Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]([CH3:16])([CH3:15])[C:3]([NH:5][C:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[O:8][N:7]=1)=[O:4].[C:17]([O-:20])(=[S:19])[CH3:18].[K+]>CN(C=O)C.C(OCC)C>[C:11]([C:9]1[O:8][N:7]=[C:6]([NH:5][C:3]([C:2]([S:19][C:17](=[O:20])[CH3:18])([CH3:16])[CH3:15])=[O:4])[CH:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC([O-])=S
Reactant: CC(C)(Br)C(=O)Nc1cc(C(C)(C)C)on1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)SC(C)(C)C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a solution of 200 mg (0.69 mmol) of 2-bromo-N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-propionamide (prepared as described in Method B, step 2) in DMF (3 mL) were added 157 mg (1.4 mmol) of potassium thioacetate. The reaction was stirred at room temperature for 3 h. The reaction mixture was diluted with diethyl ether (5 mL) and washed with 2M aqueous HCl solution (5 mL). The organic layer was dried over Na2SO4. Filtration and concentration under reduced pressure afforded 151 mg of thioacetic acid S-[1-(5-tert-butyl-isoxazol-3-ylcarbamoyl)-1-methyl-ethyl]ester.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9]C(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[N:14]1([CH2:19][CH2:20][CH2:21][NH2:22])[CH:18]=[N:17][CH:16]=[N:15]1>>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][C:6]=1[C:7]([NH:22][CH2:21][CH2:20][CH2:19][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)=[O:9]
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: NCCCn1cncn1
Product: Nc1ccc(Cl)cc1C(=O)NCCCn1cncn1

Procedure:
When 5-chloroisatoic anhydride was reacted with 3-(1H-1,2,4-triazol-1-yl)propanamine by the procedure of Example 11, this compound, mp 116°-118° C., was obtained.
Reaction SMILES: [CH3:1][C:2]1[O:13][C:5]([CH:6](O)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.C(O)C[OH:16].O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH2:7]([CH:6]1[C:2]([OH:13])([CH3:1])[CH:3]=[CH:4][C:5]1=[O:16])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: OCCO
Reactant: CCCCCC(O)c1ccc(C)o1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCCC1C(=O)C=CC1(C)O
Yield: 84 %

Procedure:
In the same apparatus as in Example 1 5-methyl-α-n-pentyl-furfuryl alcohol (40 parts), ethylene glycol (20 parts) and a buffer solution prepared from water (1200 parts) and sodium acetate (0.5 part) and adjusted to pH 5.2 with acetic acid were charged, and the resultant mixture was stirred at 100° C. in a nitrogen stream for 20 hours. The reaction mixture was cooled and extracted with toluene. The extract was concentrated to give 2-n-pentyl-3-hydroxy-3-methyl-4-cyclopentenone in a yield of 84 %.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[N+:18]([CH3:21])([O-:20])=[O:19].C(NCC)C>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:17])[CH2:9][CH:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:21][N+:18]([O-:20])=[O:19])=[CH:6][CH:7]=1
Reactant: O=C(/C=C/c1ccccc1)c1ccc(Br)cc1
Reactant: C[N+](=O)[O-]
Solvent: CCNCC
Solvent: CO
Product: O=C(CC(C[N+](=O)[O-])c1ccccc1)c1ccc(Br)cc1
Yield: 85.7 %

Procedure:
In a 1 L flask, 46.9 g (154 mmol) of (2E)-1-(4-bromophenyl)-3-phenylprop-2-en-1-one were dissolved in 450 g of methanol, admixed with 46.9 g (768 mmol) of nitromethane and 56.2 g (768 mmol) of diethylamine and refluxed for 16 h. The solvent was half distilled off in vacuo and the precipitated solid was separated off and dried to constant weight in vacuo to obtain 46 g (132 mmol) of 1-(4-bromophenyl)-4-nitro-3-phenylbutan-1-one.
Reaction SMILES: [NH:1]1C2(CCCCC2)[NH:4][CH2:3][C:2]1=[O:11].[O:12]1[CH2:22][CH:13]1[CH2:14][C:15]([O:17]CC(C)C)=O.O>C(O)C>[CH2:14]1[C:15](=[O:17])[N:4]([CH2:3][C:2]([NH2:1])=[O:11])[CH2:22][CH:13]1[OH:12]
Reactant: CC(C)COC(=O)CC1CO1
Reactant: O=C1CNC2(CCCCC2)N1
Solvent: CCO
Solvent: O
Product: NC(=O)CN1CC(O)CC1=O
Reaction time: 2 h

