Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1Br.[CH3:11][S:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:6]1[CH:7]=[C:2]([C:16]2[CH:17]=[CH:18][C:13]([S:12][CH3:11])=[CH:14][CH:15]=2)[C:3]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)=[CH:4][C:5]=1[F:9]
Reactant: CSc1ccc(B(O)O)cc1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Fc1cc(Br)c(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CSc1ccc(-c2cc(F)c(F)cc2-c2ccc(F)cc2)cc1

Procedure:
Under nitrogen, 3 g (2.6 mmol) of Pd(PPh3)4 was added to a stirred solution of 5.0 g (18 mmol) of 1,2-dibromo-4,5-difluorobenzene (Aldrich), 4.2 g (25 mmol) of 4-methylthiophenylboronic acid (Example 1, Step 2), and 3.1 g (22 mmol) of 4-fluorophenylboronic acid in 100 mL of toluene, 100 mL of ethanol, and 100 mL of 2M Na2CO3. After vigorous stirring at reflux overnight, the solvent was removed in vacuo and the residue dissolved in ethyl acetate. The resulting solution was washed with water and dried over MgSO4. Purification by silica gel chromatography gave 1,2-difluoro-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]benzene as a semi-solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31](O)[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH2:37]2)=[CH:24]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31]([O:9][C:8](=[O:10])[C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:14][CH:13]=2)([CH3:12])[CH3:11])[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:45])[CH3:46])[CH2:37]2)=[CH:24]1)([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16]
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](OC(=O)C(C)(C)Oc3ccc(Cl)cc3)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1

Procedure:
A procedure similar to that described in Example 10, above, was followed, but using 0.78 g of 2-(4-chlorophenoxy)-2-methylpropionic acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give1.08 g of the title compound as a colorless foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@H:10]([N:12]=[N+]=[N-])[C@@H:9]([NH:15][C:16](=[O:18])[CH3:17])[C@H:8]([O:19][CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:7]=1)=[O:5])[CH3:2].O.C(O)(=O)C.C(P(CCCC)CCCC)CCC>CCO>[CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@H:10]([NH2:12])[C@@H:9]([NH:15][C:16](=[O:18])[CH3:17])[C@H:8]([O:19][CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N=[N+]=[N-])C1
Agent: CCCCP(CCCC)CCCC
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1
Temperature: 3 °C
Reaction time: 1.5 h

Procedure:
To a solution of 50.0 g (0.147 mol) of 30, 300 mL of EtOH, 50 mL of water and 0.09 g of acetic acid in a nitrogen-purged 1000 mL glass reactor fitted with a mechanical stirrer, a condenser, and a 250 mL dropping funnel was added a solution of 31.4 g (0.155 mol) of tributylphosphine in 150 mL EtOH at a temperature of 5° C. (+/−5° C.) over a period of 30-90 min. The reaction temperature was maintained at this temperature by slight cooling of the jacket (ca. 3° C.). The funnel was rinsed with 20 mL of EtOH. The clear reaction mixture was stirred for additional 90 min at 5° C. (+/−5° C.) under slight jacket cooling. Subsequently the temperature was raised within 30-60 min to 20-25° C. and the solution was stirred for another 3 h (nitrogen evolution). After the reaction was finished (HPLC assay) 0.18 g of acetic acid were added to the clear solution and the mixture was concentrated to near dryness under reduced pressure (300 to 50 mbar) at a maximum temperature of 60° C. and a maximum jacket temperature of 75° C. The oily residue (80-100 mL) was diluted with 160 mL of EtOH, the resulting solution was then again concentrated following the method described above. The oily residue was dissolved in EtOH up to a volume of 250 mL. The water content of this solution was determined by KF(Karl Fischer) titration to be less than 1.0% wt. %. Yield: 44.4 g (97% area by HPLC) of 32 in EtOH solution.
Reaction SMILES: C([N:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH:10]([CH3:17])[N:11]([CH3:16])[CH2:12]2)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:16][N:11]1[CH:10]([CH3:17])[CH:9]2[CH:13]([CH2:14][CH2:15][NH:8]2)[CH2:12]1
Reactant: CC1C2C(CCN2Cc2ccccc2)CN1C
Agent: [Pd]
Solvent: CCO
Product: CC1C2NCCC2CN1C

