Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]([CH3:21])[C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.C(O)C.Cl.[S-:26][C:27]#[N:28].[Na+]>O>[C:17]([C:8]1[CH:7]=[C:6]([C:4]2[NH:28][C:27](=[S:26])[NH:2][C:3]=2[CH3:21])[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]=1[OH:16])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(N)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: N#C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1[nH]c(=S)[nH]c1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
To a mixed solution of 4.3 g of 4-(2-aminopropionyl)-2,6-di-tert-butylphenol hydrochloride, 50 ml of ethanol, and 1.2 ml of concentrated hydrochloric acid was added a solution of 2.2 g of sodium thiocyanate in 4 ml of water at room temperature. After stirring the mixture for 1.5 hours at room temperature and further refluxing the mixture for 2 hours, the solvent was distilled off under reduced pressure. Then, 30 ml of acetic acid was added to the residue and the mixture was refluxed for 2-3 hours. The reaction mixture thus formed was poured into water and the precipitates formed were recovered by filtration. The product was recrysltallized from isopropanol to provide 3.1 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-thioxo-4-imidazoline.
Reaction SMILES: [CH2:1]([S:16][CH:17]([CH2:23][CH3:24])[C:18]([O:20]CC)=[O:19])[CH2:2]/[CH:3]=[CH:4]\[CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH3:15].[Li+].[OH-].Cl>C(O)C.O>[CH2:1]([S:16][CH:17]([CH2:23][CH3:24])[C:18]([OH:20])=[O:19])[CH2:2]/[CH:3]=[CH:4]\[CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH3:15]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\CCSC(CC)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC/C=C\C/C=C\C/C=C\C/C=C\CCSC(CC)C(=O)O
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
Ethyl 2-((3Z,6Z,9Z,12Z)-pentadeca-3,6,9,12-tetraenylthio)butanoate (14.1 g, 40.2 mmol) was dissolved in ethanol (200 mL) and added a solution of LiOH×H2O (13.5 g, 322 mmol) in water (50 mL). The resulting turbid solution was stirred at 70° C. under inert atmosphere for 90 minutes, cooled, added water (100 mL) and 3M HCl until pH=2. The mixture was extracted three times with heptane (100 mL each). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to afford 11.8 g (91% yield) of the title compound as oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])=[O:18])[C@@H:13]([OH:24])[C@H:12]2[OH:25])=[C:4](Cl)[N:3]=1.[NH2:27][C@@H:28]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:29][OH:30].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])=[O:18])[C@@H:13]([OH:24])[C@H:12]2[OH:25])=[C:4]([NH:27][C@H:28]([CH2:29][OH:30])[CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:3]=1
Reactant: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: N[C@H](CO)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(N[C@H](CO)Cc4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reaction time: 8 h

Procedure:
The title compound is prepared by combining acetic acid [(1S,2R,3S,4R)-4-(2,6-dichloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl-carbamoyl]-methyl ester (1 equivalent) and (S)-2-amino-3-phenyl-propan-1-ol 1 equivalent) in dichloromethane with triethylamine (1.1 equivalents) and stirring overnight. The reaction is diluted with dichloromethane, and washed consecutively with 0.1M hydrochloric acid, water and brine, before drying over magnesium sulfate. Filtration and removal of the volatile components under reduced pressure, affords the title compound.
Reaction SMILES: C([O:4][CH2:5][CH:6]=[C:7]([CH3:9])[CH3:8])(=O)C.[CH3:10][C:11]([CH3:15])=[CH:12][CH:13]=O.C(O)(=O)C1C=CC=CC=1>>[CH3:10][C:11](=[CH:12][CH2:13][CH2:9][C:7](=[CH:6][CH:5]=[O:4])[CH3:8])[CH3:15]
Reactant: CC(C)=CC=O
Reactant: CC(=O)OCC=C(C)C
Agent: O=C(O)c1ccccc1
Product: CC(C)=CCCC(C)=CC=O
Yield: 48 %