Procedure:
1 g of 2,2-dimethyl-4-imidazolidinone ((5); R4 =R5 =CH3) (8.76 mmoles) are heated at 165° C. (external temperature) for 1 h 30 min with 2 g 2-methylpropyl 3,4-epoxybutanoate ((4); X=isobutyl) (12.64 mmoles). 0.17 ml of water and 5 ml ethanol are added, and boiling is continued for a further 2 h. The mixture is cooled and filtered. Oxiracetam is obtained as a white crystalline powder, m.p. 167°-70° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]([F:13])([F:12])[F:11])=[CH2:9])[CH:5]=[C:4]([Cl:14])[CH:3]=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N+:23]#[C-:24])=[CH:18][C:17]=1[CH3:25]>C1(C)C=CC=CC=1.[Cu-]=O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:9][C:8]([C:6]3[CH:5]=[C:4]([Cl:14])[CH:3]=[C:2]([Cl:1])[CH:7]=3)([C:10]([F:11])([F:13])[F:12])[CH:24]=[N:23]2)=[CH:18][C:17]=1[CH3:25]
Reactant: [C-]#[N+]Cc1ccc(Br)c(C)c1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=[Cu-]
Solvent: Cc1ccccc1
Product: Cc1cc(C2CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C=N2)ccc1Br
Temperature: 110 °C
Reaction time: 16 h
Yield: 26.8 %

Procedure:
A mixture of 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (8.03 g) (made as described in EP 1,731,512), 1-bromo-4-isocyanomethyl-2-methyl-benzene (Example I3) (4.16 g) and copper(I) oxide (0.13 g) in toluene (50 ml) was stirred at 110° C. for 16 hours. The reaction mixture was concentrated and the residue purified by chromatography on silica gel (eluent: ethyl acetate/heptane) to give 2-(4-bromo-3-methyl-phenyl)-4-(3,5-dichloro-phenyl)-4-trifluoromethyl-3,4-dihydro-2H-pyrrole (2.39 g). 1H-NMR (400 MHz, CDCl3): 7.39-6.86 (m, 7H), 5.39-4.98 (m, 1H), 3.24-2.77 (m, 1H), 2.35 (m, 3H), 2.32-2.09 (m, 1H) ppm.
Reaction SMILES: C(N(CC)C1C=CC([C:8]([C:10]2[C:18]([Cl:19])=[C:17]([Cl:20])[C:16]([Cl:21])=[C:15]([Cl:22])[C:11]=2[C:12]([OH:14])=[O:13])=O)=CC=1)C.CN(C)C1C=CC=C(N(C)C)C=1.C(OC(=O)C)(=O)C>CO>[Cl:19][C:18]1[C:17]([Cl:20])=[C:16]([Cl:21])[C:15]([Cl:22])=[C:11]2[C:10]=1[CH2:8][O:13][C:12]2=[O:14]
Reactant: CCN(CC)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)cc1
Agent: CN(C)c1cccc(N(C)C)c1
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: O=C1OCc2c(Cl)c(Cl)c(Cl)c(Cl)c21
Temperature: 90 °C
Yield: 103 %

Procedure:
A mixture of 2-(4-(diethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (8.70 g.), N,N,N',N'-tetramethyl-m-phenylenediamine (3.61 g.) and acetic anhydride (5 ml.) was heated (to 90° C.). Addition of methanol (10 ml.) and slurrying the resulting product with methanol afforded 3-(2,4-bis(dimethylamino)phenyl)-3-(4-diethylamino)phenyl)-4,5,6,7-tetrachlorophthalide (I: X=(CH3)2N, Y2 =H, Y4 =(CH3CH2)2N, Z4 =Z5 =Z6 =Z7 =Cl) (5.60 g., m.p. 206°-207.5° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[B:26](OC(C)C)([O:31]C(C)C)[O:27]C(C)C.P(=O)(O)(O)O>C1(C)C=CC=CC=1.O1CCCC1>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:4]2[CH:3]=[C:2]([B:26]([OH:31])[OH:27])[CH:7]=[CH:6][CH:5]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)c2)CC1
Agent: O=P(O)(O)O
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(B(O)O)c2)CC1
Temperature: -70 °C

