Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:18])[C:8]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[N:9][CH:10]=1)=[O:4].[Se](=O)=[O:20]>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:18])[C:8]([C:11]2[CH:12]=[N:13][C:14]([CH:17]=[O:20])=[CH:15][CH:16]=2)=[N:9][CH:10]=1)=[O:4]
Reactant: O=[Se]=O
Reactant: COC(=O)c1cnc(-c2ccc(C)nc2)c(Cl)c1
Solvent: C1COCCO1
Product: COC(=O)c1cnc(-c2ccc(C=O)nc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
0.6 g of 3-chloro-6′-methyl-[2,3′]bipyridyl-5-carboxylic acid methyl ester (12) (2.3 mmol) prepared in Example 8 was dissolved in 10 mL of 1,4-dioxane, and 0.75 g of selenium dioxide (6.9 mmol) was added thereto. The mixture was refluxed under heating and stirring for 18 hours, and cooled to room temperature. The mixture was concentrated under reduced pressure, and then dissolved in ethyl acetate to be washed with water. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=10/1) to obtain 0.51 g of yellow crystal, 3-chloro-6′-formyl-[2,3′]bipyridyl-5-carboxylic acid methyl ester (yield 81%)
Reaction SMILES: [CH3:1][C:2]1([CH:10]=[O:11])[CH:7]([CH3:8])[CH2:6][C:5]([CH3:9])=[CH:4][CH2:3]1.[CH2:12]=[CH:13][C:14](=C)C>>[CH3:1][C:2]1([C:10](=[O:11])[CH2:12][CH2:13][CH3:14])[CH:7]([CH3:8])[CH2:6][C:5]([CH3:9])=[CH:4][CH2:3]1
Reactant: CC1=CCC(C)(C=O)C(C)C1
Reactant: C=CC(=C)C
Product: CCCC(=O)C1(C)CC=C(C)CC1C

Procedure:
The 1,4,6-trimethylcyclohex-3-ene-1-carbaldehyde according to the invention and the analogous ketones according to the invention are directly accessible by means of 1,4-cycloaddition of isoprene with tiglic aldehyde or with the corresponding 2-propenylalkyl ketones. The carbaldehyde according to the invention and the analogous ketones are directly accessible by 1,4-cycloaddition of tiglic aldehyde or the corresponding 2-propenylalkyl ketones with isoprene.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH:14]=O)=[C:8]([CH:13]=1)[C:9]([O:11]C)=O.[N+:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])#[C-].C(O)(=O)C>CN(C=O)C>[Cl:3][C:4]1[CH:13]=[C:8]2[C:7]([CH:14]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:16][C:9]2=[O:11])=[CH:6][CH:5]=1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: COC(=O)c1cc(Cl)ccc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(Cl)cc2c(=O)[nH]1
Temperature: 20 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
To a stirred mixture of NaH (1.81 g, 30.3 mmol) in DMF (20 mL) was added a solution of methyl 5-chloro-2-formylbenzoate (5.0 g, 25 mmol) and ethyl 2-isocyanoacetate (2.85 g, 25 mmol) in DMF (60 mL) at 40° C. over a 20 minute period. The reaction mixture was stirred at 20° C. for 2 hours. Its pH was adjusted to 7.0 with acetic acid (10%) and the mixture was extracted with DCM (3×200 mL). The organic layers were combined, washed with brine (200 mL), dried over Na2SO4, and concentrated. The crude product was purified by silica gel column chromatography eluting with petroleum ether and ethyl acetate (PE/EtOAc=15:1-5:1 gradient) to give the title compound (2.0 g, 31%). ESI-MS m/z [M+H]+252.1.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[OH-].[NH4+:17]>O1CCCC1.O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([NH2:17])=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(Cl)N1CC(Oc2ccc(Br)cc2)C1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)N1CC(Oc2ccc(Br)cc2)C1
Reaction time: 18 h
Yield: 87.6 %

