Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](O)=O.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[SH:16].B(O)(O)O>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=1
Reactant: Nc1ccccc1S
Reactant: O=C(O)c1ccc[nH]1
Agent: OB(O)O
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: c1c[nH]c(-c2nc3ccccc3s2)c1
Yield: 14 %

Procedure:
A mixture of 5.55 g (50 mmol) of pyrrole-2-carboxylic acid, 6.26 g (50 mmol) of 2-aminothiophenol and 3.09 g (50 mmol) of boric acid in 250 mL of xylene was heated under reflux for 3 days while removing water which was generated from reaction using a Dean-Stark trap. the cooled reaction mixture was diluted with 200 mL of ethyl acetate, washed with 200 mL of 5% sodium hydroxide solution and then with 200 mL of water. The separated organic layer was dried over anhydrous sodium sulfate. The resulting crude product was purified by column chromatography on silica gel with 10% ethyl acetate in hexane as eluant. The desired product, 2-(pyrrol-2-yl)benzothiazole (1.40 g, 14%) was obtained as a pale yellow solid. m.p. 150°-151° C.; 1H-NMR (CDCl3) 6.32-6.35 (m, 1H, ArH), 6.87-6.89 (m, 1H, ArH), 6.94-6.96 (m, 1H, ArH), 6.33 (t, 1H, ArH), 6.43 (t, 1H, ArH), 7.84 (d, 1H, ArH), 7.90 (d, 1H, ArH).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[Br:20]Br>C(O)(=O)C>[C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]([Br:20])[C:7]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: COc1cccc2cc(C(C)=O)oc12
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(Br)c2cc(C(C)=O)oc12
Reaction time: 1 h

Procedure:
2-Acetyl-7-methoxybenzofuran (1.0 g, 5.3 mmol) was dissolved in glacial acetic acid (29 mL) followed by addition of sodium acetate (1.3 g, 15.8 mmol). The reaction was treated dropwise with a solution of bromine (0.26 mL, 5.26 mmol) in glacial acetic acid (10 mL) at room temperature followed by stirring for one hour. The solvent was removed under vacuum. The residue was dissolved in water and extracted three times with dichloromethane. The combined organic extracts were washed with 2% aqueous sodium bicarbonate, dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel using a 50-100% dichloromethane/hexane gradient affording the product as a white solid. (1.00 g, 75%). 1H NMR (CDCl3, 300 MHz) δ 7.44 (s, 1H), 7.32 (d, 1H), 6.80 (d, 1H), 4.0 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br-:19].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C1[CH2:44][O:43][CH2:42]C1>O>[Br:19][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH2:42][O:43][CH3:44])[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[O:3]
Reactant: [Br-]
Reactant: C1CCOC1
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2nccs2)cc1
Agent: c1cc[nH+]cc1
Solvent: O
Product: COCN(c1nccs1)S(=O)(=O)c1ccc(C(=O)CBr)cc1
Reaction time: 4 h

Procedure:
To a solution of 4-acetyl-N-thiazol-2-yl-benzenesulfonamide (10 mmol) in THF (50 mL) was added pyridinium tribromide (10 mmol), and the mixture was stirred for 4 h. The reaction mixture was diluted with water (30 mL) and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography to give 4-(2-bromo-acetyl)-N-methoxymethyl-N-thiazol-2-yl-benzenesulfonamide (8.2 mmol) as a white solid.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)=[N:19][N:20]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(CC)CC)C.[CH2:35]([C@H:38]1[CH2:43][CH2:42][C@H:41]([CH2:44][CH2:45][C:46](Cl)=[O:47])[CH2:40][CH2:39]1)[CH2:36][CH3:37]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1.CCOCC>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][C:18]([C:21]3[CH:22]=[CH:23][C:24]([O:27][C:46](=[O:47])[CH2:45][CH2:44][C@H:41]4[CH2:42][CH2:43][C@H:38]([CH2:35][CH2:36][CH3:37])[CH2:39][CH2:40]4)=[CH:25][CH:26]=3)=[N:19][N:20]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(-c2nnc(-c3ccc(O)cc3)s2)cc1
Reactant: CCC[C@H]1CC[C@H](CCC(=O)Cl)CC1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(-c2nnc(-c3ccc(OC(=O)CC[C@H]4CC[C@H](CCC)CC4)cc3)s2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2-(4-n-Octyloxyphenyl)-5-(4-hydroxyphenyl)-1,3,4-thiadiazole (0.1 mole, 3.82 g) is suspended in 50 mL of absolute toluene and, after addition of 10 mL triethylamine and 100 mg 4-dimethylaminopyridine, treated with stirring with 0.011 moles (2.38 g) 3-(trans-4-n-propylcyclohexyl)-propionyl chloride. The mixture is stirred for 12 hours at room temperature and for 2 hours at 80° C. After being allowed to cool to room temperature, the reaction solution is diluted with 100 mL ether and washed once with 100 mL water, once with 100 mL 5% sodium bicarbonate solution and once again with 100 mL water. After drying over Na2SO4, the solvent is distilled off in a rotary evaporator. The residue is recrystallized from ethanol and methanol until the transition temperature is constant.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]=[C:13]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:12]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38](O)=[O:39].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]=[C:13]([N:21]3[CH2:22][CH2:23][N:24]([C:38]([C:34]4[S:33][CH:37]=[CH:36][CH:35]=4)=[O:39])[CH2:25][CH2:26]3)[C:12]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nc(N3CCNCC3)c2-c2ccccc2)cc1
Reactant: O=C(O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nc(N3CCN(C(=O)c4cccs4)CC3)c2-c2ccccc2)cc1
Temperature: 37 °C
Yield: 48.6 %