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 4-(3-bromophenyl)piperazine-1-carboxylate (3.8 g, 11.14 mmol, 1.00 equiv) in toluene/tetrahydrofuran=1:1 (40 mL). This was followed by the addition of n-BuLi (4.9 mL, 2.5M/L) dropwise with stirring at −70° C. The resulting solution was stirred for 30 min at −70° C. To this was added triisopropyl borate (2.5 g, 13.30 mmol, 1.19 equiv) dropwise with stirring at −70° C. The mixture was warmed to 0° C., the reaction was then quenched by the addition of 13 mL of saturated ammonium chloride and 3.4 mL of water. Phosphoric acid (85 wt %, 1.5 g, 1.2 equiv) was added and the mixture was stirred for 30 min. The organic layer was separated and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was dissolved in 20 mL of toluene. The product was precipitated by the addition of 80 mL of heptane. The solids were washed with 20 mL of heptane and collected by filtration. This resulted in 2.9 g (85%) of 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenylboronic acid as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH2:10][CH2:9]1.CCCCCC.CO[CH:27](OC)[N:28]([CH3:30])[CH3:29]>>[CH3:27][N:28]([CH:30]=[C:10]1[CH2:9][C@@H:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:18])[CH3:29]
Reactant: COC(OC)N(C)C
Reactant: O=C1CC[C@@H](c2ccccc2F)c2ccccc21
Solvent: CCCCCC
Product: CN(C)C=C1C[C@@H](c2ccccc2F)c2ccccc2C1=O
Temperature: 25 °C
Yield: 70 %

Procedure:
A solution of (R)-4-(2-fluorophenyl)-3,4-dihydronaphthalen-1(2H)-one (8.0 g, 33.33 mmol) in N,N-dimethylformamide dimethylacetal (80 mL) was heated at 100° C. for 40 h. After the reaction mixture was cooled to room temperature, hexane (50 mL) was added. Product was collected by filtration and dried under high vacuum overnight to yield the title compound as yellow needles (6.95 g, 70% yield). 1H-NMR (DMSO-d6) δ 7.92 (dd, J=7.2 and 1.6 Hz, 1 H), 7.57 (s, 1 H), 7.42-7.34 (m, 2 H), 7.31-7.21 (m, 2 H), 7.09 (t, 1 H), 6.91-6.88 (m, 2 H), 4.48 (t, J=7.2 Hz, 1 H), 3.25-3.13 (m, 2 H), 3.02 (s, 6 H). LCMS m/e 296 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([O:23]CC)=O)[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][S:35]([C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][NH2:46])=[CH:40][CH:39]=1)(=[O:37])=[O:36]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([NH:46][CH2:45][CH2:44][C:41]4[CH:40]=[CH:39][C:38]([S:35]([CH3:34])(=[O:37])=[O:36])=[CH:43][CH:42]=4)=[O:23])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(CCN)cc1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Solvent: CCN(CC)CC
Product: Cn1c(=O)c(C(=O)NCCc2ccc(S(C)(=O)=O)cc2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 25.7 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (30 mg, 0.084 mmol) described in example 92, triethylamine (0.5 mL, 4.08 mmol), and {2-[4-(methylsulfonyl)phenyl]ethyl}amine (250 mg, 1.25 mmol), was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-N-{2-[4-(methylsulfonyl)phenyl]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (11 mg, 26% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.28 (br s, 1 H), 8.56 (s, 1 H), 7.87 (d, J=8 Hz, 2 H), 7.44 (d, J=8 Hz, 2 H), 7.38 (s, 1 H), 7.16-7.14 (m, 2 H), 7.04-6.99 (m, 2 H), 4.13 (s, 2 H), 3.72 (m, 2 H), 3.56 (s, 3 H), 3.06-3.02 (m, 5 H); HRMS m/z calcd for: C26H25FN3O5S: 510.1493. Found: 510.1498.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([CH:14]=[O:15])=[CH:11][CH:10]=2)[CH:6]=[C:5]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:4]=1.[Mn]([O-])(=O)(=O)=[O:28].[K+]>CC(C)=O.O>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([C:14]([OH:28])=[O:15])=[CH:11][CH:10]=2)[CH:6]=[C:5]([NH:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[N:4]=1
Reactant: COc1ccc(CCNc2cc(-c3ccc(C=O)s3)nc(OC)n2)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(CCNc2cc(-c3ccc(C(=O)O)s3)nc(OC)n2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.6 %

