3) and the corresponding dimer (compound (401), Table 4), prepared according to Example 1b in 7 ml of toluene is degassed using argon and then 58 mg (0.05 mmol) of tetrakis(triphenylphosphine)-palladium(0) and 23 mg (0.20 mmol) of trifluoroacetic acid are added. The autoclave is flushed with carbon monoxide and sealed, and a carbon monoxide pressure of 5 bar is then applied. The reaction mixture is maintained at 80° C. for 20 hours. After cooling to room temperature, the reaction mixture is poured into water and extracted three times using ethyl acetate. The organic phases are combined, dried over sodium sulfate and concentrated using a vacuum rotary evaporator. Crystallisation of the residue from ethanol yields 464 mg (66%) of 5,7-di-tert-butyl-3-(3,4-dimethyl-phenyl)-3H-benzofuran-2-one (compound (101), Table 1), m.p. 130-132° C. Analysis, calculated: C 82.24; H 8.63%. Analysis, found: C 82.20; H 8.68%.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]2[C:8]([F:28])=[C:9]([N:13]([CH2:25][O:26][CH3:27])[S:14]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[F:24])(=[O:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[N:4][NH:5][CH:6]=1.[H-].[Na+].Br[CH2:32][CH2:33][O:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([C:7]2[C:8]([F:28])=[C:9]([N:13]([CH2:25][O:26][CH3:27])[S:14]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[F:24])(=[O:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[N:4][N:5]([CH2:32][CH2:33][O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH:6]=1
Reactant: BrCCOC1CCCCO1
Reactant: COCN(c1cccc(-c2n[nH]cc2Br)c1F)S(=O)(=O)c1cc(F)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCN(c1cccc(-c2nn(CCOC3CCCCO3)cc2Br)c1F)S(=O)(=O)c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
A solution of N-[3-(4-Bromo-1H-pyrazol-3-yl)-2-fluoro-phenyl]-2,5-difluoro-N-methoxymethyl-benzenesulfonamide (346 mg, 0.726 mmol)(prepared as described in Preparation 1) in anhydrous DMF (4 mL) was cooled to 0° C. under an argon atmosphere and sodium hydride (60% in mineral oil, 87 mg, 2.179 mmol, 3 eq) was added. The mixture was stirred at 0° C. for 30 minutes, then 2-(2-bromo-ethoxy)-tetrahydro-pyran (0.165 mL, 1.089 mmol, 1.5 eq) was added dropwise and the mixture was stirred at 0° C. for 1 hour. The reaction mixture was then diluted with AcOEt and washed with water and brine. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (cyclohexane/AcOEt 55:45) affording 243 mg (55%) of the desired regioisomer N-(3-{4-Bromo-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-3-yl}-2-fluoro-phenyl)-2,5-difluoro-N-methoxymethyl-benzenesulfonamide. HPLC (254 nm): Rt: 7.21 min; 1H NMR (DMSO-d6) Shift (selected signals): 8.07 (s, 1H), 7.55-7.69 (m, 2H), 7.47-7.53 (m, 2H), 7.39-7.45 (m, 1H), 7.30-7.35 (m, 1H), 5.09 (s, 2H), 4.51-4.57 (m, 1H), 4.29-4.35 (m, 2H), 3.89-3.97 (m, 1H), 3.70-3.78 (m, 1H), 3.42-3.51 (m, 1H), 3.38 (s, 3H), 1.29-1.69 (3 m, 6H); HRMS (ESI) calcd for C24H26BrF3N3O5S [M+H]+ 604.0723. found 604.0693.
Reaction SMILES: [O:1]=[C:2]([CH2:16][CH2:17][CH:18]1[NH:21][C:20](=[O:22])[CH:19]1[NH:23][C:24](=[O:32])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:5].O=C(CCC1NC(=O)C1NC(=O)COC1C=CC=CC=1)CC(OCC1C=CC([N+]([O-])=O)=CC=1)=O.C1(C)C=CC(S([N:76]=[N+:77]=[N-])(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C>C(#N)C>[N+:76](=[C:3]([C:2](=[O:1])[CH2:16][CH2:17][CH:18]1[NH:21][C:20](=[O:22])[CH:19]1[NH:23][C:24](=[O:32])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:5])=[N-:77]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: COc1ccc(COC(=O)CC(=O)CCC2NC(=O)C2NC(=O)Cc2ccccc2)cc1
Agent: O=C(CCC1NC(=O)C1NC(=O)COc1ccccc1)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COC(=O)C(=[N+]=[N-])C(=O)CCC2NC(=O)C2NC(=O)Cc2ccccc2)cc1
Reaction time: 0.17 h
Yield: 86.8 %

Procedure:
A solution of 4-methoxybenzyl 3-oxo-5-[(3SR,4RS)-3-phenylacetamidoazetidin-2-on-4-yl]pentanoate (1.38g, 3.15mmol) [prepared by the method described for 4-nitrobenzyl 3-oxo-5-[(3SR,4RS)-3-phenoxyacetamidoazetidin-2-on-4-yl]pentanoate, C. Bodurow and M. A. Carr, Tetrahedron Lett., 1989, 30, 4801] in acetonitrile (60ml) was treated with 4-toluenesulphonyl azide (870mg, 4.42mmol) and N,N-diisopropylethylamine (822μl, 4.73mmol) at 0° C. After 10 min., the ice-bath was removed and stirring was continued at room temperature for 2h. The reaction mixture was diluted with ethyl acetate and washed with brine. After drying over MgSO4, the solvent was evaporated in vacuo and the residue purified by chromatography on silica gel eluting with ethyl acetate to yield the title compound (1.27g, 87%); vmax (KBr) 2134, 1775, 1717, 1654, 1513 and 1304cm-1 ; δH (CDCl3, 250MHz) 1.59-1.70 (2H,m), 2.68-2.95 (2H,m), 3.55 and 3.65 (2H, ABq, J 15.6Hz), 3.78 (1H,m), 3.82 (3H,s), 5.19 (2H,s), 5.25 (1H, ddd, J 8.1, 4.9, 1.0Hz), 6.25 (1H, br s, exch.), 6.49 (1H, br d, J 8.1Hz, exch.), 6.90 (2H,d, J 8.7Hz) and 7.23-7.70 (7H,m). [Mass spectrum : +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (487)].
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8][N:9]2[CH:14]2[CH2:16][CH2:15]2)=[CH:4][C:3]=1[F:23].[C:24]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])#[N:25].CC(C)([O-])C.[K+].Cl>O1CCOCC1>[C:12]([C:11]1[C:2]([CH:26]([C:24]#[N:25])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:3]([F:23])[CH:4]=[C:5]2[C:10]=1[N:9]([CH:14]1[CH2:16][CH2:15]1)[CH:8]=[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:6]2=[O:22])#[N:13]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(C#N)c(Cl)c(F)cc2c1=O
Reactant: CCOC(=O)CC#N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C2CC2)c2c(C#N)c(C(C#N)C(=O)OCC)c(F)cc2c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2.8 g of ethyl 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylate and 1.92 g of ethyl cyanoacetate are initially introduced into 30 ml of dioxane. 1.91 g of potassium tert-butoxide are metered in at room temperature. The mixture is stirred overnight and then ice-water is added. It is rendered acidic using HCl and extracted using methylene chloride. The organic phase is dried and concentrated. The residue is stirred once more with water and the solid is isolated.
Reaction SMILES: [C:1]([C:3]([OH:10])([CH2:7][CH2:8][CH3:9])[CH2:4][CH2:5][CH3:6])#[CH:2].Br[C:12]1[CH:13]=[C:14]([CH:18]([OH:22])[CH2:19][C:20]#[N:21])[CH:15]=[CH:16][CH:17]=1>>[OH:22][CH:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:2]#[C:1][C:3]([OH:10])([CH2:7][CH2:8][CH3:9])[CH2:4][CH2:5][CH3:6])[CH:13]=1)[CH2:19][C:20]#[N:21]
Reactant: C#CC(O)(CCC)CCC
Reactant: N#CCC(O)c1cccc(Br)c1
Product: CCCC(O)(C#Cc1cccc(C(O)CC#N)c1)CCC

Procedure:
Coupling of 4-ethynylheptan-4-ol with 3-(3-bromophenyl)-3-hydroxypropanenitrile following the method described in Example 12 gives 3-hydroxy-3-(3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)propanenitrile as a light yellow oil.