Procedure:
To a solution of 6-[4-(methylsulfonyl)phenyl]-5-phenyl-4-piperazin-1-yl-2-(trifluoromethyl)pyrimidine (0.2 g, 0.43 mmol, prepared according to the procedure described in preparation 2) in dimethylformamide (20 ml) was added thiophene-2-carboxylic acid (0.149 g, 0.78 mmol) under stirring at 37° C., and then after 10 minutes EDCI (0.149 g, 0.78 mmol), and HOBt (0.023 g, 0.173 mmol) were added. Further TEA (0.179 ml, 2.9 mmol) was added to the resultant clear solution and it was stirred for 18 hours. Subsequently the reaction mixture was diluted with ethyl acetate (50 ml) and the organic layer was washed successively with water, 10% sodium bi carbonate solution (100 ml), and brine (100 ml) respectively and dried over anhydrous sodium sulphate. Evaporation of the solvent and purification by column chromatography (0.4% MeOH:DCM) gave the title compound (0.12 g, yield 48.6%); m.p. 189-194° C. 1H-NMR (CDCl3) δ: 2.98 (s, 3H), 3.4-3.41 (t, 4H), 3.66-3.68 (t, 4H), 7.02-7.77 (m, 12H). MS m/z: 573.2 (M++1).
Reaction SMILES: C([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([F:33])[F:32])[CH:26]=2)=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1>C(O)C.O1CCCC1>[F:33][CH:31]([F:32])[C:27]1[CH:26]=[C:25]([CH2:24][CH2:23][C:12]2[CH:13]=[C:14]([OH:15])[C:9](=[O:8])[NH:10][N:11]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: FC(F)c1cccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Solvent: CCO
Solvent: C1CCOC1
Product: O=c1[nH]nc(CCc2cccc(C(F)F)c2)cc1O
Yield: 32 %

Procedure:
Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(3-(difluoromethyl)phenyl)ethynyl]pyridazine (Intermediate 22) except that the reaction was carried out in a mixture of ethanol and tetrahydrofuran (1:1). The crude material was purified by reverse phase chromatography (25 g C18) cartridge eluting with 5-100% acetonitrile/water with acidic modifier and the appropriate fractions combined to give a pale orange solid (yield=32%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:11]([CH:15]=1)[C:12]([OH:14])=O.[F:32][C:33]([F:42])([F:41])[C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[C:11]([CH:15]=1)[C:12]([NH:38][C:37]1[CH:39]=[CH:40][C:34]([C:33]([F:32])([F:41])[F:42])=[CH:35][CH:36]=1)=[O:14]
Reactant: COc1c(C)c(Cc2ccc(-c3ccncc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C)c(Cc2ccc(-c3ccncc3)c(C(=O)Nc3ccc(C(F)(F)F)cc3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.2 %

