Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C1COCC1>[N+:9]([C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)([O-:11])=[O:10]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(CN2CCOCC2)c1
Yield: 94 %

Procedure:
A solution of 1-bromomethyl-3-nitrobenzene (2.16 g, 10 mmol), morpholine (1.76 g, 20.2 mmol) and triethylamine (1.0 mL) in THF (60 mL) was heated for two hours at 60° C. The solvent was evaporated, water was added and the product was isolated by extraction with ether. The ether extract was dried over Mg2SO4 and the solvent was evaporated. The crystalline residue was used in the next step without further purification. The product, 4-(3-nitrobenzyl)morpholine, was obtained in 94% yield (2.09 g).
Reaction SMILES: C1(C)C=CC(S(O[C:11]2[C:12](Br)=[CH:13][CH:14]=[C:15]3[C:20]=2[N:19]=[CH:18][CH:17]=[CH:16]3)(=O)=O)=CC=1.[O:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1.C([Li])CCC.O>C1COCC1>[O:23]1[CH:27]2[C:11]3[C:12](=[CH:13][CH:14]=[C:15]4[C:20]=3[N:19]=[CH:18][CH:17]=[CH:16]4)[CH:24]1[CH:25]=[CH:26]2
Reactant: c1ccoc1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(Br)ccc3cccnc23)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C1=CC2OC1c1ccc3cccnc3c12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A stirred solution of the tosyl ester (4a) (5.00 g, 13.2 mmol) in dry THF (150 mL) and freshly distilled furan (24.3 mL, 22.6 g, 0.33 mol, 25 equiv.) cooled at −78° C. under nitrogen was treated dropwise with n-butyllithium in hexanes (2.5 M, 5.55 mL, 13.8 mmol, 1.05 equiv.). The reaction was stirred for 1 hr at −78° C. and then allowed to warm to room temperature over 3 hours. The reaction mixture was treated with water (5 mL) and then heated under reduced pressure to remove most of the THF. This mixture was then diluted with water (150 mL), extracted with dichloromethane (3×100 mL). The organic layers were combined, dried (MgSO4) and concentrated to give a crude brown solid (2.31 g). This material was dissolved in the minimum amount of dichloromethane/petroleum and absorbed onto a pad of neutral alumina. Gradient elution with ethyl acetate/petroleum ether afforded the product, which was recrystallized from dichloromethane/ether/petroleum ether to afford the endoxide (7,10-epoxy-7,10-dihydrobenzo[h]quinoline (6) as cream colored crystals (1.07 g, 42%). 1H NMR (CDCl3, 300 MHz) δ ppm 8.88 (dd, 1H, J=4.1, 1.7 Hz); 8.14 (dd, 1H, J=8.4, 1.7 Hz); 7.60 and 7.57 (ABq, 2H, J=7.8 Hz); 7.27-7.33 (m, 2H); 7.21 (dd, 1H, J=5.5, 1.8 Hz); 6.54 (bs, 1H); 5.95 (m, 1H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:15]=2)[C:10](O)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:24]([O:26][C:27](=[O:36])[CH2:28][S:29][C:30]1[S:34][C:33]([NH2:35])=[N:32][CH:31]=1)[CH3:25]>>[CH2:24]([O:26][C:27](=[O:36])[CH2:28][S:29][C:30]1[S:34][C:33]([NH:35][C:10](=[O:11])[C:9]2[CH:13]=[C:14]([O:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH:15]=[C:7]([O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:8]=2)=[N:32][CH:31]=1)[CH3:25]
Reactant: O=C(O)c1cc(Oc2ccc(F)cc2)cc(OC2CCCC2)c1
Reactant: CCOC(=O)CSc1cnc(N)s1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(Oc3ccc(F)cc3)cc(OC3CCCC3)c2)s1

Procedure:
The title compound was prepared from 3-cyclopentyloxy-5-(4-fluoro-phenoxy)benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[N:21]1([CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(#N)C>[N:21]1([CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][N:29]2[CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: C1CCC(CN2CCOCC2)NC1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Solvent: CC#N
Product: O=C1Nc2cccnc2N(C(=O)CN2CCCCC2CN2CCOCC2)c2ccccc21

Procedure:
The title compound is prepared analogously to Example 2 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[(4-morpholinyl)methyl]piperidine to give colorless crystals, mp. 203°-205° C. (acetonitrile using activated charcoal).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:19]=[O:20])[C:11]=1[O:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[C:5]([O:7][CH3:8])=[O:6].[C:21]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=1)(=[O:28])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([NH:25][S:26]([C:29]1[CH:30]=[C:31]([C:2]2[C:11]([O:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:10]([CH:19]=[O:20])[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=2)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COCCOCOc1c(Br)cc(C(=O)OC)cc1C=O
Product: COCCOCOc1c(C=O)cc(C(=O)OC)cc1-c1cccc(S(=O)(=O)NC(C)(C)C)c1
Yield: 78.2 %