Procedure:
To a solution of 5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carbaldehyde [700 mg, 1.895 mmol, Example 8(b)] in acetone (20 mL) is added a solution of potassium permanganate (898 mg, 5.684 mmol) and NaH2PO4.H2O (79 mg, 0.568 mmol) in water (20 mL) followed by the addition of silica gel (4 g). The mixture is allowed to stir at ambient temperature for 6 hours, allowed to stand overnight, evaporated to remove the acetone and extracted several times with ethyl acetate. The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated. The residual crude product is dissolved in refluxing acetonitrile and the solids that formed upon cooling are collected by filtration to afford 5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic acid [362 mg, 50%, Example 61].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.[Br:10]N1C(=O)CCC1=O.CCCCCCC.C1(=O)NC(=O)CC1>C(OC(=O)C)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:7]=1)[CH2:8][Br:10]
Reactant: Cc1cc(Cl)ccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Fc1ccc(Cl)cc1CBr
Temperature: 80 °C
Reaction time: 3 h
Yield: 104.8 %

Procedure:
5-Chloro-2-fluoro-toluene (100 g, 692 mmol) was dissolved in ethylacetate (300 ml) at 20° C. To this solution N-bromosuccinimide (147.7 g, 830 mmol) and dibenzoyl peroxide (2 g, 8.25 mmol) was added. The mixture was stirred at 80° C. for 3 hours. Heptane (300 ml) was added and the solution was cool to 0° C. whereupon succinimide precipitates. After filtration and washing with heptane, the residue was washed with water (1500 ml). The filtrate was concentrated in vacuo to dryness, yielding 162 grams of crude 5-chloro-2-fluoro-benzylbromide. Purification of the crude product (141 grams) was done by vacuum distillation at 99° C. and 33 mbar, this 5-chloro-2-fluoro-benzylbromide (99 grams, 75%). Purity according to GC is 87.1% a/a.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:18][CH3:19])([CH2:16][CH3:17])[C:4]=2[CH:3]=1.BrC1C=CC([N:25]([C:32]2[CH:37]=[CH:36][CH:35]=CC=2)[C:26]2C=CC=CC=2)=CC=1>>[Br:15][C:8]1[CH:7]=[C:6]2[C:11]([C:12]3[CH:13]=[CH:14][C:2]([C:35]4[N:25]([CH3:26])[CH:32]=[CH:37][CH:36]=4)=[CH:3][C:4]=3[C:5]2([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:10][CH:9]=1
Reactant: CCC1(CC)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Product: CCC1(CC)c2cc(Br)ccc2-c2ccc(-c3cccn3C)cc21