Procedure:
To a solution of 5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridyl)benzoic acid (200 mg, 0.4716 mmol) in methylene chloride (10 ml) were added 4-trifluoromethylaniline (114 mg, 0.7080 mmol), triethylamine (95 mg, 0.9405 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (239 mg, 1.4142 mmol) followed by stirring at room temperature for 16 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (166 mg, 0.2932 mmol, 62%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]=[CH2:12])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([P:20]([CH3:23])([CH3:22])=[O:21])=[CH:16][CH:15]=2)[N:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.I[C:47]1[C:52]([CH3:53])=[CH:51][CH:50]=[CH:49][C:48]=1[CH3:54].CCN(C(C)C)C(C)C>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:54][C:48]1[CH:49]=[CH:50][CH:51]=[C:52]([CH3:53])[C:47]=1/[CH:12]=[CH:11]/[N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([Cl:1])=[N:3][C:4]=2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([P:20]([CH3:22])([CH3:23])=[O:21])=[CH:16][CH:15]=1
Reactant: C=Cn1cnc2c(Nc3ccc(P(C)(C)=O)cc3)nc(Cl)nc21
Reactant: Cc1cccc(C)c1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C)c1/C=C/n1cnc2c(Nc3ccc(P(C)(C)=O)cc3)nc(Cl)nc21
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To an oven-dried 50 mL round-bottom flask were added 2-chloro-N-(4-(dimethylphosphoryl)phenyl)-9-vinyl-9H-purin-6-amine (0.32 g, 0.93 mmol), Pd(OAc)2 (10 mg, 0.05 mmol), tri-o-tolylphosphine (30 mg, 0.1 mmol), 2-iodo-m-xylene (0.39 g, 1.67 mmol). The mixture was flushed with Ar and then dissolved in ˜10 mL anhydrous DMF. DIEA (0.39 g, 2.79 mmol) was then added via syringe. The reaction was stirred at 110° C. overnight. The reaction was diluted with EtOAc and filtered through celite, washed with ample ˜5% MeOH/EtOAc, the combined organic layer was washed with water twice, dried over Na2SO4. Final product was purified by silica gel column chromatography (4˜8% MeOH/DCM).
Reaction SMILES: [OH-:1].[K+].COC([C:7]1([C:20]2[C:29]3[C:24](=[CH:25][C:26](Cl)=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=O.[CH3:31]O>>[C:16]([O:15][C:13]([N:10]1[CH2:9][CH2:8][CH:7]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:1][CH3:31])=[CH:27][CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:12][CH2:11]1)=[O:14])([CH3:17])([CH3:19])[CH3:18]
Reactant: CO
Reactant: [OH-]
Reactant: COC(=O)C1(c2ncnc3cc(Cl)ccc23)CCN(C(=O)OC(C)(C)C)CC1
Agent: [K+]
Product: COc1ccc2c(C3CCN(C(=O)OC(C)(C)C)CC3)ncnc2c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Solid KOH (224 mg, 4 mmol) was added to a solution of 4-(7-chloro-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (3a; 41 mg, 0.1 mmol), prepared as described in Example 3, in anhydrous MeOH (1 mL). The mixture was stirred at 100° C. for 3 h. It was then cooled to rt and concentrated in vacuo. The residue was dissolved in DCM and washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain crude 4-(7-methoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (4a). This was dissolved in 2 mL of 3M HCl/MeOH was stirred at rt for 1 h and then concentrated in vacuo to obtain crude 4-(7-methoxy-quinazolin-4-yl)-piperidine (4b) as a di-HCl salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]3[CH2:18][O:17][CH2:16]3)[CH:10]=2)=[CH:7][C:6]([C:19](O)=[O:20])=[CH:5][CH:4]=1.[CH3:22][O:23][C:24]([C:26]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25]>>[CH3:22][O:23][C:24]([C:26]1([NH:33][C:19]([C:6]2[CH:7]=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]4[CH2:18][O:17][CH2:16]4)[CH:10]=3)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:20])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1)=[O:25]
Reactant: COc1ccc(C(=O)O)cc1-c1cccc(C2COC2)c1
Reactant: COC(=O)C1(N)CCCCCC1
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(-c3cccc(C4COC4)c3)c2)CCCCCC1

