Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:6]1[C:12]([OH:13])=[CH:11][C:10]([OH:14])=[CH:9][C:7]=1[OH:8])[CH:2]=[C:3]([CH3:5])[CH3:4].[C:15](Cl)(=[O:19])[CH2:16][CH2:17][CH3:18]>>[OH:8][C:7]1[C:9]([C:15](=[O:19])[CH2:16][CH2:17][CH3:18])=[C:10]([OH:14])[C:11]([C:7](=[O:8])[CH2:6][CH2:1][CH3:2])=[C:12]2[C:6]=1[CH2:1][CH2:2][C:3]([CH3:5])([CH3:4])[O:13]2
Reactant: CCCC(=O)Cl
Reactant: CC(C)=CCc1c(O)cc(O)cc1O
Product: CCCC(=O)c1c(O)c2c(c(C(=O)CCC)c1O)OC(C)(C)CC2

Procedure:
Phloroglucinol was treated with prenylchloride using the same procedure as described in Example 2 to yield prenylphloroglucinol. Prenylphloroglucinol was treated with butyrylchloride, according to the same procedure as described for the preparation of 2,4-dibutyrylphoroglucinol in Example 34 (Method 2) to yield 5,7-dihydroxy-6,8-dibutyryl-2,2-dimethylchroman (36 after chromatography with silica gel (petroleum ether, ethyl acetate, 4:1).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.[CH2:31]([OH:36])[CH2:32][CH2:33][C:34]#[CH:35].CCN(CC)CC>C(Cl)(Cl)Cl.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.[Cu]I>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:35]=[C:34]([CH2:33][CH2:32][CH2:31][OH:36])[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCCCO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c(CCCO)cc3cc(CN4CCOCC4)cc(c1=O)c32
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
A suspension of N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (800 mg), PdCl2(PPh3)2 (104.6 mg), CuI (34.1 mg), 4-pentyn-1-ol (0.17 mL), and Et3N (0.42 mL) in CHCl3 (14.9 mL) is stirred at room temperature overnight. Reaction condensed to remove CHCl3. The solvent is replaced with EtOH (15 mL) and additional Et3N (0.38 mL) is added to the reaction mixture. N2 is passed over the surface and the reaction is heated at 76° C. for 6 h, then allowed to cool to room temperature. Reaction mixture is condensed, adsorbed onto silica, and chromatographed eluting with 1% MeOH in CH2Cl2 to 3% MeOH in CH2Cl2. Product-containing fractions are combined, condensed, and recrystallized from hot acetonitrile to afford 408.9 mg (56%) of N-(4-chlorobenzyl)-2-(3-hydroxypropyl)-8-(4-morpholinylmethyl)-6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12][C:11]=3[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](O)[CH3:20].C1C=CC=CC=1.S(=O)(=O)(O)O>O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]([C:15]([O:17][CH2:19][CH3:20])=[O:16])[CH2:12][C:11]=3[CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1Cc2cc(-c3ccccc3)ccc2O1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C1Cc2cc(-c3ccccc3)ccc2O1

Procedure:
A mixture of 2.5 g of 1D, 60 ml of ethanol, 20 ml of dry benzene and 2 ml of concentrated sulfuric acid was refluxed for seven hours, with removal of water as it formed. The resulting mixture was concentrated, and the residue dissolved in ether. The solution was washed with saturated sodium bicarbonate solution and water. The aqueous portion was extracted with ether. The combined organic layers were dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was distilled to give ethyl 2,3-dihydro-5-phenylbenzofuran-2-carboxylate (1E), as a colorless liquid, bp: 180°-181° C., 0.35 Torr.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][O:40][C:41]1[CH:46]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:44]=[CH:43][C:42]=1[OH:56].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[OH:56][C:42]1[CH:43]=[CH:44][C:45]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)=[CH:46][C:41]=1[O:40][CH3:39]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)ccc1O
