Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][NH2:6])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16].O>ClCCl>[C:18]1([O:17][C:15]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[NH2:6])=[O:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCCNN
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCN(N)C(=O)Oc1ccccc1
Temperature: 25 °C
Yield: 28.6 %

Procedure:
To a solution of butylhydrazine (370 mg, 4.20 mmol) and triethylamine (0.88 mL, 6.30 mmol) in dichloromethane (15 mL) at 0° C. was added phenyl chloroformate (0.53 mL, 4.20 mmol). The reaction mixture was stirred and allowed to warm up to room temperature overnight. Water (20 mL) was then added to the reaction mixture. The aqueous layer was extracted with dichloromethane (20 mL×2). The combined organic layers were dried (MgSO4). Filtration and evaporation under vacuum, followed by purification by flash column chromatography provided the title compound (250 mg, 29%). 1H NMR (400 MHz, CHCl3) δ 7.40-7.10 (m, 5H), 4.20 (t, J=7.1 Hz, 2H), 3.60 (br s, 2H), 1.71 (m, 2H), 1.41 (m, 2H), 0.98 (t, J=7.3 Hz, 3H). MH+209.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15]O)[N:10]=[CH:9]2)C=CC=CC=1.[F:29][C:30]1[CH:44]=[CH:43][C:33]([C:34]([C:36]2[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=2)=[O:35])=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:44]=[CH:43][C:33]([C:34]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:15][CH2:14][CH2:13][C:11]3[N:10]=[CH:9][NH:8][CH:12]=3)=[CH:38][CH:37]=2)=[O:35])=[CH:32][CH:31]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(F)cc1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: O=C(c1ccc(F)cc1)c1ccc(OCCCc2c[nH]cn2)cc1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 5 mmol of 4-fluoro-4′-hydroxybenzophenone are treated as described in Example 76.
Reaction SMILES: Cl.[CH3:2][NH2:3].[CH3:4][C:5]1[CH:6]=[C:7]2[C:16](=[O:17])[O:15][C:14]([C:22]3[NH:26][C:25]4[CH:27]=[CH:28][C:29]([C:31]#[N:32])=[CH:30][C:24]=4[N:23]=3)([C:18]([F:21])([F:20])[F:19])[C:8]2=[C:9]2[C:13]=1[NH:12][CH:11]=[CH:10]2>C1COCC1.C([Mg]Cl)(C)C>[C:31]([C:29]1[CH:28]=[CH:27][C:25]2[NH:26][C:22]([C:14]([C:8]3[C:7]([C:16]([NH:3][CH3:2])=[O:17])=[CH:6][C:5]([CH3:4])=[C:13]4[C:9]=3[CH:10]=[CH:11][NH:12]4)([OH:15])[C:18]([F:19])([F:21])[F:20])=[N:23][C:24]=2[CH:30]=1)#[N:32]
Reactant: CN
Reactant: Cc1cc2c(c3cc[nH]c13)C(c1nc3cc(C#N)ccc3[nH]1)(C(F)(F)F)OC2=O
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)c1cc(C)c2[nH]ccc2c1C(O)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of methylamine hydrochloride (102 mg, 1.51 mmol) in THF (0.5 mL), 2N isopropylmagnesium chloride in THF (1.51 mL, 3.03 mmol) was added. The reaction was stirred at room temperature for 3 hr, then a solution of (±)-2-(5-methyl-3-oxo-1-(trifluoromethyl)-3,6-dihydro-1H-furo[3,4-e]indol-1-yl)-1H-benzo[d]imidazole-5-carbonitrile (30 mg, 0.076 mmol) in THF (0.5 mL) was added. The reaction was allowed to stir at room temperature for 16 hours. The reaction mixture was quenched with 1N HCl aqueous solution and then neutralized by adding NaHCO3. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4. After concentration under reduced pressure, the residue was separated via silica gel flash column chromatography (CH2Cl2/EtOAc=0 to 100%) to give the title compound. 1H NMR (400 MHz, DMSO-d6, with about 3% METHANOL-d4) δ ppm 7.85 (d, J=2.0 Hz, 1H), 7.41-7.46 (m, 2H), 7.39 (d, J=0.8 Hz, 1H), 7.19 (dd, J=8.3, 1.8 Hz, 1H), 6.50 (d, J=2.5 Hz, 1H), 2.96 (s, 3H), 2.58 (s, 3H). HRMS calcd. for C21H16F3N5O2 (M+H)+ 428.1329. found 428.1333.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:25])[N:22]=[C:23]([CH3:24])[N:16]2[N:15]=1)[CH3:2].[OH:26][CH2:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(OC1C=CC(S(N2CCC(O)CC2C)(=O)=O)=CC=1C1NC(=O)C2=C(C)N=C(C)N2N=1)C>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:31]2[CH2:32][CH2:33][CH:28]([CH2:27][OH:26])[CH2:29][CH2:30]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:25])[N:22]=[C:23]([CH3:24])[N:16]2[N:15]=1)[CH3:2]
Reactant: OCC1CCNCC1
Reactant: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1
Agent: CCOc1ccc(S(=O)(=O)N2CCC(O)CC2C)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1
Product: CCOc1ccc(S(=O)(=O)N2CCC(CO)CC2)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1

