Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:49][N:50]2[CH:54]=[N:53][CH:52]=[N:51]2)[O:13][CH:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH:38]=[N:37][N:36]([CH:39]([CH3:47])[CH:40](OS(C)(=O)=O)[CH3:41])[C:35]5=[O:48])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH2:11][O:10]1.[N-:55]=[N+:56]=[N-:57].[Na+].O>CN(C=O)C>[N:55]([CH:40]([CH3:41])[CH:39]([N:36]1[C:35](=[O:48])[N:34]([C:31]2[CH:32]=[CH:33][C:28]([N:25]3[CH2:24][CH2:23][N:22]([C:19]4[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH:12]5[CH2:11][O:10][C:9]([C:3]6[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=6[F:1])([CH2:49][N:50]6[CH:54]=[N:53][CH:52]=[N:51]6)[O:13]5)=[CH:17][CH:18]=4)[CH2:27][CH2:26]3)=[CH:29][CH:30]=2)[CH:38]=[N:37]1)[CH3:47])=[N+:56]=[N-:57]
Reactant: CC(OS(C)(=O)=O)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(N=[N+]=[N-])C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Temperature: 85 °C
Reaction time: 48 h

Procedure:
A mixture of [2S-[2α,4α(S*,S*)]]-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[1-methyl-2-[(methylsulfonyl)oxy]propyl]-3H-1,2,4-triazol-3-one (0.0039 mol) and NaN3 (0.005 mol) in DMF (50 ml) was stirred at 85° C. for 48 hours, poured out into H2O and stirred for 30 minutes. The precipitate was filtered off and dissolved in CH2Cl2. The organic solution was washed, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/2). The pure fractions were collected and the solvent was evaporated. The residue was triturated in DIPE and 2-propanol, filtered off and dried, yielding 1.1 g (41%) of [2S-[2α,4α(R*,S*)]]-2-(2-azido-1-methylpropyl)-4-[4-[4-[4-[[2-(2,4difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]-phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one; (compound 19).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[CH:23][C:22]([CH2:25][CH2:26][CH3:27])=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:11][CH2:12][N:13]([C:19]4[N:24]=[CH:23][C:22]([CH2:25][CH2:26][CH3:27])=[CH:21][N:20]=4)[CH2:14][CH2:15]3)[S:8][C:4]=2[CH:3]=1
Reactant: Brc1ccc2nc(OC3CCNCC3)sc2c1
Reactant: CCCc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cnc(N2CCC(Oc3nc4ccc(Br)cc4s3)CC2)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of 6-bromo-2-(piperidin-4-yloxy)benzo[d]thiazole (10 g, 31.9 mmol) and 2-chloro-5-propylpyrimidine (7.5 g, 47.9 mmol) in DMF (150 mL) was added potassium carbonate (17.65 g, 128 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was cooled to rt, diluted with water (300 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by chromatography (silica gel, hexanes-EtOAc gradient 0 to 50% EtOAc) to afford 6-bromo-2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazole (11.9 g, 27.5 mmol, 86% yield) as a white solid. 1H NMR (500 MHz, chloroform-d) δ ppm 8.17 (2H, s), 7.77 (1H, d, J=1.9 Hz), 7.52-7.55 (1H, m), 7.45-7.49 (1H, m), 5.41-5.49 (1H, m), 4.23 (2H, ddd, J=13.4, 6.8, 4.0 Hz), 3.62-3.74 (2H, m), 2.42 (2H, t, J=7.6 Hz), 2.14-2.23 (2H, m), 1.89-1.99 (2H, m), 1.56-1.63 (2H, m), 0.95 (3H, t, J=7.4 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[CH2:16][CH2:17][CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([Cu])#[N:30].C(N)CN.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:29]#[N:30])=[CH:11][C:10]=1[CH2:16][CH2:17][CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(CCCc2cc(Br)ccc2OCc2ccccc2)cc1
Reactant: N#C[Cu]
Solvent: O
Solvent: NCCN
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCCc2cc(C#N)ccc2OCc2ccccc2)cc1
Yield: 66.1 %

Procedure:
A mixture of methyl 4-[3-(2-benzyloxy-5-bromophenyl)propyl]-benzoate (0.5 g) and CuCN (250 mg) in DMF (20 ml) was heated at reflux for 18 hours, poured into ethylene diamine (20 ml) and water (60 ml) and extracted with ethyl acetate (3×100 ml). The combined extracts were washed with brine (100 ml), dried (magnesium sulphate), filtered and evaporated to give methyl 4-[3-(2-benzyloxy-5-cyanophenyl)propyl]-benzoate (290 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:4]=1[C:5]#[N:6].[CH3:13][O-:14].[Na+]>CO.CCOC(C)=O>[Cl:12][C:7]1[CH:8]=[C:9]([Cl:11])[CH:10]=[C:3]([CH2:2][O:14][CH3:13])[C:4]=1[C:5]#[N:6]
Reactant: N#Cc1c(Cl)cc(Cl)cc1CBr
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COCc1cc(Cl)cc(Cl)c1C#N
Temperature: 50 °C

Procedure:
To a suspension of 2-(bromomethyl)-4,6-dichlorobenzonitrile (1.04 mmol) (A.2.2.1.) in 2.5 mL MeOH was added a solution of NaOMe (1.27 mmol, 0.5M in MeOH). The reaction mixture was heated to 50° C. for 1 h. The mixture was conc. in vacuo, redissolved in EtOAc and it was then washed twice with an aq. soln. of KHSO4, twice with a sat. aq. NaHCO3 soln. and once with brine. The org. layer was dried over MgSO4 and conc. in vacuo to give the desired product as orange oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])[CH2:6][CH3:7])[CH3:2].[CH:18]1([CH:21]([C:23]2[S:27][C:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[N:25][C:24]=2[CH3:38])O)[CH2:20][CH2:19]1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:21]([CH:18]2[CH2:19][CH2:20]2)[C:23]2[S:27][C:26]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:32][CH:33]=3)=[N:25][C:24]=2[CH3:38])=[CH:11][C:10]=1[CH3:16])[CH2:6][CH3:7])[CH3:2]
Reactant: CCOC(=O)C(CC)Cc1ccc(O)cc1C
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(CC)Cc1ccc(OC(c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)C2CC2)cc1C

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-(4-hydroxy-2-methyl-benzyl)-butyric acid ethyl ester (example 125 c]) was reacted with [rac]-cyclopropyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol (example 121 a]) in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield 2-(4-{cyclopropyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methoxy}-2-methyl-benzyl)-butyric acid ethyl ester as a mixture of two diastereomeric racemates as light yellow liquid.
Reaction SMILES: O1CCOCC1.[Cl:7][CH:8]1[C:13](Cl)([NH2:14])[CH:12]=[N:11][CH:10]=[N:9]1.[CH3:16][NH2:17]>O>[Cl:7][C:8]1[N:9]=[CH:10][N:11]=[C:12]([NH:17][CH3:16])[C:13]=1[NH2:14]
Reactant: NC1(Cl)C=NC=NC1Cl
Reactant: CN
Solvent: C1COCCO1
Solvent: O
Product: CNc1ncnc(Cl)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
A 50 mL 3-necked flask fitted with a thermometer was charged with 1,4-dioxane (20 mL) and 4,5-dichloropyrimdine-5-amine (5.00 g, 30.5 mmol). The reaction mixture was then stirred for 30 minutes at room temperature to ensure complete dissolution of the 4,5-dichloropyrimidine-5-amine, after which a solution of methylamine in water (40% by weight, 120 mmol, 9.3 mL) was added over a period of 30 minutes by means of a pressure-equalized dropping funnel. Upon completion of addition, the dropping funnel was replaced with a reflux condenser. The stirred reaction mixture was then heated to 75° C. over a period of 40 minutes, and the progress was monitored by LCMS. The reaction was complete after 16 hours. The resulting mixture was then cooled to 50° C. and poured into 120 mL of ice and water (approximetely 1:1 by volume), which resulted in the rapid precipitation of a solid. The resulting suspension was then for a period of 2 hours. The precipitated solids were collected by vacuum filtration, washed with ice-cold water (20 mL) and dried on the filter to give 4.76 g (98.4% yield) of 6-chloro-N4-methylpyrimidine-4,5-diamine as a light yellow solid. This material was submitted to the next step without further purification. 1H-NMR (400 MHz, DMSO-d6): δ 7.73 (s, 1H), 6.87 (d, 1H), 4.94 (broad s, 2H), 2.86 (d, 3H). MS (EI) for C5H7ClN4: 159 (MH+).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH:14]3[CH:12]([C:13]3([C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)[CH3:16])[CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH:14]3[CH:12]([C:13]3([C:17]3[CH:18]=[C:19]([NH:23][S:31]([CH3:30])(=[O:33])=[O:32])[CH:20]=[CH:21][CH:22]=3)[CH3:16])[CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2cccc(N)c2)C2CN(CCCC3CCCCC3)CC21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(CCCC3CCCCC3)CC21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.6 %

Procedure:
To a solution of 3-[3-(3-cyclohexylpropyl)-6-methyl-3-azabicyclo[3.1.0]-hex-6-yl]phenylamine (Preparation 10, 25 mg, 0.08 mmol) in dichloromethane (2 ml) at 0° C. under nitrogen was added pyridine (20 μl, 0.24 mmol) then dropwise over 5 minutes methanesulfonylchloride (25 μl, 37 mg, 0.32 mmol). The mixture was allowed to warm to room temperature and was stirred for 90 minutes. Further methanesulfonylchloride (10 μl, 15 mg, 0.13 mmol) was added and the mixture was stirred for 1 hour. The mixture was concentrated in vacuo and the residue was purified by silica (5 g) column chromatography eluting with 80:20:1 ethyl acetate:hexane:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (18 mg, 58%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:16]2[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][N:8]=1.[Cl:23][C:24]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:29][C:25]=1[C:26](O)=[O:27].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:29][C:25]=1[C:26]([NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[N:10]=[CH:9][N:8]=[C:7]2[O:6][C:5]1[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=1)=[O:27]
Reactant: Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)ncnc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4cccc(C(F)(F)F)c4)ncnc23)c1
Yield: 32.8 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(3-(trifluoromethyl)phenoxy)quinazolin-8-amine (Intermediate-8, 50 mg, 0.164 mmol), 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-5, 88 mg, 0.326 mmol), oxalyl chloride (59 mg, 0.47 mmol), DMF (1 drop) and DIPEA (63 mg, 0.49 mmol) in CH2Cl2 (2 mL) to afford 30 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.35 (s, 1H), 8.92 (d, 1H), 8.77 (s, 1H), 8.13 (d, J=7.8 Hz, 1H), 7.85 (m, 2H), 7.73 (s, 3H), 7.59-7.53 (m, 2H), 7.39 (d, J=7.2 Hz, 1H), 4.29 (d, J=5.4 Hz, 2H), 1.11 (s, 9H); MS [M+H]+: 557.14.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.C1(C)C=CC=CC=1.ClS([N:26]=[C:27]=[O:28])(=O)=O>O>[Cl:1][C:2]1[C:7]([NH:8][C:27]([NH2:26])=[O:28])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: NC(=O)Nc1c(Cl)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
370 Parts of 6-chloro-2,4-dinitroaniline are stirred for 4 hours at 80° C. in 2600 parts of toluene with 312 parts of chlorosulfonyl isocyanate. At 25° C., 360 parts of water are added to the resulting suspension of N-6-chloro-2,4-dinitrophenyl-N'-chlorosulfonyl urea without intermediate isolation, and the mixture is saponified at 60° C. within 4 hours to yield 6-chloro-2,4-dinitrophenyl urea. After diluting said mixture with water, it is neutralized with 33% sodium hydroxide solution, filtered while hot, and the product is thoroughly washed with hot toluene and water. After drying in vacuo, there are obtained 383 parts of 6-chloro-2,4-dinitrophenyl urea having a melting point of from 219° to 221° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].O=S(Cl)[Cl:13]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1F
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccccc1F
Temperature: 50 °C
Yield: 69.8 %

Procedure:
To 100 mL of toluene were added 0.714 mol of 2-fluorobenzoic acid (100 g) then the mixture was heated to 50° C. and added 5.7 mol (414 mL) sulfoxide chloride. The reaction mixture was refluxed for 7 h. After completion of the reaction, sulfoxide chloride was evaporated to give 2-fluorobenzoyl chloride 79 g. Yield: 70%.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][OH:6])=[CH2:2].C(N(CC)CC)C.[C:14](Cl)(=[O:16])[CH3:15].C(OCC)C>O>[CH:1]([O:3][CH2:4][CH2:5][O:6][C:14]([CH3:15])=[O:16])=[CH2:2]
Reactant: C=COCCO
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: C=COCCOC(C)=O

Procedure:
In a 1 L three neck flask fitted with a thermometer, a dropping funnel and a mechanical stirrer, there was added 1 mol (81.0 g) of ethylene glycol monovinyl ether and 1.05 mol (106.26 g) of triethylamine and 300 mL of tetrahydrofuran(THF). The mixture was cooled to 10°-15° C. using an ice-bath. To the cooled solution, there was added 1.05 mol (84.93 g) of acetyl chloride drop by drop over two hours such that the temperature of the reaction mixture was maintained below 15° C. and the reaction mixture was stirred constantly. After 10 hours of reaction, 500 mL of diethyl ether followed by 500 mL of deionized water was added to the reaction mixture. The organic layer was washed three times with 300 mL of deionized water, and dried using anhydrous magnesium sulfate for 24 hours. The dried organic layer was separated by filtration and diethyl ether was distilled off to obtain the crude product. It was purified by two subsequent distillations under reduced pressure. The compound has a boiling point of 33°-35° C./1 torr, 115°-116° C./20 torr. The yield after purification was 110.7 g (90%). The compound was characterized by IR and NMR. The infrared spectrum shows a strong peak at 1745 cm-1 (νc=0) and the NMR spectra has signals at2.1 ppm(3H), 3.89 ppm(2H), 4.05 ppm(1H), 4.22 ppm(1H), 4.3 ppm(2H), and 6.25 ppm(1H) confirming that the isolated compound is indeed 2-methanecarbonyloxyethyl vinyl ether.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]=[C:16]([NH:20][NH2:21])[C:15]=3[CH2:22][CH2:23][CH3:24])[CH:10]=[CH:11][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.BrBr.[CH3:35]CO>>[F:1][C:2]1[C:3]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:35][N:20]4[N:21]=[C:18]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[N:17]=[C:16]4[C:15]=3[CH2:22][CH2:23][CH3:24])[CH:10]=[CH:11][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: CCCc1c(Cn2ccnc2-c2ncccc2F)ncnc1NN
Reactant: O=Cc1ccccc1
Agent: BrBr
Product: CCCc1c(Cn2ccnc2-c2ncccc2F)ncn2nc(-c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of {6-[2-(3,-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-propyl-pyrimidin-4-yl}-hydrazine (131) (60 mg, 0.18 mmol), benzaldehyde (21 mg, 0.2 mmol) in EtOH is refluxed for 4 hours. Solvent is removed in vacuo. HOAc (2 mL) is added to the residue, and then bromine (0.3 mmol) is slowly added. The mixture is stirred at room temperature overnight. Solvent is removed in vacuo and the residue is treated with NaHCO3 (aq) and DCM. The organic layer is separated and the aqueous layer is extracted with DCM (2×0 mL). The combined organic layers are dried (MgSO4), the solvent is removed, and the crude purified by PTLC (10% MeOH in DCM) to give a white solid; 1H-NMR (CDCl3) δ: 8.93 (s, 1H), 8.44 (dd, 1H), 7.78–7.88 (m, 2H), 7.51–7.63 (m, 4H), 7.22–7.36 (m, 3H), 5.82 (s, 2H), 3.05 (q, 2H), 1.70–1.80 (m, 2H), 1.02 (t, 3H).
Reaction SMILES: O[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:13].P(Cl)(Cl)(Cl)=O>>[Cl:13][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1ccnc(O)c1[N+](=O)[O-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccnc(Cl)c1[N+](=O)[O-]

Procedure:
A mixture of 25 g of 2-hydroxy-4-methyl-3-nitropyridine, 12.5 g of phosphorous pentachloride, and 62 ml of phosphorous oxychloride was refluxed for 2 hrs. After cooling, the mixture was poured onto crashed ice and stirred until a precipitate formed. The product was extracted with methylene chloride, dried (sodium sulfate) and concentrated to a brown oil, which was washed with hot hexane. Concentration in vacuo provided 16.2 g of the the title compound, m.p. 45°-47° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[C:21]([O:26][CH3:27])=[C:22]([F:25])[CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.[ClH:29]>CO.O1CCOCC1>[ClH:29].[ClH:29].[F:25][C:22]1[CH:23]=[CH:24][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:13]=2[C:21]=1[O:26][CH3:27]
Reactant: COc1c(F)ccc2nc([C@H](C)NC(=O)OC(C)(C)C)n(-c3ccccc3)c12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1c(F)ccc2nc([C@H](C)N)n(-c3ccccc3)c12
Yield: 100 %

Procedure:
[(S)-1-(6-Fluoro-7-methoxy-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (349 mg, 0.91 mmol) was dissolved in methanol (1 mL) and hydrochloric acid in dioxane (3 mL, 4M) and the reaction stirred at RT for 1 hour. The reaction mixture was concentrated in vacuo to yield the title compound as an off-white solid (321 mg, 100%). LCMS (Method C): RT=2.02 min, [M+H]+=286.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([F:22])[CH:9]=2)=[N:6][CH:7]=1.[Na+].[CH3:24][S:25]([O-:27])=[O:26].[OH-].[Na+].O>CS(C)=O>[F:22][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:7][N:6]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CS(=O)[O-]
Reactant: Fc1cc(-c2ccc(Br)cn2)ccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2ccc(OCc3ccccc3)c(F)c2)nc1
Yield: 33.6 %

Procedure:
2-{3-Fluoro-4-[(phenylmethyl)oxy]phenyl}-5-(methylsulfonyl)pyridine (0.168 g, 34%) was prepared as a white solid from 5-bromo-2-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}pyridine (0.50 g, 1.40 mmol), methanesulfinic acid sodium salt (0.72 g, 80%, 5.58 mmol) Cul (0.80 g, 4.19 mmol), NaOH (67 mg, 1.68 mmol) and water (0.4 mL) in DMSO (15 mL) in a manner similar to Example 83, Step 2. The crude product was triturated with hot MeOH containing 5% of CHCl3. 1H NMR (400 MHz, CDCl3): δ 9.14 (d, 1H, J=2.4 Hz), 8.22 (dd, 1H, Ja=8.3 Hz, Jb=2.5 Hz), 7.91 (d, 1H, J=2.2 Hz), 7.90-7.70 (m, 2H), 7.50-7.30 (m, 5H), 7.11 (t, 1H, J=8.6 Hz), 5.23 (s, 2H), 3.13 (s, 3H); LRMS (ESI), m/z 358 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([CH:17]=[O:18])=[CH:11][C:10]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)([CH3:7])[CH3:6])C.CO.[OH-].[Li+]>O1CCCC1.O>[CH:17]([C:12]1[C:13]([O:15][CH3:16])=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:24])=[O:3])=[C:10]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH:11]=1)=[O:18]
Reactant: CCOC(=O)C(C)(C)Oc1cc(OC)c(C=O)cc1-c1cccs1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC(C)(C)C(=O)O)c(-c2cccs2)cc1C=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.9 %

Procedure:
Ex-47D: To a solution of 2-(4-formyl-5-methoxy-2-thiophen-2-yl-phenoxy)-2-methyl-propionic acid ethyl ester (0.29 g, 0.83 mmol) in a mixture of tetrahydrofuran, water and methanol (9 mL, 4:1:1) was added lithium hydroxide (0.10 g, 2.49 mmol) and the resulting yellow slurry was stirred at rt for 5 h. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (1×5 mL). The aqueous layer was acidified with a 1 N HCl solution and extracted with ethyl acetate (3×15 mL). The combined organic layers was dried over sodium sulfate and concentrated to afford 0.13 g (87%) of 2-(4-formyl-5-methoxy-2-thiophen-2-yl-phenoxy)-2-methyl-propionic acid as a pale green solid, mp 183–184° C. 1H-NMR (300 MHz, CDCl3) δ 10.32 (s, 1H), 8.12 (s, 1H), 7.40 (d, 1H, J=3.6 Hz), 7.32 (d, 1H, J=4.8 Hz), 7.08 (dd, 1H, J=4.8, 3.6 Hz), 6.47 (s, 1H), 3.86 (s, 3H), 1.78 (s, 6H). MS (EI) m/z=320 ([M]+, 100%). Anal. Calcd. for C16H16O5S: C, 59.99; H, 5.03; S, 10.01. Found: C, 60.04; H, 5.26; S, 9.70.
Reaction SMILES: [CH3:1][N:2]1[C:6](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3]1.[CH2:24]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:25][CH2:26][C:27]#[CH:28]>CCCCCCC.C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:28]#[C:27][CH2:26][CH2:25][CH2:24][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:5][C:4]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:3]1
Reactant: C#CCCCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(-c3ccccc3)nn2C)cc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: Cn1nc(-c2ccccc2)cc1C#CCCCc1ccccc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 2-methyl-5-phenyl-2H-pyrazol-3-yl ester and pent-4-ynyl-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 1:1; yield (80 mg, 53%); 1H NMR δ (CDCl3): 7.78 (d, J=8.21 Hz, 2H), 7.43-7.22 (m, 8H), 6.62 (s, 1H), 3.98 (s, 3H), 2.78 (t, J=7.30 Hz, 2H), 2.43 (t, J=7.19 Hz, 2H), 1.96 (p, J=7.33 Hz, 2H); LCMS m/z: 300.
Reaction SMILES: C(O[C:5]1[O:6][CH2:7][C:8](=[O:16])[C:9]=1[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])(C)C.C(OC(C)C)(=O)CC(OC(C)C)=O.ClCC(Cl)=O.[CH:35]1([NH2:41])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.[NH:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][N:49]=2)[C:44]([CH:51]=O)=[CH:43]1.N1CCCCC1>CC(O)C>[NH:42]1[C:50]2=[N:49][CH:48]=[CH:47][CH:46]=[C:45]2[C:44]([CH:51]=[C:7]2[O:6][C:5]([NH:41][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[C:9]([C:10]([O:12][CH:13]([CH3:14])[CH3:15])=[O:11])[C:8]2=[O:16])=[CH:43]1
Reactant: CC(C)OC(=O)C1=C(OC(C)C)OCC1=O
Reactant: NC1CCCCC1
Reactant: O=Cc1c[nH]c2ncccc12
Agent: CC(C)OC(=O)CC(=O)OC(C)C
Agent: O=C(Cl)CCl
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CC(C)OC(=O)C1=C(NC2CCCCC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 4.5 %

Procedure:
A solution of isopropyl 2-isopropoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.44 mmol) which similarly prepared according to the procedure described in the Example 74, Third step using diisopropyl malonate and chloroacetyl chloride, and cyclohexylamine (0.055 mL, 0.48 mmol) in 2-propanol (2.0 mL) was stirred at ambient temperature for 14 h. To this reaction mixture, 7-azaindole-3-carboxaldehyde (0.065 g, 0.44 mmol) and piperidine (0.0044 mL, 0.044 mmol) were added then the mixture was refluxed for further 8 days. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0079 g, y. 4%).