Procedure:
The compound of the present example was synthesized by the same method as described in example 1, except that 3.80 parts of 2,7-dibromo-9,9-diethyl-9H-fluorene (21) was used to substitute 4-bromo-N,N-diphenylaniline.
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:3]=1.[CH3:29][C:30]1([CH3:46])[C:42]2[CH:41]=[C:40](B(O)O)[CH:39]=[CH:38][C:37]=2[C:36]2[C:31]1=[CH:32][CH:33]=[CH:34][CH:35]=2.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([C:4]2[C:5]3[C:16]4=[C:17]5[C:8](=[CH:7][CH:6]=3)[CH:9]=[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:11]=[C:12]5[CH:13]=[CH:14][C:15]4=[C:2]([C:40]3[CH:39]=[CH:38][C:37]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[C:30]([CH3:29])([CH3:46])[C:42]=4[CH:41]=3)[CH:3]=2)=[CH:27][CH:26]=1
Reactant: CC1(C)c2ccccc2-c2ccc(B(O)O)cc21
Reactant: CC(C)(C)c1cc2ccc3c(Br)cc(-c4ccc(Cl)cc4)c4ccc(c1)c2c34
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)c1cc2ccc3c(-c4ccc(Cl)cc4)cc(-c4ccc5c(c4)C(C)(C)c4ccccc4-5)c4ccc(c1)c2c34
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
A mixed solution of 10.0 g of 1-bromo-7-t-butyl-3-(4-chlorophenyl)pyrene, 5.86 g of 9,9-dimethylfluoren-2-yl boronic acid, 0.016 g of bis(triphenylphosphine)palladium dichloride, 33 ml of an aqueous 1.5M sodium carbonate solution and 112 ml of 1,2-dimethoxyethane was heated and stirred for 3 hours under a nitrogen stream and under refluxing. After the mixture was cooled to room temperature, 223 ml of water was added, and this was extracted with 236 ml of toluene. The organic layer was washed with 640 ml of an aqueous sodium chloride solution two times, dried with magnesium sulfate, and evaporated, 50 ml of 2-propanol was added, and the mixture was stirred for 2 hours, and filtered. After the mixture was vacuum dried, 9.5 g of 1-(4-chlorophenyl)-3-(9,9-dimethylfluoren-2-yl)-7-t-butylpyrene was obtained.
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:21]2[S:25][C:24]([S:26]([NH2:29])(=[O:28])=[O:27])=[C:23]([CH3:30])[CH:22]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][C:11]=1[CH3:31])(C)(C)C.[C:38](O)(=[O:41])[CH2:39][CH3:40]>>[C:38]([NH:29][S:26]([C:24]1[S:25][C:21]([C:16]([CH2:19][CH3:20])([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH:7]([OH:6])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:11]([CH3:31])[CH:12]=2)[CH2:17][CH3:18])=[CH:22][C:23]=1[CH3:30])(=[O:28])=[O:27])(=[O:41])[CH2:39][CH3:40]
Reactant: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Reactant: CCC(=O)O
Product: CCC(=O)NS(=O)(=O)c1sc(C(CC)(CC)c2ccc(OCC(O)C(C)(C)C)c(C)c2)cc1C
Yield: 66 %

Procedure:
Using procedures analogous to Example 158B and Example 158C, 5-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-sulfonic acid amide and propionic acid give the title compound (66%).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([O:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([C:29]#[N:30])=[C:27]([S:31][CH2:32][C:33]3[N:34]=[C:35]([C:38]4[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=4)[S:36][CH:37]=3)[N:26]=[C:25]([N:45]3[CH2:48][CH2:47][CH2:46]3)[C:24]=2[C:49]#[N:50])=[CH:19][CH:18]=1)=[O:12])[CH3:10])=O)(C)(C)C.[F:51][C:52]([F:57])([F:56])[C:53]([OH:55])=[O:54]>ClCCl>[F:51][C:52]([F:57])([F:56])[C:53]([OH:55])=[O:54].[NH2:8][C@H:9]([C:11]([O:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([C:29]#[N:30])=[C:27]([S:31][CH2:32][C:33]3[N:34]=[C:35]([C:38]4[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=4)[S:36][CH:37]=3)[N:26]=[C:25]([N:45]3[CH2:46][CH2:47][CH2:48]3)[C:24]=2[C:49]#[N:50])=[CH:19][CH:18]=1)=[O:12])[CH3:10]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCC3)c2C#N)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCC3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
39 mg (0.053 mmol) of 2-{4-(2-(azetidin-1-yl)-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyanopyridin-4-yl)phenoxy}ethyl N-(tert-butoxycarbonyl)-L-alaninate (Example 13A) were initially charged in 1.5 ml dichloromethane. 0.5 ml (6.49 mmol) of trifluoroacetic acid was added, and the reaction solution was then stirred at RT for 1.5 h. The reaction solution was concentrated by evaporation and the residue was purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 40 mg (100% of theory) of the target compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10].[C:12]1([CH:18]([CH3:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[Cl:5][CH2:6][CH2:7][CH2:8][C:9]([C:15]1[CH:16]=[CH:17][C:12]([CH:18]([CH3:20])[CH3:19])=[CH:13][CH:14]=1)=[O:10]
Reactant: CC(C)c1ccccc1
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)c1ccc(C(=O)CCCCl)cc1
Temperature: 6.5 °C
Reaction time: 14 h
Yield: 86.9 %

Procedure:
Slurry aluminum chloride (140.9 g, 1.075 mol) and 4-chlorobutyryl chloride (148 g, 1.5 mol) in methylene chloride (1.0L) add, by dropwise addition, cumene (125 g, 1.04 mol) over a thirty minute period under a nitrogen atmosphere while maintaining the internal temperature between 5-8° C. with an ice bath. Allow the stirred solution to come to room temperature and continue stirring under nitrogen for 14 hours. Cautiously add the methylene chloride solution to 1L of crushed ice with stirring and add additional methylene chloride (400 mL). Separate the organic phase and wash with 10% hydrochloric acid (3×300 mL), water (3×300 mL), 10% sodium bicarbonate (3×300 mL) and water (3×300 mL). Dry (MgSO4), filter and wash with methylene chloride (150 mL). Evaporate the solvent to give the title compound (203 g, 86%) as a clear oil which crystallizes on standing; mp 35-37° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([CH2:26][OH:27])=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:44][O:45][CH2:46][C:47](O)=[O:48]>O1CCCC1>[CH2:1]([N:8]1[C:12]2=[C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([CH2:26][O:27][C:47](=[O:48])[CH2:46][O:45][CH3:44])=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCC(=O)O
Reactant: Cc1c(CO)c2cnnc(OCc3ccc(F)cc3)c2n1Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: COCC(=O)OCc1c(C)n(Cc2ccccc2)c2c(OCc3ccc(F)cc3)nncc12
Yield: 60 %

Procedure:
0.1 g (0.25 mmol) of 1-benzyl-7-(4-fluorobenzyloxy)-3-hydroxymethyl-2-methylpyrrolo [2,3-d]pyridazine, 0.164 g (0.8 mmol) of dicyclohexylcarbodiimide and 0.061 ml (0.8 mmol) of methoxyacetic acid are reacted in 5 ml of anhydrous tetrahydrofuran as described for Example 7a. Yield: 60%, m.p.: 119°-121° C.
Reaction SMILES: [S:1]([N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=O)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].Cl.[NH2:23][OH:24].N1C=CC=CC=1>CCO>[S:1]([N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=[N:23][OH:24])[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)cccc32)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C=NO)cccc32)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of 42 (900 mg, 3 mmol) in EtOH (10 mL) was added hydroxylamine hydrochloride (1.0 g, 15 mmol) and pyridine (1.0 mL). After the reaction mixture was stirred at 70° C. overnight, the solvent was removed in vacuo to afford 800 mg (85%) of 1-tosyl-1H-indole-4-carbaldehyde oxime (44) as white solid: MS (ESI) m/z=315 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:21]3[C:20](=[O:30])[NH:19][C:18](=[O:31])[N:17]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50]Br)=[CH:45][CH:44]=1>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:21]3[C:20](=[O:30])[N:19]([CH2:50][CH2:49][C:46]4[CH:47]=[CH:48][CH:43]=[CH:44][CH:45]=4)[C:18](=[O:31])[N:17]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)Cn1c(=O)[nH]c(=O)c2c1nc(N1CCN(C(=O)OC(C)(C)C)CC1)n2-c1ccccc1Cl
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(=O)n(CCc2ccccc2)c(=O)c2c1nc(N1CCN(C(=O)OC(C)(C)C)CC1)n2-c1ccccc1Cl
Temperature: 50 °C
Reaction time: 8 h

Procedure:
4-[7-(2-Chlorophenyl)-3-methoxycarbonylmethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (49 mg) was dissolved in N,N-dimethylformamide (1 ml), and potassium carbonate (20 mg) and 2-phenethyl bromide (0.03 ml) were added to the solution. Then, the mixture was stirred at 50° C. overnight. The reaction mixture was diluted with ethyl acetate, and washed with water and 1N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed by distillation to give 52 mg of the title compound.