Procedure:
60 parts of prenyl acetate, 40 parts of 3,3-dimethylacrolein and 2parts of benzoic acid are heated together for five hours thirty minutes at 140°C and the product is worked up. 11.1 parts of citral is obtained having a boiling point of 104°C at 12 mm in a yield of 48% at a conversion of 32% (based on 3,3-dimethylacrolein).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)O1.Br[C:24]1[N:25]=[C:26]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[S:27][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>CS(C)=O.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:38][C:35]1[CH:34]=[CH:33][C:32]([S:29]([C:26]2[S:27][CH:28]=[C:24]([C:9]3[CH:21]=[CH:20][C:12]4[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=4[CH:10]=3)[N:25]=2)(=[O:31])=[O:30])=[CH:37][CH:36]=1
Reactant: O=S(=O)(c1ccc(F)cc1)c1nc(Br)cs1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
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: C1COCCO1
Solvent: CS(C)=O
Product: CC(=O)Nc1nc2ccc(-c3csc(S(=O)(=O)c4ccc(F)cc4)n3)cc2s1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A RBF was charged with N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.5 g, 1 mmol), 4-bromo-2-(4-fluorophenylsulfonyl)thiazole (0.4 g, 1 mmol), 2 M Na2CO3 (1 mL, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (0.2 g, 0.2 mmol), and dioxane (6 mL). The flask was placed into a pre-heated (95° C.) bath and allowed to stir under an inert atmosphere overnight. The mixture was diluted with DMSO and filtered. The crude was purified by reverse-phase HPLC to give N-(6-(2-(4-fluorophenylsulfonyl)thiazol-4-yl)benzo[d]thiazol-2-yl)acetamide as an off-white solid. MS (ESI pos. ion) m/z: 434 (MH+). Calculated exact mass for C18H12FN3O3S3: 433. 1H NMR (400 MHz, DMSO-d6): 8.53 (s, 1H), 8.30 (s, 1H), 8.21 (s, 2H), 7.81 (s, 1H), 7.56 (s, 3H), 2.07 (s, 3H).
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([OH:26])=O)[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:57][N:58]1[CH2:63][CH2:62][CH:61]([N:64]2[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]2)[CH2:60][CH2:59]1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:67]3[CH2:66][CH2:65][N:64]([CH:61]4[CH2:62][CH2:63][N:58]([CH3:57])[CH2:59][CH2:60]4)[CH2:69][CH2:68]3)=[O:26])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)O)co2)C2CC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCN(C4CCN(C)CC4)CC3)co2)C2CC2)c(C)c1
Reaction time: 0.25 h

Procedure:
2-({Cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3-oxazole-4-carboxylic acid (100 mg, 0.26 mmol) was dissolved in DCM (15 mL) and EDCI (70 mg, 0.36 mmol), HOBt (53 mg, 0.39 mmol) and DIPEA (0.057 mL, 0.33 mmol) were added. The resulting solution was stirred for 15 min prior to the addition of 1-(1-methylpiperidin-4-yl)piperazine (57 mg, 0.31 mmol) dissolved in DCM (2 mL) and stirred at ambient temperature for 12 h. The reaction was diluted with DCM (20 mL) and washed with water (10 mL), saturated aqueous NaHCO3 (10 mL), saturated brine (5 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by FCC with 0-2% MeOH in DCM to afford the title compound as pale yellow oil.
Reaction SMILES: [OH-:1].[Na+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[N:13][C:12]=12)=[O:7])C.Cl>C(O)C>[C:17]([C:15]1[CH:14]=[N:13][C:12]2[N:11]([N:10]=[CH:9][C:8]=2[C:6]([OH:5])=[O:7])[CH:16]=1)(=[O:1])[NH2:18]
Reactant: [OH-]
Reactant: CCOC(=O)c1cnn2cc(C#N)cnc12
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cnc2c(C(=O)O)cnn2c1
Temperature: 60 °C
Yield: 75 %

Procedure:
An aqueous solution of sodium hydroxide (10%, 5 mL) was added to a suspension of 6-cyano-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (0.35 mg, 1.62 mmol) in ethanol (5 mL) and the reaction mixture was heated at 60° C. for 5 hours. Ice-water was added and the resulting mixture was acidified until pH<1 by addition of an aqueous solution of hydrochloric acid (3 M). The solid which crashed out was collected by filtration, washed twice with water, methanol and diethyl ether, dried under reduced pressure to afford 0.25 g (75% yield) of 6-carbamoyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=O)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:50][CH2:51][C:52]([C:54]1[CH:59]=[CH:58][C:57]([Br:60])=[CH:56][CH:55]=1)=[O:53]>CN(C=O)C>[Br:60][C:57]1[CH:56]=[CH:55][C:54]([C:52](=[O:53])[CH2:51][NH:50][C:19]([C@@H:18]2[CH2:22][CH2:23][CH2:24][N:17]2[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[O:21])=[CH:59][CH:58]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: NCC(=O)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCC(=O)c1ccc(Br)cc1
Yield: 95.9 %

Procedure:
N,N-Diisopropylethylamine (18 mL, 103.3 mmol) was added dropwise, over 15 minutes, to a heterogeneous mixture of N-Boc-L-proline (7.139 g, 33.17 mmol), HATU (13.324 g, 35.04 mmol), the HCl salt of 2-amino-1-(4-bromo-phenyl)ethanone (8.127 g, 32.44 mmol), in DMF (105 mL) and stirred at ambient condition for 55 minutes. DMF was removed in vacuo, and the resulting residue was partitioned between ethyl acetate (300 mL) and water (200 mL). The organic layer was washed with water (200 mL) and brine, dried (MgSO4), filtered, and concentrated. A silica gel mesh was prepared from the residue and submitted to flash chromatography (silica gel; 50-60% ethyl acetate/hexanes) to provide Example 14, (S)-tert-butyl 2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)pyrrolidine-1-carboxylate as a white solid (12.8 g). 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): δ 8.25-8.14 (m, 1H), 7.92 (br d, J=8.0, 2H), 7.75 (br d, J=8.6, 2H), 4.61 (dd, J=18.3, 5.7, 1H), 4.53 (dd, J=18.1, 5.6, 1H), 4.22-4.12 (m, 1H), 3.43-3.35 (m, 1H), 3.30-3.23 (m, 1H), 2.18-2.20 (m, 1H), 1.90-1.70 (m, 3H), 1.40/1.34 (two app br s, 9H). RT=1.70 min (condition 1); LCMS: Anal. Calcd. for C18H23BrN2NaO4: 433.07. found 433.09 [M+Na]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)=[O:21])=[CH:15][CH:14]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:27](OCC)=[O:28].[O-]CC.[Na+].Cl>C(O)C>[OH:28][CH:27]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)=[O:21])=[CH:15][CH:14]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: O=C1Cc2ccc(C(=O)c3ccc(NC(=O)c4cccs4)cc3)cc2N1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1Nc2cc(C(=O)c3ccc(NC(=O)c4cccs4)cc3)ccc2C1=CO
Temperature: 78 °C
Yield: 75.4 %

Procedure:
Thiophene-2-carboxylic acid [4-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.857 g, 2.36 mmol) and ethyl formate (0.567 mL, 7.09 mmol) were dissolved in anhydrous ethanol (4.73 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (4.41 mL, 11.83 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure Thiophene-2-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.695 g, 1.78 mmol, 75%).
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:23][C:22]([SH:24])=[N:21][N:20]=4)[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)=[CH:6][CH:5]=1)=[O:3].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br>>[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][S:24][C:22]1[O:23][C:19]([C:16]2[CH:17]=[CH:18][C:13]3[O:12][CH:11]=[C:10]([C:7]4[CH:6]=[CH:5][C:4]([S:2]([CH3:1])=[O:3])=[CH:9][CH:8]=4)[C:14]=3[CH:15]=2)=[N:20][N:21]=1
Reactant: CS(=O)c1ccc(-c2coc3ccc(-c4nnc(S)o4)cc23)cc1
Reactant: Fc1cccc(CBr)c1
Product: CS(=O)c1ccc(-c2coc3ccc(-c4nnc(SCc5cccc(F)c5)o4)cc23)cc1
Yield: 87 %

Procedure:
In the same manner as in Example 7 and using 5-[3-[4-(methylsulfinyl)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(1H-indazol-5-yl)-1,3,4-oxadiazole-2-thiol and 3-fluorobenzyl bromide instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 87%) was obtained as colorless crystals.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1/[CH:12]=[CH:13]/[C:14]([OH:16])=O)(=[O:3])[CH3:2].[Cl:17][C:18]1[CH:31]=[CH:30][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH:25]([CH3:29])[CH2:24]2)=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:11][C:9]1[CH:8]=[CH:7][C:6](/[CH:12]=[CH:13]/[C:14]([N:26]2[CH2:27][CH2:28][N:23]([CH2:22][C:21]3[CH:30]=[CH:31][C:18]([Cl:17])=[CH:19][CH:20]=3)[CH2:24][CH:25]2[CH3:29])=[O:16])=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=1
Reactant: CC1CN(Cc2ccc(Cl)cc2)CCN1
Reactant: CC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)N1CCN(Cc2ccc(Cl)cc2)CC1C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
0.10 g (0.42 mmol) (E)-3-(2-Acetylamino-4-chloro-phenyl)-acrylic acid, 85 mg 1-(4-Chloro-benzyl)-3-methyl-piperazine (0.38 mmol), 87 mg EDCI (0.45 mmol) and 61 mg HOBt (0.45 mmol) were dissolved in 5 ml DMF. The reaction mixture was stirred overnight, then partitioned between ethylacetate and aq. sodiumbicarbonate solution. The organic phase was further washed with water and brine. Removal of the solvent gave a crude product which was further purified by prep. HPLC (Waters XT column, acetonitrile/water). 0.11 mg (0.24 mmol, 63%) of the title compound was obtained as an pale yellow solid.
Reaction SMILES: [CH3:1]C1(C)CCCC(C)(C)N1.[Li]C(CC)C.[C:16]([O:20][C:21]([N:23]([C:31]1[C:36]([F:37])=[CH:35][CH:34]=[C:33]([Br:38])[C:32]=1[CH3:39])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:22])([CH3:19])([CH3:18])[CH3:17].IC.[NH4+].[Cl-]>C1COCC1>[C:16]([O:20][C:21]([N:23]([C:31]1[C:36]([F:37])=[C:35]([CH3:1])[CH:34]=[C:33]([Br:38])[C:32]=1[CH3:39])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:22])([CH3:17])([CH3:18])[CH3:19]
Reactant: Cc1c(Br)ccc(F)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC1(C)CCCC(C)(C)N1
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc(Br)c(C)c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F
Temperature: -65 °C
Reaction time: 0.33 h
Yield: 85.2 %

Procedure:
To a stirred solution of 2,2,6,6-tetramethylpiperidine (699 mg, 4.9 mmol, 2.0 eq) in THF (7.5 mL) at −50° C. was added sec-BuLi (3.8 mL, 1.3 M, 4.9 mmol, 2.0 eq) dropwise. The reaction was stirred for 20 min at −15° C. to −10° C., then cooled to −65° C. and a solution of tert-butyl N-tert-butoxycarbonyl-N-(3-bromo-6-fluoro-2-methylphenyl)carbamate (See example 13) (1 g, 2.47 mmol, 1.0 eq) in THF (7.5 mL) added dropwise. The reaction was stirred a further 2 h at −65° C. Iodomethane (1.05 g, 7.41 mmol, 3.0 eq) was added in one portion and the reaction allowed to warm to −10° C. over 30 min. The reaction was then poured into saturated aqueous NH4Cl and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4) filtered and evaporated in vacuo to give a crude residue, which was purified by column chromatography (petroleum ether:EtOAc, 100:0 to 30:1) to give the title compound as a white solid (880 mg, 85%).
Reaction SMILES: O.Cl.O[C:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:8][CH2:7][C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)=[C:5]1[CH3:19].N>O1CCCC1>[CH3:19][C:5]1[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:8][CH2:7][C:6]=1[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2
Reactant: CC1=C(c2cccc3cccnc23)CCC1(O)c1ccccc1
Agent: Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: CC1=C(c2cccc3cccnc23)CC=C1c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.3 %

Procedure:
A mixture of 5 ml of water and 5 ml of concentrated hydrochloric acid was added to a solution of 1.717 g (5.7 mmol) of 3-hydroxy-2-methyl-3-phenyl-1-(8-quinolyl)cyclopentene in 100 ml of tetrahydrofuran. The mixture was stirred at room temperature for 90 minutes and ammonia solution was then added until the pH was 12. The aqueous phase was then separated off from the organic phase and the aqueous phase was extracted twice with diethyl ether. The organic phases were combined, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue obtained in this way was distilled at 157-170° C. and 2×10−2 mbar to give 1.12 g (3.95 mmol, 69.3%) of 2-methyl-3-phenyl-1-(8-quinolyl)cyclopentadiene.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1.C([Sn](CCCC)(CCCC)/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)CCC>C1(C)C=CC=CC=1>[CH3:9][O:8][C:4]1[CH:3]=[C:2](/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CCCC[Sn](/C=C/c1ccccn1)(CCCC)CCCC
Reactant: COc1cc(Cl)ccn1
Solvent: Cc1ccccc1
Product: COc1cc(/C=C/c2ccccn2)ccn1
Temperature: 100 °C
Yield: 83 %

Procedure:
4-Chloro-2-methoxypyridine (182 mg, 1.27 mmol) and (E)-2-(2-(tributylstannyl)vinyl)pyridine (R. A. Hacck, et al. Tet. Lett 1988, 29, 2783-2786) (500 mg, 1.27 mmol) were stirred in dry toluene (4 mL) and degassed with a nitrogen stream as the temperature was increased to 100° C. Palladium tetrakistriphenylphosphine (146 mg, 0.127 mmol) was added and the reaction mixture was maintained at 100° C. under a nitrogen atmosphere for 16 h. Upon cooling, the mixture was purified by column chromatography (12 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 80% methylene chloride over 30 min at 25 mL/min) to provide the title compound (225 mg, 83%) as a green oil: 1H NMR (500 MHz, CD3OD) δ 8.63 (d, J=4.7 Hz, 1H), 8.15 (d, J=5.4 Hz, 1H), 7.71-7.67 (dt, J=7.5, 1.6 Hz, 1H), 7.53 (d, J=16.4 Hz, 1H), 7.40 (d, J=7.9 Hz, 1H), 7.28 (d, J=16.4 Hz, 1H), 7.22-7.18 (dd, J=7.2, 4.7 Hz, 1H), 7.06 (d, J=5.4 Hz, 1H), 6.85 (s, 1H), 3.96 (s, 3H).
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:21])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:20])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17].[NH2:22][CH2:23][C:24]12[CH2:31][CH2:30][CH2:29][N:28]1[CH2:27][CH2:26][CH2:25]2>C(O)C>[CH3:21][C:4]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:20])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:3][CH2:2][NH:22][CH2:23][C:24]12[CH2:31][CH2:30][CH2:29][N:28]1[CH2:27][CH2:26][CH2:25]2
Reactant: NCC12CCCN1CCC2
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCBr
Solvent: CCO
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCNCC12CCCN1CCC2
Reaction time: 5 h
Yield: 49.8 %

Procedure:
Under an atmosphere of argon, a solution of 1-bromo-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraene [6.90 g, 19.5 mmol, prepared as described in Example 5-a)] in 138 ml of ethanol was added in dropwise to a solution of 5-aminomethyl-1-azabicyclo[3.3.0]octane (3.3 g, 23.6 mmol) in 35 ml of ethanol at the temperature below 0° C. The reaction mixture was allowed to warm slowly from 0°-20° C. and then stirred at 20°-25° C. for 5 hours. The resulting solution was treated as described in Example 8 to afford 4.0 g (49.8%) of the desired compound, as a pale brown oil.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([NH:27][CH3:28])[N:13]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[C:17]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=[C:15]([N:13]2[CH:14]=[C:9]([OH:8])[C:10](=[O:29])[CH:11]=[C:12]2[NH:27][CH3:28])[CH:16]=1
Reactant: CNc1cc(=O)c(OCc2ccccc2)cn1-c1cccc(-c2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: CNc1cc(=O)c(O)cn1-c1cccc(-c2ccccc2)c1
Reaction time: 2 h

Procedure:
A mixture of 5-(benzyloxy)-1-(biphenyl-3-yl)-2-(methylamino)pyridin-4(1H)-one (1.3 Ig, 3.43 rnmol) 10% Pd/C (150 mg) in MeOH (200 mL) was stirred under an ¾ balloon for 2 h. After this time, LCMS indicated that the reaction was complete. The catalyst was filtered and washed with MeOH (4×50). The combined MeOH solution was concentrated to give 1-(biphenyl-3-yl)-5-hydroxy-2-(methylamino)pyridin-4(1H)-one as slightly yellow solid. ′H NMR (500 MHz, DMSO): δ 7.84-7.81 (m, 1H); 7.78-7.74 (mf 2H); 7.70-7.62 (m, 2H); 7.52-7.46 (m, 2H); 7.42-7.36 (m, 2H); 6.93 (s, 1H); 5.42-5.32 (m, 2H); 2.58 (d, J=4.7 Hz, 3H). LC/MS (M+H), 293. HRMS Calculated for (Ci8H,6N2O2+H)+ 293.1285. found 293.1285.
Reaction SMILES: OC1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)([CH2:10][CH3:11])[CH3:9])=CC=1.[CH3:19]C(=C)C>C1(C)C=CC=CC=1>[OH:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[C:8]([CH3:9])([CH2:10][CH3:11])[CH2:5][C:6]2([CH3:7])[CH3:19]
Reactant: C=C(C)C
Reactant: CCC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: Cc1ccccc1
Product: CCC1(C)CC(C)(C)c2cc(O)ccc21

Procedure:
121 g (0.5 mol) of 2,2-bis-(4-hydroxyphenyl)-butane, 22 g of an acid-activated fuller's earth and 90 g (1.6 mol) of isobutylene are stirred in an autoclave for 6 hours at 180° C. After cooling, the reaction mixture is taken up in 150 ml of toluene, the catalyst filtered off and the solvent evaporated. The residue is fractionated through a 1 meter glass-packed column, giving at a boiling temperature of 155° to 160° C./12 Torr 37 g of a fraction from which 24.8 g (20 % of the theoretical) of 5-hydroxy-1,3,3-trimethyl-1-ethyl indane (V) melting at 86° C. are obtained by recrystallisation from 90 ml of petroleum ether. ##STR23##