Yield: 76 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.13 mmol) was treated with 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (101 mg, 0.32 mmol), sodium carbonate (34 mg, 0.32 mmols) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (8 mg, 0.01 mmol) using 1,2-dimethoxyethane (0.96 ml) and water (0.24 ml) as a solvents according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 80%, hexane-ethyl acetate) to give 63 mg (68% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:27])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1([OH:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(OB(O)OC(=O)C)(=O)C.[CH:38]1([N:41]2[C:50]3[C:45](=[CH:46][C:47]([F:54])=[C:48](F)[C:49]=3[O:51][CH3:52])[C:44](=[O:55])[C:43]([C:56]([OH:58])=[O:57])=[CH:42]2)[CH2:40][CH2:39]1.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[C:24]([NH:23][CH2:22][C@@H:20]1[O:19][C:18](=[O:27])[N:17]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]3([OH:16])[CH2:15][CH2:14][N:13]([C:48]4[C:49]([O:51][CH3:52])=[C:50]5[C:45]([C:44](=[O:55])[C:43]([C:56]([OH:58])=[O:57])=[CH:42][N:41]5[CH:38]5[CH2:40][CH2:39]5)=[CH:46][C:47]=4[F:54])[CH2:12][CH2:11]3)=[C:2]([F:1])[CH:3]=2)[CH2:21]1)(=[O:26])[CH3:25]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(O)CCNCC3)c(F)c2)C(=O)O1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: CC(=O)OB(O)OC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(N2CCC(O)(COc3ccc(N4C[C@H](CNC(C)=O)OC4=O)cc3F)CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
In analogy to example 76 with 114 mg N-[{(5S)-3[3-fluoro-4-(4-hydroxy-piperidin-4-ylmethoxy)-phenyl]-2-oxo-oxazolidin-5-yl-methyl}]-acetamide. (MW: 381.40 0.3 mmol), 127 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid diacetylborate (Sakurai, Nobuhiro; Sano, Mitsuharu; Hirayama, Fumihiro; Kuroda, Tsuyoshi; Uemori, Satoru; Bioorg. Med. Chem. Lett.; 8; 16; 1998; 2185-2190) (MW: 423.137, 0.3 mmol) and 38 mg of ethyl diisopropylamine (MW: 129.25, 0.3 mmol) in 1 ml N-methyl-pyrrolidin-2-one. Yield: 137 mg, 69.5%. MS: 658.2 (M+H)+, 655.8 (M+H)−, Method ESI+, ESI−.
Reaction SMILES: COC(OC)C[C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](N)=[O:8].[NH+:16]1C=CC=[CH:18][CH:17]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1>C1C=CC=CC=1>[N:13]1[C:5]2[N:16]=[CH:17][CH:18]=[C:7]([OH:8])[C:6]=2[CH:10]=[CH:11][CH:12]=1
Reactant: c1cc[nH+]cc1
Reactant: COC(Cc1ncccc1C(N)=O)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccccc1
Product: Oc1ccnc2ncccc12

Procedure:
The product from Example 228c (1.36 g, 6.47 mmol) was dissolved in benzene (35 ml) and to this solution was added pyridinium-para-toluenesulfonate (0.20 g, 0.8 mmol). The mixture was heated to reflux for 23 h then concentrated under vacuum to give the title compound in quantitative yield sufficiently pure for use as isolated.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:15][O:14][C:13]2[CH:16]=[C:17](C)[CH:18]=[CH:19][C:12]=2[NH:11][C:10]1=[O:21].C(OC(N[C@@H](CO)C(O)=O)=O)(C)(C)C.FC1C=CC([C:43]([F:46])([F:45])[F:44])=CC=1[N+]([O-])=O>CCCCCC>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:15][O:14][C:13]2[CH:16]=[CH:17][C:18]([C:43]([F:46])([F:45])[F:44])=[CH:19][C:12]=2[NH:11][C:10]1=[O:21]