Procedure:
10.8 g (46.9 mmol) of 2-benzyl-7,8-dimethyl-2,7-diazabicyclo[3.3.0]octane in 200 ml of ethanol are hydrogenated on 2.5 g of palladium/active carbon at 100° C. and 100 bar. The catalyst is filtered off with suction, the filtrate is concentrated, and the residue is distilled.
Reaction SMILES: [C@H:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[NH:21][C:20]3=[O:28])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[H-].[Na+].[C:31](Cl)(=[O:33])[CH3:32].O>CN(C=O)C>[C:31]([N:21]1[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:19]([CH:16]2[CH2:17][CH2:18][N:13]([C@H:1]3[C:11]4=[C:12]5[C:7](=[CH:8][CH:9]=[CH:10]4)[CH:6]=[CH:5][CH:4]=[C:3]5[CH2:2]3)[CH2:14][CH2:15]2)[C:20]1=[O:28])(=[O:33])[CH3:32]
Reactant: O=c1[nH]c2ccccc2n1C1CCN([C@@H]2Cc3cccc4cccc2c34)CC1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)n1c(=O)n(C2CCN([C@@H]3Cc4cccc5cccc3c45)CC2)c2ccccc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
(R)-1-[1-(Acenaphthen-1-yl)piperidin-4-yl]-1,3-dihydro-2H-benzoimidazol-2-one (6.2 g, 16.8 mmol) was dissolved in DMF (60 ml). Sodium hydride (0.9 g, 60%) was added and the suspension was stirred at 50° C. for 30 min. It was cooled to room temperature and acetyl chloride (1.5 g, 19 mmol) was added and the mixture was stirred for 3 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated aqueous ammonium chloride solution, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (6.3 g) as pale-yellow crystals
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[CH:9][C:8]([CH3:19])=[CH:7][C:6]=2[CH3:20].[C:21]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:33]=1[OH:34])[C:28](O)=[O:29])([CH3:24])([CH3:23])[CH3:22].C(P(C#N)(CC)=O)C.C(N(CC)CC)C>CN(C=O)C.O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[C:10]2[C:5](=[C:6]([CH3:20])[CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:28](=[O:29])[C:27]1[CH:31]=[C:32]([C:35]([CH3:36])([CH3:37])[CH3:38])[C:33]([OH:34])=[C:25]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:26]=1
Reactant: Cc1cc(C)c2ncc(N)c(-c3ccccc3Cl)c2c1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: CCP(=O)(C#N)CC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c2ncc(NC(=O)c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)c(-c3ccccc3Cl)c2c1
Temperature: 0 °C
Yield: 24.2 %

Procedure:
To a mixture of 3-amino-4-(2-chlorophenyl)-6,8-dimethylquinoline (1.02 g), 3,5-di-tert-butyl-4-hydroxy benzoic acid (750 mg), diethylphosphoryl cyanide (DEPC) (587 mg) and N,N-dimethylformamide (100 mg) was dropwise added a solution of triethylamine (0.51 ml) in DMF (2 ml) under stirring at 0° C. The mixture was stirred at 0° C. for 30 minutes and at room temperature for one night. Then, the mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was concentrated after being washed with water and dried (MgSO4). The residue was purified by a silica gel column chromatography with hexane-ethyl acetate (85:15,V/V), and then crystallized from methanol to give 4-(2-chlorophenyl)-3-(3,5-di-tert-butyl-4-hydroxybenzamido)-6,8-dimethylquinoline (373 mg, 24.2%). Recrystallization from methanol gave colorless prisms of mp 127°-129° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]([CH3:14])[N:9]([CH2:15][CH2:16][NH:17]C(=O)C1C=CC([N+]([O-])=O)=CC=1)[CH2:8][CH2:7]2.[N+:29]([C:32]1[CH:37]=[CH:36][C:35]([S:38]([Cl:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1)([O-:31])=[O:30]>>[ClH:41].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]([CH3:14])[N:9]([CH2:15][CH2:16][NH:17][S:38]([C:35]1[CH:34]=[CH:33][C:32]([N+:29]([O-:31])=[O:30])=[CH:37][CH:36]=1)(=[O:39])=[O:40])[CH2:8][CH2:7]2
Reactant: COc1ccc2c(c1)CCN(CCNC(=O)c1ccc([N+](=O)[O-])cc1)C2C
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: COc1ccc2c(c1)CCN(CCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1)C2C