Procedure:
A stirred solution of 5.8 g (0.02 mole) of 3-(4-bromophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 3.8 g (4 ml) (0.06 mole) of 57% ammonium hydroxide. After stirring for 18 hr, the reaction mixture was diluted with 200 ml of water and the solid which separated was collected by filtration, 5.3 g. Recrystallization from ethanol-water yielded 4.75 g (87.6%) of fine white crystals, m.p. 193°-194° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:11]2[N:18]3[C:14]([O:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:26][C:27]([CH3:31])([CH3:30])[CH2:28][NH2:29]>C(#N)C>[CH3:26][C:27]([CH3:31])([CH3:30])[CH2:28][NH:29][C:2]1[CH:3]=[C:4]([C:11]2[N:18]3[C:14]([O:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)(C)CN
Reactant: O=[N+]([O-])c1ccc(-c2c(-c3ccc(F)cc3)nc3occn23)cc1F
Solvent: CC#N
Product: CC(C)(C)CNc1cc(-c2c(-c3ccc(F)cc3)nc3occn23)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 99 %

Procedure:
To a suspension of 5-(3-fluoro-4-nitrophenyl)-6-(4-fluorophenyl)-imidazo[2,1-b]oxazole (0.80 g, 2.2 mmol; Preparation #C.1) in ACN (6.0 mL) was added TEA (0.63 mL, 4.5 mmol) and 2,2-dimethylpropylamine (0.24 g, 2.7 mmol; TCI). The reaction was heated at about 80° C. for about 4 h then cooled to about 4° C. The resulting solid was filtered, washing with cold ACN (ca. 4° C.), and dried in a vacuum oven at about 55-65° C. to give the title compound (0.89 g, 96%): LC/MS (Table 1, Method b) Rt=2.62 min; MS m/z: 409.2 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.Cl.[NH:9]1[CH2:12][CH:11]([OH:13])[CH2:10]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Br:7][C:5]1[N:6]=[C:2]([N:9]2[CH2:12][CH:11]([OH:13])[CH2:10]2)[S:3][CH:4]=1
Reactant: Brc1csc(Br)n1
Reactant: OC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: OC1CN(c2nc(Br)cs2)C1
Temperature: 70 °C
Reaction time: 18 h
Yield: 55.2 %

Procedure:
A mixture of 2,4-dibromothiazole (1.00 g, 4.12 mmol), azetidin-3-ol hydrochloride (0.543 g, 4.96 mmol), and cesium carbonate (4.03 g, 12.37 mmol) in acetonitrile (30 mL) was stirred for 18 h at 70° C. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum, and the residue was purified via column chromatography on silica gel (eluting with 10:1, dichloromethane/methanol) to afford 1-(4-bromothiazol-2-yl)azetidin-3-ol (0.535 g, 53%) as a light yellow solid. MS (ESI, pos. ion) m/z 235, 237 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.[N:23]([O-])=O.[Na+]>O>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]3[N:13]=[N:23][N:14]([CH2:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Nc1ccc(Cn2ccnc2)cc1NCc1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: c1ccc(Cn2nnc3ccc(Cn4ccnc4)cc32)cc1
Temperature: 0 °C
Reaction time: 0.21 h
Yield: 40.9 %

Procedure:
To a stirred and cooled (0° C.) mixture of 3.9 parts of 4-(1H-imidazol-1-ylmethyl)-N2 -(phenylmethyl)-1,2-benzenediamine and 9.6 parts of concentrated hydrochloric acid was added dropwise a solution of 1.86 parts of sodium nitrite in 8 parts of water. Upon complete addition, stirring was continued for 10-15 minutes at this low temperature. The reaction mixture was allowed to reach room temperature and poured into ice water. The whole was extracted with dichloromethane. The acid aqueous layer was treated with a concentrated ammonium hydroxide solution while cooling and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by filtration over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was further purified by column chromatography over silica gel using a mixture of ethyl acetate, methanol and methanol, saturated with ammonia (95:2.5:2.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The product was filtered off, washed with 2,2'-oxybispropane and dried in vacuo at 50° C., yielding 1.6 parts (40.9%) of 6-(1H-imidazol-1-ylmethyl)-1-(phenylmethyl)-1H-benzotriazole; mp. 85.4° C. (compound 80).
Reaction SMILES: C(=O)([O-])O.[Na+].[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.O.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C1COCC1>[CH2:25]([O:24][C:22]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCc1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCCCCc1ccc(C(=O)O)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
Sodium hydrogencarbonate (0.95 g, 11.32 mmol) was added into a suspension of 30 in THF (120 mL), followed by water (10 mL), affording a clear solution. Benzyl chloroformate (1.21 mL, 8.49 mmol) was then added into the reaction mixture at 0° C. The reaction mixture was then stirred at room temperature overnight. After that, the solvent was removed under reduced pressure. Ethyl acetate (70 mL) was added to the residue and the solution was washed with 2N HCl (2×30 mL) and water (2×50 mL), then dried in vacuum. 1.82 g (98%) of 31 was obtained as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.11 (m, 2H), 1.28 (m, 2H), 2.33 (m, 2H), 3.02 (m, 2H), 5.01 (m, 2H), 7.15 (m, 7H), 7.93 (d 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:25]4[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:27][CH:26]=4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.Cl.[CH3:37]O>>[CH3:37][O:34][C:33](=[O:35])[CH2:32][CH2:31][C:28]1[CH:27]=[CH:26][C:25]([C:21]2[CH:20]=[C:19]3[C:24]([C:15]([C:8]4[C:7]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)=[N:11][N:10]5[CH2:12][CH2:13][CH2:14][C:9]=45)=[CH:16][CH:17]=[N:18]3)=[CH:23][CH:22]=2)=[CH:30][CH:29]=1
Reactant: CO
Reactant: O=C(O)CCc1ccc(-c2ccc3c(-c4c(-c5ccccn5)nn5c4CCC5)ccnc3c2)cc1
Agent: Cl
Product: COC(=O)CCc1ccc(-c2ccc3c(-c4c(-c5ccccn5)nn5c4CCC5)ccnc3c2)cc1

Procedure:
Into a 100 mL roundbottom flask is placed 3-{4-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinolin-7-yl]phenyl}propionic Acid (Example 30 before reverse phase purification) (160 mg, 0.35 mmol), 20 mL of MeOH, and 1.5 mL of conc HCl solution. The mixture is refluxed 3 h, and solvent removed under reduced pressure. The product is partitioned between CH2Cl2 (20 mL) and saturated K2CO3 solution. The organic layer is collected and dried (MgSO4) and concentrated under vacuum. The title compound, 88.4 mg (54%), is crystallized from a concentrated CH2Cl2-Hexanes mixture.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:14]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:25](Cl)(=[O:27])[CH3:26]>>[C:25]([NH:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]([F:24])([F:22])[F:23])[CH:14]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: CC(NC(=O)c1ccnc(N)n1)c1cccc(OCC(F)(F)F)c1
Product: CC(=O)Nc1nccc(C(=O)NC(C)c2cccc(OCC(F)(F)F)c2)n1

Procedure:
The title compound is prepared from 2-amino-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pyrimidine-4-carboxamide (15 mg, 0.04 mmol, Step-1, single enantiomer) and acetyl chloride (10 mg, 0.13 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: O.[NH3:2].[F:3][C:4]([F:20])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17])[C:5]([F:8])([F:7])[F:6]>C(Cl)Cl>[F:3][C:4]([F:20])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH2:2])(=[O:18])=[O:17])[C:5]([F:8])([F:7])[F:6]
Reactant: N
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)c1ccccc1OC(F)(F)C(F)(F)F

Procedure:
To a mixture of 250 ml of methylene chloride, 250 ml of water and 250 ml of 30% ammonia solution is slowly added a solution of the crude 2-pentafluoroethoxyphenylsulfonyl chloride obtained in Example 2a, in 50 ml of methylene chloride. After the exothermic reaction has subsided, the reaction mixture is refluxed for 2 hours. The organic phase is washed with water, dried over sodium sulfate, and evaporated to dryness. Recrystallisation from methanol yields 65 g of 2-pentafluoroethoxyphenylsulfonamide with a melting point of 145°-146° C.
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][C@@H:14]3[CH3:19])=[N:10][CH:9]=[N:8][C:7]=2[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:27]([O:31][C:32]([NH:34][C@H:35]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([F:47])[CH:41]=1)[C:36](O)=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][C@@H:35]([NH:34][C:32](=[O:33])[O:31][C:27]([CH3:28])([CH3:29])[CH3:30])[C:36]([N:16]2[CH2:17][CH2:18][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][CH2:6][C:7]=4[N:8]=[CH:9][N:10]=3)[C@@H:14]([CH3:19])[CH2:15]2)=[O:37])=[CH:41][C:42]=1[F:47]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)c(F)c1)C(=O)O
Reactant: C[C@@H]1CCc2ncnc(N3CCNC[C@@H]3C)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)[C@@H](Cc4ccc(Cl)c(F)c4)NC(=O)OC(C)(C)C)C[C@@H]3C)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To a solution of (R)-5-methyl-4-((S)-2-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (32 mg, 0.14 mmol) in DCM (5 mL) were added triethylamine (1 mL), (R)-2-(tert-butoxycarbonylamino)-3-(4-chloro-3-fluorophenyl)propanoic acid (44 mg, 0.14 mmol) and HBTU (52 mg, 0.14 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was removed and the residue was purified by silica gel chromatography, eluting with ethyl acetate to afford tert-butyl (R)-3-(4-chloro-3-fluorophenyl)-1-((S)-3-methyl-4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (55 mg, 82%). 1H NMR (CDCl3, 400 MHz) δ 8.46 (s, 1H), 7.31-6.85 (m, 3H), 5.45-5.18 (m, 1H), 4.90-4.60 (m, 2H), 4.50-4.30 (m, 1H), 4.20-4.00 (m, 1H), 3.90-3.60 (m, 2H), 3.40 (m, 1H), 3.20-2.70 (m, 2H), 2.24 (m, 1H), 1.70 (m, 1H), 1.42 (s, 9H), 1.30-0.98 (m, 6H). MS (APCI+) [M+H] +532.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[CH3:22][O:23][NH:24][CH3:25]>>[CH3:22][O:23][N:24]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1)[CH3:25]
Reactant: CNOC
Reactant: COC(=O)c1cccc2nc(-c3ccc(CBr)cc3)oc12
Product: COC(=O)c1cccc2nc(-c3ccc(CN(C)OC)cc3)oc12
Yield: 65 %

Procedure:
Following the experimental procedure as described in Example 144 C, and replacing methyl 2-(4-(bromomethyl)phenyl)benzo[d]oxazole-4-carboxylate with methyl 2-(4-(bromomethyl)phenyl)benzo[d]oxazole-7-carboxylate and substituting dimethylamine with methoxy(methyl)amine, methyl 2-(4-((methoxy(methyl)amino)methyl)phenyl)benzo[d]oxazole-7-carboxylate (Yield: 65%. LC-MS (ESI) m/z: 327 (M+1)+) was made.
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:34][C@H:35]([CH2:37][OH:38])[CH3:36]>C1COCC1>[C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([NH:34][C@H:35]([CH2:37][OH:38])[CH3:36])=[O:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: C[C@H](N)CO
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C[C@@H](CO)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
4.98 g (20 mmol) N-carbobenzoxy-L-proline, 2.73 g (20 mmol) isobutyl chloroformate, 2.02 g (20 mmol) N-methylmorpholine, and 1.50 g (20 mmol) L-alaninol were contacted and reacted in THF substantially according to the mixed anhydride procedure described in Example 1. Recrystallization of crude product from 50 ml ehtyl acetate provided 3.61 g (11.8 mmol, 59%) of colorless, crystalline N-carbobenzoxy-L-prolyl-L-alaninol; m.p. 126.5°-127.6°, α25D-48.9° (C=1.03 g/100 mL in acetone).
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([CH3:11])[C:4]=1[CH3:12].B(Br)(Br)Br>C(Cl)Cl.O>[OH:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([CH3:11])[C:4]=1[CH3:12]
Reactant: COc1ccc(C=O)c(C)c1C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1c(O)ccc(C=O)c1C
Temperature: -78 °C
Reaction time: 12 h
Yield: 10.2 %