Reactant: Cc1ccc2c(c1)OC[C@H](N)C(=O)N2
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1COc2ccc(C(F)(F)F)cc2NC1=O

Procedure:
In a similar manner to that described for the preparation of (S)-3-amino-8-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one trifluoroacetate except in Step 3 the reaction mixture was stirred for 4 h and in the material obtained in Step 4 was triturated with hexane, (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (4.1 g, 20.0 mmol) and 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (4.18 g, 20.0 mmol) were converted to the title compound (1.06 g) which was used without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])=[O:13])=[CH:8][CH:7]=1.[C:25]([C:27]1[CH:28]=[C:29]([CH:44]=[CH:45][CH:46]=1)[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:32]=1)#[CH:26].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCCCCC>[O:37]([C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[O:30][C:29]1[CH:28]=[C:27]([C:25]#[C:26][C:2]2[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=2)[O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])=[O:13])=[CH:8][CH:7]=2)[CH:46]=[CH:45][CH:44]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=C(C(=O)c1ccc(Oc2cccc(Br)c2)cc1)c1ccccc1
Reactant: C#Cc1cccc(Oc2cccc(Oc3ccccc3)c2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: O=C(C(=O)c1ccc(Oc2cccc(C#Cc3cccc(Oc4cccc(Oc5ccccc5)c4)c3)c2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.1 %

Procedure:
To a 250 ml flask fitted with a reflux condenser, nitrogen inlet and thermometer were added 4(3-bromophenoxy)benzil (11.08 g, 29.08 mmol), 1-(3-ethynylphenoxy)-3-phenoxybenzene (21.64 g, 75.66 mmol), triethylamine (150 ml), and triphenylphosphine (0.40 g). After stirring at room temperature under a nitrogen atmosphere for 10 minutes, cuprous iodide (Alfa 98%, 0.20 g) and dichlorobis (triphenylphosphine) palladium (II) (0.20 g) were added. The flask was heated to an internal temperature of 90° C. and maintained by oil bath heating under nitrogen until TLC indicated reaction completion (4 hr). The triethylamine was distilled from the residue and the residue was suspended in toluene. The toluene was washed with 15% HCl (560 ml) twice and separated. The organic layer was washed with ethylenediamine (20 ml) by adding the ethylenediamine at room temperature, heating to 60° C. for 0.5 h and cooling. Water (250 ml) was added and the toluene was separated from the aqueous layer. The ethylenediamine wash was repeated once more. After washing with water (3×500 ml), the organic layer was dried over anhydrous magnesium sulfate (3.00 g) and the toluene distilled by rotary evaporation at reduced pressure to give a dark brown oil. The oil was dissolved in 4:1 hexane:methylene chloride and chromatographed on a silica gel column (Woelm DCC, 230 g, 5 cm dia×25 cm H) using 4:1 hexane:methylene chloride as the eluent. The product was dried in a 70° C. oven under reduced pressure to afford a light brown tacky oil (7.52 g, 44%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][CH2:17]C[C:15]2=[O:20])[C:3]=1[CH3:21].[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]([NH2:34])[CH:31]=[N:32][CH:33]=2)[CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:34][C:30]1[CH:31]=[N:32][CH:33]=[C:28]([N:25]3[CH2:26][CH2:27][O:22][CH2:23][CH2:24]3)[CH:29]=1)=[C:3]([CH3:21])[C:4]([N:14]1[CH2:19][CH2:18][CH2:17][C:15]1=[O:20])=[N:5]2
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: Cc1c(N2CCCCC2=O)nc2cc(F)cc(F)c2c1Br
Solvent: Cc1ccccc1
Product: Cc1c(N2CCCC2=O)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Essentially prepared according to Procedure H using 1-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)piperidin-2-one (75.0 mg, 0.21 mmol) and 5-morpholinopyridin-3-amine in toluene to give 1-(5,7-difluoro-3-methyl-4-((5-(4-morpholinyl)-3-pyridinyl)amino)-2-quinolinyl)-2-pyrrolidinone. 1H NMR (400 MHz, CDCl3) δ ppm 7.90 (1H, d, J=2.5 Hz), 7.86 (1H, d, J=2.3 Hz), 7.46 (1H, ddd, J=9.6, 2.5, 1.4 Hz), 7.24 (1H, d, J=14.1 Hz), 6.99 (1H, ddd, J=13.9, 8.6, 2.5 Hz), 6.54 (1H, t, J=2.4 Hz), 4.22-4.33 (1H, m), 3.82 (4H, t, J=4.8 Hz), 3.48-3.58 (1H, m), 3.13-3.28 (4H, m), 2.50-2.58 (2H, m), 2.07-2.14 (1H, m), 1.95-2.04 (3H, m), 1.94 (3H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[F:14][C:15]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:16]=1[CH:17]=[N:18][CH:19]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:20][OH:21]>CCOCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C@H:17]([NH:18][C@@H:19]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:20][OH:21])[C:16]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:15]=2[F:14])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CC(C)CC(CO)N=Cc1ccc(F)cc1F
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)C[C@@H](CO)N[C@@H](c1ccc(Br)cc1)c1ccc(F)cc1F
Reaction time: 1 h

Procedure:
To a solution of 1,4-dibromobenzene (24.5 g, 100 mmol, 5eq) in dry ether (200 mL) under nitrogen atmosphere at −30° C., nBuLi (64.75 mL, 1.6 M solution in hexanes, 5 eq) was added and the reaction mixture was stirred for 1 h. A solution of 2-[(2,4-difluorobenzylidene)-amino]-4-methylpentan-1-ol (5 g, 20 mmol) in dry ether was added slowly at −30° C. After stirring for 4 h, the reaction was quenched with water. The ether layer was washed with saturated solution of NaCl, and dried over MgSO4. The solvent was removed under reduced pressure and the crude was flash chromatographed on 500 cm3 of silica gel using 8:2 hexanes:EtOAc as an eluant to yield (2S)-2-{(S)-[(4-bromophenyl)-(2,4-difluorophenyl)-methyl]-amino}-4-methylpentan-1-ol.
Reaction SMILES: [C:1]1([CH2:14][O:15][C:16](Cl)=[O:17])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[S-:19][C:20]#[N:21].[K+]>>[C:1]1([CH2:14][O:15][C:16]([N:21]=[C:20]=[S:19])=[O:17])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)OCc1cccc2c1Cc1ccccc1-2
Reactant: N#C[S-]
Agent: [K+]
Product: O=C(N=C=S)OCc1cccc2c1Cc1ccccc1-2

Procedure:
The title compound was prepared from Fluorenylmethyloxycarbonyl chloride and potassium thiocyanate according to the procedure of Kearney et al. J. Org. Chem. 1998, 63, 199; 1H NMR (CDCl3) δ7.75 (d, J=7.5 Hz, 2H), 7.56 (d, J=7.5 Hz, 2H), 7.41 (t, J=7.5 Hz, 2H), 7.32 (t, J=7.5 Hz, 2H), 4.44 (d, J=7.4 Hz, 2H), 4.23 (t, J=7.4 Hz, 1H).