Procedure:
The title compound was prepared by Method A using 2-(2-aminoethyl)-1,2,3,4-tetrahydro-6-methoxy-1-methylisoquinoline (described in Example 178) and 4-nitrobenzenesulfonyl chloride to produce the desired product in 100% yield. This material was purified by flash silica gel chromatography using 10-100% EtOAc in hexane. The material obtained was treated with HCl/2-propanol (1.1 eq) to afford a beige solid; mp 167°-172° C.; IR (KBr) 1611, 1531,1507,1443,1347,1309,1248,1232,1168,1092,1029,852,745,739 and 607 cm-1.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]OC[CH2:38]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C:3]=1[CH:22]([CH2:38][CH2:37][CH3:41])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1cccc(Cl)c1)CCCC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1cccc(Cl)c1)CCCC3
Yield: 86.4 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(3-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.290 g; 0.76 mmol), LHMDS 1N in THF (0.84 mL; 0.84 mmol), 1-iodopropane (0.111 mL; 1.14 mmol) in DMF (3 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.281 g (88%) of the title compound as a yellow oil.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:20]([C:31]([OH:33])=[O:32])[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:34][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[CH3:34][O:32][C:31]([CH:20]1[CH2:19][N:18]([C:16]([O:15][CH2:14][CH:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:17])[CH2:23][CH2:22][N:21]1[C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C1CN(C(=O)OCC2c3ccccc3-c3ccccc32)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of piperazine-1,2,4-tricarboxylic acid 1-tert-butyl ester 4-(9H-fluoren-9-ylmethyl) ester (2.21 mmol) in toluene:methanol (9:1) was added equimolar trimethylsilyldiazomethane (2.0 M in hexanes) and the resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and purified using gradient elution from hexane/ethyl acetate (5%) to hexane/ethyl acetate (30%). ESI-MS m/z: 467 (M+1), UV retention time: 3.04 min.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc([N+](=O)[O-])cc23)cc1OC
Reactant: c1c[nH]cn1
Product: COc1ccc(CNc2nc(-n3ccnc3)nc3sc([N+](=O)[O-])cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-nitro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-nitro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[C:3]1[Cl:13].CCO.[C:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:18].C(N(CC)CC)C>O>[C:17]([C:19](=[CH:11][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[C:3]=1[Cl:13])[C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:18]
Reactant: Cn1c(Cl)c(C=O)c2ccccc21
Reactant: CCOC(=O)CC#N
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C#N)=Cc1c(Cl)n(C)c2ccccc12
Reaction time: 19 h

Procedure:
To 2 g of 1-methyl-2-chloroindole-3-carbaldehyde, dissolved in 50 ml of abs. EtOH, was added 2.3 g of ethyl 2-cyanoacetate and 4.2 g of triethylamine. After 19 hours with stirring, the solution was added to 200 ml of water, and the precipitate collected by filtration and dried to give (2a). Yield 2.68 g of (2a), m.p. 131°-132° C.
Reaction SMILES: [OH:1][N:2]([CH3:17])[C:3](=[NH:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[C:18]([C:25]([O:27][CH2:28][CH3:29])=[O:26])#[C:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[CH2:28]([O:27][C:25]([C:18]1([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[O:1][N:2]([CH3:17])[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:16]1)=[O:26])[CH3:29]
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: CN(O)C(=N)c1ccccc1N1CCOCC1
Solvent: CCO
Product: CCOC(=O)CC1(C(=O)OCC)N=C(c2ccccc2N2CCOCC2)N(C)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
To a stirred solution of N-hydroxy-N-methyl-2-morpholin-4-yl-benzamidine (3.8 g) in ethanol (100 mL, 200 proof) was added diethyl acetylene-dicarboxylate (3.2 mL, 20 mmol) and the resulting mixture stirred at room temperature for 30 min. The mixture was then concentrated and purified on a silica gel column (10%–30% ethyl acetate/hexanes) to afford the title compound (3.64 g, 45% yield). 1HNMR (300 MHz, CDCl3) δ: 7.64 (1H, dd, J=7.69, 1.83 Hz), 7.40 (1H, td, J=8.05, 1.83 Hz), 7.02 (1H, t, J=7.32 Hz), 6.97 (1H, d, J=8.05 Hz) 4.31–4.20 (2H, m), 4.15 (2H, q, J=7.08 Hz), 3.88–3.74 (4H, m), 3.38 (1H, d, J=16.46 Hz), 3.12–2.92 (4H, m), 3.05 (3H, s), 3.03 (1H, d, J=16.47 Hz), 1.29 (3H, t, J=6.95 Hz), 1.25 (3H, t, J=6.96 Hz). HRMS (ESI) calcd for C20H28N3O6 (M+H): 406.1978; found: 406.1975.
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:36])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([CH:15]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:16])[CH:6]=[CH:5][C:4]1=2.[N:37]1[CH:42]=[CH:41][C:40]([CH:43]=O)=[CH:39][CH:38]=1>C1OCCC1>[CH3:2][C:3]1([CH3:36])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7](/[C:15](/[CH3:16])=[CH:43]/[C:40]3[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC(c1ccc2c(c1)C(C)(C)CCC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccncc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C/C(=C\c1ccncc1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
378 g of [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl]triphenylphosphonium bromide were suspended in 4 l of butylene oxide. After the addition of 51 ml of 4-pyridinecarbaldehyde the mixture was boiled at reflux for 1.5 hours. After cooling the majority of the solvent was evaporated in a water-jet vacuum, the residue was poured into 1.5 l of a methanol/water mixture (ratio 6:4) and extracted repeatedly with hexane. The organic phase was washed three times with water and, after drying over sodium sulphate, evaporated. After flash chromatography (eluting agent hexane/ether=2:1) and recrystallization from hexane there were obtained 216 g of 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8,-tetramethyl-2-naphthyl) propenyl]pyridine in colorless crystals, melting point 84°-85°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:15][CH:12]1[CH2:14][CH2:13]1)=[O:7]
Reactant: NC1CC1
Reactant: O=C(O)c1ccc(F)c(O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1CC1)c1ccc(F)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To a mixture of 3-hydroxy-4-fluorobenzoic acid (1.56 g, 10 mmol), cyclopropylamine (0.6 g, 10.5 mmol), triethylamine (1.02 g, 10 mmol) and HOBt (0.3 g, 2 mol) in DMF (10 mL) was added EDCI (2.0 g, 10.5 mmol) at RT. The mixture was stirred at RT overnight. The mixture was diluted with water and extracted with ethyl acetate (3×20 mL). The extract was washed with water and concentrated to afford 3-hydroxy-4-fluoro-N-cyclopropylbenzamide as a solid (1.2 g, 61.5%).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11](=[O:13])[NH2:12].[C:14]1([CH2:20][C:21](O)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.ON1C2C=CC=CC=2N=N1.OC1C2N=NNC=2C=CC=1>ClCCl.CN(C)C=O>[C:11]([C:3]1[C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[S:6][C:2]=1[NH:1][C:21](=[O:22])[CH2:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])[NH2:12]
Reactant: NC(=O)c1c(N)sc2c1CCCC2
Reactant: O=C(O)Cc1ccccc1
Agent: Oc1cccc2[nH]nnc12
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)c1c(NC(=O)Cc2ccccc2)sc2c1CCCC2
Temperature: 20 °C
Reaction time: 170 h

Procedure:
A mixture of commercially available 2-amino-3-carbamoyl-4,5,6,7-tetrahydrobenzo[b]thiophene (5 mg, 0.026 mmol), phenylacetic acid (7 mg, 0.05 mmol), N-hydroxybenzotriazole (8.5 mg, 0.065 mmol), and N-cyclohexylcarbodiimide-N′-methylpolystyrene (loading about 1.5 mmol/g resin, 50 mg) in dichloromethane (2 ml)/dimethylformamide (0.5 ml) was agitated at 20° C. for 170 h. Afterward tris-(2-aminoethyl)-amine polystyrene (loading about 4 mmol/g resin 40 mg) was added for scavenging the hydroxybenzotriazole and the excess of acid, and the agitation was maintained for additional 24 h.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[C:12]([C:14](O)=[O:15])[N:13]=1.O.OC1C2N=N[NH:29]C=2C=CC=1.N.O1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[C:12]([C:14]([NH2:29])=[O:15])[N:13]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)c1nc(-c2c(F)cccc2F)oc1-c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1cccs1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 4 %