Procedure:
By the same method, starting with 100 mg (0.261 mmol) of 4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 90 mg (0.784 mmol) of 4-hydroxymethylpiperidine, 22 mg (18% of theory) of 2-[2-ethoxy-5-(4-hydroxy-methylpiperidine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one are obtained.
Reaction SMILES: [F:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[N:5][C:4]=1[CH2:18][O:19]C1CCCCO1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CO>[F:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[N:5][C:4]=1[CH2:18][OH:19]
Reactant: FCc1sc(-c2cccc(C(F)(F)F)c2)nc1COC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1nc(-c2cccc(C(F)(F)F)c2)sc1CF
Temperature: 70 °C
Reaction time: 4 h
Yield: 55.4 %

Procedure:
To a solution (10 mL) of the compound (350 mg, 0.93 mmol) obtained in Example 89d in methanol was added p-toluenesulfonic acid monohydrate (530 mg, 2.8 mmol), and the mixture was stirred at 70° C. for 4 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=75/25) to give the title compound (150 mg, 56%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[C:5]([NH:7][C:8]1[C:9]([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH2:23]O)[CH2:17][CH2:16]2)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48]>C(Cl)Cl>[Br:48][CH2:23][CH2:22][CH2:21][CH:18]1[CH2:19][CH2:20][N:15]([C:9]2[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][CH:27]=[C:2]([Cl:1])[CH:3]=3)=[CH:13][C:12]([Cl:14])=[CH:11][N:10]=2)[CH2:16][CH2:17]1
Reactant: BrC(Br)(Br)Br
Reactant: O=C(Nc1cc(Cl)cnc1N1CCC(CCCO)CC1)c1cccc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1cc(Cl)cnc1N1CCC(CCCBr)CC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 39.3 %