Procedure:
4-Methoxy-2,3-dimethyl-benzaldehyde (2.0 g, 12.18 mmol) was dissolved in DCM (48 mL), and the solution was cooled to −78° C. 1M BBr3(24 mL, 24.13 mmol) was added slowly thereto, and the mixture was stirred at room temperature for 12 hours. After the termination of the reaction, the residue was diluted with water and extracted with DCM. The organic layer was dried with MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography (eluent, EtOAc/Hex=1/5) to obtain the title compound (187 mg, 10%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][S:6]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])=[O:7].[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17]1>C(=S)=S>[CH3:5][S:6]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:15]=1)(=[O:8])=[O:7]
Reactant: CS(=O)(=O)Nc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CS(=O)(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mechanically stirred suspension of aluminum chloride (88.0 g, 0.66 moles) and 150 ml of carbon disulfide under N2 is cooled in an ice bath. Methanesulfonanilide as prepared in Preparation 1 (30.0 g, 0.175 mol) and succinic anhydride (17.5 g, 0.175 mol) are combined and added rapidly to the cooled reaction mixture. The ice bath is removed and the mixture is stirred at ambient temperature for 6 hours. The reaction mixture is then heated to 55° C. and allowed to continue for 18 hours. The reaction mixture is separated into two layers the bottom of which solidifies. The upper layer is decanted and the remaining solid layer is decomposed with ice. The resulting suspension is filtered and the solid is washed several times with methylene chloride and dissolved in a mixture of saturated sodium bicarbonate (500 ml) and water (500 ml). This solution is acidified (pH2) with HCl and the resulting precipitate is collected by filtration, redissolved in NaHCO3 and reprecipitated with HCl. The solid, 4-[(methylsulfonyl)amino]-γ-oxobenzenebutanoic acid, is collected by filtration and dried to give the title compound with mp 198°-200° C.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[H-].[Na+].[CH:7]([O:10][C:11](=[O:21])[C:12]1[C:17](Cl)=[CH:16][C:15]([Cl:19])=[N:14][C:13]=1[CH3:20])([CH3:9])[CH3:8]>C1COCC1.[Cu]I>[CH:7]([O:10][C:11](=[O:21])[C:12]1[C:17]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:16][C:15]([Cl:19])=[N:14][C:13]=1[CH3:20])([CH3:9])[CH3:8]
Reactant: CC(C)O
Reactant: Cc1nc(Cl)cc(Cl)c1C(=O)OC(C)C
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(OC(C)C)c1C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Anhydrous isopropanol (1.5 mL, 20 mmol) is added to a suspension of NaH (1.5 g of 60% dispersion in mineral oil, 37 mmol) in THF (90 mL) at 0° C. and the mixture is stirred for 30 minutes at ambient temperature. To this is added a solution of 4,6-dichloro-2-methyl-nicotinic acid isopropyl ester (4.6 g, 19 mmol) in THF (10 mL) and CuI (178 mg, 0.94 mmol) The mixture is refluxed for 1 hour, cooled to room temperature, and poured into water-ice mixture. The layers are separated and the aqueous layer is extracted with EtOAc. The combined organic layers are dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography (elution with Hex/EtOAc 61) to yield 6-chloro-4-isopropoxy-2-methyl-nicotinic acid isopropyl ester as a pale yellow oil. 1H NMR (CDCl3) 6.65 (s, 1H), 5.24 (m, 1H), 4.60 (m, 1H), 2.41 (s, 3H), 1.28 (d, 12H).
Reaction SMILES: I[CH2:2][CH2:3][CH3:4].[Br:5][C:6]1[CH:7]=[CH:8][C:9]([OH:29])=[C:10]([CH:28]=1)[CH2:11][N:12]([C:15]1[N:20]=[N:19][C:18]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:17][CH:16]=1)[CH2:13][CH3:14]>>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([O:29][CH2:2][CH2:3][CH3:4])=[C:10]([CH:28]=1)[CH2:11][N:12]([C:15]1[N:20]=[N:19][C:18]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:17][CH:16]=1)[CH2:13][CH3:14]
Reactant: CCCCOC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2O)nn1
Reactant: CCCI
Product: CCCCOC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2OCCC)nn1

Procedure:
The title compound was prepared by reacting 1-iodopropane and butyl 6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridazine-3-carboxylate (reference example 3) using a similar method to that of reference example 4.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:18]#N)=[CH:14][N:13]3[CH:20]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][Si](C#C)(C)C.N1CCCCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl-].[NH4+]>[C:18]([C:15]1[CH:16]=[CH:17][C:12]2[N:13]([CH:20]=[C:10]([C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])[N:11]=2)[CH:14]=1)#[CH:21]
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCNCC1
Product: C#Cc1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.2 g of 6-iodo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide (Intermediate 2), 156 μL of trimethylsilylacetylene, 20 mg of dichlorobis(triphenylphosphine)palladium and 2 mL of piperidine are placed in a 20 mL microwave tube. The mixture is heated for 15 minutes in a microwave machine set at 130° C. After cooling, the mixture is poured into 50 mL of saturated aqueous ammonium chloride solution. The resulting mixture is extracted twice with 70 mL of ethyl ether. The combined organic phases are separated out by settling, dried and concentrated to dryness under reduced pressure. The residue is taken up in 4 mL of a 1M solution of tetrabutylammonium fluoride in THF and stirred for 16 hours at 25° C. After evaporating the reaction medium to dryness, the residue is chromatographed on silica, eluting with a mixture of cyclohexane and ethyl acetate (gradient from 0 to 35%) to give 30 mg of 6-ethynyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a beige-coloured solid.