Procedure:
The title compound was synthesized from 6-Methoxy-3′-oxetan-3-yl-biphenyl-3-carboxylic acid and 1-amino-cycloheptanecarboxylic acid methyl ester in analogy to example 126, step 4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14](Br)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[I:27]I>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[I:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CCC(=C(Br)c2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=C(I)c2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
To a solution of 4-(1-bromo-1-phenyl-methylene)-piperidine-1-carboxylic acid tert-butyl ester (0.742 g, 2.11 mmol), in dry THF (15 mL) at −78° C., was added n-BuLi (1.7 M solution in hexanes, 1.6 mL, 2.72 mmol) dropwise over about 5 min. After stirring the mixture at −78° C. for 20 min, solid I2 (0.729 g, 2.87 mmol) was added and the reaction mixture was allowed to slowly warm to room temperature. The mixture was then quenched with saturated NH4Cl and saturated Na2S2O3, diluted with water and extracted with EtOAc (×3). The combined organic phase was washed (H2O, brine), dried (Na2SO4) and concentrated to give the title compound as a yellow orange solid (0.800 g) which was used in subsequent steps without further purification. An analytical sample was obtained by recrystallization from hexane (5° C.) to afford the pure iodide as a cream coloured powder:
Reaction SMILES: O[CH:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.S(Cl)([Cl:20])=O>>[Cl:20][CH:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: OC(CCc1ccc(Cl)cc1)Cn1ccnc1
Reactant: O=S(Cl)Cl
Product: Clc1ccc(CCC(Cl)Cn2ccnc2)cc1

Procedure:
1-[2-Hydroxy-4-(4-chlorophenyl)-n-butyl]imidazole (2.0 g) in thionyl chloride (10 ml) is warmed for one hour at 65°. The excess thionyl chloride is removed in vacuo, the residue dissolved in dichloromethane (75 ml) and shaken with excess aqueous potassium carbonate. The organic layer is washed with water, dried over MgSO4, evaporated and the residue evacuated to remove all traces of dichloromethane, affording 1-[2-chloro-4-(4-chlorophenyl)-n-butyl]imidazole.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N[C:15](NC2C=CC=CC=2)=[O:16])C=CC=CC=1.N[C:25](N)=[O:26]>CCCCCCCC([O-])=O.CCCCCCCC([O-])=O.[Zn+2].CO>[CH3:25][O:26][C:15](=[O:16])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccccc1)Nc1ccccc1
Reactant: NC(N)=O
Reactant: Nc1ccccc1
Agent: CCCCCCCC(=O)[O-]
Agent: [Zn+2]
Solvent: CO
Product: COC(=O)Nc1ccccc1

Procedure:
Following the procedure described in Example 1, 745 g of aniline, 255 g of N,N'-diphenyl urea, 481 g of urea, 1333 g of methanol and 6.0 g of zinc octoate were reacted for 3.5 hours at 200° C. in the pressure apparatus described in Example 1. The mixture was then cooled and, after the apparatus had been vented, another 72 g of urea were added. The mixture was then reheated and reacted for 4 hours at 200° C. After cooling and venting of the apparatus, the mixture was removed, filtered and subjected to fractional distillation. Most of the methanol excess was separated off at atmospheric pressure. The product was then distilled at 0.2 mbar. 1323 g (84.1% of the theoretical yield) of N-phenyl carbamic acid methyl ester melting at from 45° to 47° C. were obtained.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]([C:5](F)=[O:6])[C:3]=1[C:14](F)=[O:15].FC1(F)C2C(=C(F)C(F)=C(F)C=2F)C(=O)[O:19]1.ClC1C=C(Cl)C=CC=1C(O)=O>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]2[C:5](=[O:19])[O:6][C:14](=[O:15])[C:3]=12
Reactant: O=C(F)c1c(F)c(F)c(F)c(F)c1C(=O)F
Reactant: O=C1OC(F)(F)c2c(F)c(F)c(F)c(F)c21
Agent: O=C(O)c1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1C
Product: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Yield: 72.05 %

Procedure:
Into a 300 ml glass reactor equipped with a reflux condenser and a stirrer, and 50 g (0.207 mol) of the mixture (1:1) of the 3,4,5,6-tetrafluorophthaloyldifluoride and the 3,3,4,5,6,7- hexafluoro-1-[3H]-isobenzofuranone, 59.3 g (0.31 mol) of 2,4-dichlorobenzoic acid and 100 ml of xylene were charged, and the mixture was reacted at 150° C. for 12 hours with vigorous stirring. Then, the reaction mixture was separated by distillation to obtain 32.8 g of tetrafluorophthalic anhydride. The yield was 72.05%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]([O:11][C:12]2[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]([O:11][C:12]2[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[C:6]([CH:10]=1)[C:7]([N:22]([CH2:23][CH3:24])[CH2:20][CH3:21])=[O:9]
Reactant: O=C(O)c1cc(Br)cc(F)c1Oc1ccc(Cl)nc1
Reactant: CCNCC
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cc(Br)cc(F)c1Oc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(N,N,N′,N′-tetramethyl-o-(1H-benzotriazol-1-yl)uronium tetrafluoroborate (53.1 g, 165 mmol) was added to a solution of 5-bromo-2-(6-chloropyridin-3-yloxy)-3-fluorobenzoic acid (38.2 g, 110 mmol) and diethylamine (63.3 mL, 606 mmol) in CH2Cl2 (500 mL) at 0° C. After stirring 5 hours at RT, the reaction was quenched with saturated aqueous sodium bicarbonate (250 mL) at RT and diluted with water (100 mL) and the organics was removed in vacuo. The mixture was diluted with EtOAc (250 mL) and the layers were separated and the aqueous layer was extracted with EtOAc (3×100 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate, water, 1N HCl, water, brine, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to provide a residue that was purified by filtering through a pad of silica gel by eluting with 1:2 EtOAc in hexane to provide 5-bromo-2-(6-chloropyridin-3-yloxy)-N,N-diethyl-3-fluorobenzamide.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[C:8]=2[C:7]([C:17]([OH:19])=[O:18])=[CH:6][CH:5]=1.[CH:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[C:23](O)[CH:22]=1.CCN=C=NCCCN(C)C.CC1(C)C=CN=C(N)C1>CN(C=O)C>[F:20][CH:2]([F:1])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[C:8]=2[C:7]([C:17]([O:19][C:23]2[CH:22]=[CH:21][C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=2)=[O:18])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)c1ccc(OC(F)F)c2oc3ccncc3c12
Agent: CC1(C)C=CN=C(N)C1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC(F)F)c2oc3ccncc3c12
Temperature: 72.5 °C

Procedure:
A mixture of 6-Difluoromethyloxybenzo[4,5]furo[3,2-c]pyridine-9-carboxylic acid (5.5 g, 0.0197 moles), p-nitro phenol (4.1 g, 0.0295 moles), EDCI (5.7 g, 0.295 moles), 4,4-dimethyl amino pyridine (250 mg, 0.00197 moles) in DMF (603.0 mL) was heated to 70-75° C. for 4-5 hours. The residue obtained after removal of solvent under vacuo was triturated with water (50.0 mL) to give intermediate-18 (6.0 mg) as yellow solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]1([CH:16]([N:20]2[CH:24]=[C:23]([C:25]3[C:26]4[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:27]=4[N:28]=[CH:29][N:30]=3)[CH:22]=[N:21]2)[CH2:17][CH2:18][OH:19])[CH2:15][CH2:14][CH2:13][CH2:12]1.O>C(Cl)Cl>[CH:11]1([CH:16]([N:20]2[CH:24]=[C:23]([C:25]3[C:26]4[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:39])([CH3:41])[CH3:40])[C:27]=4[N:28]=[CH:29][N:30]=3)[CH:22]=[N:21]2)[CH2:17][CH:18]=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CCO)C4CCCC4)c3)ncnc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC=O)C4CCCC4)c3)ncnc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.6 %

Procedure:
To a solution of oxalyl chloride (0.108 mL, 1.28 mmol) in DCM (10.0 mL) at −78° C. was added DMSO (151 μL, 2.13 mmol). After stirring for 5 minutes, 3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propan-1-ol (471 mg, 1.07 mmol) in DCM (3.00 mL) was added. The mixture was stirred for 30 minutes at −78° C. TEA (594 μL, 4.26 mmol) was then added. The resulting mixture was then allowed to warm to room temperature over the course of 30 minutes. Water was added, and the layers were separated. The organic layer was washed successively with 0.1 N HCl, water, saturated sodium bicarbonate solution, and brine, and was then dried over sodium sulfate and the solvent was removed in vacuo. Flash column chromatography (eluting with a gradient of 0-60% ethyl acetate in hexanes) afforded the product (384 mg, 82%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Br:12].[CH2:13]([O:20]CC1C=CC=CC=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na]>O1CCCC1>[CH2:13]([O:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Br:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(COCc2ccccc2)cc1
Reactant: BrCCCCCCCCCCBr
Agent: [Na]
Solvent: C1CCOC1
Product: BrCCCCCCCCCCOCc1ccccc1

Procedure:
10-Benzyloxydecanyl bromide was prepared by reacting 100 g of 1,10-dibromodecane with an equimolar amount of sodium benzyloxide in tetrahydrofuran under reflux conditions, filtering the precipitated material, concentrating the filtrate and distilling the concentrated filtrate under reduced pressure. Yield 46 g. B.P. 185° to 189° C./3 mmHg.