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[N:10]1([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3([CH2:31][N:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1.N1C=CC=CC=1>ClCCl>[CH3:1][S:2]([N:35]1[CH2:36][CH2:37][N:32]([CH2:31][C:25]2([C:22]3[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][CH2:15][N:10]4[CH2:11][CH2:12][CH2:13][CH2:14]4)=[CH:24][CH:23]=3)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[CH2:33][CH2:34]1)(=[O:5])=[O:3]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: c1cc(C2(CN3CCNCC3)CCCCC2)ccc1OCCCN1CCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCCCC2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.2 %

Procedure:
Methanesulphonic acid anhydride (49 mg, 0.28 mmol) was added at 0° C. to a solution of 1-({1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexyl}methyl) piperazine (90 mg, 0.23 mmol) and pyridine (47 μl, 0.58 mmol) in dichloromethane (1 ml). The reaction was stirred at 0° C. for 10 minutes, then allowed to warm up to room temperature and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure and partitioned between dichloromethane (20 ml) and aqueous sodium carbonate (20 ml). The layers were separated. The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.4 by volume) to provide the title compound (61 mg, 56%). 1H NMR (400 MHz, CDCl3) δ 1.29-1.36 (m, 3H), 1.45-1.52 (m, 5H), 1.85-1.90 (m, 4H), 2.08-2.15 (m, 4H), 2.22 (t, 4H), 2.32 (s, 2H), 2.67-2.79 (m, 9H), 3.00-3.03 (m, 4H), 4.02 (t, 2H), 6.83 (d, 2H), 7.24 (d, 2H). HRMS ESI+ m/z 464.2931 [MH]+.
Reaction SMILES: [Mg].C(Br)C.CC#C.[O:8]([C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1C=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[O:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[C:26]([CH:25]([OH:24])[C:21]1[CH:20]=[CH:19][CH:16]=[C:15]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:22]=1)#[C:27][CH3:28]
Reactant: O=Cc1ccccc1Oc1ccccc1
Reactant: C1CCOC1
Agent: C#CC
Agent: Cl
Agent: [Mg]
Solvent: CCBr
Product: CC#CC(O)c1cccc(Oc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A Grignard solution, freshly prepared from 4 g of magnesium and 20 g of ethyl bromide in 20 ml of tetrahydrofuran, is slowly added at 0° C. to a solution of 8 g of methylacetylene in 100 ml of tetrahydrofuran, and the mixture is stirred under argon for 15 minutes. There is then added dropwise to this mixture at 0° to 5° C. a solution of 27 g of o-phenoxybenzaldehyde in 100 ml of tetrahydrofuran. After being stirred for 14 hours at room temperature, the reaction mixture is cooled to 0° C. with 50 g of ice; 25 ml of conc. hydrochloric acid is subsequently slowly added, and extraction is performed with ether. The ether extract is washed twice with water and twice with saturated sodium chloride solution; it is then dried over sodium sulfate, filtered, and concentrated by evaporation. The product is chromatographed through silica gel with ethyl acetate/hexane (1:1) as the eluant. There is thus obtained the compound of the formula ##STR5## having a refractive index of nD20 =1.5898.
Reaction SMILES: Cl[S:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:4])=[O:3].[CH2:17]([NH2:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(N(CC)C(C)C)(C)C.Cl>ClCCl>[CH2:17]([NH:23][S:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:4])=[O:3])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCN
Reactant: CCOC(=O)CCCCCCCS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCNS(=O)(=O)CCCCCCCC(=O)OCC
Temperature: 25 °C
Reaction time: 22 h
Yield: 95 %

Procedure:
Ethyl 8-chlorosulfonyl-octanoate (No. 6804260; 692.3 mg, 2.56 mmol) was dissolved in dichloromethane (4.0 mL), and a solution of hexylamine (310.5 mg, 3.07 mmol) in dichloromethane (3.0 mL) and N,N-diisopropylethylamine (668 μL, 3.84 mmol) were added in order. The mixture was stirred at room temperature for 22 hours. After completing the reaction, the mixture was neutralized by adding 1 M hydrochloric acid, and extracted with dichloromethane. The organic layer was washed with water and a saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off. The resulting residue was then purified with SP1 (SiO2 cartridge, 25% ethyl acetate/n-hexane, Rf=0.5) to obtain ethyl 8-hexylsulfamoyl-octanoate (No. 6804262; 818.3 mg, 95% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([C:11]1[CH:12]=[CH:13][C:14]([F:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:16]=1)#[CH:10]>C1COCC1.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.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([C:10]#[C:9][C:11]2[CH:12]=[CH:13][C:14]([F:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([F:20])([F:21])[F:22])[CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C#Cc1ccc(F)c(NC(=O)C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: O=C(Nc1cc(C#Cc2ccnc(Cl)n2)ccc1F)C(F)(F)F
Temperature: 60 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To an oven-dried flask under N2 was added 2,4-dichloropyrimidine (5.1 g, 34 mmol), anhydrous degassed THF (250 mL), dichlorobis(triphenylphosphine)-palladium(II) (595 mg, 0.85 mmol), copper(I) iodide (97 mg, 0.5 mmol), and TEA (9.5 mL, 68 mmol), and the resulting suspension was heated to 60° C. A solution of N-(5-ethynyl-2-fluorophenyl)-2,2,2-trifluoroacetamide (3.9 g, 17 mmol) in THF (100 mL) was added dropwise, and the resulting mixture stirred overnight at 60° C. After 16 h, the crude reaction mixture was filtered through celite, adsorbed to silica gel, and purified by column chromatography to afford the desired product (4.6 g, 78%) as an off white solid. 1H NMR (400 MHz, CDCl3): δ 8.65 (d, J=5.1 Hz, 1H), 8.58 (d, J=7.3 Hz, 1H), 7.49 (m, 1H), 7.41 (d, J=5.0 Hz, 1H), 7.24 (m, 1H). ES-LC/MS m/z=344 [M+H]+.
Reaction SMILES: [N:1]1([C:6]2[C:11]([F:12])=[CH:10][C:9]([N:13]3[CH2:17][C@H:16]([C:18]([O:20]C)=O)[O:15][C:14]3=[O:22])=[CH:8][C:7]=2[F:23])[CH2:5][CH:4]=[CH:3][CH2:2]1.[NH3:24]>CO>[N:1]1([C:6]2[C:11]([F:12])=[CH:10][C:9]([N:13]3[CH2:17][C@H:16]([C:18]([NH2:24])=[O:20])[O:15][C:14]3=[O:22])=[CH:8][C:7]=2[F:23])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: N
Reactant: COC(=O)[C@H]1CN(c2cc(F)c(N3CC=CC3)c(F)c2)C(=O)O1
Solvent: CO
Product: NC(=O)[C@H]1CN(c2cc(F)c(N3CC=CC3)c(F)c2)C(=O)O1
Yield: 58 %

Procedure:
A solution of methyl (5R)-3-[4-(2,5-dihydro-1H-pyrrol-1-yl)-3,5-difluorophenyl]-2-oxo-5-oxazolidine-5-carboxylate (Step 4, 0.09 g, 0.28 mmol) in 2.0M ammonia in MeOH (2.8 mL) is heated to 55° C. for 4 h. The reaction mixture is cooled, concentrated and the residue purified by pTLC (5% MeOH/CH2Cl2) to give the title compound (50 mg, 58%); MS for C14H13F2N3O3MS m/z 310.5 (M+H)+; 1H NMR (300 MHz, d6-DMSO): δ 3.93-3.98 (m, 1H), 4.17-4.25 (m, 5H), 4.97-5.02 (m, 1H), 5.93 (s, 2H), 7.27 (d, 2H), 7.61 (s, 1H), 7.85 (s, 1H).
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:2]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]2C(=O)C3=CC=CC=C3C2=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.O.NN>C(O)C>[NH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][C:2]1[C:1]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCOc1ccccc1-c1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCCCOc1ccccc1-c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of N-[6-(2-biphenyloxy)hexyl]phthalimide (15.1 g), ethanol (400 ml) and hydrazine hydrate (30 ml) was heated at reflux for 4 hours, cooled to room temperature, filtered, and evaporated to dryness. The material that remained was stirred with dichloromethane (500 ml), filtered and evaporated to yield 1-amino-6-(2-biphenyloxy) as an oil, which was converted to the hydrochloride salt, (m.p. 86°-88° CC.) according to the method of Example IV.