Procedure:
A mixture of 0.080 g (0.20 mmol) of the above amide and 0.056 g (0.22 mmol) of triphenylphosphine in anhydrous methylene chloride (10 mL), under an atmosphere of nitrogen, is stirred at room temperature for 20 minutes. To this mixture is added 0.071 g (0.22 mmol) of carbon tetrabromide and the resulting mixture is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and the residue is purified by flash silica gel chromatography to give 0.037 g (40%) of N-[4-(3-bromo-propyl)-5′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-3-chloro-benzamide.
Reaction SMILES: O[C@H:2]1[C@H:7]([OH:8])[O:6][CH2:5][CH2:4][O:3]1.[H-].[Na+].[O:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.S(C1C=CC(C)=CC=1)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][O:42][C:43](=[O:46])[CH:44]=[CH2:45])=[CH:29][N:28]=2)=[CH:23][CH:22]=1)(=O)=O>O>[C:43]([O:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:33][C:30]1[CH:29]=[N:28][C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][O:19][C@H:2]3[C@H:7]([O:8][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[N:32]=[CH:31][C:30]([O:11][CH2:15][CH2:14][CH2:13][CH2:12][CH2:38][CH2:39][CH2:40][CH2:41][O:42][C:43](=[O:46])[CH:44]=[CH2:45])=[CH:29][N:28]=5)=[CH:23][CH:22]=4)[O:6][CH2:5][CH2:4][O:3]3)=[CH:22][CH:23]=2)=[N:32][CH:31]=1)(=[O:46])[CH:44]=[CH2:45]
Reactant: O[C@@H]1OCCO[C@H]1O
Reactant: C=CC(=O)OCCCCCCCCOc1cnc(-c2ccc(COS(=O)(=O)c3ccc(C)cc3)cc2)nc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: C=CC(=O)OCCCCCCCCOc1cnc(-c2ccc(CO[C@@H]3OCCO[C@H]3OCc3ccc(-c4ncc(OCCCCCCCCOC(=O)C=C)cn4)cc3)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 0.2 g of trans-2,3-dihydroxy-1,4-dioxane, 0.5 g of sodium hydride and 50 ml of tetrahydrofuran is stirred for 7 hours. 1.1 g of 4-(5-[8-acryloyloxyoctyloxy]pyrimidin-2-yl)benzyl tosylate are added and the mixture is stirred at room temperature overnight, poured into 100 ml of water and then extracted three times with 50 ml of diethyl ether each time. The organic phases are combined, washed twice with 100 ml of water each time, dried over magnesium sulphate, filtered and the filtrate is concentrated. Chromatographic purification of the residue on silica gel with cyclohexane/ethyl acetate (vol. 8:2) and two-fold recrystallization from a cyclohexane/ethyl acetate mixture (vol. 8:2) of the fractions which are pure according to thin-layer chromatography gives 1.1 g of trans-2,3-bis[4-(5-[8-acryloyloxyoctyloxy]pyrimidin-2-yl)benzyloxy]-1,4-dioxane.
Reaction SMILES: [O:1]=[C:2]([C@H:4]([CH2:6][C:7]1[CH:14]=[C:12]([OH:13])[C:10]([OH:11])=[CH:9][CH:8]=1)[NH2:5])[OH:3].S(Cl)(Cl)=O.Cl.[C:20]1(C)C(S(O)(=O)=O)=CC=C[CH:25]=1>C(O)C>[CH3:20][CH2:25][O:1][C:2]([C@@H:4]([NH2:5])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:11])=[C:12]([OH:13])[CH:14]=1)=[O:3]
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Reactant: Cc1ccccc1S(=O)(=O)O
Agent: Cl
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@@H](N)Cc1ccc(O)c(O)c1

Procedure:
reacting L-DOPA with ethanol in the presence of thionyl chloride or an acid catalyst selected from the group consisting of hydrochloric acid and toluene sulfonic acid to yield crude L-DOPA ethyl ester;
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20]>OS(O)(=O)=O>[Br:8][C:18]1[CH:17]=[C:13]([CH:12]=[C:11]([N+:19]([O-:21])=[O:20])[C:10]=1[F:9])[C:14]([OH:16])=[O:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(Br)c(F)c([N+](=O)[O-])c1
Temperature: 65 °C
Reaction time: 5 h

Procedure:
NBS (47.9 g, 0.268 mol) was added portion-wise to a solution of 4-fluoro-3-nitro-benzoic acid (41.5 g, 0.224 mol) in conc. H2SO4 (0.35 L). The reaction mixture was stirred for 5 h at 65° C. and then poured into ice-water (1.5 L). The precipitate was filtered off, washed twice with water (300 mL) and dried to give the title compound as a white solid. 1H-NMR (300 MHz, CDCl3): δ (ppm) 10.7 (s, br, 1H), 8.76 (m, 1H), 8.62 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19](O)=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1.[O:22]([C@@H:29]1[CH2:33][NH:32][C@H:31]([CH2:34][O:35][C:36]2[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=2)[CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([N:32]3[CH2:33][C@@H:29]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:30][C@H:31]3[CH2:34][O:35][C:36]3[CH:37]=[CH:38][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:44][CH:45]=3)=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2o1
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccccc3)CN2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccccc3)CN2C(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 101.1 %

Procedure:
In DMF (10 ml), a mixture of 2-(2-methylphenylamino)-6-benzoxazolylacetic acid (351 mg, 1.07 mmol), methyl 4-((2S,4S)-4-phenoxy-2-pyrrolidinylmethoxy)benzoate (303 mg, 1.07 mmol), EDC•HCl (308 mg, 1.61 mmol), HOBt (218 mg, 1.61 mmol) and triethylamine (0.74 ml, 5.35 mmol) was stirred at room temperature for 21 hours. The reaction mixture was poured in ice water (30 ml), followed by extraction with ethyl acetate. The extract was washed with ice water and saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 40 g), whereby from chloroform/acetone (10/1) eluate fractions, the title compound (640 mg, 100%) was obtained as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[N:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=2)[N:5]=[CH:4][CH:3]=1.[OH-].[Na+].CO>O>[Br:1][C:2]1[N:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cn2nccc2Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(Cn2nccc2Br)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.9 %

Procedure:
Methyl 4-((5-bromo-1H-pyrazol-1-yl)methyl)benzoate (264 mg, 0.95 mmol), NaOH (200 mg, 5 mmol) were placed in a 100-mL flask with covered with MeOH and H2O (1:1) and stirred for 4 h at room temperature. The solution was then evaporated, taken up in water and acidified with 2M HCl with the resulting the solid filtered off yielding the desired product as a white solid (200 mg, 90%). LCMS (m/z): 281.1 [M+H]
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:9]([NH:16][C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH:32]([CH3:41])[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34]>CO>[CH3:41][CH:32]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([N:16]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])=[O:5])[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34]
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1C(C)C(=O)c1ccccc1
Yield: 25.8 %

Procedure:
Using the procedure described in example 5, treatment of L-proline-L-isoleucine benzylamide (196 mg, 0.62 mmol), with sodium carbonate (85 mg, 0.80 mmol), and 2-bromopropiophenone (210 mg, 0.98 mmol, 1.6 eq) in MeOH (12 mL), provided 72 mg (26%) of L-isoleucine, N-[1-(1-methyl-2-phenyl-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [C:1]1([CH2:7][SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:7]([S:8][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Fc1cc(C(F)(F)F)ccn1
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccnc(SCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
To a solution of phenylmethanethiol (356 μl, 3.03 mmol) and 2-fluoro-4-(trifluoromethyl)pyridine (369 μl, 3.03 mmol) in dimethylformamide (5 mL) was added potassium carbonate (628 mg, 4.54 mmol). The reaction mixture was stirred at 60° C. for 2 hours, then cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution (20 mL), brine (20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give a pale yellow oil. The crude product was purified by chromatography on silica gel (gradient: 0-20% ethyl acetate in isohexane) to afford 2-(benzylthio)-4-(trifluoromethyl)pyridine (510 mg) as a colourless oil. LCMS (Method F, ES-API): RT 3.04 min, m+H=270.1.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:28]=[CH:27][C:21]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:41]1(O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[H-].[Na+]>O1CCCC1>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH2:23][C:24]([O:26][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:25])=[CH:27][CH:28]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Oc1ccccc1
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)Oc2ccccc2)cc1

Procedure:
A solution of 0.05 mole of 4-(hexadecylamino)hydrocinnamic acid and 0.05 mole of 1,1'-carbonyldiimidazole in 50 ml. of tetrahydrofuran is treated with 0.052 mole of phenol and a trace of sodium hydride. The reaction is heated to reflux for 3 hours, then cooled, filtered and evaporated in vacuo providing phenyl 4-(hexadecylamino)hydrocinnamate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[N:14]=[CH:13][N:12]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:11]=2)[O:6][N:5]=1)[CH3:2].C1C(=O)N([Br:41])C(=O)C1>ClC(Cl)(Cl)Cl>[Br:41][CH2:9][C:8]1[C:4]([O:3][CH2:1][CH3:2])=[N:5][O:6][C:7]=1[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1noc(-c2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1C
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1noc(-c2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1CBr
Yield: 98.8 %

Procedure:
A mixture of 3-(3-ethoxy-4-methylisoxazol-5-yl)-1-trityl-1H-1,2,4-triazole (2.4 g, 5.5 mmol) and NBS (1.1 g, 6.2 mmol) in tetrachloromethane (150 mL) was boiled under reflux for 3 h. The reaction mixture was cooled, filtered and concentrated in vacuo to give crude title compound (2.8 g). The crude product was used in the next step without further purification.
Reaction SMILES: C(C1C=CC(C2ON=C3C4C(CCC=23)=CC(C=C)=CC=4)=CC=1C(F)(F)F)C(C)C.[CH:30]([C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[C:38](=[N:42][OH:43])[CH2:37][CH2:36][CH2:35]2)=[CH2:31].[CH2:44]([O:46][C:47]1[CH:48]=[C:49]([CH:54]=[CH:55][C:56]=1[O:57][CH2:58][CH3:59])[C:50](OC)=O)[CH3:45]>>[CH2:44]([O:46][C:47]1[CH:48]=[C:49]([C:50]2[O:43][N:42]=[C:38]3[C:39]4[C:34]([CH2:35][CH2:36][C:37]=23)=[CH:33][C:32]([CH:30]=[CH2:31])=[CH:41][CH:40]=4)[CH:54]=[CH:55][C:56]=1[O:57][CH2:58][CH3:59])[CH3:45]
Reactant: CCOc1ccc(C(=O)OC)cc1OCC
Reactant: C=Cc1ccc2c(c1)CCCC2=NO
Agent: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(CC(C)C)c(C(F)(F)F)c1
Product: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(OCC)c(OCC)c1

Procedure:
This compound was prepared according to the general procedure described for Preparation 23C, employing 200 mgs of 6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (I-1) and methyl 3,4-diethoxybenzoate (1 eq). Yield: 217 mgs (25%); LC/MS M+1=362.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[Cl:9][C:10]1[CH:16]=[C:15](I)[C:13]([NH2:14])=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:11]=[C:12]2[C:13](=[CH:15][CH:16]=1)[NH:14][C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)=[CH:2]2
Reactant: Nc1ccc(Cl)cc1I
Reactant: C#Cc1cccnc1
Product: Clc1ccc2[nH]c(-c3cccnc3)cc2c1

Procedure:
3-Ethynylpyridine and 4-chloro-6-iodoaniline are processed according to the method described in Example 86 to give 5-chloro-2-pyridin-3-yl-1H-indole. 1H NMR (400 MHz, MeOD) δ ppm 6.96 (s, 1H), 7.14 (dd, J=8.6, 2.0 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.54 (dd, J=8.0, 4.9 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H), 8.25 (dt, J=8.0, 1.9 Hz, 1H), 8.50 (d, J=4.5 Hz, 1H), 9.02 (s, 1H). HRMS (ESI) m/z 229.0522 [(M+H)+ Calcd for C13H10ClN2: 229.0533].
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.[NH2:23][C:24]1[N:25]=[C:26]([CH3:29])[S:27][CH:28]=1>>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([NH:23][C:24]3[N:25]=[C:26]([CH3:29])[S:27][CH:28]=3)[N:3]=[CH:4][C:5]=2[C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)[N:10]=1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Reactant: Cc1nc(N)cs1
Reactant: OB(O)c1cccnc1
Product: Cc1ccc2c(-c3cccnc3)cnc(Nc3csc(C)n3)c2n1