Procedure:
Proceeding as in Reference 19, but substituting methyl 3-bromo-5-formyl-4-(2-methoxyethoxymethoxy)-benzoate (2.00 g, 5.76 mmol, 1.0 eq.) and N-tert-butyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzenesulfonamide (1.95 g, 5.76 mmol, 1.0 eq.), gave methyl 3′-tert-butylsulfamoyl-5-formyl-6-(2-methoxyethoxymethoxy)-biphenyl-3-carboxylate (2.16 g) as a yellow gum.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[I:12]I>CN(C)C=O.S([O-])([O-])(=O)=O.[Ag+2]>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:4]=[C:5]([I:12])[C:6]([NH2:9])=[N:7][CH:8]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Product: Nc1ncc(C(F)(F)F)cc1I
Reaction time: 14 h

Procedure:
A solution of 5-(trifluoromethyl)pyridin-2-amine (3-a with R4═CF3, 1.6 g, 9.87 mmol) (Maybridge Chemical company, Cornwall, England) in N,N-dimethylformamide (30 mL) was treated at room temperature with silver sulfate (3.1 g, 9.87 mmol) and iodine (2.5 g, 9.87 mol). The reaction mixture was stirred for 14 h and filtered. The filtrated solution was concentrated in vacuo. The residue was chromatographed (SiO2, 25% ethyl acetate in hexanes) to give 5-(trifluoromethyl)-3-iodopyridin-2-amine (3-b, with R4═CF3). The iodide (3-b, with R4═CF3, 1.0 g, 3.47 mmol) and cuprous cyanide (CuCN, 78 g, 8.68 mmol) was dissolved in N,N-dimethylformamide (6 mL) and heated under the microwave at 100 C for 30 min, cooled to ambient temperature, and diluted with ethyl acetate. The precipitates were removed by filtration. The filtrated solution was partitioned between ethyl acetate and water. The organic layer was washed with brine, separated, dried (MgSO4) and concentrated in vacuo. Trituration of the residue with hexanes afforded the desired product, 2amino-5-(trifluoromethyl)pyridine-3-carbonitrile (3-c, with R4═CF3). 2amino-5-(trifluoromethyl)pyridine-3-carbonitrile (3-c, with R4═CF3, 545 mg, 29.2 mmol) was stirred in methanol (10 mL, saturated with ammonia) under hydrogen atmosphere in the presence of Pd/C (200 mg) overnight. The reaction mixture was filtered and the filtrate solution was concentrated in vacuo to afford the crude amine (3-d, with R4═CF3). A solution of (S)-2-phenylbutanoic acid (300 mg, 18.3 mmol) and diisopropylethylamine (888 uL, 52.4 mmol) in N,N-dimethylformamide (5 mL) was treated at room temperature with benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBop, 953 mg, 18.3 mmol). After 15 min, 3-(aminomethyl)-5-(trifluoromethyl)pyridin-2-amine (500 mg, 26.2 mmol) was added. The reaction mixture was stirred for 2 h, partitioned between ethyl acetate and 0.5N—NaOH. The aqueous layer was removed and the organic layer was washed with brine. The organic layer was separated, dried (MgSO4) and concentrated in vacuo to give the desired product (3-g); HRMS (M+1)=338.1405.
Reaction SMILES: C[S:2][C:3](=S)[NH:4][N:5]=[CH:6][C:7]1[N:8]=[C:9]([CH3:13])[NH:10][C:11]=1[CH3:12].C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:13][C:9]1[N:8]2[C:3](=[S:2])[NH:4][N:5]=[CH:6][C:7]2=[C:11]([CH3:12])[N:10]=1
Reactant: CSC(=S)NN=Cc1nc(C)[nH]c1C
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1nc(C)n2c(=S)[nH]ncc12

