Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3](=[C:9]([S:12][CH3:13])SC)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH2:14]([N:16]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)[CH2:17][CH3:18])[CH3:15]>>[CH2:14]([N:16]([C:19]1[CH:20]=[CH:21][C:22]([NH:23][C:9]([S:12][CH3:13])=[C:3]([C:1]#[N:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:24][CH:25]=1)[CH2:17][CH3:18])[CH3:15]
Reactant: CCN(CC)c1ccc(N)cc1
Reactant: CCOC(=O)C(C#N)=C(SC)SC
Product: CCOC(=O)C(C#N)=C(Nc1ccc(N(CC)CC)cc1)SC
Yield: 81 %

Procedure:
21.7 g of ethyl 2-cyano-3,3-bis(methylthio)acrylate and 16.5 g of 4-(N,N-diethylamino)aniline are heated for 2 hours at 120° C. The residue is purified by chromatography on a silica column, the eluent being a toluene/ethanol (97/3) mixture; the expected product is recrystallised from cyclohexane. M.p.=100° C. (Yield 81%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:31]1[CH2:36][CH2:35][N:34]([C:37]([C:39]2[CH:44]=[CH:43][C:42](B3OC(C)(C)C(C)(C)O3)=[CH:41][CH:40]=2)=[O:38])[CH2:33][CH2:32]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:42]2[CH:41]=[CH:40][C:39]([C:37]([N:34]3[CH2:35][CH2:36][O:31][CH2:32][CH2:33]3)=[O:38])=[CH:44][CH:43]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCOCC3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(C(=O)N3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 67.6 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (300 mg, 0.63 mmol) and morpholino(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone (260 mg, 0.82 mmol) in dioxane (10 mL), aqueous 2M Na2CO3 solution (1.13 mL, 2.27 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (72 mg, 0.06 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (250 mg, 68%). LCMS: 587.35 (M+1)+; HPLC: 93.85% (@254 nm) (Rt; 4.535; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 1.46 (bs, 1H), 8.21 (t, 1H), 7.69-7.71 (m, 2H), 7.45-7.49 (m, 3H), 7.26 (s, 1H), 5.86 (s, 1H), 4.29 (d, 2H, J=4 Hz), 3.82-3.84 (m, 2H), 3.48-3.60 (m, 8H), 3.23-3.25 (m, 2H), 3.09-3.11 (m, 3H), 2.26 (s, 3H), 2.21 (s, 3H), 2.11 (s, 3H), 1.52-1.68 (m, 4H), 0.83 (t, 3H, J=6.8 Hz).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[C:17]([F:20])([F:19])[F:18])[O:8][N:7]=1)=[O:5])C.[OH-].[Li+]>CO.O>[F:20][C:17]([F:18])([F:19])[C:16]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:9]1[O:8][N:7]=[C:6]([C:4]([OH:5])=[O:3])[N:10]=1
Reactant: CCOC(=O)c1noc(-c2cnccc2C(F)(F)F)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1noc(-c2cnccc2C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
15.8 g of 3-ethoxycarbonyl-5-(4-trifluoromethyl-3-pyridyl)-1,2,4-oxadiazole are initially charged in 13 ml of methanol, and, with ice-cooling at 0° C., a solution of 2.8 g of lithium hydroxide in 50 ml of water is added dropwise. The mixture is stirred at room temperature for 2 h, 20 ml of ice-water are added and the mixture is extracted with 200 ml of diethyl ether. The aqueous phase is adjused to pH=2 using dil. HCl, and the precipitated product is filtered off with suction. After drying, 13.8 g of 5-(4-trifluoromethyl-3-pyridyl)-1,2,4-oxadiazole-3-carboxylic acid are obtained as a white solid of mp. 157-159° C.
Reaction SMILES: C.[C:2]([C:6]1[CH:7]=[C:8](O)[C:9](=[CH:11][CH:12]=1)O)([CH3:5])(C)C.[C:14]1(C)C=CC(S(O)(=O)=O)=C[CH:15]=1.C[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=1[CH3:32]>O>[CH:2]([C:6]1[CH:12]=[CH:11][C:9]([CH2:32][C:31]2[CH:26]=[CH:27][C:28]([CH:14]=[CH2:15])=[CH:29][CH:30]=2)=[CH:8][CH:7]=1)=[CH2:5]
Reactant: Cc1ccccc1C
Reactant: CC(C)(C)c1ccc(O)c(O)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C
Solvent: O
Product: C=Cc1ccc(Cc2ccc(C=C)cc2)cc1

Procedure:
The mixture of 10.02 g (0.0391 mole) of bis-[4-(]-hydroxyethyl)phenyl]-methane (BHEPM) 0.010 g of 4-tert-butyl catechol, 0.125 g (1.248% of BHEPM weight or 5.050 mmole/L) p-toluenesulfonic acid (monohydrate) (TSA), and 120 mL of o-xylene was heated at the boiling temperature for 1.5 hours. Water released during the dehydration was azeotroped from the system. Then, the reaction mixture was washed successively by the distilled water, 2-3% solution of sodium bicarbonate (NaHCO3), and by water again for attaining pH=7. The solution of the product in o-xylene was dried over CaCl2 passed through a layer of alumina, and the solvent removed by distillation under the reduced (1-2 mm Hg) pressure at 40° C. in the presence of about 0.00168 g tert-butyl catechol. The yield of the unsaturated composition riched with bis-(4-vinylphenyl) methane (BVPM) was 7.59 g (88% of theor.), mp 30-33° C., nD40 1.603. According to the reversed phase chromatography (column Separon Si C18, toluene was used as eluate, the elution rate was 0.1 mL minute, a refractometric detector was used). The content of components was as follows, wt-%: Monomer M1 (BVPM) 79, its unsaturated dimer 16.5, its insaturated trimer 4, unsaturated tetramer and higher oligomers <0.5%. The pure BVPM (purity was >99.5%), mp 36-38° C. was obtained by sublimation of the monomer at 130° C. for 1 hour under vacuum (1-2 mmHg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@@H:12]([CH3:14])[NH:11][CH2:10][C@@H:9]1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.[BH3-]C#N.[Na+].[N-]=C=O>C1COCC1.CCO>[CH2:1]([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11]([CH:19]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)[CH2:10][C@@H:9]1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCOCC1
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](C)CN1
Agent: [BH3-]C#N
Agent: [N-]=C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](C)CN1C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
To a mixture of (2S,5R)-1-benzyl-2,5-dimethylpiperazine (11.0 g, 53.8 mmol) and of tetrahydro-4H-pyran-4-one (5.39 g, 53.8 mmol) at 0° C. was added Ti(IV) isopropoxide (19.2 mL, 67.3 mmol). The resulting mixture was stirred at rt overnight and an orange suspension was obtained. To the suspension was added EtOH (25 mL) and NaCNBH3 (4.27 g, 64.6 mmol, 1.20 eq). The resulting mixture was stirred at rt for 24 h. The reaction mixture was then quenched with water (5.0 mL) and a yellow solid was generated. The suspension was diluted with EtOAc (400 mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was again diluted with EtOAc (500 mL), dried over Na2SO4, and filtered. The filtrate was collected and concentrated under reduced pressure to afford a yellow oil. The oil was diluted in THF (400 mL) and PS-isocyanate was added to remove secondary amine. The suspension was filtered and the filtrate concentrated. The residue was purified by column chromatography using 50:5:1 CHCl3/MeOH/Et3N to afford the desired compound as yellow oil (13.0 g, 84%)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.C1COCC1.[CH3:15][S:16]SC>O.C(OCC)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:16][CH3:15])[CH:3]=1
Reactant: Cc1cccc([Mg]Br)c1
Reactant: CSSC
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CSc1cccc(C)c1
Temperature: 25 °C
Yield: 70 %

Procedure:
Add 1M 3-methyl-phenylmagnesium bromide in THF (25 mL, 25 mmol) to −30° C. diethyl ether (50 mL). Add dimethyl disulfide (1.8 mL, 20 mmol) to the reaction over 3 minutes allowing the reaction to warm to room temperature. Dilute the reaction in H2O (75 mL) and diethyl ether (50 mL). Separate and extract the cloudy aqueous layer with diethyl ether (25 mL). Combine the organic layers and wash with H2O (25 mL). Dry the organic layer with Na2SO4 (30 g), filter over Celite 501 (10 g) and concentrate in vacuo to give 3.0 g of crude material. Combine with another batch of crude title compound that yielded 6.0 g crude. Chromatograph the entire 9.0 g crude on a SiO2 column in hexanes to give 7.2 g (70%) of 1-methyl-3-methylsulfanyl-benzene.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH2:7])[CH:3]=1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16].O>O1CCCC1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([NH:7][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])[CH:3]=1
Reactant: Cc1cc(N)no1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)OCC(Cl)(Cl)Cl)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a solution of 5-methylisoxazole-3-amine (1.00 g, 10.2 mmol) and pyridine (0.998 ml, 12.2 mmol) in tetrahydrofuran (34 ml) was added 2,2,2-trichloroethyl chloroformate (1.69 ml, 12.2 mmol) with ice-cooling and the mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. Hexane was poured to the residue and a solid was collected by filtration to obtain the desired product (2.55 g, 91.4%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:33])[CH2:17][CH:18]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:25]=1[O:31][CH3:32])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:4])([CH3:3])[CH3:2].Br[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:33])[CH2:17][CH:18]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:26][C:25]=1[O:31][CH3:32])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)OC)ccc1C(C)(C)C)c1ccc(O)cc1OC
Reactant: CC(C)(C)OC(=O)CBr
Product: CCCCCC(CC(=O)Nc1cc(C(=O)OC)ccc1C(C)(C)C)c1ccc(OCC(=O)OC(C)(C)C)cc1OC

Procedure:
Following a similar procedure to that described in Preparation 45A(i), but using N-(2-t-butyl-5-methoxycarbonylphenyl)-3-(4-hydroxy-2-methoxyphenyl)octanamide (prepared as described in Preparation 46) and t-butyl bromoacetate, the title compound was obtained as a foam-like substance.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1>>[N:14]1[CH:15]=[CH:16][CH:17]=[N:18][C:13]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: Brc1ncccn1
Product: OCc1ccc(-c2ncccn2)cc1
Yield: 100.6 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Reference Example 13 except for using 4-hydroxymethylphenylboronic acid (144 mg, 0.948 mmol), and using 2-bromopyrimidine (101 mg, 0.635 mmol) in place of 4-bromopyridazine to afford the title compound (119 mg) substantially quantitatively as a slightly yellow solid.
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](O)=[CH:4][C:3]=1Cl.CN1CCN(C)C1=O.C(=O)([O-])[O-].[K+].[K+].C(N(CCCCCCCC)C1C=C(O)C=CC=1)CCCCCCC>O>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1c(Cl)cc(O)c2c1C(=O)c1ccccc1C2=O
Agent: CCCCCCCCN(CCCCCCCC)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: O=C1c2ccccc2C(=O)c2ccccc21
Temperature: 150 °C
Reaction time: 5 h

Procedure:
One part of 1-amino-2-chloro-4-hydroxyanthraquinone, 10 parts of 1,3-dimethyl-2-imidazolidinone, 1.0 part of potassium carbonate and 2.0 parts of N,N-di-n-octyl-m-aminophenol were mixed at room temperature, and then heated to 150° C. While this temperature was maintained, the reaction was conducted for 5 hours. The reaction mixture was cooled, then charged into 100 parts of water, extracted with toluene and thereafter purified through silica gel column chromatography to obtain an anthraquinone compound as coloring matter No. 1 (yield 90%).
Reaction SMILES: C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].[CH3:18][C:19]1([CH3:29])[CH2:24][CH2:23][C:22](=[O:25])[CH:21]([CH2:26][CH:27]=[CH2:28])[CH2:20]1>O1CCCC1.C(OCC)(=O)C>[CH3:18][C:19]1([CH3:29])[CH2:24][CH2:23][C@@H:22]([OH:25])[C@H:21]([CH2:26][CH:27]=[CH2:28])[CH2:20]1
Reactant: C=CCC1CC(C)(C)CCC1=O
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC[C@@H]1CC(C)(C)CC[C@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
A solution of 4,4-dimethyl-2-cyclohexen-1-one (500 mg) in dry tetrahydrofuran (2 ml) was added to a well stirred solution of lithium (141 mg) in liquid ammonia (5 ml). The mixture was stirred at -33° C. for 1 hr. And then, to this solution allyl bromide (2.4 g) was added, and stirred for 30 min. The reaction was quenched by addition of methanol, and the ammonia was allowed to evaporate. The residue was diluted with water, and extracted with diethyl ether. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue with silica gel column chromatography (using n-hexane:ethyl acetate=30:1 as an eluent) gave 4,4-dimethyl-2-(2-propenyl)cyclohexanone (345 mg, 52% yield) as a colorless oil. (b) To a solution of lithium tri-tert-butoxyaluminohydride (460 mg) in dry tetrahydrofuran (3.5 ml) there was added a solution of 4,4-dimethyl-2-(2-propenyl)cyclohexanone (250 mg) at 0° C., and the mixture was stirred at room temperature for 2 hrs. The reaction was quenched by addition of water. The pH of the mixture was adjusted to pH 7 with 0.1N hydrochloric acid. The mixture was extracted with diethyl ether, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the residue by silica gel column chromatography (using n-hexane: ethyl acetate=20:1 as an eluent) gave (1R*,2R*)-4,4-dimethyl-2-(2-propenyl)cyclohexanol (185 mg, 73% yield) as a colorless oil; EI-MS: m/z 168 (M+); 1H-NMR (CDCl3)d: 0.90 (3H,s), 0.93 (3H, s), 1.2~1.8 (7H,m), 1.95 (1H,m), 2.46 (1H,m), 3.23 (1H,dt,J=5 & 11 Hz), 5.02 (1H,br.d,J=10 Hz), 5.06 (1H,br.d,J=17 Hz), 5.85 (1H,m).
Reaction SMILES: [CH3:1][C:2]1([C:11]([OH:13])=[O:12])[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.C(Cl)(Cl)=O.[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]3[N:34]=[C:35]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[O:36][C:37]=3[C:38]([F:41])([F:40])[F:39])=[O:32])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)Cl.C1COCC1>[CH3:1][C:2]1([C:11]([OH:13])=[O:12])[CH2:3][CH2:4][CH:5]([C:8]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:25]=[CH:26][C:27]([NH:30][C:31]([C:33]4[N:34]=[C:35]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[O:36][C:37]=4[C:38]([F:39])([F:40])[F:41])=[O:32])=[CH:28][CH:29]=3)[CH2:20][CH2:19]2)=[O:10])[CH2:6][CH2:7]1
Reactant: CC1(C(=O)O)CCC(C(=O)O)CC1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C(=O)O)CCC(C(=O)N2CCC(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)CC1
Reaction time: 0.5 h
Yield: 24.3 %

Procedure:
Methyl-cyclohexane-1,4-dicarboxylic acid (34.1 mg, 0.183 mmol) in dry CH2Cl2 (3 mL) was treated with phosgene (2M in CH2Cl2, 366 uL, 0.732 mmol) for 30 minutes. THF (0.5 mL) was added and stirred for an additional 30 minutes. The reaction was evaporated and re-evaporated from toluene three times and re-dissolved in 5 mL CH2Cl2. 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (76.2 mg, 0.183 mmol) and triethylamine (77 uL, 0.549 mmol) in 3 mL of CH2Cl2 were added dropwise over 15 minutes to the above solution. The mixture was stirred at room temperature for 90 minutes and then diluted with 10 mL CH2Cl2. Following work-up, the crude residue was purified by flash chromatography to yield 1-methyl-4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-cyclohexanecarboxylic acid as a white solid (26 mg, 24%). ES-MS calcd for C31H32F3N3O5 (m/e) 583.61, obsd 584 (M+H).
Reaction SMILES: C([C:8]([NH2:12])([OH:11])[CH2:9][CH3:10])(OC(C)(C)C)=O.[CH3:13][C:14]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:21][CH:22]=1)=[O:15].[ClH:27].C(OCC)(=O)C.C(OCC)C>ClCCl>[NH2:12][CH:8]([OH:11])[CH2:9][CH3:10].[CH3:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:18]=1)=[O:15].[ClH:27]
Reactant: CCC(N)(O)C(=O)OC(C)(C)C
Agent: CC(=O)Nc1ccc(CC(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCC(N)O
Reaction time: 3 h

Procedure:
In 2 ml of dichloromethane, 201.3 mg (0.574 mmol) of the Boc-aminopropanol-actarit obtained above was dissolved, and 3 ml of 4 M hydrochloric acid/ethyl acetate was added thereto under ice-cooling, followed by stirring for 3 hours. Diethyl ether was added thereto for precipitation, and the precipitate was washed twice with diethyl ether and then dried under reduced pressure to give 161.3 mg (98%) of the titled compound. The structure was identified by 1H-NMR.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([NH:21][O:22]C3CCCCO3)=[O:20])=[CH:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1>CO.O>[CH3:29][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([NH:21][OH:22])=[O:20])=[CH:13]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NOC3CCCCO3)c2)cc1
Solvent: CO
Solvent: O
Product: CN(C)c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NO)c2)cc1

Procedure:
The method used for preparation of this compound is analogous to the method described for compound 2. Starting materials: (E)-3-[1-(4-dimethylamino-benzene sulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (compound A4) (0200 g), methanol/water 3/2 (50 ml), amberlyst IR15 (0.402 g).
Reaction SMILES: [O:1]=[C:2]1[CH:5]([NH:6][C:7](=[O:16])[CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]([S:17]NCCC)[N:3]1[CH:22]([C:27]([CH3:29])=[CH2:28])[C:23]([O:25][CH3:26])=[O:24].[ClH:30]>C(Cl)Cl>[Cl:30][C:27]1([CH3:29])[CH:22]([C:23]([O:25][CH3:26])=[O:24])[N:3]2[C:2](=[O:1])[CH:5]([NH:6][C:7](=[O:16])[CH2:8][O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C@H:4]2[S:17][CH2:28]1
Reactant: C=C(C)C(C(=O)OC)N1C(=O)C(NC(=O)COc2ccccc2)C1SNCCC
Reactant: Cl
Solvent: ClCCl
Product: COC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SCC1(C)Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Methyl 2-oxo-3-(2-phenoxyacetamido)-4-propylaminothio-α-isopropenylazetidine-1-acetate (0.43 g) was dissolved in dried methylene chloride. To this solution was added 5% methanolic hydrochloric acid (2ml) and the mixture was stirred for 10 hours at room temperature. After the reaction, the reaction mixture was concentrated under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was distilled off and the residue was subjected to column chromatography on silica gel using chloroform as developing solvent to give oily methy 3-chloro-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate (310 mg).
Reaction SMILES: [C:1](#N)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH:10]1([Mg]Br)[CH2:14][CH2:13][CH2:12][CH2:11]1.Cl.[OH-:18].[Na+].O>C(OCC)C.O.C(OCC)(=O)C>[NH2:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:18]
Reactant: Br[Mg]C1CCCC1
Reactant: N#Cc1ccccc1N
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCC
Product: Nc1ccccc1C(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.6 %

Procedure:
To a solution of anthranilonitrile (15.0 g) in diethyl ether (600 mL) was added a solution of 2.0 M cyclopentylmagnesium bromide in diethyl ether (159 mL) at 0° C. under nitrogen. The mixture was stirred at room temperature overnight (20 hours). 500 ml of 5 N HCl in H2O was added very slowly at 0° C. The mixture was stirred at room temperature for 1 hour. The aqueous layer was neutralized with 50% NaOH/H2O to pH=12. 2×500 mL of ethyl acetate was used to extract the aqueous layer. The combined organic layers were dried over Na2SO4. The solvent was removed to give the crude product 22.5 g (93.6% yield). H1NMR(CDCl3): δ 6.62-7.82 (m, 4H), 3.64-3.78 (m, 1H), 1.50-1.96 (m, 8H).
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH:9]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[NH:20][C:21]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=5)[N:25]([CH3:36])[CH:24]=4)=[CH:22][C:15]=23)[CH2:10]1)(C)(C)C.[OH-].[Na+]>CO.ClCCl.O>[CH3:33][O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:34][CH3:35])[N:25]([CH3:36])[CH:24]=[C:23]2[C:21]1[NH:20][C:16]2=[N:17][CH:18]=[CH:19][C:14]([CH2:13][N:11]3[CH2:12][CH:9]([NH2:8])[CH2:10]3)=[C:15]2[CH:22]=1
Reactant: COc1cc2c(-c3cc4c(CN5CC(NC(=O)OC(C)(C)C)C5)ccnc4[nH]3)cn(C)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(-c3cc4c(CN5CC(N)C5)ccnc4[nH]3)cn(C)c2cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 19.7 %

Procedure:
0.27 cm3 of hydrochloric acid (4N in dioxane) is added to a solution of 0.051 g of {1-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]azetidin-3-yl}carbamic acid tert-butyl ester in 3 cm3 of methanol and 0.5 cm3 of dichloromethane, at a temperature in the region of 20° C. The reaction medium is stirred at room temperature for 24 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up in 4 cm3 of water and is then neutralized with 1N sodium hydroxide to pH 10. 12 cm3 of dichloromethane are added. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. 0.008 g of 1-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]azetidin-3-ylamine is obtained, the characteristics of which are as follows: