Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].NC(C1N=NC(N[C:42]2[CH:47]=[C:46]([O:48]C)[C:45](OC)=[C:44](OC)[CH:43]=2)=NC=1)C.O(C1C=C(C=CC=1)C(O)=O)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:48]([C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6])[C:46]1[CH:47]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1cccc(Oc2ccccc2)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Oc4ccccc4)c3)nn2)cc(OC)c1OC
Yield: 100 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (87 mg, 0.28 mmol), 3-phenoxybenzoic acid (80 mg, 0.37 mmol), diisopropylethylamine (0.13 mL, 0.75 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (140 mg, 0.37 mmol) in dimethylformamide (2 mL) gave 3-phenoxy-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (140 mg, 100%) as a yellow oil. MS m/z 501 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=2)[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:21](Br)[CH2:22][CH2:23][CH3:24]>CN(C)C=O>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([O:14][CH2:21][CH2:22][CH2:23][CH3:24])=[O:13])[CH:8]=2)[CH:3]=1
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1ccc2cc(O)ccc2c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
The mixture of 2-hydroxy-6-naphthoic acid of 18.8 g, N,N-dimethylformamide of 150 g and anhydrous sodium carbonate of 13.3 g was heated to 70° C., and n-butyl bromide of 16.4 g was dropwise added thereto in one hour. After finishing dropwise adding, the suspension was further stirred at 70° to 80° C. for 6 hours. The reaction mixture was cooled down to room temperature and filtrated off the inorganic salt. Then the filtrate was discharged into water of 1000 g. The deposited solid was separated, and sludging was carried out in n-hexane, whereby n-butyl 2-hydroxy-6-naphthoate of 22.0 g was obtained in the form of brown crystal.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[CH:24]=[C:23]([C:34]([F:37])([F:36])[F:35])[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:25]2[CH:24]=[C:23]([C:34]([F:36])([F:37])[F:35])[N:22]=[C:21]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=4)[CH:20]=3)[N:26]=2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.3 %

Procedure:
To a cooled and stirred solution of 3-{4-[4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide (0.41 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as an off-white solid (0.31 g, 63%). MS (ISN) 489.1 [(M−H)−]; mp 182° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH:7]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=O>C(O)C>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][CH:7]1[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=[O:13])[O:12]1
Reactant: O=Cc1ccccc1C(=O)O
Reactant: Nc1nccs1
Solvent: CCO
Product: O=C1OC(Nc2nccs2)c2ccccc21
Yield: 81.3 %

Procedure:
2-Aminothiazole (I31) (1.0 equiv., 5.00 mmol, 0.500 g) and 2-formylbenzoic acid (I32) (1.2 equiv., 6.00 mmol, 0.900 g) were mixed in ethanol (8 ml) and heated at reflux for 2 h. Upon cooling, a precipitate was formed. The product was isolated by filtration and washed with isopropyl ether to afford 3-(2-thiazolylamino)-isobenzofuran-1(3H)-one (I33) (0.944 g, yield=81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([CH3:23])[C:17]=1[CH3:24].[CH2:25]([N:27]1[CH:32]=[C:31]([C:33](O)=[O:34])[C:30](=[O:36])[N:29]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[C:28]1=[O:44])[CH3:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:33]([C:31]2[C:30](=[O:36])[N:29]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[C:28](=[O:44])[N:27]([CH2:25][CH3:26])[CH:32]=2)=[O:34])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: CCn1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Product: CCn1cc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(C)c2C)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 4-(6,7-Dimethoxy-quinolin-4-yloxy)-2,3-dimethyl-phenylamine and 1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid using the procedure for example 1. mp=283-285° C.; LCMS m/z=585 (M+1); 1H NMR (DMSO-d6) δ: 10.81 (s, 1H), 8.88 (s, 1H), 8.43 (d, 1H, J=5.5 Hz), 8.07 (d, 1H, J=8.5 Hz), 7.56 (s, 1H), 7.46-7.42 (m, 2H), 7.40 (s, 1H), 7.39-7.33 (m, 2H), 7.10 (d, 1H, J=9 Hz), 6.26 (d, 1H, J=6 Hz), 4.02 (q, 2H, J=7 Hz), 3.95 (s, 6H), 2.21 (s, 3H), 2.07 (s, 3H), 1.3 (t, 3H, J=7 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[CH:3]=1.BrC1C=CC(C(C)C)=C(F)C=1.[CH:21]1([C:26]([OH:39])([C:37]#[CH:38])[CH2:27][C:28]2[O:33]C(C)(C)O[C:30](=[O:36])[CH:29]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([C:26]2([CH2:37][CH2:38][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[CH:3]=3)[O:39][C:30](=[O:36])[CH2:29][C:28](=[O:33])[CH2:27]2)[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CCc1cccc(Br)c1
Reactant: C#CC(O)(CC1=CC(=O)OC(C)(C)O1)C1CCCC1
Agent: CC(C)c1ccc(Br)cc1F
Product: CCc1cccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)c1

Procedure:
The title compound was prepared analogously to Example A(64), where 1-Bromo-3-ethyl-benzene was substituted in place of 4-bromo-2-fluoro-1-isopropylbenzene in that example, and Enantiomer A of 6-(2-cyclopentyl-2-hydroxybut-3-ynyl)-2,2-dimethyl-4H-1,3-dioxin-4-one was used in place of the racemic alkyne. 1H NMR (CDCl3): δ 1.23 (t, 3H, J=7.6 Hz), 1.50-1.83 (br m, 8H), 1.91-2.05 (m, 2H), 2.29 (m, 1H), 2.59-2.68 (m, 4H) 2.27, (s, 2H), 3.42 (s, 2H), 6.96 (m, 2H), 7.06 (d, 1H, J=7.01 Hz), 7.21 (t, 1H, J=8.0 Hz). ESIMS: MH+ 315.20, MH− 313.20.
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[OH:31][C:32]1[CH:45]=[CH:44][C:35]([CH:36]([NH2:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:34][CH:33]=1>>[OH:31][C:32]1[CH:33]=[CH:34][C:35]([CH:36]([NH:43][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:30])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:44][CH:45]=1
Reactant: NC(c1ccccc1)c1ccc(O)cc1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccccc1)c1ccc(O)cc1
Yield: 83 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 4-hydroxybenzhydrylamine (prepared as described in Preparation 13) as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 83%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:11])=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[NH2:12][OH:13].Cl>C(O)C.O>[CH3:1][O:2][C:3]1[C:4]([CH3:11])=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[N:12][OH:13]
Reactant: COc1cccc(C=O)c1C
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cccc(C=NO)c1C
Temperature: 0 °C

Procedure:
To an ice-cooled and stirred suspension of 3-methoxy-2-methylbenzaldehyde (0.269 g, 1.8 mmol) in ethanol (15 ml) a solution of NaOAc.3H2O (1.3 eq) and NH2OH.HCl (1.3 eq) in water (5 ml) was added dropwise within 5 minutes. The resulting suspension was stirred at room temperature until the starting material was consumed (monitored by TLC). After evaporation of the ethanol in vacuo, water was added to the residue. Then the precipitated crystals were filtered off. The crude product was purified by column chromatography with a mixture of chloroform:ethyl acetate (95:5) as the eluent.
Reaction SMILES: [Li]I.O.[CH:4]([C:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)(C)[C:7](OC)=O)=[O:5]>CN(P(N(C)C)(N(C)C)=O)C>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH:6]([CH3:7])[CH:4]=[O:5])=[CH:18][CH:17]=1)([CH3:21])([CH3:20])[CH3:22]
Reactant: COC(=O)C(C)(C=O)Cc1ccc(C(C)(C)C)cc1
Agent: [Li]I
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Reaction time: 0.02 h
Yield: 105.1 %

Procedure:
5 ml of hexamethylphosphortriamide (HMPT) and 1 g of LiI.H2O are heated to 240° C. under a nitrogen atmosphere. 1.1 g of crude methyl 2-formyl-2-p-tert.butyl-benzyl-propionate (82%) in 1 ml of HMPT are added thereto, the mixture is stirred for 1 minute, poured on to ice and extracted with hexane. After washing with 2N HCl, with sodium bicarbonate solution and water the organic phase is dried over magnesium sulphate and the solvent is evaporated. 0.9 g of crude p-tert.butyl-α-methyl-hydrocinnamaldehyde is obtained. After bulb-tube distillation 500 mg of this aldehyde give 300 mg of pure material. The yield therefore amounts to 78.8%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]([NH:26]C=O)[CH:6]=[C:7]([CH2:15][P:16]([O:22]C(C)C)([O:18]C(C)C)=[O:17])[CH2:8][CH2:9][CH2:10][O:11]C(=O)C)[CH3:2].C[Si](C)(C)Br.C(O)C>ClCCl>[CH2:1]([O:3][C:4](=[O:29])[CH:5]([NH2:26])[CH:6]=[C:7]([CH2:15][P:16]([OH:18])([OH:22])=[O:17])[CH2:8][CH2:9][CH2:10][OH:11])[CH3:2]
Reactant: CCOC(=O)C(C=C(CCCOC(C)=O)CP(=O)(OC(C)C)OC(C)C)NC=O
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(N)C=C(CCCO)CP(=O)(O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4.3 g (9.9 mmol) of 7-acetoxy-4-diisopropylphosphonomethyl-2-formylamino-hept-3-enoic acid ethyl ester are dissolved in 25 ml of dichloromethane, and 5.1 ml (39.5 mmol) of trimethylbromosilane are added dropwise at room temperature. The mixture is left to stand at room temperature for 24 hours, 25 ml of ethanol are added dropwise, the mixture is left to stand for a further 24 hours and is concentrated by evaporation, the residue is dissolved in 25 ml of ethanol, and a mixture of 25 ml of propylene oxide and 25 ml of ethanol is added dropwise. A suspension forms, which is stirred for one hour at room temperature and for one hour in an ice bath and is then filtered with suction. Drying yields 2-amino-7-hydroxy-4-phosphonomethyl-hept-3-enoic acid ethyl ester having a melting point of 210° C. (decomp.).
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])(=O)=O.O[C@H:17]([C:21]([CH3:38])=[CH:22][C:23]1[N:24]=[C:25]([CH2:28][O:29][C:30]([O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=[O:31])[S:26][CH:27]=1)[CH2:18][CH:19]=[CH2:20].N1C(C)=CC=CC=1C.Cl>C(Cl)Cl>[CH2:12]([Si:7]([CH2:8][CH3:9])([CH2:10][CH3:11])[O:6][C@H:17]([C:21]([CH3:38])=[CH:22][C:23]1[N:24]=[C:25]([CH2:28][O:29][C:30]([O:32][CH2:33][C:34]([Cl:36])([Cl:37])[Cl:35])=[O:31])[S:26][CH:27]=1)[CH2:18][CH:19]=[CH2:20])[CH3:13]
Reactant: C=CC[C@H](O)C(C)=Cc1csc(COC(=O)OCC(Cl)(Cl)Cl)n1
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C=CC[C@H](O[Si](CC)(CC)CC)C(C)=Cc1csc(COC(=O)OCC(Cl)(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Triethylsilyl trifluromethanesulfonate (15 mL) is added dropwise to a −78° C. solution of (4S)-4-hydroxy-5-methyl-6-(2-(2,2,2-trichloroethoxycarbonyloxymethyl)thiazol-4-yl)-1,5-hexadiene (7.65 g) and 2,6-lutidine (10 mL) in 50 mL of CH2Cl2. After the addition, the reaction mixture is allowed to warm to ambient temperature and is stirred for 5 hours. The reaction mixture is poured into 2 N HCl and extracted with ether. The combined organic layers were washed with 10% aq NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated. Flash chromatography on SiO2 (hexanes/ethyl acetate, 20:1) provides the product as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>C(#N)C.C1OCCOCCOCCOCCOCCOC1>[N:25]([CH2:2][C:3]1[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1cc(CCl)n(Cc2ccccc2)cc1OCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CC#N
Product: [N-]=[N+]=NCc1cc(=O)c(OCc2ccccc2)cn1Cc1ccccc1
Yield: 89.5 %

Procedure:
To a suspension of 2.0 g (6 mmol) of 2-(chloromethyl)-5-(phenylmethoxy)-1-(phenylmethyl)-4(1H)-pyridinone in 20 ml of acetonitrile was added 3.9 g (60 mmol) of sodium azide and 0.1 g of 18-crown-6, and the mixture was heated to reflux for four hours. The salts were filtered off by suction, and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate-methanol 8:2) yielding 1.86 g of the title compound, melting point 120° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:11]=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.Cl[C:21](Cl)([F:26])[C:22]([O:24][CH3:25])=[O:23]>[Zn].[Cu]Cl.O1CCCC1>[F:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:11][C:8]1([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1
Reactant: COC(=O)C(F)(Cl)Cl
Reactant: O=CC1(c2ccc(F)cc2)CC1
Agent: Cl[Cu]
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(F)=CC1(c2ccc(F)cc2)CC1
Yield: 40.8 %

Procedure:
The method of Example 1 was repeated using zinc powder (1 g), copper (I) chloride (0.12 g) and molecular sieve 4A (1 g), tetrahydrofuran (18 ml), 1-(4-fluorophenyl)-1-formyl-cyclopropane (0.54 g), acetic anhydride (0.38 ml) and methyl dichlorofluoroacetate (0.69 g) to yield the title compound (0.32 g, 42%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][CH3:12].[OH-].[K+].Br[CH2:16][S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C(=O)C>[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([O:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([S:9][CH2:10][CH2:11][CH3:12])[CH:4]=2)=[CH:20][CH:19]=1
Reactant: BrCSc1ccccc1
Reactant: CCCSc1cc(O)ccc1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCSc1cc(Oc2ccc(SC)cc2)ccc1C
Reaction time: 14 h

Procedure:
4-Methyl-3-(n-propylthio)phenol (4.0 g, 0.02 mole) and 85.5 % potassium hydroxide (1.4 g, 0.02 mole) were dissolved in N,N-dimethylacetamide (40 ml) above 90° C. 4-Bromomethylthiobenzene (4.0 g, 0.02 mole) and Cu powder (0.5 g, 0.008 mole) were added to this solution below 90° C and the mixture was stirred at 120° - 160° C for 14 hr. After cooling, the reaction mixture was poured into water (100 ml) and extracted twice with benzene. The combined organic layers were washed with 5 % sodium hydroxide solution, 5 % hydrochloric acid solution, and water, then dried over sodium sulfate. The solvent was removed, and the residue was distilled under reduced pressure. The yield of 4-methyl-3-n-propylthiophenyl 4-methylthiophenyl ether was 4.1 g (61.5 %), colorless oil, bp 188° - 190° C/2 mmHg. Anal. Found: C, 67.12; H, 6.59. Calcd. for C17H20OS2 : C, 67.06; H, 6.62 %
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH:2]1([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH2:31])[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCCCCCCCCCCCCCCCN
Product: NCCCCCCCCCCCCCCCCCCC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
The preparation is analogous to Example 1, starting from 11 g of glucose and 20 g of octadecylamine.
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:15]([C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH:18]=1)#[N:16].C1CCN2C(=NCCC2)CC1>C(#N)C>[O:1]=[C:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:3]([CH:18]1[CH2:19][CH2:20][C:21]2[C:26](=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)[CH:17]1[C:15]#[N:16])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COc1ccc2c(c1)CCC=C2C#N
Reactant: COC(=O)CC(=O)Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)C(C(=O)Cc1ccccc1)C1CCc2cc(OC)ccc2C1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
Methyl 3-oxo-4-phenylbutyrate (29.33 g, 153 mmol) and 1-cyano-6-methoxy-3,4-dihydronaphthalene (25.7, 139 mmol), the product of Step 2 of Example 1, were dissolved in 25 mL of acetonitrile. DBU (1.5 mL) was added and the reaction mixture was stirred for 2 h at ambient temperature. A second aliquot of DBU (1.5 mL) was then added and stirring continued overnight. The reaction mixture was partitioned between diethyl ether and 1N aqueous hydrochloric acid solution (4:1) and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with 1N aqueous hydrochloric acid and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluted with hexane/ethyl acetate (6:1) to give 33.9 g (65% yield) of the title compound; MS DCl--NH3M/Z: 395 (M+NH4)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[C:5]([CH3:40])([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[C:18](=[O:32])[NH:17]2)=[CH:9][CH:8]=1)[CH3:2].[H-].[Na+].I[CH2:45][CH3:46]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:41])[C:5]([CH3:40])([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=3)[C:18](=[O:32])[N:17]2[CH2:45][CH3:46])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2)cc1)Oc1ccccc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2CC)cc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A slurry of 2-Methyl-3-(4-{2-[2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid ethyl ester (0.500 g, 0.875 mmol) and sodium hydride (0.039 g, 0.96 mmol, 60% dispersion on mineral oil) in DMF (10 mL) is stirred for 1 hour, then cooled to 0° C. Iodoethane (0.70 mL, 8.75 mmol, d=1.975) is added, then the reaction mixture is stirred 18 hours at ambient temperature and diluted with ethyl acetate. The organic layer is washed, dried, and concentrated to provide the title compound. 1H NMR (400 MHz, CDCl3): δ 7.55 (d, 2 h, J=8.8 Hz), 7.37 (d, 2H, J=8.0 Hz), 7.21 (t, 2H, J=8.8 Hz), 7.15 (d, 2H, J=8.0 Hz), 6.96 (t, 1H, J=7.2 Hz), 6.82 (d, 2H, J=7.2 Hz), 6.74 (d, 2H, J=8.8 Hz), 4.43, 4.39 (ABq, 2H, J=15.2 Hz), 4.22, 4.17 (ABq, 2H, J=7.2 Hz), 3.96 (t, 1H, J=6.4 Hz), 3.85-3.78 (m, 1H), 3.61-3.55 (m, 1H), 3.35 (t, 1H, J=8.8 Hz), 3.26, 3.12 (ABq, 2H, J=13.6 Hz), 3.16-3.07 (m, 2H), 2.99 (t, 1H, J=8.0 Hz), 2.26-2.19 (m, 1H), 1.90-1.83 (m, 1H), 1.39(s, 3H), 1.21 (t, 3H, J=7.2 Hz), 1.14 (t, 3H, J=7.2 Hz). MS [EI+] 599 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[N:21]12[CH2:28][CH:25]([CH2:26][CH2:27]1)[NH:24][CH2:23][CH2:22]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:24]4[CH:25]5[CH2:28][N:21]([CH2:27][CH2:26]5)[CH2:22][CH2:23]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1CN2CCC(C2)N1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCN4CCC3C4)c(F)cc2c1=O
Temperature: 25 °C
Yield: 36.6 %

Procedure:
A mixture of 1.14 g (4 mmol) 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 0.62 g (5.5 mmol) 1,4-diazabicyclo[3.2.1]octane and 0.40 g (4 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene in 20 ml acetonitrile was refluxed 6.5 hours. After cooling to room temperature the solid product was filtered, suspended in 10 ml hot ethanol, cooled, and filtered to afford 0.55 g of 1-cyclopropyl-7-(1,4-diazabicyclo[3.2.1]octan-4-yl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 280° C. (dec).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][CH3:12])[C:6]=2[CH:13]=1.[O:14]1[C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1>>[CH2:11]([N:7]1[C:6]2[CH:13]=[C:2]([C:21]3([OH:24])[CH2:22][CH2:23][C:18]4([O:17][CH2:16][CH2:15][O:14]4)[CH2:19][CH2:20]3)[CH:3]=[CH:4][C:5]=2[O:9][C:8]1=[O:10])[CH3:12]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CCn1c(=O)oc2ccc(Br)cc21
Product: CCn1c(=O)oc2ccc(C3(O)CCC4(CC3)OCCO4)cc21

Procedure:
The title compound was prepared as a white solid from 5-bromo-3-ethyl-3H-benzooxazol-2-one (prepared by ethylation of 5-bromo-3H-benzooxazol-2-one) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 1.