Procedure:
A mixture of 30.26 gm. of 3-[(2,5-dimethyl-4-imidazolyl)methylene]dithiocarbazic acid methyl ester and 125 ml. of diphenyl ether is reacted as described in Example 23 giving a solid which is the desired product, m.p. 287.5°-290° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]O)(=[O:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:47]I>C(Cl)Cl.C1C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][I:47])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCCCCCCCCCCCCCCO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccccc1
Product: CC(=O)OCCCCCCCCCCCCCCCCCI
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
17-Acetoxy-heptadecanol (4.4 g, 13.99 mmol), Ph3P (4.4 g, 16.78 mmol) and imidazole (1.57 g, 23.08 mmol) were dissolved in the mixture of CH2Cl2 (40 ml) and benzene (20 ml). The mixture was cooled to 0° C. and solid I2 (4.26 g, 16.78 mmol) was added in one portion. The mixture was stirred at 0° C. for 15 min and at room temperature for 30 min. The reaction was quenched by the addition of EtOH (1.5 ml), stirred for 10 min at room temperature, diluted with hexane-EtOAc (1:1) mixture and washed with aqueous NaHCO3—Na2S2O3 solution. The organic extract was dried Na2SO4 and evaporated. Residue was stirred with hexane (300 ml) for 20 min and the suspension was filtered to remove Ph3PO. The filtrate was evaporated and the residue was chromatographed on silica gel in hexane-EtOAc (98:2) to give 17-acetoxy-heptadecyl iodide (5.89 g, 99%).
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[Li+].[OH-]>O.CO>[C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]([OH:21])=[O:2])=[CH:7][CH:8]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C=Cc1ccc(NC(=O)c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C=Cc1ccc(NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
(Method H5) A mixture of 3-(4-benzoylamino-phenyl)-acrylic acid methyl ester (4b) (1.650 g, 5.87 mmol) and LiOH (0.630 g, 15 mmol) in water (30 ml) and methanol (30 ml) was stirred at ambient temperature for 24 hours. Methanol was evaporated and the residue was treated with hydrochloric acid to pH 4. The resulting precipitate was filtered off, washed with water (3×20 ml), and dried to give the title compound as a white solid (1.443 g, 92%). 1H NMR (DMSO-d6, HMDSO), δ: 6.44 (1H, d, J=16.0 Hz); 7.33-8.11(10H, m); 10.40 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)[CH:16]=1
Reactant: OCc1ccccn1
Reactant: Nc1c(C(=O)c2cccc(O)c2)cnn1-c1ccc(F)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Nc1c(C(=O)c2cccc(OCc3ccccn3)c2)cnn1-c1ccc(F)cc1
Reaction time: 16 h

Procedure:
5-Amino-1-(4-fluorophenyl)-4-[3-hydroxybenzoyl]pyrazole, from Example 10, step 2, (0.5 g, 1.68 mmol), 2-pyridylcarbinol (0.81 mL, 8.41 mmol), triphenylphospine (1.81 g, 6.9 mmol), and diethylazodicarboxylate (1.09 mL, 6.9 mmol)) were combined in toluene (50 mL). The reaction mixture was stirred for 16 hours then quenched with a saturated aqueous solution of NH4Cl and extracted three times with ethyl acetate. The product was then extracted from the ethyl acetate into a 10% aqueous solution of HCl. The aqueous layer was then neutralized with NaOH and extracted with ethyl acetate. The organic extracts were dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel using 1:1 hexane/ethyl acetate to give 0.165 g of 5-amino-1-(4-fluorophenyl)-4-[3-(pyridin-2-ylmethoxy)benzoyl]pyrazole (mpt. 176.1-177.3° C.).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].Br[CH2:15][C:16]([C:18]1[CH:22]=[C:21]([CH3:23])[O:20][C:19]=1[CH3:24])=O>>[CH3:24][C:19]1[O:20][C:21]([CH3:23])=[CH:22][C:18]=1[C:16]1[N:2]=[C:1]([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[S:3][CH:15]=1
Reactant: COC(=O)c1ccc(C(N)=S)cc1
Reactant: Cc1cc(C(=O)CBr)c(C)o1
Product: COC(=O)c1ccc(-c2nc(-c3cc(C)oc3C)cs2)cc1
Yield: 36 %

Procedure:
In the same manner as in Example 74, methyl 4-thiocarbamoylbenzoate was reacted with 3-bromoacetyl-2,5-dimethylfuran to obtain methyl 4-[4-(2,5-dimethyl-3-furyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 36%. Pale yellow prisms. Melting point: 103 to 105° C.
Reaction SMILES: [CH2:1]([C:3]1([CH2:7][OH:8])[CH2:6][O:5][CH2:4]1)[CH3:2].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([C:3]1([CH2:7][O:8][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:9])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH2:6][O:5][CH2:4]1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC1(CO)COC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC1(COS(=O)(=O)c2ccc(C)cc2)COC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a mixture of (3-ethyl-oxetan-3-yl)-methanol (11.6 g, 0.1 mol) and DMAP (18.3 g, 0.15 mol) in DCM (100 mL) was added 4-methyl-benzenesulfonyl chloride (19 g, 0.1 mol). The mixture was stirred at room temperature for 1 h, then filtered. The filtrate was washed with HCl aq. (1 M) and water, dried over anhydrous Na2SO4 and concentrated to give the title compound (19 g).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[CH2:4][N:5]1[C@@H:9]([CH3:10])[C@@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:7][C:6]1=[O:17].[CH3:23][O:24][C:25](=[O:44])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=1>>[CH3:23][O:24][C:25](=[O:44])[CH2:26][C:27]1[CH:28]=[C:29]([C:2]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=2[CH2:4][N:5]2[C@@H:9]([CH3:10])[C@@H:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]2=[O:17])[C:30]([O:33][CH3:34])=[CH:31][CH:32]=1
Reactant: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(F)ccc1Br
Reactant: COC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(F)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (4S,5R)-3-(2-bromo-5-fluoro-benzyl)-4-methyl-5-phenyl-oxazolidin-2-one and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester.
Reaction SMILES: C(OC([NH:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccncc1C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccncc1C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 4-(N-t-butoxycarbonylamino)nicotinic acid (2.72 g, 11.4 mmol), TFA (10 mL), and CH2Cl2 (20 mL) is stirred at room temperature for 12 h. The volatiles are removed under reduced pressure, and the resulting crude 4-amino nicotinic acid is used directly in the next reaction.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH2:10]([O:12][C:13](=[O:18])[CH2:14]C(O)=O)[CH3:11].N1CCCCC1>N1C=CC=CC=1>[CH2:10]([O:12][C:13](=[O:18])[CH:14]=[CH:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=1)[CH3:11]
Reactant: CCOC(=O)CC(=O)O
Reactant: Cc1ccc(C=O)cc1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CCOC(=O)C=Cc1ccc(C)cc1
Yield: 79 %

Procedure:
Application of the previously unused Knoevenagel condensation (Silva, N. M. et al., Eur. J. Med. Chem. 2002, 37, 163-170; Diaz, J. L. et al., Chem. Mater. 2002, 14, 2240-2251; Ren, X. et al., Tetrahedron: Asymmetry 2002, 13, 1799-1804) of p-tolualdehyde with malonic acid monoethyl ester (Breslow, D. S. et al., J. Am. Chem. Soc. 1944, 66, 1286-1288) in pyridine containing a catalytic amount of piperidine gave the known α,β-unsaturated ethyl cinnamate 5 (Tsuge, O. et al., J. Org. Chem. 1982, 47, 5171-5177; Colas, C.; Goeldner, M. Eur. J. Org. Chem. 1999, 1357-1366; Chuzel, O.; Piva, O. Synth. Commun. 2003, 33, 393-402) in 79% yield. Reaction of 5 with (p-tolylsulfonyl)methyl isocyanide (TosMIC) afforded β-substituted pyrrole 6 (a known compound with incomplete data (Di Santo, R. et al., Med. Chem. Res. 1997, 7, 98-108)) in 74% yield. Removal of the ethoxycarbonyl group of pyrrole 6 by treatment with NaOH in ethylene glycol at 160° C. gave the known β-substituted pyrrole 7 (Sakai, K. et al., Chem. Pharm. Bull. 1980, 28, 2384-2393; Campi, E. M. et al., Aust. J. Chem. 1992, 45, 1167-1178; Pavri, N, P.; Trudell, M. L. J. Org. Chem. 1997, 62, 2649-2651) in 71% yield. Vilsmeier-Haack formylation of 7 yielded a mixture of regioisomers owing to substitution at the 2- or 5-position. After column chromatography, the two regioisomers were determined to be present in ˜13:1 ratio by 1H NMR integration of the methyl unit of the p-tolyl group. Selective precipitation readily afforded the major regioisomer 8 in 64% yield (Scheme 3).
Reaction SMILES: [Si]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)(C(C)(C)C)(C)C.C([Li])CCC.[CH2:18]([N:21]([CH2:35][CH2:36][CH3:37])[C:22]([C:24]1[CH:25]=[C:26]([CH:31]=[C:32](I)[CH:33]=1)[C:27]([O:29][CH3:30])=[O:28])=[O:23])[CH2:19][CH3:20]>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH2:35]([N:21]([CH2:18][CH2:19][CH3:20])[C:22]([C:24]1[CH:25]=[C:26]([CH:31]=[C:32]([C:9]2[NH:8][CH:12]=[CH:11][N:10]=2)[CH:33]=1)[C:27]([O:29][CH3:30])=[O:28])=[O:23])[CH2:36][CH3:37]
Reactant: CC(C)(C)[Si](C)(C)n1ccnc1
Reactant: CCCN(CCC)C(=O)c1cc(I)cc(C(=O)OC)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2ncc[nH]2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a −70° C. stirred solution of 1-tert-butyldimethylsilylimidazole (602 mg, 3.3 mmol) in tetrahydrofuran (10 mL) is added n-butyllithium (1.6 M in hexanes, 2.3 mL, 3.63 mmol). After 30 min, zinc chloride (1 M in diethyl ether, 9.9 mL, 9.9 mmol) is added and the reaction mixture is warmed to 0° C. for 1 h. To this mixture is then added methyl 3-[(dipropylamino)carbonyl]-5-iodobenzoate prepared by the method in Example SP-281, step 2 (1.17 g, 3 mmol) followed by palladium(0)tetrakis(triphenylphosphine) (173 mg, 0.15 mmol). The reaction mixture is heated at reflux for 15 h. The reaction mixture is diluted with ethyl acetate (50 mL), washed with water, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 1-5% methanol/methylene chloride) provides the title compound in pure form. 1H NMR (300 MHz, CDCl3) δ 8.64 (s, 1H), 8.14 (s, 1H), 7.97 (s, 1H), 7.19 (s, 2H), 3.96 (s, 3H), 3.51 (m, 2H), 3.32 (m, 2H), 1.73 (m, 2H), 1.57 (m, 2H), 1.01 (m, 3H), 0.73 (m, 3H).
Reaction SMILES: Cl[Si:2](Cl)([CH3:4])[CH3:3].[C:6]([C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([C:20]2[C:21]([OH:34])=[C:22]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:23]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:25]=2)[C:11]=1[OH:35])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>>[C:16]([C:14]1[CH:15]=[C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:11]2[O:35][Si:2]([CH3:4])([CH3:3])[O:34][C:21]3[C:22]([C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:23][C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:25][C:20]=3[C:12]=2[CH:13]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: C[Si](C)(Cl)Cl
Reactant: CC(C)(C)c1cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)O[Si](C)(C)Oc1c-2cc(C(C)(C)C)cc1C(C)(C)C
Yield: 46.8 %

Procedure:
Utilizing procedure of Example 1, this compound is prepared from 25.8 grams (0.20 mole) dichlorodimethylsilane, 82.1 grams (0.20 mole) 3,3',5,5'-tetra-tert-butyl-biphenyl-2,2'-diol and 40.5 grams (0.40 mole) of triethylamine. Recrystallization from 2-butanone gives 43.7 grams (47%) of a white powder, mp 170°-176° C.
Reaction SMILES: [Li]CCCC.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[C:12]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>CCOCC.C1COCC1>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][C:22]([OH:25])([C:7]2[S:8][CH:9]=[CH:10][N:11]=2)[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: Brc1nccs1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2nccs2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) and stirred solution of n-BuLi (2.6 mL, 1.05 eq., 10.0 M in hexanes) in dry Et2O (20 mL) was added dropwise a solution of 2-bromothiazole (4.0 g, 24.4 mmol) in THF (10 mL) over a 10 minute period. After the yellow mixture had been stirred at −78° C. for 30 minutes, a solution of 1-Boc-4-piperidone (4.9 g, 1 eq.) in THF (20 mL) was added slowly. The mixture was then continued to stir for another 30 minutes before the reaction was quenched by addition of water (5 mL). The mixture was warmed to room temperature and extracted with EtOAc. The organic phase was separated, washed with brine and dried over Na2SO4. After removal of the solvent, the crude product was purified on silica gel (45% EtOAc in hexanes) to afford the desired product as a thick oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([NH:14][C:23](=[O:24])[O:25][CH2:26][CH3:27])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: NC1CCN(c2ccc(Br)cc2)CC1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NC1CCN(c2ccc(Br)cc2)CC1
Reaction time: 2 h

Procedure:
1-(4-Bromophenyl)piperidin-4-amine (255 mg) and triethylamine (280 μL) are dissolved in dichloromethane (3 mL), treated with ethyl chloroformate (105 μL) and stirred for 2 hours. The mixture is partitioned between dichloromethane and water. The organic phase is washed with water and the combined aqueous phases are extracted with dichloromethane. The organic phases are combined, washed with brine and dried (MgSO4). The solvents are evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→70:50) to give the title compound. LC (method 2): tR=1.04 min; Mass spectrum (ESI+): m/z=327 [M+H]+.