Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[F:20])[CH3:10])=[CH:4][N:3]=1.[C:21]([C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1)#[N:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:9]([N:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[F:20])[C:30]([NH:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([C:21]#[N:22])[CH:24]=2)=[O:31])[CH3:10])=[CH:4][N:3]=1
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: COc1ccc(NC(C)c2cnc(Cl)nc2Cl)c(F)c1
Solvent: Cc1ccccc1
Product: COc1ccc(N(C(=O)Nc2cccc(C#N)c2)C(C)c2cnc(Cl)nc2)c(F)c1
Temperature: 25 °C

Procedure:
(±)-[1-(2,4-Dichloro-pyrimidin-5-yl)-ethyl]-(2-fluoro-4-methoxy-phenyl)-amine (1.15 g; 3.63 mmol) (from Example 8b supra) was combined with 3-cyanophenyl isocyanate (0.55 g; 3.81 mmol) (Aldrich) in toluene (10 mL) and heated in an oil bath at 110–115° C. for 2 hours and then up to 128° C. over the next 3 hours. Upon cooling to room temperature, the reaction was concentrated and triturated with hexanes. The crude material was purified by flash chromatography (Biotage, 40M; 50:50 ethyl acetate-hexanes) to give the intermediate (±)-1-[1-(2-chloro-pyrimidin-5-yl)-ethyl]-3-(3-cyano-pheny)-1-(2-fluoro-4-methoxy-phenyl)-urea. (Yield 1.20 g; 71.8%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([CH2:12][C:13]([OH:15])=[O:14])[CH:8]2O)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:21]O>>[CH3:21][O:15][C:13](=[O:14])[CH2:12][C:7]1[CH2:6][C:5]2[C:9]([CH:8]=1)=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2
Reactant: O=C(O)CC1Cc2ccc(Br)cc2C1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CC1=Cc2cc(Br)ccc2C1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
The product from Example 52B (1.35 g, 5 mmol) in methanol (12 mL) was treated with concentrated sulfuric acid (2 mL) and heated to gentle reflux. After 2 hours, additional sulfuric acid was added (1 mL) and heating was continued for another 2 hours. The mixture was concentrated under vacuum and the residue was diluted with water (15 mL). The mixture was cooled to 10° C., filtered, and the filter cake washed with water (5 mL) and dried to provide the title compound. 1H NMR (CDCl3) δ 3.42 (s, 2H); 3.55 (s, 2H); 3.74 (s, 3H); 6.65 (m, 1H); 7.22-7.31 (m, 2H), 7.44 (m, 1H).
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[CH:40]=[C:41]4[C:45](=[CH:46][CH:47]=3)[CH2:44][CH2:43][CH2:42]4)[CH:32]=2)[O:11][C@@H:10]1[CH2:48][O:49]CC1C=CC=CC=1)C1C=CC=CC=1.CO>C1COCC1.[Pd]>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C@H:12]2[C@H:13]([OH:23])[C@@H:14]([OH:15])[C@H:9]([OH:8])[C@@H:10]([CH2:48][OH:49])[O:11]2)=[CH:32][C:33]=1[CH2:38][C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[CH2:44][CH2:43][CH2:42]2
Reactant: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc2c(c1)CCC2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)CCC4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 2 h
Yield: 17.9 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(4-chloro-3-((2,3-dihydro-1H-inden-5-yl)methyl)phenyl)-tetrahydro-2H-pyran (122) (425 mg, 0.56 mmol) in THF:MeOH(v/v=1:1)(8 mL) at room temperature was added Pd/C. The mixture was stirred under H2 for 2 h, Pd/C was removed by filtration and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC to furnish the title compound (42 mg, 0.10 mmol, 18%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([CH3:18])[N:10]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=4)[CH:17]=3)=[C:11]([CH3:18])[N:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1-c1c[nH]cn1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(F)(F)F)cn2)cn1
Temperature: 120 °C
Yield: 61.4 %

Procedure:
A mixture of 1-(4-fluoro-phenyl)-5-(1H-imidazol-4-yl)-4-methyl-1H-[1,2,3]triazole (100 mg, 0.411 mmol), 2-chloro-5(trifluoromethyl)pyridine (75 mg, 0.411 mmol) and potassium carbonate (114 mg, 0.82 mmol) in DMF (2.0 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 48 h. After cooling to room temperature the mixture was poured into water and the solid that formed was filtered off and purified by chromatography (silica, 0 to 100% ethyl acetate in heptane) to afford the title compound (98 mg, 60%) as a white solid. MS: m/e=389.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:24])[C:5]([OH:23])=[C:6]([C:8](=[N:16][CH:17]=[CH:18][CH2:19][C:20](O)=[O:21])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:7]=1.C(N1C=CN=C1)([N:27]1C=CN=C1)=O.N>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:24])[C:5]([OH:23])=[C:6]([C:8](=[N:16][CH:17]=[CH:18][CH2:19][C:20]([NH2:27])=[O:21])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:7]=1
Reactant: Cc1cc(Cl)cc(C(=NC=CCC(=O)O)c2ccc(Cl)cc2)c1O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C(=NC=CCC(N)=O)c2ccc(Cl)cc2)c1O
Reaction time: 2 h

Procedure:
To 3.3 g of the acid obtained in Example 1, dissolved in 100 ml of tetrahydrofuran (THF), 1.6 g of carbonyldiimidazole is added and the mixture is stirred for 2 hrs. A solution is prepared of ammonia gas in 250 ml of anhydrous THF, into which the first solution obtained is introduced slowly. The mixture is stirred for 3 h and left to stand overnight. It is evaporated to dryness under reduced pressure and the residue is distributed between 150 ml of CH2Cl2 and 100 ml of water. The organic phase is decanted, dried over MgSO4, filtered and evaporated to dryness. An oil is obtained which is purified by chromatography on silica (eluent: ethyl acetate). The 3 final fractions containing the products are dried over MgSO4. The fractions are filtered and the filtrates evaporated to dryness. One of the 3 residues obtained, a mixture of both cis (32%) and trans (68%) isomers, is recrystallised in a mixture of ether and petroleum ether.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]12([N:14]=[C:15]=[S:16])[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2>CCO>[C:4]12([NH:14][C:15](=[S:16])[NH:2][NH2:3])[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2
Reactant: S=C=NC12CC3CC(CC(C3)C1)C2
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=S)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
A solution of 1.5 g (0.03 mol) of hydrazine hydrate in 50 mL of EtOH was treated with 3.86 g (0.02 mol) of 1-adamantyl isothiocyanate, and stirred for 1 hr at room temp. The product was collected and washed 2 times with EtOH, affording 4.33 g (96%) of 4-(1-adamantyl)-3-thiosemicarbazide, mp 206°-207° C. dec. This thiosemicarbazide is disclosed in Chemical Abstracts, 70:11223 (1969); and in U.S. Pat. No. 3,406,180.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1.[N:39]1([CH2:45][CH2:46][OH:47])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:38])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:42]3[CH2:43][CH2:44][N:39]([CH2:45][CH2:46][OH:47])[CH2:40][CH2:41]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:31])([CH3:32])[C:33]#[N:34])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1
Reactant: OCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCO)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-ethanol (Chemical Dynamics) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). LR-MS: 662.2 [(M+H)+]
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[CH3:15])C>ClC1C=CC=CC=1.O>[CH3:15][C:8]1[C:7]2[S:6][CH:5]=[CH:4][C:12]=2[CH:11]=[C:10]([O:13][CH3:14])[CH:9]=1
Reactant: CCOC(CSc1ccc(OC)cc1C)OCC
Solvent: Clc1ccccc1
Solvent: O
Product: COc1cc(C)c2sccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
To the hot (130° C.) solution of polyphosphoric acid (20 mL) in chlorobenzene (50 mL) was added dropwise a solution of 1-(2,2-diethoxy-ethylsulfanyl)-4-methoxy-2-methyl-benzene from step 2 (6.8 g, 0.025 mol) in chlorobenzene (25 mL) over a period of 2 h and stirred for 2 h at same temperature. The reaction mixture was cooled to room temperature and stirred for 12 h. The mixture was then cooled and diluted with water and the layers were separated. The aqueous layer was extracted in ethyl acetate. The combined organic layers were washed with water, dried and concentrated. The crude material was purified by chromatography (silica gel: hexane:ethyl acetate/4:1) to provide 2 g of 7-methyl-5-methoxy benzothiophene. MS m/z 178 (M+).
Reaction SMILES: [CH:1]1([N:6]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:15])[CH:12]=3)[C:7]2=[O:16])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][C:25]1[CH:26]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([C:38]([O:40][CH3:41])=[O:39])[CH:32]=2)[CH:28]=[CH:29][CH:30]=1>CC(C)=O>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][O:15][C:11]3[CH:12]=[C:13]4[C:8](=[CH:9][CH:10]=3)[C:7](=[O:16])[N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH2:14]4)[CH:26]=2)=[CH:32][C:33]=1[C:38]([O:40][CH3:41])=[O:39]
Reactant: COC(=O)c1cc(-c2cccc(CBr)c2)ccc1Cl
Reactant: O=C1c2ccc(O)cc2CN1C1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(-c2cccc(COc3ccc4c(c3)CN(C3CCCC3)C4=O)c2)ccc1Cl

Procedure:
To a solution of 2-cyclopentyl-5-hydroxyisoindolin-1-one (50 mg, 0.23 mmol) in acetone (15 mL), K2CO3 (181 mg, 1.31 mmol) was added methyl 3′-(bromo-methyl)-4-chlorobiphenyl-3-carboxylate (92 mg, 0.27 mmol) and the mixture was heated at reflux for 1 h. The reaction mixture was filtered and the solvent was evaporated in vacuo to obtain methyl 4-chloro-3′-((2-cyclopentyl-1-oxoisoindolin-5-yloxy)methyl)biphenyl-3-carboxylate as a yellow oil.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CC(C)([O-])C.[K+].[F:18][C:19]1([F:24])[CH2:21][CH:20]1[CH:22]=O>C1COCC1>[F:18][C:19]1([F:24])[CH2:21][CH:20]1[CH:22]=[CH:3][C:1]#[N:2]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=CC1CC1(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC=CC1CC1(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of diethyl cyanomethylphosphonate (4.09 g; 23.1 mmol) in dry THF (200 mL) at 0° C. under nitrogen was added potassium t-butoxide (23.1 mmol; 1M solution in THF). The mixture was stirred for 1 hour. The solution of 2,2-difluorocyclopropanecarbaldehyde from Step A was added and the mixture was stirred while allowing to warm to ambient temperature. A portion of the solvent was removed under reduced pressure and the remaining solution was diluted with ammonium chloride solution (50 mL). The mixture was extracted into ethyl acetate (2×50 mL). The combined extracts were dried (magnesium sulfate and sodium sulfate), filtered and evaporated under reduced pressure. The material was purified by chromatography on silica gel, eluting with hexane/ethyl acetate (3:1) to give 3-(2,2-difluorocyclopropyl)acrylonitrile (0.50 g) as a pale yellow oil (containing some ethyl acetate).
Reaction SMILES: CS(O)(=O)=O.[CH3:6][CH:7]1[C:12](=[O:13])[CH2:11][CH2:10][O:9][CH2:8]1.[N-:14]=[N+]=[N-].[Na+]>COCCOC>[CH3:6][CH:7]1[NH:14][C:12](=[O:13])[CH2:11][CH2:10][O:9][CH2:8]1
Reactant: CC1COCCC1=O
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: COCCOC
Product: CC1COCCC(=O)N1
Temperature: 23 °C
Reaction time: 20 h

Procedure:
Methanesulfonic acid (20 mL) was added to a solution of 3-methyltetrahydro-4H-pyran-4-one (4-1, prepared by the method of Smith, A. B. et al. J. Am. Chem. Soc. 1991, 113, 2071, 3.00 g, 26.3 mmol, 1 equiv) in DME (30 mL) at −40° C. Sodium azide (5.13 g, 79.0 mmol, 3.00 equiv) was added in four equal portions over 30 min as cooling was maintained. The cold bath was then removed and the reaction mixture was warmed to 23° C. and stirred for 20 h. The mixture was diluted with DME (20 mL) and basified to pH 9 with concentrated aqueous ammonium hydroxide solution. The resulting mixture was partitioned between brine (200 mL) and a solution of 10% n-propanol in ethyl actetate (2×400 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 3-methyl-1,4-oxazepan-5-one (4-2) as a pasty white solid. 1H NMR (300 MHz, CDCl3) δ 5.73 (br s, 1H), 3.97 (ddd, 1H,J=12.4, 5.6, 2.8 Hz), 3.83 (d, 1H,J=12.2 Hz), 3.76 (m, 1H), 3.66 (dd, 1H,J=12.4, 10.8 Hz), 3.35 (dd, 1H, J=12.2, 8.2 Hz), 2.89 (ddd, 1H,J=15.8, 10.8, 2.8 Hz), 2.54 (dd, 1H,J=15.8, 5.6 Hz), 1.15 (d, 3H,J=7.1 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[C:11]2[NH:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Cc1ccc(C(=O)O)c2cccnc12
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(C(=O)O)c2c1NCCC2
Reaction time: 48 h

Procedure:
0.1 mol of 8-methylquinoline-5-carboxylic acid was suspended in 1.5 l of ethanol and admixed with 10.0 g of palladium on activated carbon (5%). Over a period of 48 hours, the mixture was reduced in an autoclave at 50° C. using hydrogen (1 bar) (HPLC control). The reaction mixture was then filtered, the filter cake was washed with ethanol and the combined organic filtrates were concentrated.
Reaction SMILES: [OH:1][CH:2]([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].CCN(CC)CC.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:20][S:21]([O:1][CH:2]([CH3:12])[CH2:3][NH:4][C:5]([O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:11])(=[O:23])=[O:22]
Reactant: CC(O)CNC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CNC(=O)OC(C)(C)C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a solution of tert-butyl 2-hydroxypropylcarbamate (14.3 g, 81.7 mmol) and Et3N (35.6 ml, 245.1 mmol) in CH2Cl2 (250 mL) at 0° C. was slowly added a solution of methanesulfonyl chloride (9.5 mL, 122.6 mmol) in CH2Cl2 (250 mL). The mixture was stirred at 0° C. for 2 h, diluted with CH2Cl2 (300 mL) and washed with water, 1 N HCl, 5% NaHCO3 and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure to afford 1-(tert-butoxycarbonylamino)propan-2-yl methanesulfonate (19.5 g, 94%) as a light yellow oil. Mass calculated for C9H19NO5S=253.32; found: [M+H]+=254.2.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[CH3:7][O:8][CH2:9][O:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]([O:18][CH2:19][O:20][CH3:21])[C:12]=1[C:22](=[CH2:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>CS(C)=O>[CH3:7][O:8][CH2:9][O:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]([O:18][CH2:19][O:20][CH3:21])[C:12]=1[C:22]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:2][CH2:28]1
Reactant: C=C(C(=O)OCC)c1c(OCOC)ccc(C)c1OCOC
Reactant: C[S+](C)(C)=O
Agent: [I-]
Solvent: CS(C)=O
Product: CCOC(=O)C1(c2c(OCOC)ccc(C)c2OCOC)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a solution of trimethylsulfoxonium iodide (4.4 g, 20 mmol) in dry dimethyl sulfoxide (30 mL) sodium hydride (60% dispersion in mineral oil) (0.720 g, 18 mmol) was added and the reaction mixture was stirred for 1 hour at room temperature. A solution of ethyl 2-[2,6-bis(methoxymethoxy)-3-methyl-phenyl]prop-2-enoate (Intermediate 9, 3.5 g, 11.29 mmol) in dry dimethyl sulfoxide (15 mL) was slowly added and the reaction mixture was stirred for 1 hour at room temperature. The reaction was quenched with an aqueous saturated solution of ammonium chloride (10 ml), diluted with water (40 ml) and extracted with ethyl acetate (2×100 ml). The organic layer was washed with water (2×50 ml), dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a 100 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 8:2 as eluents affording the title compound (3.1 g) as a colourless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([OH:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].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>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22][C:30]2[CH:31]=[CH:32][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:28][CH:29]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(C(C)(C)C)cc1
Yield: 41.7 %

Procedure:
In a similar manner to that described in Example 122, a reaction was carried out using ethyl 3-(4-benzyloxyphenyl)lactate (5.00 g), which is the product of Reference example 1(b), 4-t-butylphenol (2.50 g), triphenylphosphine (5.24 g) and a solution of diethylazodicarboxylate in toluene (40%, 8.80 ml) and the reaction mixture was treated to afford the desired compound (3.00 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[N:4][C:5]([CH2:8]O)=[CH:6][CH:7]=1.[BrH:16].C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)C>[CH3:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[N:4][C:5]([CH2:8][Br:16])=[CH:6][CH:7]=1
Reactant: Br
Reactant: Cc1ccc(CO)nc1-c1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(CBr)nc1-c1ccccn1

Procedure:
0.9 g (4.5 mmols) of 3-methyl-6-hydroxymethyl-2,2'-bipyridine are boiled under reflux for 6 hours, together with 5 ml of 62% hydrobromic acid. After cooling, 10 ml of water and 20 ml of diethyl ether are added. The water phase is rendered alkaline with potassium carbonate, separated from the ether phase and washed with a further 10 ml of diethyl ether. The combined ether phases are dried over sodium sulfate and concentrated to dryness in vacuo (maximum bath temperature: 30° C.). 1.16 g (98% of theory) of 3-methyl-6-bromomethyl-2,2'-bipyridine remains as an oily product which decomposes at room temperature, giving a red colouration, and crystallises at 0° C. The 3-methyl-6-bromomethyl-2,2'-bipyridine is immediately used further.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:5](/[CH:14]=[CH:15]\OCC)=[CH:4][N:3]=1.Cl>CCO>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:14]=[CH:15][N:8]([CH:9]([CH2:10][CH3:11])[CH2:12][CH3:13])[C:6]=2[N:7]=1
Reactant: CCO/C=C\c1cnc(Cl)nc1NC(CC)CC
Agent: Cl
Solvent: CCO
Product: CCC(CC)n1ccc2cnc(Cl)nc21
Temperature: 100 °C

Procedure:
To a solution of [2-Chloro-5-((Z)-2-ethoxy-vinyl)-pyrimidin-4-yl]-(1-ethylpropyl)-amine (1.1 g, 4.07 mmol) in EtOH (8 mL) is added concentrated HCl (0.1 mL) at ambient temperature. The reaction mixture is sealed in a microwave reactor and heated at 100° C. for 10 mins. After cooling down the mixture is concentrated in vacuo to provide 2-Chloro-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine. The crude product is used as it is. The material can be purified by flash chromatography (SiO2, EtOAc:Hexane=1:5).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[O:27].NC(N)=O>>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:19]2[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=2[F:17])=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=Nc1ccc(F)cc1F
Agent: NC(N)=O
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1c(Br)cnn1C

Procedure:
reacting 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with 2,4-difluorophenyl-isocyanate in the presence of a urea-forming solvent to form 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.
Reaction SMILES: [ClH:1].CO[C:4](=O)[CH:5]([NH2:10])[CH2:6][CH2:7][C:8]#[CH:9].[N:12]#[C:13][NH2:14]>>[ClH:1].[CH2:6]([C:5]1[N:10]=[C:13]([NH2:14])[NH:12][CH:4]=1)[CH2:7][C:8]#[CH:9]
Reactant: C#CCCC(N)C(=O)OC
Reactant: N#CN
Agent: Cl
Product: C#CCCc1c[nH]c(N)n1
Yield: 48 %

Procedure:
2-Amino-hex-5-ynoic acid methyl ester hydrochloride (2.53 g, 14.2 mmol) was treated to an Akabori reduction followed by a cyanamide condensation employing conditions previously reported to produce 4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (1.17 g, 48%) as a pale yellow oil (Olofson et al., Journal of Organic Chemistry 1997, 62, (23), 7918-7919). 1H NMR (300 MHz, CD3OD) δ 6.52 (s, 1H), δ 2.61 (t, 2H), δ 2.42 (m, 2H), δ 2.27 (t, 1H) ppm; 13C NMR (75 MHz, CD3OD) δ 147.4, 126.2, 109.4, 81.9, 69.9, 23.8, 17.4 ppm; HRMS (ESI) calcd for C7H10N3 (M+) 136.0869, found 136.0865.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].[C:20]([O:24][C:25]([NH:27][C:28]1[CH:39]=[CH:38][CH:37]=[CH:36][C:29]=1[CH2:30]OS(C)(=O)=O)=[O:26])([CH3:23])([CH3:22])[CH3:21].C([O-])([O-])=O.[K+].[K+].C1CCN2C(=NCCC2)CC1>CO>[C:20]([O:24][C:25](=[O:26])[NH:27][C:28]1[CH:39]=[CH:38][CH:37]=[CH:36][C:29]=1[CH2:30][N:4]1[C:5]2[C:10](=[CH:9][C:8]([NH2:11])=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=2)[C:2]([CH3:1])([CH3:19])[C:3]1=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1COS(C)(=O)=O
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccccc1CN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Yield: 115.6 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (0.55 g) is alkylated using methanesulfonic acid 2-tert-butoxycarbonylamino-benzyl ester (0.69 g; 2.09 mmol) and K2CO3 (0.99 g; 7.19 mmol) at RT for 18 h. After aqueous work-up the crude material is de-acetylated in MeOH (50 ml) using DBU (0.3 ml) at reflux. After aqueous work-up [2-(5-amino-3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-indol-1-ylmethyl)-phenyl]-carbamic acid tert-butyl ester (1.03 g) is obtained and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[Br:18])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(C(Br)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a solution of bis(4-chlorophenyl)methanol (2.0 g) and carbon tetrabromide (5.2 g) in tetrahydrofuran (30 ml) was added triphenylphosphine (4.2 g). The mixture was stirred at room temperature for 1 hours. After the mixture was filtered off, the solvent was removed in vacuo. The residue was dissolved in n-hexane (30 ml) and filtered off. The filtrate was evaporated and the residue was purified by distillation at reduced pressure to give bis(4-chlorophenyl)bromomethane as an oil (2.43 g).