Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][CH2:16][F:17])[N:10]=[N:9]2)=[C:4]([F:18])[CH:3]=1.[N+:19]([O-])([OH:21])=[O:20].OS(O)(=O)=O>>[OH:1][C:2]1[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][CH2:16][F:17])[N:10]=[N:9]2)=[C:4]([F:18])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=c1n(CCCF)nnn1-c1ccc(O)cc1F
Agent: O=S(=O)(O)O
Product: O=c1n(CCCF)nnn1-c1cc([N+](=O)[O-])c(O)cc1F

Procedure:
From 4-hydroxy-2-fluoroaniline there is produced (in the manner described in published PCT International Application No. WO 85/01939 published May 9, 1985) 1-(4-hydroxy-2-fluorophenyl)-1,4-dihydro-4-(3-fluoropropyl) -5H-tetrazol-5-one. The latter is the nitrated by treatment with a mixture of HNO3 and H2SO4 to form 1-(4-hydroxy-2-fluoro-5-nitrophenyl)-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one. The latter is then dissolved in N,N-dimethylformamide ("DMF") and mixed with a dispersion of NaH in DMF, after which a solution of ethyl bromoacetate is added, resulting in a reaction yielding 1-(4-carboethoxy-methoxy-2-fluoro-5-nitrophenyl)-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one. The latter is then dissolved in acetic acid and then added to a hot suspension of iron powder in acetic acid and reacted at elevated temperature (e.g. 80°-90° C.) for about an hour to form 1-(7-fluoro-2H-1,4-benzoxazin-3(4H)-one-6-yl)1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one. The latter is then dissolved in DMF and added to a suspension of NaH in DMF and warmed to, e.g 50° C. Then a solution of 1-iodopropane in DMF is added and the mixture allowed to react to form 1-[7-fluoro-4-propyl-2H-1,4-benzoxazin-3(4H)-on-6-yl]-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:12]=1[CH2:13][OH:14].CC(C)([O-])C.[K+]>O1CCCC1>[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:12]=1[CH2:13][O:14][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccnc(F)c1
Reactant: OCc1c(F)cccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccnc(OCc2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
To a solution of 3.5 g (27.53 mmol) of 2-fluoro-4-methoxypyridine (CAS: 175965-83-0) and 3.97 g (27.53 mmol) of 2,6-difluorobenzyl alcohol in 97 ml of dry tetrahydrofuran, cooled beforehand to 0° C., were added dropwise 27.5 ml (27.53 mmol) of a 1M solution of potassium tert-butoxide in tetrahydrofuran. The resulting mixture was stirred at room temperature for 18 hours. The solvent was evaporated off and the residue was partitioned between water and ethyl acetate. The organic phase was removed, washed with water and aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure, which gave 5.77 g (66% yield, 79% purity) of the product.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[F:6][C:7]1[CH:8]=[C:9]([NH2:16])[C:10](=[CH:14][CH:15]=1)[C:11]([OH:13])=[O:12].C(N(CC)CC)C>O1CCOCC1>[F:6][C:7]1[CH:8]=[C:9]([NH:16][C:1](=[O:4])[CH2:2][CH3:3])[C:10](=[CH:14][CH:15]=1)[C:11]([OH:13])=[O:12]
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCC(=O)Nc1cc(F)ccc1C(=O)O

Procedure:
Propionyl chloride (1.7 ml) was added to a solution of 4-fluoroanthranilic acid (1 g) and triethylamine (2.8 ml) in 1,4-dioxane (30 ml). The mixture was heated under reflux for 4 hours, cooled and concentrated under reduced pressure. The residue was suspended in ethyl acetate and extracted with water. The organic phase was dried and evaporated and the residue purified by silica gel chromatography to give 4-fluoro-N-propionylanthranilic acid, mp 170°-171°. (Compound 9).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:13]=[CH:12][O:11][CH:10]=2)O1.Br[C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)[CH2:19][NH:20][C:21](=[O:23])[OH:22]>>[O:11]1[CH:12]=[CH:13][C:9]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=2)[CH2:19][NH:20][C:21](=[O:22])[OH:23])=[CH:10]1
Reactant: O=C(O)NCc1cccc(Br)c1
Reactant: CC1(C)OB(c2ccoc2)OC1(C)C
Product: O=C(O)NCc1cccc(-c2ccoc2)c1

Procedure:
Using the same method as in Example 5-(i), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furan was reacted with the (3-bromobenzyl)carbamic acid.tert-butyl to give [3-(furan-3-yl)benzyl]carbamic acid.tert-butyl (yield: 96%).
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:13][CH3:14])[C:8](=[O:12])[CH:9]([OH:11])[CH3:10])=[CH:5][N:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:3]=1.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>C(Cl)Cl>[CH3:21][N:22]([CH3:26])[C:23](=[O:24])[O:11][CH:9]([CH3:10])[C:8]([N:7]([C:6]1[C:2]([Cl:1])=[N:3][N:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:5]=1)[CH2:13][CH3:14])=[O:12]
Reactant: CCN(C(=O)C(C)O)c1cn(-c2cccnc2)nc1Cl
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Product: CCN(C(=O)C(C)OC(=O)N(C)C)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-hydroxypropanamide (0.10 g, 0.34 mmol) in CH2Cl2 (1.1 mL) was added dimethylcarbamic chloride (0.073 g, 0.68 mmol). The reaction mixture was stirred at room temperature for 16 hours, and then diluted with CH2Cl2, washed with water. The phases were separated, dried and concentrated. The residue was purified by basic alumina gel chromatography eluting with 0%-70% acetone/hexanes to afford the title compound F93 as a light yellow oil (0.11 g, 87%).
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:11].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>O>[Cl:11][C:3]1[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[C:9]([CH3:10])[C:2]=1[NH:1][S:13]([CH3:12])(=[O:15])=[O:14]
Reactant: Cc1cc(C#N)cc(Cl)c1N
Reactant: CS(=O)(=O)Cl
Solvent: O
Product: Cc1cc(C#N)cc(Cl)c1NS(C)(=O)=O
Temperature: 150 °C
Yield: 46.1 %

Procedure:
A mixture of 4-amino-3-chloro-5-methylbenzonitrile (155 mg, 930 μmol) and methanesulfonylchloride (2.13 g, 18.6 mmol, 1.44 mL) is heated under microwave conditions to 150° C. for 7 h. The mixture is cooled to rt, diluted with water and extracted with EA. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC using heptane:EA 1:1 to give N-(2-chloro-4-cyano-6-methyl-phenyl)-methanesulfonamide (105 mg) as an orange solid; LC-MS**: tR=0.48 min; 1H NMR (CDCl3): δ2.59 (s, 3H), 3.18 (s, 3H), 6.27 (s, 1H), 7.55 (d, J=1.3 Hz, 1H), 7.65 (d, J=1.5 Hz, 1H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C(O[C:18]([CH3:21])([CH3:20])C)(=O)CC(OC(C)(C)C)=O.[Br:22][C:23]1[N:24]=[C:25](Cl)[C:26]2[N:27](C(C)=[N:30][N:31]=2)[CH:28]=1.Cl>CN1C(=O)CCC1>[Br:22][C:23]1[N:24]=[C:18]([CH3:20])[C:21]2[N:27]([C:26]([CH3:25])=[N:31][N:30]=2)[CH:28]=1
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: Cc1nnc2c(Cl)nc(Br)cn12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Cc1nc(Br)cn2c(C)nnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Caesiumcarbonate (7.25 g; 22.3 mmol) is suspended in 5 ml NMP. To this suspension di-tert-butyl malonate (4.80 g; 22.3 mmol) is added and the resulting mixture is stirred for 30 min at 25° C. Finally 6-bromo-8-chloro-3-methyl-[1,2,4]-triazolo[4,3-a]pyrazine J-1 (1.00 g; 4.04 mmol) is added and the reaction mixture is stirred for 18 h at 25° C. The reaction mixture is treated with aqueous 1 N HCl until the pH value is below 5 and then extracted with DCM. The organic layer is separated and dried over MgSO4 and is evaporated to dryness. The crude intermediate is purified using reverse phase chromatography (method prep. HPLC2). The intermediate is dissolved in 5 ml DCM and 5 ml TFA and stirred for 16 h at 40° C. The reaction mixture is evaporated and the crude product is purified using reverse phase chromatography (method prep. HPLC2).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C@H:24]3[CH2:28][NH:27][CH2:26][C@H:25]3[C:29]([OH:31])=[O:30])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:32]([N:34]=[C:35]=[O:36])[CH3:33]>>[CH2:32]([NH:34][C:35]([N:27]1[CH2:28][C@H:24]([NH:23][S:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)=[CH:15][CH:16]=2)(=[O:21])=[O:22])[C@H:25]([C:29]([OH:31])=[O:30])[CH2:26]1)=[O:36])[CH3:33]
Reactant: CCN=C=O
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CNC[C@H]3C(=O)O)cc2)c2ccccc2n1
Product: CCNC(=O)N1C[C@H](NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)[C@H](C(=O)O)C1
Yield: 84.7 %

Procedure:
According to the procedure of Example 17, Step 3, the reaction of 178 mg of cis-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxylic acid (Example 21, Step 1) and 44 mg of ethyl isocyanate provided 175 mg of cis-1-[(ethylamino)carbonyl]-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxylic acid in quantitative yield. MS: 513.2 (M+H)+
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:10]#CC(=O)CCCCC>>[CH:4]1([C:3](=[O:9])[C:2]#[CH:1])[CH2:10][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: C#CC(=O)CCCCC
Reactant: C#CC(O)CCCCC
Product: C#CC(=O)C1CCCCC1

Procedure:
In like manner, but replacing the 3-cyclohexylprop-1-yn-3-ol with oct-1-yn-3-ol, oct-1-yn-3-one was prepared. C. Similarly, but starting with other appropriate 3-hydroxy-1-alkynes, prepared as shown above, the following 3-oxo-1-alkynes are prepared:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[N:14][C:13]([CH3:16])=[C:12]3[O:17][C:18]([CH3:22])([CH3:21])[O:19][CH2:20][C:11]=23)[OH:9])=[CH:4][CH:3]=1.C(Cl)(Cl)[Cl:24]>O=[Mn]=O>[Cl:24][C:3]1[CH:4]=[C:5]([C:8]([C:10]2[CH:15]=[N:14][C:13]([CH3:16])=[C:12]3[O:17][C:18]([CH3:22])([CH3:21])[O:19][CH2:20][C:11]=23)=[O:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Cc1ncc(C(O)c2ccc(F)cc2)c2c1OC(C)(C)OC2
Reactant: ClC(Cl)Cl
Agent: O=[Mn]=O
Product: Cc1ncc(C(=O)c2ccc(F)c(Cl)c2)c2c1OC(C)(C)OC2

Procedure:
6.6 g of (4-fluorophenyl)(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-yl)methanol was dissolved with heat in 150 mL of CHCl3. 12 g of MnO2 was added to this solution and the suspension was refluxed for 2 h. The MnO2 was then filtered over a 1 cm pad of silica gel and the clear organic phase evaporated to yield pure (3-Chloro-4-fluorophenyl)(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-yl)methanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]=[C:11]([C:17](OCC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:17]1[C:5]2[C:6](=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C(=CNc1ccc(OC)cc1)C(=O)OCC
Product: CCOC(=O)c1cnc2ccc(OC)cc2c1Cl
Yield: 94.8 %

Procedure:
Diethyl {[(4-methoxyphenyl)amino]methylene}malonate (63.5 g, 0.22 mol) was dissolved into POCl3 (300 mL, 3.0 mol), and the reaction mixture was heated at reflux for 16 h. After removal of solvent, toluene was added and the mixture was concentrated to remove remaining POCl3. The residue was diluted with DCM, washed with aqueous Na2CO3 and brine, dried over Na2SO4 and concentrated to give ethyl 4chloro-6methoxyquinoline-3-carboxylate (55.4 g, 96% yield) as a yellow solid which was used without further purification. LCMS: (FA) ES+ 266.1.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][CH:12]([CH2:15][CH3:16])[CH2:13]O.S(=O)(=O)(O)O>C1C=CC=CC=1>[CH3:11][CH:12]([CH2:15][CH3:16])[CH2:13][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCC(C)CO
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CCC(C)COC(=O)c1ccc(O)cc1

Procedure:
690 g of p-hydroxybenzoic acid, 650 g of (-)2-methylbutanol, 3 l of benzene, and 30 ml of conc. sulfuric acid were stirred under heating in a container provided with a Dean-Stark reflux condenser to remove generated water. After the reflux for about 11 hours, the solution was cooled and stripped of sulfuric acid by the addition of ice water. The reaction mother liquor was distilled of benzene after being washed by an aqueous solution of sodium carbonate and water to obtain oily p-hydroxybenzoic acid 2-methylbutyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[CH:8]=[N:7]2.[CH2:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][C:24]=2[CH3:38])=[O:22])[CH2:17][CH2:16]1)[CH3:14].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:26]1[CH:27]=[CH:28][C:23]([C:21]([N:18]3[CH2:19][CH2:20][N:15]([CH2:13][CH3:14])[CH2:16][CH2:17]3)=[O:22])=[C:24]([CH3:38])[CH:25]=1)[CH:8]=[N:7]2
Reactant: CCN1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2C)CC1
Reactant: Clc1cnc2cccc(Br)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCN1CCN(C(=O)c2ccc(-c3cnc4cccc(Br)c4n3)cc2C)CC1
Temperature: 105 °C

Procedure:
A microwave tube is charged with 8-Bromo-2-chloro-quinoxaline (Step 1.4, 298 mg, 1.226 mmol), (4-Ethyl-piperazin-1-yl)-[2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (439 mg, 1.226 mmol), K3PO4 (532 mg, 2.450 mmol) and Pd(PPh3)4 (43.8 mg, 0.0368 mmol). After several cycles of vacuum/purge with argon, 5 ml of dry DMA are added. The reaction mixture is then heated to 105° C. for 4 h. After cooling, the suspension is poured onto 70 ml de-ionized water and filtered. The cake is re-taken in EtOAc, washed with saturated brine and dried over Na2SO4. After filtration, the mixture is concentrated in vacuo. The residue is purified by chromatography (silicagel, CH2Cl2/CH2Cl2:EtOH:NH3 90:9:1 from 1:0=>0:1) to afford the title compound as a pale brown foam, Rt=0.833 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 439 (M+1, 79Br)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]1[C:25]([OH:34])=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[CH3:30]>>[CH3:23][C:24]1[C:25]([OH:34])=[C:26]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=4[OH:22])[N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH:27]=[CH:28][C:29]=1[CH3:30]
Reactant: COc1cccc(-c2cccc(-c3cccc(Br)n3)n2)c1O
Reactant: Cc1ccc(B(O)O)c(O)c1C
Product: COc1cccc(-c2cccc(-c3cccc(-c4ccc(C)c(C)c4O)n3)n2)c1O
Yield: 11 %

Procedure:
6-(3,4-Dimethyl-2-hydroxyphenyl)-6′-(2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine and 3,4-dimethyl-2-hydroxyphenyl boronic acid in 11% yield using method F; δH [2H6]-DMSO 13.32,(1H, s), 8.38-8.22,(4H, m), 8.14,(1H, d), 8.10,(1H, d), 7.88,(1H, d), 7.72,(1H, d), 7.10,(1H, d), 6.94,(1H, t), 6.82,(1H, d), 3.84,(3H, s), 2.31,(3H, s), 2.20,(3H, s); MS 339 (MH)+; HPLC retention time (system 1) 4.39 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[O:8][CH2:7][C:6]2=1.Cl.Cl[CH2:22][C:23]1[CH:38]=[CH:37][C:26]([O:27][CH2:28][CH2:29][NH:30][CH:31]2C[CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)=[CH:37][CH:38]=1)[C:11]1[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[O:8][CH2:7][C:6]2=1
Reactant: ClCc1ccc(OCCNC2CCCCC2)cc1
Reactant: COc1ccc2[nH]c3c(c2c1)COc1ccccc1-3
Agent: Cl
Product: COc1ccc2c(c1)c1c(n2Cc2ccc(OCCN3CCCCC3)cc2)-c2ccccc2OC1

Procedure:
Following the procedure described in Example 102, using 8-methoxy-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene (150 mg, 0.562 mmol) and [2-(4-chloromethyl-phenoxy)-ethyl]-cyclohexanyl-amine hydrochloride salt as the starting material, the title compound was prepared as a brown solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]([Br:24])(Br)Br.OC[CH2:27][N:28]1[C:36]2[C:31](=[C:32]([O:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29]1.C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[Br:24][CH2:21][CH2:27][N:28]1[C:36]2[C:31](=[C:32]([O:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29]1
Reactant: COC(=O)COc1cccc2c1ccn2CCO
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)COc1cccc2c1ccn2CCBr
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
Under argon atmosphere, triphenylphosphine (1.05 g) and tetrabromomethane (2.00 g) were added to methyl (1-(2-hydroxyethyl)indole-4-yloxy)acetate (500 mg) in methylene chloride (10 ml) at room temperature, and the resulting mixture was stirred at room temperature for 15 minutes. Since the reaction had not been completed, triphenylphosphine (1.00 g) was added and the reaction mixture was stirred at room temperature for 30 minutes. To the reaction mixture, aqueous sodium hydrogen carbonate solution (5 ml) and water (10 ml) were added and the resultant was extracted with ethyl acetate (3×20ml). The obtained organic layers were washed with saturated brine and dried over sodium sulfate. After removing solids by filtration, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain the desired compound (602 mg, yield: 96%).
Reaction SMILES: [Na].[S:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13]Br>CN(C)C=O>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][N:4]1[C:5](=[O:7])[CH2:6][S:2][C:3]1=[O:8]
Reactant: BrCCCCBr
Reactant: O=C1CSC(=O)N1
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1CSC(=O)N1CCCCBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
The 2,4-thiazolidinedione sodium salt (13.91 g., 0.1 mole) is added to a solution of 1,4-dibromobutane (64.77 g., 0.3 mole) in 500 ml. of dry dimethylformamide. After stirring the mixture at room temperature for a 16 hr. period, the resulting clear solution is concentrated in vacuo and residual material dissolved in chloroform, filtered, and concentrated in vacuo to an amber oil. Distillation of the oil affords 20.62 g. (81% yield) of 3-(4-bromobutyl)-2,4-thiazolidinedione, b.p. 105°-115° C. at 0.02 mmHg.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:46]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:46]=3[Cl:52])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1ccc(Cl)c(CBr)c1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3cc(Cl)ccc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-1,4-dichlorobenzene and isolated as white solid (4.6 mg, 25%). MS (m/e): 441.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([CH2:19]O)=[CH:7]2.O=S(Cl)[Cl:23]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([CH2:19][Cl:23])=[CH:7]2
Reactant: OCc1cc2cccc(Cl)c2nc1Oc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCc1cc2cccc(Cl)c2nc1Oc1ccccc1

Procedure:
Prepared according to Procedure C using (8-chloro-2-phenoxyquinolin-3-yl)-methanol (1.0 eq) and SOCl2 (5 eq) in CHCl3 (0.25M) at rt. 8-chloro-3-(chloromethyl)-2-phenoxyquinoline was obtained after purification as a yellow oil.
Reaction SMILES: [CH:1]1[C:6](O)=CC=C(C)[CH:2]=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>>[CH2:6]([O:19][C:16]1[CH:15]=[CH:14][C:13]([C:9]([CH3:12])([CH3:10])[CH3:11])=[CH:18][CH:17]=1)[C:1]#[CH:2]
Reactant: Cc1ccc(O)cc1
Reactant: CC(C)(C)c1ccc(O)cc1
Product: C#CCOc1ccc(C(C)(C)C)cc1
Yield: 98 %

Procedure:
Example 14 is repeated except that p-cresol is replaced by 4-t-butylphenol. The product, 4-t-butylphenyl propargyl ether, is isolated as a colorless liquid in 98% yield and characterized by pmr spectroscopy. The product is represented by the following formula: ##STR24##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[CH3:17]O>>[CH3:17][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[N:4][C:5]=1[Cl:11]
Reactant: CO
Reactant: O=C(O)c1cc(Br)cnc1Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)cnc1Cl
Temperature: 60 °C
Reaction time: 36 h

Procedure:
To 0.5 L flask charged with 5-Bromo-2-chloronicotinic acid (25.0 g, 106.4 mmol) in MeOH (250 mL) was added H2SO4 (5 mL). The mixture was heated to 60° C., stirred for 1.5 day. LC-MS indicated full conversion of starting material at this time. The reaction was cooled to RT and the volatile components removed in vacuo. The crude residue was dissolved in EtOAc (300 mL), quenched with sat. aqueous Na(HCO3)2 (200 mL). The organic layer was separated, washed with brine, dried over MgSO4 and concentrated to afford the compound, methyl-5-bromo-2-chloronicotinate, as a while solid (quantitative yield). LC-MS (M+H)=250.1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.CC(C)=O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:19]([O:18][CH3:17])[CH:20]=3)[CH:8]=2)[N:3]=1
Reactant: COc1cccc(CBr)c1
Reactant: Oc1ccc2nc(Cl)ccc2c1
Solvent: CC(C)=O
Solvent: O
Product: COc1cccc(COc2ccc3nc(Cl)ccc3c2)c1
Yield: 44.5 %

Procedure:
To a stirred solution of 2-chloro-6-hydroxy-quinoline (0.6 g, 3.0 mmol) in aceton (15 ml) potassium carbonate (0.55 g, 4.0 mmol) and 3-methoxybenzylbromide (0.8 g, 4.0 mmol) were added at ambient temperature. Then the reaction mixture was heated to reflux for 3 h. Upon cooling to ambient temperature water was added and the whole mixture extracted twice with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (heptane, ethyl acetate 1:0=>1:4) yielded 2-chloro-6-(3-methoxy-benzyloxy)-quinoline as a white solid (0.4 g, 40%), MS 300.8 [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)[C:10](OC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:24]>CO>[NH2:24][C:10](=[O:11])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1
Reactant: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(N)=O
Temperature: 85 °C
Reaction time: 24 h

Procedure:
In a reactor under 200 psi of pressure was added (6.2 g, 22 mmol) of methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propanoate and 120 ml of methanol saturated with NH3. The solution was stirred at about 85° C. for about 24 hours. After cooling, the solution was evaporated and the residue precipitated by the addition of diisopropyl ether. Filtration gave 5.4 g of the title product as a white powder. Melting point: 142-143° C.