Procedure:
To a solution of 2-(2,6-difluorophenyl)-5-(thiophen-2-yl)oxazole-4-carboxylic acid (0.078 g, 0.25 mmol) and hydroxybenzotriazole monohydrate (0.039 g, 0.25 mmol) in DMF (2 mL) was added a 0.5M ammonia in dioxane solution (1.5 mL, 0.75 mmol) and the reaction mixture was stirred at room temperature for 10 minutes. 1-(3-(Dimethylamino)propyl)-3-ethyl-carbodiimide hydrochloride (0.054 g, 0.28 mmol) was then added and the resulting mixture stirred at room temperature overnight. The solvent was removed in vacuo and the residue was purified by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-(thiophen-2-yl)oxazole-4-carboxamide (0.0031 g, 0.01 mmol, 4%) as a white solid. 1H NMR (DMSO) 7.25 (1H, dd), 7.40 (2H, t), 7.69-7.76 (3H, m), 7.84 (1H, dd), 8.17 (1H, dd). LCMS (2) Rt: 2.73 min; m/z (ES+) 307.
Reaction SMILES: [CH3:1][C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH3:14])[N:3]=1.[Cl:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)=[O:21])=[CH:18][CH:17]=1.C(OC(=O)C)(=O)C>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH:26]=[CH:1][C:2]3[N:11]([CH3:12])[C:10](=[O:13])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][C:8]=4[CH3:14])[N:3]=3)=[CH:24][CH:23]=2)=[O:21])=[CH:30][CH:31]=1
Reactant: O=Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: Cc1cccc2nc(C)n(C)c(=O)c12
Solvent: CC(=O)OC(C)=O
Product: Cc1cccc2nc(C=Cc3ccc(C(=O)c4ccc(Cl)cc4)cc3)n(C)c(=O)c12
Temperature: 140 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
To a mixture of 2,3,5-trimethyl-4(3H)-quinazolinone (376 mg) and 4-(4-chlorobenzoyl)benzaldehyde (1.1 g) was added acetic anhydride (0.5 ml) and the mixture was stirred at 140° C. for 2 hours. This reaction mixture was concentrated and the residue was washed with diethyl ether and dried to provide 504 mg of yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:24])OCC2C=CC=CC=2)[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH:25]1([NH2:35])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1.[CH2:36]([N:39]([CH2:53][CH2:54][CH3:55])[C:40]([C:42]1[CH:43]=[C:44]([CH:48]=[C:49]([CH2:51]C)[CH:50]=1)C(O)=O)=[O:41])[CH2:37][CH3:38]>>[F:8][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([F:1])[CH:7]=1)[CH2:9][C@H:10]([NH:14][C:15](=[O:24])[C:44]1[CH:48]=[C:49]([CH3:51])[CH:50]=[C:42]([C:40]([N:39]([CH2:36][CH2:37][CH3:38])[CH2:53][CH2:54][CH3:55])=[O:41])[CH:43]=1)[C@H:11]([OH:12])[CH2:13][NH:35][CH:25]([C:34]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:26][C:27]1[CH:28]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: CCCN(CCC)C(=O)c1cc(CC)cc(C(=O)O)c1
Reactant: NC1CCCc2ccccc21
Reactant: O=C(N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1)OCc1ccccc1
Product: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNC(Cc2ccccc2)c2ccccc2)c1

Procedure:
Following the general procedure of EXAMPLEs 4, 5 and 6 and making non-critical variations but using tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V), NH2—CH( )—CH2-phenyl (VI) and “5-Me-PHTH” (IX), the title compound is obtained, MH+=642.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6]C)=[O:5].CO[CH:14](OC)[N:15](C)C.O.Cl.NO>CO>[CH2:8]([C:2]1[O:1][N:15]=[CH:14][C:3]=1[C:4]([OH:6])=[O:5])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCC(=O)CC(=O)OC
Reactant: COC(OC)N(C)C
Agent: Cl
Agent: NO
Solvent: CO
Solvent: O
Product: CCCCc1oncc1C(=O)O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Methyl 3-oxoheptanoate (0.16 g, 1 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (0.12 g, 1 mmol) was mixed and heated for 1 h at 60° C. The bright yellow oil was dissolved in methanol (2 mL) and water (1 mL) whereby and hydroxylamine hydrochloride (0.07 g, 1 mmol) was added, resulting in a pH of ca 5. The reaction was heated at 60° C. for 3 days. The solvents were evaporated and the residue refluxed in acetic acid: conc. HCL (1+1 mL) for 4 h. The solvents were evaporated to dryness and the residue dissolved in water at ca pH 10, filtered and acidified with HCl and extracted to DCM, dried (Na2SO4) and evaporated to yield the title compound as a light brown solid. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.93 (t, J=7.32 Hz, 3 H) 1.33-1.45 (m, 2 H) 1.69-1.78 (m, 2 H) 3.12 (t, J=7.57 Hz, 2 H) 8.50 (s, 1H)