Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([NH:28][S:29]([CH2:32][CH2:33][CH2:34]Cl)(=[O:31])=[O:30])=[O:27])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>O1CCCC1>[C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([NH:28][S:29]([CH2:32][CH2:33][CH2:34][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)(=[O:31])=[O:30])=[O:27])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCNCC1
Reactant: O=C(C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1)NS(=O)(=O)CCCCl
Solvent: C1CCOC1
Product: O=C(C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1)NS(=O)(=O)CCCN1CCCCC1

Procedure:
Prepared by coupling 2i and piperidine (15 eq)in tetrahydrofuran at reflux. The product was isolated as the HCL salt. Yield (70%); 1H NMR (d6-DMSO) δ 11.90 (br s, 1H), 7.53 (d, J=15.7 Hz, 1H), 7.34-7.10 (m, 12H), 6.88 (d, J=8.4 Hz, 2H), 6.70 (d, J=7.3 Hz, 1H), 6.55 (d, J=15.7 Hz, 1H), 3.52 (t, J=7.3 Hz, 2H), 3.09 (br, 2H), 2.77 (br m, 4H), 2.26 (br t, 2H), 2.08 (br, 4H), 1.71 (br, 5H); APcI m/z: 555 (M+H+).
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([SH:10])=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Cl[C:14]1[C:15]([C:20]#[N:21])=[N:16][CH:17]=[CH:18][N:19]=1>CN(C=O)C.C1C=CC=CC=1>[CH2:1]([C:5]1[S:9][C:8]([S:10][C:14]2[C:15]([C:20]#[N:21])=[N:16][CH:17]=[CH:18][N:19]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1nccnc1Cl
Reactant: CCCCc1nnc(S)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCCCc1nnc(Sc2nccnc2C#N)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The title compound was prepared according to Example 1 by using 5-butyl-1,3,4-thiadiazole-2-thiol (260 mg, 1.49 mmol), NaH (60% dispersion in mineral oil, 66 mg, 1.65 mmol), and 3-chloropyrazine-2-carbonitrile (210 mg, 1.50 mmol) in DMF and benzene (4 ml, 1/1) by stirring at room temperature under nitrogen atmosphere for 3 hr.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].I[CH2:12][CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(Br)c(C=O)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a solution of 2-bromo-5-hydroxybenzaldehyde (5 g, 24.87 mmol) in DMF (20 mL) was added iodoethane (5.82 g, 37.3 mmol) and K2CO3 (6.88 g, 49.7 mmol) portion wise. The resulting reaction mixture was stirred at 50° C. overnight. After cooling, the mixture was diluted with EtOAc/hexanes (1:1) and water. Layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give the title intermediate (4.6 g) as white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]([CH3:28])([CH3:27])[C:11](=O)[CH2:12][NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24][CH3:25])[CH:18]=2)=[S:15])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].C1(C)C=CC=CC=1>CC(O)=O>[F:9][C:8]1[CH:7]=[CH:6][C:5]([C:10]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[C:14]([SH:15])=[N:13][CH:12]=2)([CH3:28])[CH3:27])=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: COc1cc(NC(=S)NCC(=O)C(C)(C)c2ccc(F)c(C#N)c2)ccc1F
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1cc(-n2c(C(C)(C)c3ccc(F)c(C#N)c3)cnc2S)ccc1F
Yield: 65.1 %

Procedure:
A solution of 1-(3-(3-cyano-4-fluorophenyl)-3-methyl-2-oxobutyl)-3-(4-fluoro-3-methoxyphenyl)thiourea (3.7 g, 9.17 mmol) in AcOH (50 mL) was refluxed 2 h at 110° C. After the reaction was complete, it was cooled to room temperature and co-evaporated with toluene in vacuo. The residue was purified by flash column chromatography (Hex:EA=1:3) to give 2-fluoro-5-(2-(1-(4-fluoro-3-methoxyphenyl)-2-mercapto-1H-imidazol-5-yl)propan-2-yl)benzonitrile (2.3 g, 65%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.6 (bs, 1H), 7.26-7.23 (m, 1H), 7.08 (t, J=9.2 Hz, 1H), 6.96 (t, J=8.8 Hz, 1H), 6.84 (d, J=2.0 Hz, 1H), 6.25-6.25 (m, 1H), 6.17-6.15 (m, 1H), 3.59 (s, 3H), 1.51 (s, 6H).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]([F:11])([F:10])[F:9])[CH:6]=1.[Si:12]([C:16]#[CH:17])([CH3:15])([CH3:14])[CH3:13].C(NC(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Cu]I>[F:9][C:8]([F:11])([F:10])[CH2:7][N:5]1[CH:6]=[C:2]([C:17]#[C:16][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=[N:4]1
Reactant: FC(F)(F)Cn1cc(I)cn1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cnn(CC(F)(F)F)c1
Temperature: 60 °C
Yield: 97.6 %

Procedure:
4-Iodo-1-(2,2,2-trifluoroethyl)-1H-pyrazole (Preparation 146, 970 mg, 3.51 mmol) was dissolved in DMF (4.9 mL) and TMS-acetylene (0.7 ml, 486 mg, 4.96 mmol) was added; followed by di-isopropylamine (0.65 mL), copper(I) iodide (44 mg) and triphenylphosphine (184 mg). The reaction was flushed with nitrogen. Palladium acetate (52.5 mg) was added and the reaction flushed again with nitrogen (×3) before heating at 60° C. for 60 minutes. The reaction was cooled and added to water (50 mL). The product was extracted with ether (3×25 mL). The combined organic layers were washed with water (3×20 mL) and brine, then dried (MgSO4) and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 1:2 ethyl acetate:cyclohexane to afford the title compound (844 mg, 97%). 1H-NMR (CDCl3, 500 MHz): δ 0.24 (s, 9H), 4.68 (q, J=8.20, 2H), 7.66 (s, 1H), 7.67 (s, 1H).
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3]1.C(O[K])(C)(C)C.O.Cl>C(O)(C)(C)C>[C:13]1([C:4]2[CH:3]=[CH:2][CH2:7][CH2:6][C:5]=2[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C1CCC(Cl)C=C1c1ccccc1
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)C1=C(c2ccccc2)C=CCC1
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To a stirred solution of ethyl 4-chloro-2-phenylcyclohex-2-enecarboxylate (110 mg, 0.407 mmol) in tert-BuOH(2 ml), tert-BuOK(93 mg, 0.832 mmol) was added by portion on a water bath. After stirring for 1 hr. at room temperature, water was added to the reaction mixture, and it was acidified with dil. HCl aq. and extracted with AcOEt. The organic layer was washed with brine and dried over MgSO4. After removal of the solvent, the residue was purified by column chromatography on silica gel with n-hexane-AcOEt to afford 70 mg of ethyl 2-phenylcyclohexa-1,3-dienecarboxylate (y=74.0%) as a pale yellow oil. 1H-NMR(ppm, 300 MHz, CDCl3) δ 7.14-7.39(5H, m), 6.03-6.24(2H, m), 3.94(2H, q, J=6.9 Hz), 2.55-2.65(2H, m), 2.26-2.35(2H, m), 0.90(3H, t, J=6.9 Hz)
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:24]
Reactant: O=C(Cl)c1ccccc1F
Reactant: NC(=O)c1c(N)ncn1CCCOc1ccccc1
Product: NC(=O)c1c(NC(=O)c2ccccc2F)ncn1CCCOc1ccccc1
Yield: 92 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 22, using 1.00 g (3.84 mmol) of 4-amino-1-(3-phenoxypropyl)-5-imidazolecarboxamide prepared in the same manner as in Example 156 and 2-fluorobenzoyl chloride instead of benzoyl chloride to obtain 1.35 g of 4-(2-fluorobenzoylamino)-1-(3-phenoxypropyl)-5-imidazolecarboxamide (yield 92%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:13]O>>[CH3:13][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:2]=1[OH:1]
Reactant: O=C(O)c1cc(O)ccc1O
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(O)ccc1O

Procedure:
2,5-Dihydroxybenzoic acid (30 g) was added to methanol (100 ml) which had been acidified with hydrogen chloride gas. The solution was refluxed for 12 hours when the solvent was removed. The resulting solid was taken up in diethyl ether (200 ml) and washed with water (2×100 ml). The organic layer was dried over magnesium sulphate and the solvent removed under vacuum. The resulting solid (30 g) (m.p. 83°-84° C.) was identified as the desired methyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]2[C:6](=[CH:7][C:8]([CH3:23])=[C:9]([CH2:13][C:14]3[O:18][C:17]([C:19]([O:21]C)=[O:20])=[CH:16][CH:15]=3)[C:10]=2[CH3:12])[O:5][CH2:4][CH2:3]1.CO.Cl>O>[CH3:1][C:2]1([CH3:24])[C:11]2[C:6](=[CH:7][C:8]([CH3:23])=[C:9]([CH2:13][C:14]3[O:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][CH:15]=3)[C:10]=2[CH3:12])[O:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(Cc2c(C)cc3c(c2C)C(C)(C)CCO3)o1
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1cc2c(c(C)c1Cc1ccc(C(=O)O)o1)C(C)(C)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
In a 100-mL round-bottom flask, methyl 5-[(4,4,5,7-tetramethyl-3,4-dihydro-2H-chromen-6-yl)methyl]-2-furoate (532 mg, 1.62 mmol) and methanol (5 mL) were placed. The reaction was stirred at room temperature overnight, and then the mixture was poured in water, acidified with HCl (6N) and extracted with ethyl acetate. The separated organic layer was washed with brine, dried over MgSO4, and concentrated to yield 5-[(4,4,5,7-tetramethyl-3,4-dihydro-2H-chromen-6-yl)methyl]-2-furoic acid (208) (343.6 mg, 67.5% yield). 1HNMR (CDCl3) δ 1.31 (s, 6H), 1.82 (m, 2H), 2.13 (s, 3H), 2.21 (s, 3H), 2.62 (t, 2H), 4.01 (s, 2H), 5.82 (d, 1H), 6.55 (s, 1H), 7.16 (d, 1H). APCI-MS m/z 315 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[C:13](F)=[CH:14][C:15]2[O:20][CH:19]([C:21]([F:24])([F:23])[F:22])[C:18]([C:25]([O:27]CC)=[O:26])=[CH:17][C:16]=2[CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([O:1][C:13]2[C:12]([Cl:11])=[CH:30][C:16]3[CH:17]=[C:18]([C:25]([OH:27])=[O:26])[CH:19]([C:21]([F:23])([F:24])[F:22])[O:20][C:15]=3[CH:14]=2)=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc(C(=O)O)cc3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 4-hydroxybenzoic acid and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4. (Note: In the step similar to step 3, an additional equivalent of potassium carbonate was added.) mp>300° C. 1H NMR (acetone-d6/300 MHz) 8.16 (d, 2H, J=8.9 Hz), 7.96 (s, 1H), 7.79 (s, 1H), 7.20 (d, 2H, J=8.9 Hz), 6.87 (s, 1H), 5.90 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz) −79.4 (d, J=7.2 Hz). ESHRMS m/z 413.0006 (M−H, Calc'd 413.0040). Anal. Calc'd for C18H10ClF3O6: C, 52.13; H, 2.43. Found: C, 51.81; H, 2.31.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:24][C:23](=[O:25])[CH2:22][CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:36][C:37]([CH3:39])=[O:38]>O1CCCC1>[Si:1]([O:18][CH2:19][C@H:20]1[O:24][C:23](=[O:25])[C@H:22]([C:37]([OH:38])([CH3:39])[CH3:36])[CH2:21]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OC[C@@H]1CCC(=O)O1)(c1ccccc1)c1ccccc1
Reactant: CC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)[C@@H]1C[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)OC1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a cooled solution of (5S)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]tetrahydrofuran-2-one (compound 40d, 5.00 g, 14.0 mmol) in dry tetrahydrofuran (28 mL) was added a solution of lithium bis(trimethylsilyl)azanide (1.3 M in THF, 11.8 mL, 15.4 mmol) dropwise at −78° C. under argon. After addition, the mixture was stirred at −78° C. for 1 hour. Then distilled acetone (1.23 mL, 15.4 mmol) was added dropwise to the mixture and the resulting mixture was stirred at −78° C. for another 2 hours. The reaction was quenched by saturated NH4Cl solution and extracted with EtOAc (30 mL) three times. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 0-30% EtOAc in petroleum ether) to afford 5.7 g of (3S,5S)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-(1-hydroxy-1-methyl-ethyl)tetrahydrofuran-2-one (compound 40e) as a light yellow oil. MS obsd. (ESI+) [(M+NH4)+]: 430. (For the synthesis, please refer to: Tetrahedron 1997, 53, 6281-6294).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][C@@H:11]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][C:16]([C:37](=[O:66])[NH:38][CH2:39][CH2:40][NH:41][C:42]([NH:44][CH:45]2[CH2:50][CH2:49][N:48]([C:51](=[O:65])[NH:52][CH:53]4[CH2:58][CH2:57][N:56]([C:59]5[CH:64]=[CH:63][CH:62]=[CH:61][N:60]=5)[CH2:55][CH2:54]4)[CH2:47][CH2:46]2)=[O:43])=[N:17][C:18]=3[NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:10]([OH:67])[C@@H:9]1[OH:68])(C)(C)C.[ClH:70]>CO.O1CCOCC1>[ClH:70].[ClH:70].[N:56]1([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][N:60]=2)[CH2:57][CH2:58][CH:53]([NH:52][C:51]([N:48]2[CH2:47][CH2:46][CH:45]([NH:44][C:42](=[O:43])[NH:41][CH2:40][CH2:39][NH:38][C:37]([C:16]3[N:15]=[C:14]4[C:19]([N:20]=[CH:21][N:13]4[C@@H:11]4[CH2:12][C@H:8]([NH2:7])[C@@H:9]([OH:68])[C@H:10]4[OH:67])=[C:18]([NH:22][CH2:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:17]=3)=[O:66])[CH2:50][CH2:49]2)=[O:65])[CH2:54][CH2:55]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(C(=O)NC5CCN(c6ccccn6)CC5)CC4)nc32)[C@H](O)[C@@H]1O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(C(=O)NC5CCN(c6ccccn6)CC5)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of {(1S,2R,3S,4R)-4-[6-(2,2-diphenyl-ethylamino)-2-(2-{3-[1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylcarbamoyl)-piperidin-4-yl]-ureido}-ethylcarbamoyl)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-carbamic acid tert-butyl ester (76.7 mg, 81 μmol) in MeOH (0.5 ml) is treated with 4M HCl in dioxane (0.5 ml). After stirring at room temperature for 1 hour, the solvent is removed in vacuo to afford the title compound which is used crude in the next step.
Reaction SMILES: [N+]([N:4]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[N:6]=[CH:5]1)([O-])=O.[CH:12]1(N)[CH2:15][CH2:14][CH2:13]1>CO>[CH:12]1([N:4]2[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[N:6]=[CH:5]2)[CH2:15][CH2:14][CH2:13]1
Reactant: NC1CCC1
Reactant: O=[N+]([O-])c1cn([N+](=O)[O-])cn1
Solvent: CO
Product: O=[N+]([O-])c1cn(C2CCC2)cn1
Reaction time: 16 h
Yield: 91.7 %

Procedure:
1,4-Dinitroimidazole (237 mg, 1.5 mmol, J. Phys. Chem. 1995, 99, 5009-5015) was added to a solution of cyclobutylamine (107 mg, 1.5 mmol) in methanol (10 mL) at 23° C. The reaction mixture was stirred for 16 h, then the solvent was removed in vacuo and the resulting residue was purified by silica gel chromatography (1:1 hexanes-ethyl acetate) to afford 230 mg (92% yield) of 1-cyclobutyl-4-nitro-1H-imidazole; 1H NMR (400 MHz, CDCl3) δ7.81 (s, 1H), 7.45 (s, 1H), 4.64 (m, 1H), 2.6 (m, 2H), 2.4 (m, 2H), 2.0 (m, 2H); MS (AP/Cl): 168.2 (M+H)+. Note: 1,4-Dinitroimidazole is a highly energetic, semi-stable substance and should be stored in a freezer at all times it is not in use. Thermodynamic measurements have shown that it can potentially generate enough energy at 35° C. under adiabatic conditions to violently explode. Extreme caution should be exercised at all times using this material.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:15]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:20][C:17]2[CH:18]=[CH:19][S:15][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=Cc1ccsc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccsc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.5 %

Procedure:
Using general procedure A, 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.800 g, 4.30 mmol), thiophene-3-carbaldehyde (0.480 g, 4.30 mmol), acetic acid (20 drops, cat.) and sodium triacetoxyborohydride (1.27 g, 6.02 mmol) were combined in 1,2-dichloroethane (40 ml) and the resulting mixture was stirred at rt for 16 h. Standard basic workup gave the crude product as a tan oil. Purification by column chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 96:3:1, v/v/v) gave 4-[(thiophen-3-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a pale yellow oil (0.886 g, 73%). 1H-NMR (CDCl3) δ 1.27 (m, 3H), 1.45 (s+m, 1H), 1.84 (d, 2H, J=12.0 Hz), 2.66 (m, 1H), 2.80 (t, 2H, J=12.0 Hz), 3.85 (s, 2H), 4.01 (br d, 2H), 7.03 (d, 1H, J=6.0 Hz), 7.12 (s, 1H), 7.29 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([CH3:8])=[N:6][CH:7]=1.Cl>[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Product: Cc1ncc(Br)cc1N

Procedure:
To a solution of 5-bromo-2-methyl-3-nitropyridine (13.8 g, 63.9 mmol) in industrial methylated spirit (330 mL) at 40° C. was added iron powder (20 g) (portionwise to avoid clumping) followed by concentrated aqueous hydrochloric acid (5 mL). The dark brown mixture was stirred vigorously at reflux for 2 hours and then cooled and filtered through Celite® (which was washed with 1 L of industrial methylated spirit). The solvent was then removed in vacuo and the residue taken up in ethyl acetate (200 mL) and washed with a saturated aqueous solution of sodium bicarbonate (200 mL), dried over magnesium sulfate and solvent removed in vacuo to give 5-bromo-2-methylpyridin-3-amine as an orange solid, (10.7 g, 57.5 mmol, 89.9%). 1HNMR (400 MHz, CDCl3): δ ppm 7.91 (s, 1H), 7.00 (s, 1H), 3.75 (br.s, 2H), 2.25 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]1.C([O-])([O-])=O.[K+].[K+].C(O)(C)C>O>[N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:3]2[C:2]([N:25]3[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:10][CH2:11]1
Reactant: OC1CCNCC1
Reactant: Clc1nccnc1OC1CCN(c2ccc3ccccc3n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: OC1CCN(c2nccnc2OC2CCN(c3ccc4ccccc4n3)CC2)CC1
Temperature: 160 °C
Yield: 13.8 %

Procedure:
To a mixture of 2-(4-((3-chloropyrazin-2-yl)oxy)piperidin-1-yl)quinoline (see PREPARATION P1.1; 0.1 g, 0.29 mmol) and piperidin-4-ol (0.029 g, 0.29 mmol) and K2CO3 (0.08 g, 0.58 mmol) was added isopropyl alcohol (i-PrOH) (2 mL) and water (0.5 ml). The solution was heated to 160° C. under microwave for 5 hours. Then the mixture was concentrated and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 60% EtOAc in petroleum ether) to give the title product (0.02 g, 0.04 mmol, 17% yield) as white solid. ESI-MS (M+1): 406 calc. for C23H27N5O2 405.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19](Cl)=[C:18]([Cl:23])[CH:17]=1)(=[O:15])=[O:14].O>CS(C)=O>[Cl:23][C:18]1[CH:17]=[C:16]([S:13]([CH3:12])(=[O:15])=[O:14])[CH:21]=[CH:20][C:19]=1[O:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(Cl)c(Cl)c1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(Oc2ccc(Cl)c(Cl)c2)c(Cl)c1
Temperature: 60 °C
Yield: 82.1 %

Procedure:
To a solution of 9.09 g (0.0558 mole) of 3,4-dichlorophenol dissolved in 150 ml of DMSO was added 2.23 g (0.0558 mole) of NaOH. The mixture was heated to 60° C. and 11.3 g (0.0502 mole) of 3,4-dichlorophenyl methyl sulfone was added and the mixture heated at 150° C. for 3.75 hrs. The mixture was cooled and poured into water. The crystalline product was collected by filtration, washed with water and dried, which gave 14.5 g (82.4% yield) of product. Recrystallization from ethanol afforded purified 4-(2-chloro-4-(methylsulfonyl)phenoxy)-1,2-dichlorobenzene, mp 102°-104° C.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)[CH2:10][CH3:11]>>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([O:12][CH2:9][CH2:10][CH3:11])[CH:18]=2)=[N:7][CH:6]=1
Reactant: CCCOc1cccc(B(O)O)c1
Reactant: Brc1cnc(Br)nc1
Product: CCCOc1cccc(-c2ncc(Br)cn2)c1

Procedure:
2,5-Dibromopyrimidine and 3-propoxybenzeneboronic acid are reacted analogously to Example 1 to give 5-bromo-2-(3-propoxyphenyl) pyrimidine. ##STR40##
Reaction SMILES: [ClH:1].CCOCC.C(OC(=O)[NH:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:34])[N:18]([C:25]1([CH3:33])[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24])(C)(C)C>C(OCC)(=O)C>[ClH:1].[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:34])[N:18]([C:25]1([CH3:33])[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24]
Reactant: CC(C)(C)OC(=O)NCc1cccc2c1C(=O)N(C1(C)CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC1(N2C(=O)c3cccc(CN)c3C2=O)CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
2N HCl/ether solution (8.5 mL) was added to a stirred solution of [2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-carbamic acid t-butyl ester (2.3 g, 5.7 mmol) in ethyl acetate (20 mL). The mixture was stirred at room temperature overnight. The mixture was filtered, and the solid was dried to gave 4-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.6 g, 80%) as a white solid: 1H NMR (DMSO-d6) δ 1.90 (s, 3H, CH3), 2.08 (m, 1H), 2.61-2.71 (m, 3H), 4.44 (M, 2H, CH2), 7.87-7.95 (m, 3H, Ar), 8.62 (s, 3H, NH3), 11.05 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.97, 28.52, 29.04, 36.98, 58.77, 123.14, 128.38, 131.10, 132.28, 134.64, 135.58, 167.31, 168.00, 171.93, 172.09.