Procedure:
The title compound, MS: m/e=334.2 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 3-pyridineboronic acid and 4-amino-2-methylthiazole (Example F).
Reaction SMILES: O[Li].O.[CH3:4][CH:5]([C:7]1[CH:8]=[CH:9][C:10]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:11]([CH:22]=1)[C:12]([O:14]CC1C=CC=CC=1)=[O:13])[CH3:6].C1COCC1.Cl>C(OCC)(=O)C.O>[CH3:6][CH:5]([C:7]1[CH:8]=[CH:9][C:10]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:11]([CH:22]=1)[C:12]([OH:14])=[O:13])[CH3:4]
Reactant: CC(C)c1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1ccc(OCc2ccccc2)c(C(=O)O)c1

Procedure:
LiOH.H2O (0.70 g, 16.65 mmol) was added to a stirred solution of phenylmethyl 5-(1-methylethyl)-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 2; 1.5 g, 4.16 mmol) in a 3:1 mixture of THF:H2O (40 ml). The mixture was heated to reflux for 12 h and then diluted with ethyl acetate (50 ml). 10% aqueous HCl was added to the mixture to adjust the pH to 2. The organic phase was isolated, washed with brine, dried over MgSO4, and concentrated to give a yellow oil. 700 mg.
Reaction SMILES: [CH3:1][CH2:2][O:3][CH:4]([O:6][CH2:7][CH:8]([C:12]([CH2:23][CH:24]=[CH2:25])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:10][CH3:11])[CH3:5]>C(O)C.[Pd]>[CH3:1][CH2:2][O:3][CH:4]([O:6][CH2:7][CH:8]([C:12]([CH2:23][CH2:24][CH3:25])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:9][CH2:10][CH3:11])[CH3:5]
Reactant: C=CCC(C(=O)OCC)(C(=O)OCC)C(CCC)COC(C)OCC
Agent: [Pd]
Solvent: CCO
Product: CCCC(COC(C)OCC)C(CCC)(C(=O)OCC)C(=O)OCC
Reaction time: 4 h
Yield: 86.5 %

Procedure:
57 mg (0.17 mmol) of diethyl 2-[1-(2-ethoxy)ethoxypent-4-yl]-2-allylmalonate prepared above was dissolved in 10 mL absolute ethanol and combined with 6 mg (56 umol) 10% palladium on carbon. The mixture was flushed with hydrogen and hydrogenated for 4 hrs at 44 psi. Removal of the catalyst by filtration through Celite® brand diatomite and concentration provided 53 mg of a colorless oil.
Reaction SMILES: CI.N12CCCN=C1CCCC[CH2:4]2.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]1[C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25](=[O:31])[CH2:24][CH2:23]1>CC(C)=O>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]1[C:27]([C:28]([O:30][CH3:4])=[O:29])=[CH:26][C:25](=[O:31])[CH2:24][CH2:23]1
Reactant: COc1ccccc1C1CCC(=O)C=C1C(=O)O
Reactant: C1CCC2=NCCCN2CC1
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)C1=CC(=O)CCC1c1ccccc1OC
Temperature: 10 °C
Yield: 94.9 %

Procedure:
235 g (1.66 mol) of methyl iodide and 212 g (1.39 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene, dropwise, were successively added to a solution of 288 g (1.17 mol) of (RS)-6-(2-methoxyphenyl)-3-oxocyclohexene-1-carboxylic acid in 2.5 dm3 of acetone and then the mixture was brought to reflux for one hour. The acetone was subsequently concentrated and then the residue was stirred with 1 dm3 of water. After cooling to 10° C., the precipitate formed was filtered off, washed with petroleum ether and then dried at 50° C. 289 g (95%) of methyl (RS)-6-(2-methoxyphenyl)-3-oxocyclohexene-1-carboxylate were thus obtained in the form of a mustard-coloured powder, the characteristics of which were as follows: